Treprostinil analogues

Abstract

Provided are novel treprostinil derivatives, including treprostinil prodrugs and treprostinil analogs, and methods of making and using these compounds.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 440,034, filed January 19, 2023, which is incorporated herein by reference in its entirety.

[0002] Field FIELD OF THE DISCLOSURE This disclosure relates generally to prostacyclin, and more specifically to treprostinil, its prodrugs and analogs, and related methods of making and using. Summary of the Invention

[0003] overview One embodiment is a compound of formula (1), an enantiomer thereof, or a pharmaceutically acceptable salt thereof:

[0004] [ka]

[0005] (In the formula, R 1 is an acid protecting group, such as H, a C1-C3 alkyl group, or a carboxylic acid protecting group; R 2 is H or an alcohol protecting group; and R 3 teeth,

[0006] [ka]

[0007] (In the formula, Y 1 is -C≡C-; -CH=CH-; or -(CH2) m - where m is an integer from 0 to 5; R 4 is H, OH or ═O; R 5 is H, OH, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted carbocyclic group; R6 are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted cycloalkyl groups), where R is each H. 1 and R 2 Regarding R 3 teeth,

[0008] [ka]

[0009] isn't it).

[0010] Another embodiment is a compound having formula (2), an enantiomer thereof, or a pharmaceutically acceptable salt thereof:

[0011] [ka]

[0012] (In the formula, X 1 is hydrogen,

[0013] [ka]

[0014] or

[0015] [ka]

[0016] (wherein q is 1, 2, or 3, p1 is an integer from 1 to 20, and R 12 is a phosphate group or COOH); X 2 and X 3 each independently represents hydrogen,

[0017] [ka]

[0018] phosphate, or

[0019] [ka]

[0020] (wherein p2 is an integer from 1 to 20, and R 11 is a C1-C8 alkyl group, one or more carbon atoms of said C1-C8 alkyl group may optionally be replaced by O, and one or more hydrogen atoms of said C1-C8 alkyl group may optionally be replaced by halogen; X 2 is hydrogen, where X 1 , X 2 and X 3 is not all hydrogen; X is hydrogen 1 and phosphate X 2 and X 3 For one of the two, X 2 and X 3 The other of X is not phosphate or hydrogen; 1 and R is an unsubstituted C1-C8 alkyl group. 11 have

[0021] [ka]

[0022] is X 2 and X 3 For one of the two, X 2 and X 3 The other is not hydrogen and X 2 or X 3 are not the same).

[0023] Yet another embodiment is a compound of formula (3):

[0024] [ka]

[0025] (In the formula, R 21 is a phenol protecting group or CH2COOR 24 and;R 22 is an alcohol protecting group; R 23 is a hydroxy-terminated alkyl, -C=CH2, -C≡CH or

[0026] [ka]

[0027] and;R 24 is a carboxylic acid protecting group). [Brief explanation of the drawings]

[0028] figure [Figure 1] 1A-B present Scheme 1, which can be used to synthesize intermediate(s), which can be further used to synthesize treprostinil, its prodrugs and analogs. [Figure 2] 2A-B present Scheme 2, which can be used to synthesize additional intermediate(s) from the intermediate(s) synthesized according to Scheme 1. The additional intermediate(s) can be used to synthesize treprostinil, its prodrugs and analogs. [Figure 3] 3A-B present Scheme 3, which can be used to synthesize intermediate(s), which can be further used to synthesize treprostinil, its prodrugs and analogs. [Figure 4] 4A-B present Scheme 4, which may be used to synthesize treprostinil from intermediate(s) synthesized according to Scheme 3. [Figure 5] 5A-B present Scheme 5, which may be used to synthesize treprostinil analogs from intermediate(s) synthesized according to Scheme 3, according to one embodiment. [Figure 6] FIG. 6 shows exemplary treprostinil analogs according to one embodiment. [Figure 7] 7A-B present Scheme 6, which may be used to synthesize treprostinil analogs from intermediate(s) synthesized according to Scheme 1, according to one embodiment. [Figure 8] 8A-B present Scheme 7, which may be used to synthesize treprostinil analogs from intermediate(s) synthesized according to Scheme 1, according to one embodiment. [Figure 9] 9A-B present Scheme 8, which may be used to synthesize treprostinil analogs from intermediate(s) synthesized according to Scheme 1, according to one embodiment. [Figure 10] 10A-B present Scheme 9, which may be used to synthesize treprostinil analogs from intermediate(s) synthesized according to Scheme 1, according to one embodiment. [Figure 11] 11A-B present Scheme 10, which may be used to synthesize treprostinil analogs from treprostinil according to one embodiment. [Figure 12] 12A-B present Scheme 11, which may be used to synthesize treprostinil analogs from treprostinil according to one embodiment. [Figure 13] FIG. 13 shows the chemical formulas of treprostinil and selected treprostinil analogs. [Figure 14] 14A-B show selected treprostinil prodrugs. [Figure 15] FIG. 15 shows exemplary fatty acid conjugates with treprostinil. DETAILED DESCRIPTION OF THE INVENTION

[0029] Detailed Description As used herein and in the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Throughout this specification, unless otherwise indicated, "comprise," "comprises," and "comprising" are used inclusively rather than exclusively, such that a stated integer or group of integers may include one or more other unstated integers or groups of integers. The term "or" is inclusive unless modified, for example, by "either." That is, unless the context dictates otherwise, the word "or" means any one member of a particular list and also includes any combination of members of that list. Except in the examples or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about."

[0030] Headings are provided for convenience only and should not be construed as limiting the invention in any way. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the claims. In order that this disclosure may be more readily understood, certain terms are first defined. Additional definitions will become apparent throughout the detailed description.

[0031] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (-) by increments of 0.05%, 1%, 2%, 5%, 10%, or 20%. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term "about." It is also to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0032] "Pharmaceutically acceptable salts" refers to salts of compounds, which salts are suitable for pharmaceutical use and are derived from a variety of organic and inorganic counterions well known in the art, and include salts of organic or inorganic acids, such as, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium when the compound contains an acidic functionality; and hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate when the molecule contains a basic functionality (see Stahl and Wermuth, ed., "Handbook of Pharmaceutically Acceptable Salts" (2002), Verlag Helvetica Chimica Acta, Zuerich, Switzerland), for a discussion of pharmaceutical salts, their selection, preparation, and use.

[0033] "Pulmonary hypertension" refers to all forms of pulmonary hypertension, WHO Groups 1 to 5. Pulmonary arterial hypertension, also known as PAH, refers to pulmonary hypertension in WHO Group 1. PAH includes idiopathic, hereditary, drug- or toxin-induced, and persistent pulmonary hypertension of the newborn (PPHN).

[0034] Generally, pharmaceutically acceptable salts are those salts that substantially retain one or more of the desired pharmacological activity of parent compound and are suitable for in vivo administration.Pharmaceutically acceptable salts include the acid addition salts formed with inorganic or organic acids.The inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, for example and not limited to, hydrohalic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, etc.

[0035] Pharmaceutically acceptable salts include salts formed when an acidic proton present in the parent compound is replaced by either a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or by an ammonium ion (e.g., ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).

[0036] Treprostinil, the active ingredient in Remodulin® (treprostinil) Injection, Tyvaso® (treprostinil) Inhalation Solution, and Orenitram® (treprostinil) Extended Release Tablets, is described in U.S. Pat. No. 4,306,075. Methods for producing treprostinil and other prostacyclin derivatives are described, for example, in Moriarty, et al., J. Org. Chem. 2004, 69, 1890-1902; Drug of the Future, 2001, 26(4), 364-374; U.S. Patents 6,441,245; 6,528,688; 6,700,025; 6,809,223; 6,756,117; 8,461,393; 8,481,782; 8,242,305; 8,497,393; 8,940,930; 9,029,607; 9,156,786; and 9,388,154. No. 9,346,738; U.S. Published Patent Application Nos. 2012-0197041, 2013-0331593, 2014-0024856, 2015-0299091, 2015-0376106, 2016-0107973, 2015-0315114, 2016-0152548, and 2016-0175319; PCT Publication Nos. WO2016 / 0055819 and WO2016 / 081658.

[0037] Various uses and / or various forms of treprostinil are described in, for example, U.S. Patents 5,153,222, 5,234,953, 6,521,212, 6,756,033, 6,803,386, 7,199,157, 6,054,486, 7,417,070, 7,384,978, 7,879,909, 8,563,614, 8,252,839, 8,536,363, 8,410,169, 8,232,316, 8,609,72 8, 8,350,079, 8,349,892, 7,999,007, 8,658,694, 8,653,137, 9,029,607, 8,765,813, 9,050,311, 9,199,908, 9,278,901, 8,747,897, 9,358,240, 9,339,507, 9,255,064, 9,278,902, 9,278,903, 9,758,465; 9,422,223; 9,878,972; 9,624,15 No. 6; U.S. Published Patent Application Nos. 2009-0036465, 2008-0200449, 2008-0280986, 2009-0124697, 2014-0275616, 2014-0275262, 2013-0184295, 2014-0323567, 2016-0030371, 2016-0051505, 2016-0030355, 2016-0143868, 2015-0328232, 2015-0148414, 2016- 0045470, 2016-0129087, 2017-0095432; 2018-0153847; 2021-0121433; 2021-0054009; 2021-0330621; 2021-0378996 and PCT Publication Nos. WO00 / 57701, WO2016 / 0105538, WO2016 / 038532, WO2018 / 058124, WO2021 / 041320, and WO2022 / 132655.

[0038] Treprostinil has the following chemical formula:

[0039] [ka]

[0040] It has.

[0041] The term "effective amount" may refer to the amount of a compound (e.g., a treprostinil analog, a treprostinil prodrug, and / or a treprostinil conjugate) that may be required to treat a disease or condition. In some embodiments, the effective amount of a treprostinil analog, a treprostinil prodrug, and / or a treprostinil conjugate may be the same as or similar to the effective amount of treprostinil for treating the same disease or condition. In some embodiments, the effective amount of a treprostinil analog, a treprostinil prodrug, and / or a treprostinil conjugate may be different from the effective amount of treprostinil for treating the same disease or condition. One of ordinary skill in the art will be able to determine an "effective amount" of a treprostinil analog, treprostinil prodrug and / or treprostinil conjugate based on, for example, the relevant disease or condition, the amount of treprostinil known to treat, ameliorate, or prevent the disease or condition, and the rate at which the prodrug is converted to treprostinil in vivo.

[0042] As used herein, when used before a group, C-C 12 , C1-C8, or C1-C6, etc. m -C n refers to a group containing m to n carbon atoms.

[0043] "Optionally substituted" refers to a group selected from the group and substituted forms of that group. The substituents may include any of the groups defined below. In one embodiment, the substituents are C-C 10 or C1-C6 alkyl, substituted C1-C 10 or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C8 cycloalkyl, C2-C 10 Heterocyclyl, C1-C 10Heteroaryl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C6-C 10 Aryl, substituted C3-C8 cycloalkyl, substituted C2-C 10 Heterocyclyl, substituted C1-C 10 Selected from heteroaryl, halo, nitro, cyano, —CO 2 H or its C 1 -C 6 alkyl ester.

[0044] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl ((CH)C-), n-pentyl (CHCHCHCHCHCH), and neopentyl ((CH)CCH-).

[0045] "Alkenyl" refers to a monovalent linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and preferably from 2 to 6 carbon atoms or preferably from 2 to 4 carbon atoms and having at least one and preferably one to two sites of vinyl (>C=C<) unsaturation. Such groups are exemplified by, for example, vinyl, allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers or mixtures of these isomers.

[0046] "Alkynyl" refers to a straight-chain or branched monovalent hydrocarbyl group having from 2 to 10 carbon atoms and preferably from 2 to 6 carbon atoms or preferably from 2 to 3 carbon atoms and having at least 1 and preferably 1 to 2 sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH), and propargyl (-CHC≡CH).

[0047] "Substituted alkyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic heterocyclic), heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0048] "Heteroalkyl" refers to an alkyl group in which one or more carbons are bonded to one or more of the following: -O-, -S-, SO2, a P-containing moiety as provided herein, -NR Q -,

[0049] [ka]

[0050] Part (in the formula, RQ is H or C1-C6 alkyl). Substituted heteroalkyl refers to an alkyl group substituted with alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkane, and heteroalkyl groups having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0051] "Substituted alkenyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, and an alkenyl group having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein, and with the proviso that no hydroxyl or thiol substitutions are attached to a vinyl (unsaturated) carbon atom.

[0052] "Heteroalkenyl" refers to an alkyl group in which one or more carbons are bonded to an alkyl group, such as -O-, -S-, SO2, a P-containing moiety as provided herein, -NR Q -,

[0053] [ka]

[0054] Part (in the formula, R Qis H or C1-C6 alkyl). Substituted heteroalkenyl refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkane ... and heteroalkenyl groups having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0055] "Substituted alkynyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, and substituted cycloalkenyloxy. , cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein, and with the proviso that any hydroxyl or thiol substitutions are not attached to an acetylenic carbon atom.

[0056] "Heteroalkynyl" refers to an alkyl group in which one or more carbons are bonded to one of the following: -O-, -S-, SO2, a P-containing moiety as provided herein, -NR Q -,

[0057] [ka]

[0058] Part (in the formula, R Qis H or C1-C6 alkyl). Substituted heteroalkynyl refers to alkynyl groups substituted with alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkene ... and heteroalkynyl groups having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0059] "Alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 and more preferably 1 to 3 carbon atoms, which is either straight-chained or branched. This term includes methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)- or -CH(CH3)CH2-), butylene (-CH2CH2CH2CH2-), isobutylene (-CH2CH(CH3-)CH2-), sec-butylene (-CH2CH2(CH 3- )CH—). Similarly, “alkenylene” and “alkynylene” refer to alkylene moieties that contain one or two carbon-carbon double bonds or carbon-carbon triple bonds, respectively.

[0060] "Substituted alkylene" refers to an alkylene group having one to three hydrogen atoms replaced with a substituent selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo, where the substituents are defined herein. In some embodiments, the alkylene has one to two of the foregoing groups or is -O-, -S-, or -NR Q -part (in the formula, R Q is H or C1-C6 alkyl). It should be noted that when alkylene is substituted by an oxo group, two hydrogens bonded to the same carbon of the alkylene group are replaced by "=O". "Substituted alkenylene" and "substituted alkynylene" refer to alkenylene and alkynylene moieties substituted with the substituents described for substituted alkylene.

[0061] "Alkynylene" refers to a straight-chain or branched divalent hydrocarbyl group having from 2 to 10 carbon atoms and preferably from 2 to 6 carbon atoms or preferably from 2 to 3 carbon atoms, and having at least 1 and preferably 1 to 2 sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynylene groups include C≡C- and CHC≡C-.

[0062] "Substituted alkynylene" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, and substituted cycloalkenyloxy. , cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein, and with the proviso that any hydroxyl or thiol substitutions are not attached to an acetylenic carbon atom.

[0063] "Heteroalkylene" refers to a heteroalkyl group in which one or more carbons are bonded to one or more of the following: -O-, -S-, SO2, a P-containing moiety as provided herein, -NR Q -,

[0064] [ka]

[0065] Part (in the formula, R Q refers to an alkylene group substituted with H or C-C alkyl. "Substituted heteroalkylene" refers to a heteroalkynylene group having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.

[0066] "Heteroalkenylene" refers to an alkyl group in which one or more carbons are bonded to an alkyl group such as -O-, -S-, SO2, a P-containing moiety as provided herein, -NR Q -,

[0067] [ka]

[0068] Part (in the formula, R Q refers to an alkenylene group substituted with H or C-C alkyl. "Substituted heteroalkenylene" refers to a heteroalkynylene group having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkenylene.

[0069] "Heteroalkynylene" refers to an alkyl group in which one or more carbons are bonded to one or more of the following: -O-, -S-, SO2, a P-containing moiety as provided herein, -NR Q -,

[0070] [ka]

[0071] Part (in the formula, R Q refers to an alkynylene group substituted with H or C-C alkyl. "Substituted heteroalkynylene" refers to a heteroalkynylene group having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkynylene.

[0072] "Alkoxy" refers to the group Oalkyl, where alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0073] "Substituted alkoxy" refers to the group O(substituted alkyl), where substituted alkyl is defined herein.

[0074] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, hetero ... "C(O)-," refers to substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" group CHC(O)-.

[0075] "Acylamino" refers to the group -NR 47 C(O) alkyl, -NR 47 C(O) substituted alkyl, -NR 47 C(O)cycloalkyl, -NR 47C(O)-substituted cycloalkyl, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47 C(O)alkenyl, -NR 47 C(O) substituted alkenyl, -NR 47 C(O)alkynyl, -NR 47 C(O) substituted alkynyl, -NR 47 C(O)aryl, -NR 47 C(O) substituted aryl, -NR 47 C(O)heteroaryl, -NR 47 C(O)-substituted heteroaryl, -NR 47 C(O) heterocyclic, and NR 47 C(O)-substituted heterocyclic 47 is hydrogen or alkyl, and refers to alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic) as defined herein.

[0076] "Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O) refers to O—, substituted heteroaryl-C(O)O, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0077] "Amino" refers to the group NH2.

[0078] "Substituted amino" refers to the group -NR 48 R 49 (In the formula, R 48 and R 49 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic; and wherein R 48 and R 49 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, with the proviso that R 48 and R 49 and R are not both hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 48 is hydrogen and R 49 When R is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. 48 and R 49 When R is alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is 48 or R 49 is hydrogen, but not both. When referring to a disubstituted amino, it means that either R48 MoR 49 This means that neither is hydrogen.

[0079] "Aminocarbonyl" refers to the group -C(O)NR 50 R 51 (In the formula, R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0080] "Aminothiocarbonyl" is the group -C(S)NR 50 R 51 (In the formula, R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0081] "Aminocarbonylamino" is the group -NR 47 C(O)NR 50 R 51 (In the formula, R 47 is hydrogen or alkyl and R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0082] "Aminothiocarbonylamino" refers to the group -NR 47 C(S)NR 50 R 51 (In the formula, R 47 is hydrogen or alkyl and R 50 and R 51is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0083] "Aminocarbonyloxy" is the group -OC(O)NR 50 R 51 (In the formula, R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0084] "Aminosulfonyl" refers to the group -SO2NR 50 R 51 (In the formula, R 50 and R 51is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0085] "Aminosulfonyloxy" refers to the group -O-SONR 50 R 51 (In the formula, R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0086] "Aminosulfonylamino" refers to the group -NR 47 SO2NR 50 R 51 (In the formula, R 47is hydrogen or alkyl and R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0087] "Amidino" is the group -C(=NR 52 )NR 50 R 51 (In the formula, R 50 , R 51 , and R 52 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R 50 and R 51 are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and in which alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0088] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl), which may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-benzoxazinone, 2H-benzoxazinone, 3(4H)-onyl, etc.), so long as the points of attachment are aromatic carbon atoms. Preferred aryl groups include phenyl and naphthyl.

[0089] "Substituted aryl" includes alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl ... "C" refers to an aryl group substituted by 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of aryl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0090] "Arylene" refers to a divalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple condensed rings. "Substituted arylene" refers to an arylene having 1 to 5, preferably 1 to 3, or more preferably 1 to 2, substituents as defined for an aryl group.

[0091] "Heteroarylene" refers to a divalent aromatic group of from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. "Substituted heteroarylene" refers to a heteroarylene group that is substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2, substituents selected from the group consisting of the same substituents defined for substituted aryl.

[0092] "Aryloxy" refers to the group --O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

[0093] "Substituted aryloxy" refers to the group --O-(substituted aryl), where substituted aryl is as defined herein.

[0094] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.

[0095] "Substituted arylthio" refers to the group S(substituted aryl), where substituted aryl is as defined herein.

[0096] "Carbonyl" refers to the divalent group -C(O)-, which is equivalent to -C(=O)-.

[0097] "Carboxyl" or "carboxy" refers to COOH or salts thereof.

[0098] A "carboxyl ester" or "carboxy ester" refers to the group -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-alkynyl, -C(O)(O)-substituted alkynyl, -C(O)(O)-aryl, -C(O)(O)-substituted-aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl "Alkenyl" refers to alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0099] "(Carboxyl ester) amino is a group -NR 47 C(O)(O)-alkyl, -NR 47 C(O)(O)-substituted alkyl, -NR 47 C(O)O-alkenyl, -NR 47 C(O)(O)-substituted alkenyl, -NR 47 C(O)(O)-alkynyl, -NR 47 C(O)(O)-substituted alkynyl, -NR 47 C(O)(O)-aryl, -NR 47 C(O)(O)-substituted-aryl, -NR 47 C(O)(O)-cycloalkyl, -NR 47 C(O)(O)-substituted cycloalkyl, -NR 47 C(O)(O)-cycloalkenyl, -NR 47 C(O)(O)-substituted cycloalkenyl, -NR 47 C(O)(O)-heteroaryl, -NR 47 C(O)(O)-substituted heteroaryl, -NR 47 C(O)(O)-heterocyclic, and -NR 47C(O)(O)-substituted heterocyclic 47 is alkyl or hydrogen, and refers to alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic) as defined herein.

[0100] "(Carboxyl ester)oxy" refers to the groups -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)(O)-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted-aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC refers to (O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0101] "Cyano" refers to the group CN.

[0102] "Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Fused rings can be aryl rings as long as the non-aryl moiety is attached to the remainder of the molecule. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0103] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of from 3 to 10 carbon atoms having a single or multiple cyclic rings and having at least one site of >C=C< ring unsaturation and preferably 1 to 2 sites of >C=C< ring unsaturation.

[0104] "Substituted cycloalkyl" and "substituted cycloalkenyl" include oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cyclo " refers to a cycloalkyl or cycloalkenyl group having from 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of alkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0105] "Cyclopropano" is:

[0106] [ka]

[0107] Refers to...

[0108] "Cyclobutano" is:

[0109] [ka]

[0110] Refers to...

[0111] "Cycloalkyloxy" refers to -O-cycloalkyl.

[0112] "Substituted cycloalkyloxy" refers to --O-(substituted cycloalkyl).

[0113] "Cycloalkylthio" refers to -S-cycloalkyl.

[0114] "Substituted cycloalkylthio" refers to --S-(substituted cycloalkyl).

[0115] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0116] "Substituted cycloalkenyloxy" refers to --O-(substituted cycloalkenyl).

[0117] "Cycloalkenylthio" refers to -S-cycloalkenyl.

[0118] "Substituted cycloalkenylthio" refers to --S-(substituted cycloalkenyl).

[0119] "Guanidino" refers to the group -NHC(=NH)NH2.

[0120] "Substituted guanidino" is -NR 53 C(=NR 53 )N(R 53)2(in the formula, each R 53 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic, and two R bonded to the common guanidino nitrogen atom 53 The groups are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, provided that at least one R 53 is not hydrogen, and wherein said substituents are as defined herein.

[0121] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0122] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0123] "Heteroaryl" refers to an aromatic group of 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), where the condensed rings may or may not be aromatic and / or contain heteroatoms, so long as the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Specific, non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thizolyl, and furanyl.

[0124] "Substituted heteroaryl" refers to a heteroaryl group that is substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2, substituents selected from the group consisting of the same substituents defined for substituted aryl.

[0125] "Heteroaryloxy" refers to -O-heteroaryl.

[0126] "Substituted heteroaryloxy" refers to the group --O-(substituted heteroaryl).

[0127] "Heteroarylthio" refers to the group -S-heteroaryl.

[0128] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

[0129] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycles encompass single rings or multiple fused rings, including fused bridged and spiro ring systems. In fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, so long as the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocycle group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0130] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl group that is substituted with one to five, or preferably one to three, of the same substituents as defined for substituted cycloalkyl.

[0131] "Heterocyclyloxy" refers to the group -O-heterocyclyl.

[0132] "Substituted heterocyclyloxy" refers to the group --O-(substituted heterocyclyl).

[0133] "Heterocyclylthio" refers to the group -S-heterocyclyl.

[0134] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocyclyl).

[0135] Examples of heterocycles and heteroaryls are azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4 tetrahydroisoquinoline, 4,5,6,7 Including, but not limited to, tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1 dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0136] "Nitro" refers to the group -NO2.

[0137] "Oxo" refers to the atom (=O).

[0138] Phenylene refers to a divalent aryl ring, wherein the ring contains 6 carbon atoms.

[0139] Substituted phenylene includes alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl. , substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0140] "Spirocycloalkyl" and "spiro ring system" refer to a ring having the following structure:

[0141] [ka]

[0142] It refers to a divalent cyclic group of 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro bond (a bond formed by a single atom that is the only common member of the ring), exemplified by:

[0143] "Sulfonyl" refers to the divalent group -S(O)2-.

[0144] "Substituted sulfonyl" refers to the group -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic (wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein). Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0145] "Substituted sulfonyloxy" refers to the groups -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0146] "Thioacyl" refers to the groups HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, refers to substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0147] "Thiol" refers to the group SH.

[0148] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[0149] "Thioxo" refers to the atom (=S).

[0150] "Alkylthio" refers to the group S-alkyl, where alkyl is as defined herein.

[0151] "Substituted alkylthio" refers to the group --S-(substituted alkyl), where substituted alkyl is as defined herein.

[0152] Substituted rings may be substituted with one or more fused and / or spiro rings. Such fused rings include fused cycloalkyl rings, fused heterocyclyl rings, fused aryl rings, and fused heteroaryl rings, each of which may be unsubstituted or substituted. Such spiro rings include fused cycloalkyl and fused heterocyclyl rings, each of which may be unsubstituted or substituted.

[0153] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups). Such impermissible substitution patterns are well known to those of skill in the art.

[0154] This application discloses a number of novel treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates. This application also discloses novel methods for synthesizing treprostinil, its analogs, its prodrugs, and / or its conjugates. Furthermore, the present invention discloses novel intermediate(s) that can be used in these methods.

[0155] One embodiment is a compound of formula (1), an enantiomer thereof, or a pharmaceutically acceptable salt thereof:

[0156] [ka]

[0157] (In the formula, R 1 can be H, a lower alkyl, such as a C-C alkyl group, or an acid protecting group, such as a carboxylic acid protecting group; R 2 can be H or an alcohol protecting group; and R 3 teeth,

[0158] [ka]

[0159] (In the formula, Y 1is -C≡C-; -CH=CH-; or -(CH2) m - and m can be an integer from 0 to 5; R 4 can be H, OH or ═O; R 5 is H, OH, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted carbocyclic group; R 6 R may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group, where each R is H. 1 and R 2 Regarding R 3 corresponds to treprostinil,

[0160] [ka]

[0161] isn't it).

[0162] In some embodiments, R 1 can be H or lower alkyl, such as C1-C3 alkyl, such as methyl, ethyl, or propyl. For example, R 1 can be H or methyl.

[0163] In some embodiments, R 2 can be H.

[0164] In some embodiments, R 3 teeth,

[0165] [ka]

[0166] (In the formula, R 7can be, for example, an alkyl, alkenyl, or alkynyl group; Z can be O, CH, NH, or S; R 8 can be a heterocyclic group; and R 4 can be H, OH or ═O).

[0167] In some embodiments, R 3 teeth,

[0168] [ka]

[0169] wherein each Z may be independently selected from, for example, CH, N, O, or S, and n is 0 or 1, while R 9 may be an alkyl group, an aryl group, an electron withdrawing group, an electron donating group, a heterocycle, or a carbocycle; and R 4 can be H, OH or ═O).

[0170] In some embodiments, R 3 teeth,

[0171] [ka]

[0172] (In the formula, R 10 is a cycloalkyl group having 3 to 8 carbon atoms, wherein one or more carbon atoms in the cycloalkyl group can optionally be replaced with a heteroatom selected from O, N, and S; and R 4 can be H, OH or ═O).

[0173] In some embodiments, R 3 teeth,

[0174] [ka]

[0175] can be selected from.

[0176] Another embodiment can be a compound having formula (2), an enantiomer thereof, or a pharmaceutically acceptable salt thereof:

[0177] [ka]

[0178] (In the formula, X 1 is hydrogen,

[0179] [ka]

[0180] or

[0181] [ka]

[0182] where q can be 1, 2, or 3, p1 can be an integer from 1 to 20, and R 12 may be a phosphate group or COOH); X 2 and X 3 each independently represents hydrogen,

[0183] [ka]

[0184] phosphate, or

[0185] [ka]

[0186] where p2 can be an integer from 1 to 20, and R 11may be a C1-C8 alkyl group, one or more carbon atoms of which may optionally be replaced by O, and one or more hydrogen atoms of which may optionally be replaced by halogen; X 2 can be hydrogen, provided that (a) X 1 , X 2 and X 3 are not all hydrogen; (b) X is hydrogen 1 and phosphate X 2 and X 3 For one of the two, X 2 and X 3 the other of which is not phosphate or hydrogen; (c) X is hydrogen; 1 and R is an unsubstituted C1-C8 alkyl group. 11 have

[0187] [ka]

[0188] is X 2 and X 3 For one of the two, X 2 and X 3 The other is not hydrogen and X 2 or X 3 are not the same).

[0189] In some embodiments, R 1 teeth,

[0190] [ka]

[0191] It could be.

[0192] In some embodiments, X 2 and X 3 can be the same group. For example, in some embodiments, X 2 and X3 Each of X can be hydrogen. 2 and X 3 Each of the

[0193] [ka]

[0194] It could be.

[0195] In some embodiments, R 1 can be hydrogen.

[0196] In some embodiments, X 2 and X 3 One of the groups is phosphate and X 2 and X 3 The other is,

[0197] [ka]

[0198] is.

[0199] In some embodiments, X 2 and X 3 at least one of R is a C1-C8 alkyl group having one or more carbon atoms replaced with O or having one or more hydrogen atoms replaced with halogen; 11 have

[0200] [ka]

[0201] is.

[0202] In some embodiments, X 2 and X 3At least one of R is a C1-C8 alkyl group having one or more hydrogen atoms replaced with halogen. 11 have

[0203] [ka]

[0204] In some embodiments, X 2 and X 3 each of which is a C1-C8 alkyl group having one or more hydrogen atoms replaced with a halogen; 11 have

[0205] [ka]

[0206] is.

[0207] In some embodiments, X 2 and X 3 are identical.

[0208] In some embodiments, X 2 and X 3 At least one of has p2 which is an integer from 12 to 16

[0209] [ka]

[0210] or X 1 has p1, an integer between 12 and 16

[0211] [ka]

[0212] is.

[0213] In some embodiments, X 2 and X 3 Each of the is hydrogen and X 1 teeth,

[0214] [ka]

[0215] (b) X 3 teeth,

[0216] [ka]

[0217] and X 2 teeth,

[0218] [ka]

[0219] and X 1 is hydrogen; (c) X 3 teeth,

[0220] [ka]

[0221] and X 2 teeth,

[0222] [ka]

[0223] and X 1 is hydrogen; (d) X 3 teeth,

[0224] [ka]

[0225] and X 2 teeth,

[0226] [ka]

[0227] and X 1 is hydrogen; (e) X 2 and X 3 Each of the

[0228] [ka]

[0229] and X 1 teeth,

[0230] [ka]

[0231] (f)X 2 and X 3 Each of the

[0232] [ka]

[0233] and X 1 teeth,

[0234] [ka]

[0235] (g) each X 1 and X 2 is H and X 3 teeth,

[0236] [ka]

[0237] (h)X 3 teeth,

[0238] [ka]

[0239] and X 2 teeth,

[0240] [ka]

[0241] and X 1 is hydrogen; (i) X 2 teeth,

[0242] [ka]

[0243] and X 3 teeth,

[0244] [ka]

[0245] and X 1 is hydrogen; (j) X 1 and X 2 Each of the is hydrogen and X 3 teeth,

[0246] [ka]

[0247] (k)X 1 and X2 Each of the is hydrogen and X 3 teeth,

[0248] [ka]

[0249] (l)X 2 and X 3 Each of the

[0250] [ka]

[0251] and X 1 is hydrogen; (m)X 2 and X 3 Each of the

[0252] [ka]

[0253] and X 1 is hydrogen; (n)X 1 and X 3 Each of the is hydrogen and X 3 teeth,

[0254] [ka]

[0255] ;(o)X 1 is hydrogen; X 2 teeth,

[0256] [ka]

[0257] and X 3 teeth,

[0258] [ka]

[0259] (p)X 1 is hydrogen; X 2 teeth,

[0260] [ka]

[0261] and X 3 teeth,

[0262] [ka]

[0263] (q)X 2 and X 3 Each of the is hydrogen and X 1 teeth,

[0264] [ka]

[0265] (r)X 1 and X 2 Each of the is hydrogen and X 3 teeth,

[0266] [ka]

[0267] (s)X 1 and X 3 Each of the is hydrogen and X 2 teeth,

[0268] [ka]

[0269] or (t)X 1 teeth,

[0270] [ka]

[0271] and each X 2 and X 3 teeth,

[0272] [ka]

[0273] is.

[0274] Yet another embodiment is a compound of formula (3):

[0275] [ka]

[0276] (In the formula, R 21 is a phenol protecting group or CH2COOR 24 and;R 22 is an alcohol protecting group; R 23 is a hydroxy-terminated alkyl, -C=CH2, -C≡CH or

[0277] [ka]

[0278] and;R 24 is an alcohol protecting group).

[0279] In some embodiments, R 23is a hydroxy-terminated alkyl, such as a C1-C8 alkyl or a C1-C4 alkyl terminated by a hydroxy group.

[0280] In some embodiments, the compound of Formula (3) has the formula (31):

[0281] [ka]

[0282] The compound may have the formula:

[0283] In some embodiments, the compound of Formula (3) has the formula (32):

[0284] [ka]

[0285] The compound may have the formula:

[0286] In some embodiments, the compound of Formula (3) has the formula (33):

[0287] [ka]

[0288] The compound may have the formula:

[0289] In some embodiments, R 21 is C1-C4 alkyl, substituted or unsubstituted benzyl, or CH2COOR 24 (In the formula, R 24 is C1-C4 alkyl or substituted or unsubstituted benzyl).

[0290] In some embodiments, R 22 is an acetyl group or a silyl-containing group.

[0291] Compounds of formula (3), such as compounds of formula (31), (32) or (33), may serve as intermediates for synthesizing treprostinil analogue(s), treprostinil prodrug(s) and / or treprostinil conjugate(s), such as compounds of formula (1) or formula (2) above.

[0292] Treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates can be used to treat any disease or condition that can be treated with treprostinil or its pharmaceutical salt. Treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates can be formulated into appropriate pharmaceutical compositions depending on the intended application and route of administration (e.g., parenteral, oral, or inhalation). In some embodiments, the disease or condition is one or more selected from the group consisting of pulmonary hypertension, congestive heart failure, peripheral vascular disease, Raynaud's phenomenon, scleroderma, renal failure, peripheral neuropathy, digital ulcers, intermittent claudication, ischemic limb disease, peripheral ischemic lesions, pulmonary fibrosis, and asthma. In some embodiments, the disease is pulmonary hypertension. Pulmonary hypertension can be any form of pulmonary hypertension, such as pulmonary arterial hypertension (WHO Group 1 pulmonary hypertension).

[0293] Administration may be via the routes described above, or, for example, orally, intravenously, intraarterially, intramuscularly, intranasally, rectally, intravaginally, or subcutaneously. In some embodiments, the composition is administered by injection. In some embodiments, administration is orally. In some embodiments, administration is subcutaneously. In some embodiments, administration is intravenously.

[0294] The subject to be treated can be a human, dog, cat, bird, non-human primate, cow, or horse. In some embodiments, the subject is a human.

[0295] The compounds (e.g., treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates) may be provided in the form of pharmaceutical compositions, which may also include pharmaceutically acceptable carriers, excipients, binders, diluents, etc. Such pharmaceutical compositions may be prepared by methods known in the art, such as granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying, or levigating processes, among others. The compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, and solutions. The compositions may be formulated for many different routes of administration, such as oral, transmucosal, rectal, transdermal, or subcutaneous administration, as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular, or intracerebroventricular injection. The compounds (e.g., treprostinil analogs, treprostinil prodrugs and / or treprostinil conjugates) may be administered by any of the above routes, for example, in a local rather than systemic manner, including as an injectable solution or in a sustained release formulation.

[0296] In one embodiment, the pharmaceutical composition may compromise a carrier, such as a compound (e.g., a treprostinil analog, a treprostinil prodrug, and / or a treprostinil conjugate) and sterile water. In some embodiments, the compound (e.g., a treprostinil analog, a treprostinil prodrug, and / or a treprostinil conjugate) is formulated for subcutaneous administration, and such formulations may or may not include m-cresol or another preservative.

[0297] The treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates described herein can be used to treat pulmonary hypertension. In some embodiments, the compounds (e.g., treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates) can be used to treat pulmonary arterial hypertension (PAH). In some embodiments, the compounds (e.g., treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates) can be used to treat one or more of WHO Groups 1 to 5 of pulmonary hypertension. Similarly, the treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates described herein can be used to treat any disease or condition for which treprostinil is indicated or useful. The treprostinil analogs, treprostinil prodrugs and / or treprostinil conjugates can be administered as the sole therapeutic agent or in addition to other active agents, including treprostinil.

[0298] For oral, buccal and sublingual administration, powder, suspension, granule, tablet, pill, capsule, gel cap and caplet can be accepted as solid dosage form.These can be prepared by mixing one or more compounds, such as treprostinil analogue, treprostinil prodrug and / or treprostinil conjugate, or its pharmaceutically acceptable salt, with at least one additive or excipient, such as starch or other additives.Suitable additive or excipient can be sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer or glyceride, methylcellulose, hydroxypropylmethylcellulose, and / or polyvinylpyrrolidone. Optionally, oral dosage forms may contain other ingredients that aid in administration, such as inert diluents, or lubricants such as magnesium stearate, or preservatives such as parabens or sorbic acid, or antioxidants such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavorings or fragrances.In addition, dyes or pigments may be added for identification.Tablets may further be treated with suitable coating materials known in the art.

[0299] The liquid dosage form for oral administration can be in the form of pharmaceutically acceptable emulsion, syrup, elixir, suspension, slurry and solution, which may contain inert diluents such as water.Pharmaceutical preparations can be prepared as liquid suspensions or solutions using sterile liquids such as, but not limited to, oil, water, alcohol and combinations thereof.Pharmaceutical suitable surfactants, suspending agents, emulsifying agents can be added for oral or parenteral administration.

[0300] As mentioned above, suspension can contain oil.Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.Suspension preparation can also contain fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.Suspension formulation can contain alcohol, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.Ethers, such as, but not limited to, poly(ethylene glycol), mineral oil and petroleum hydrocarbons such as Vaseline; and water can also be used in suspension preparation.

[0301] Injectable dosage forms generally comprise aqueous or oily suspensions, which can be prepared using suitable dispersants or wetting agents and suspending agents.Injectable forms can be in the form of a solution or suspension, prepared with a solvent or diluent.Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic saline.Alternatively, sterile oils can be used as solvents or suspending agents.Preferably, oils or fatty acids are non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or triglycerides.

[0302] For injection, the pharmaceutical preparation may be a powder suitable for reconstitution with an appropriate solution, as described above. Examples include, but are not limited to, freeze-dried, rotary-dried, or spray-dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the preparation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. The compound may be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. The unit dosage form for injection may be in an ampoule or a multi-dose container. In addition to the above-mentioned representative dosage forms, pharmaceutically acceptable excipients and carriers are commonly known to those skilled in the art and can be used. Such excipients and carriers are described, for example, in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0303] The compounds (e.g., treprostinil analogs, treprostinil prodrugs, and / or treprostinil conjugates) can be formulated in formulations suitable for parenteral administration, which can include sterile aqueous preparations of the compounds or their pharmaceutically acceptable salts, which can be isotonic with the blood of the intended recipient. These preparations can be administered by subcutaneous injection, although administration can also be achieved intravenously or by intramuscular or intradermal injection. Such preparations can conveniently be prepared by mixing the compounds with water or glycine or citrate buffer and rendering the resulting solution sterile and isotonic with blood. Injectable formulations can contain 0.1 to 5% w / v treprostinil by weight in the prodrug, analog, and / or conjugate and can be administered at a rate of 0.1 ml / min / kg. Alternatively, the prodrug, analog, and / or conjugate can be administered at a rate of 0.625 to 50 ng / kg / min based on the weight of treprostinil in the prodrug. Alternatively, the prodrugs, analogs and / or conjugates may be administered at a rate of 10 to 15 ng / kg / min based on the weight of treprostinil in the prodrug.

[0304] In some embodiments, the concentration of the treprostinil prodrug, treprostinil analog, and / or treprostinil conjugate in a formulation for parenteral administration, such as intravenous or subcutaneous infusion (including continuous subcutaneous infusion), can be 0.0005 to 30 mg / mL, or 0.0007 to 50 mg / mL, or 0.001 to 15 mg / mL, or any value or subrange within these ranges. Exemplary concentrations can include 0.1 mg / mL, 1 mg / mL, 2.5 mg / mL, 5 mg / mL, or 10 mg / mL.

[0305] In some embodiments, the formulation of treprostinil prodrug, treprostinil analogue and / or treprostinil conjugate for parenteral administration, such as intravenous infusion or subcutaneous infusion (including continuous subcutaneous infusion), can be prepared by mixing the prodrug with a vehicle, such as a buffer solution.In certain embodiments, the vehicle can be a phosphate-containing vehicle, that is, at least one phosphate, which can be, for example, dibasic phosphate, such as dibasic sodium phosphate or dibasic potassium phosphate, or tribasic phosphate, such as tribasic sodium phosphate or potassium phosphate.In certain embodiments, the vehicle can also contain a halogen salt, such as a chloride salt, which can be, for example, sodium chloride or potassium chloride.The halogen salt, such as sodium chloride, can be used to adjust the tonicity of the vehicle.In certain embodiments, it may be preferable that the phosphate and the halogen salt have the same cation.For example, when the phosphate is sodium phosphate, such as tribasic sodium phosphate or tribasic sodium phosphate, the halogen salt can be a halogen sodium salt, such as sodium chloride. Similarly, when the phosphate salt is potassium phosphate, such as tribasic potassium phosphate or tribasic potassium phosphate, the halogen salt can be a potassium halogen salt, such as potassium chloride. The solvent in the vehicle can contain water. In certain embodiments, water can be the only solvent in the vehicle. In more specific embodiments, the vehicle can contain one or more additional solvents in addition to water. In some embodiments, the additional solvent can be a preservative, such as m-cresol.

[0306] Preferably, the vehicle is isotonic with the blood of a patient, such as a human. The term isotonic may mean that the osmolarity and ionic concentration of the vehicle are consistent with those of a patient, such as a human. Non-limiting examples of vehicles include phosphate buffered saline, which is a water-based salt solution containing disodium hydrogen phosphate, sodium chloride, and in some formulations, potassium chloride and potassium dihydrogen phosphate. Other examples may include a vehicle containing 20 mM dibasic sodium phosphate with 125 mM sodium chloride, and a vehicle containing 15 mM tribasic sodium phosphate, 125 mM sodium chloride, and 0.3% w / w m-cresol.

[0307] Scheme 1 1A-B present Scheme 1, which can be used to synthesize intermediate 12, which can be further used to synthesize treprostinil, its prodrugs, and analogs. FIG. 1A presents a general flow for Scheme 1, while FIG. 1B shows Scheme 1 with exemplary conditions. In the scheme, n is a non-zero integer, such as 0, 1, 2, 3, 4, 5, etc. 1 , P 2 and P 3 Each of X is an alcohol (hydroxyl) protecting group. Various protecting groups, including but not limited to hydroxyl protecting groups and phenol protecting groups, are disclosed, for example, in Greene's Protective Groups in Organic Synthesis 5th Edition, Wiley; 5th edition, 2014. Non-limiting examples of hydroxyl protecting groups include 2-tetrahydropyranyl (THP), acetyl (Ac), and silyl ether hydroxyl protecting groups, such as tert-butyldimethylsilyl ether (TBDMS / TBS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), etc. X is alkyl, for example, C1-C4 alkyl, or substituted or unsubstituted benzyl, or CH2COOR 24 (In the formula, R24 is a phenol protecting group such as alkyl, e.g., C-C alkyl, or an alcohol protecting group such as substituted or unsubstituted benzyl. The substituted benzyl group in X may optionally be substituted at one or more meta, ortho, or para positions with one or more substituents which may independently be selected from the group consisting of -NO, -CN, halogen (e.g., -F, -Cl, -Br, or -I), (C-C)alkyl, halo(C-C)alkyl, (C-C)alkoxy, and halo(C-C)alkoxy.

[0308] Scheme 1 involves the chiral addition of protected alkyne compound 2 to aldehyde compound 3 to give chiral alcohol 6. Alkyne compound 2 can vary in length. In some embodiments, the chiral addition can be carried out in the presence of a chiral catalyst, such as one or more of (+)-N-methylephedrine, Zn(OTf) / EtN, or using (1S,2S)-3-(tertiary-butyldimethylsilyloxy)-2-N,N-dimethylamino-L-(para-nitrophenyl)-propan-1-ol. In further embodiments, the chiral addition can be carried out through intermediate compounds 4 and 5.

[0309] Chiral alcohol 6 can be reacted with an alcohol (hydroxyl) group protecting agent to form protected alcohol compound 7. An "alcohol protecting agent" converts the -OH group to -OP 2 In one embodiment, the alcohol protecting reagent is TBDMSCl.

[0310] In some embodiments, the reaction of chiral alcohol 6 with an alcohol (hydroxyl) group protecting agent can be carried out in the presence of a base. Suitable bases that can be used include, but are not limited to, alkali carbonates, alkali hydroxides, amines, and ammonium hydroxide. In some embodiments, the base can include an amine. In some embodiments, the base can include dimethylaminopyridine (DMAP).

[0311] In some embodiments, the reaction of chiral alcohol 6 with an alcohol (hydroxyl) group protecting agent can be carried out in a suitable solvent or mixture of solvents. For example, the reaction can be carried out in an organic solvent such as an ethereal solvent (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane), an aromatic solvent (e.g., benzene and toluene), a chlorinated solvent (e.g., methylene chloride and 1,2-dichloroethane), dimethylformamide, dimethyl sulfoxide, acetonitrile, or any mixture of these solvents. In one embodiment, the solvent can include one or more of dimethylformamide (DMF) and dichloromethane (DCM).

[0312] The protected alcohol compound 7 can be converted to the tricyclic compound 8 through a cyclization reaction. The cyclization reaction can be carried out in the presence of a cyclization catalyst, which can be a cobalt-containing cyclization catalyst, such as Co(CO) .

[0313] In some embodiments, the cyclization reaction is carried out in an organic solvent or a mixture of organic solvents. Suitable organic solvents include, but are not limited to, ethereal solvents (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane), dimethylformamide, dimethyl sulfoxide, acetonitrile, or a mixture of any of these solvents. In some embodiments, the cyclization reaction can be carried out in CHCl, followed by removal of the solvent by distillation. The reaction can subsequently be carried out in acetonitrile.

[0314] Tricyclic compound 8 can be hydrogenated with H to form compound 9. In some embodiments, the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst, such as Pd, C, or a combination thereof. In some embodiments, the hydrogenation reaction can be carried out in the presence of a Pd / C hydrogenation catalyst. In some embodiments, the hydrogenation reaction can be carried out in the presence of a base, such as an alkali carbonate (e.g., KCO). In some embodiments, the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst, such as Pd / C, and a base, such as an alkali carbonate (e.g., KCO).

[0315] The hydrogenation reaction can be carried out in an organic solvent, such as an ethereal solvent (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane), an aromatic solvent (e.g., benzene and toluene), a chlorinated solvent (e.g., methylene chloride and 1,2-dichloroethane), an alcoholic solvent (e.g., methanol, ethanol, 2-propanol), dimethylformamide, or any combination of these solvents. In some embodiments, the hydrogenation reaction is carried out in EtOH.

[0316] Compound 9 can be reacted with a reducing agent to form compound 10. A "reducing agent" is a reagent capable of converting a carbonyl functional group to an alcohol (hydroxyl) functional group. Suitable reducing agents include, but are not limited to, NaBH4 and LiAlH4. In some embodiments, the reaction can be carried out in the presence of a base, such as an alkali hydroxide (e.g., NaOH). The reaction can be carried out in an organic solvent, such as those discussed above for the previous reaction. In some embodiments, the reaction can be carried out in EtOH.

[0317] Compound 10 can be reacted with an alcohol (or hydroxyl) group protecting agent to form compound 11. This reaction converts the cyclopentyl hydroxyl group in compound 10 to the alcohol (or hydroxyl) group protecting group P in compound 11. 3 In some embodiments, P 3 can be acetyl (Ac) or a silyl ether hydroxyl protecting group such as tert-butyldimethylsilyl ether (TBDMS / TBS), trimethylsilyl (TMS); triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), etc. The protection reaction can be carried out in one or more organic solvents discussed above for the previous reaction.

[0318] Compound 11 can be deprotected to remove the alcohol protecting group P 1 can be replaced with hydrogen to form compound 12. 1 When is THP, the deprotection reaction may be carried out in the presence of MgBr. The deprotection reaction may be carried out in an organic solvent, such as those discussed above for the previous reaction. In some embodiments, the deprotection reaction may be carried out in diethyl ether.

[0319] Compound 12 may be used as an intermediate for synthesizing treprostinil, its analogs, its prodrugs and / or its conjugates.

[0320] Scheme 2 2A-B present Scheme 2, which shows how compound 12 can be used to synthesize treprostinil, its analogs, its prodrugs, and / or its conjugates. Figure 2A presents a general flow for Scheme 2, while Figure 2B shows Scheme 2 with exemplary conditions.

[0321] Compound 12 can be converted to tricyclic alkene 21, which can also be used as an intermediate for synthesizing treprostinil, its analogs, its prodrugs, and / or its conjugates. In some embodiments, tricyclic alkene 21 can be converted directly to treprostinil, a treprostinil analog, or a treprostinil prodrug, such as compound 25A or 25B, for example, via metathesis.

[0322] In yet some other embodiments, tricyclic alkene 21 can be converted to tricyclic aldehyde 22, which can also be used as an intermediate for synthesizing treprostinil, its analogs, prodrugs, and / or conjugates thereof. The synthesis of tricyclic alkene 21 and tricyclic aldehyde 22 is illustrated in Scheme 3 in Figures 3A-B. In some embodiments, tricyclic alkene 21 can be converted to tricyclic aldehyde 22 in the presence of an oxidizing agent, such as OsO4, NaIO4, O3, or any combination thereof. For example, the oxidizing agent can be OsO4 / NaIO4 or O3.

[0323] In some embodiments, tricyclic aldehyde 22 can be directly converted to treprostinil, a treprostinil analog, or a treprostinil prodrug, such as compound 25A or 25B, via, for example, Scheme 4 (FIGS. 4A-B) or Scheme 5 (FIGS. 5A-B). Such conversions can include coupling reactions, such as the Horner-Wadsworth-Emmons (HWE) coupling reaction.

[0324] In yet other embodiments, tricyclic aldehyde 22 can be converted to tricyclic alkyne 24, which can also be used as an intermediate for synthesizing treprostinil, its analogs, prodrugs, and / or conjugates thereof. In some embodiments, tricyclic aldehyde 22 can be converted to tricyclic alkyne 24 via the Seyfarth-Gilbert homologation reaction and / or the Corey-Fuchs reaction. Tricyclic alkyne 24 can be directly converted to treprostinil, a treprostinil analog, or a treprostinil prodrug, such as compounds 25A or 25B, for example, via reaction with compound 23. Treprostinil, a treprostinil analog, or a treprostinil prodrug, such as compounds 25A or 25B, can be further converted to a treprostinil analog or a treprostinil prodrug, such as compounds 26A or 26B. 3 , R 4 , R 5 Various combinations of (in view of Figures 2A-2B) may allow for a wide variety of treprostinil analogs and prodrugs such as compounds 25A, 25B, 26A and 26B.

[0325] Scheme 3 Scheme 3 in Figures 3A-B generally illustrates an exemplary route for synthesizing tricyclic alkenes, such as tricyclic alkene 21 in Scheme 2, and tricyclic aldehydes, such as tricyclic aldehyde 22 in Scheme 2. Figure 3A presents a general flow for Scheme 3, while Figure 3B shows Scheme 3 with exemplary conditions. The initial reactions in Scheme 3 are similar to those in Scheme 1.

[0326] Scheme 3 involves the chiral addition of protected alkyne compound 32 (compound 2 in Scheme 1, for n=0) to aldehyde compound 31 (compound 3 in Scheme 1) to give chiral alcohol 33 (compound 6 in Scheme 1, for n=0).

[0327] Chiral alcohol 33 can be reacted with an alcohol (hydroxyl) group protecting agent to form the protected alcohol compound 34 (compound 7 in Scheme 1 for n=0).

[0328] The protected alcohol compound 34 can be converted to the tricyclic compound 35 (compound 8 in Scheme 1 for n=0) through a cyclization reaction.

[0329] Tricyclic compound 35 can be hydrogenated with H to form compound 36, which can be compound 9 in Scheme 1 for n=0 and X=H when X is Bn in the previous compound in the scheme, or compound 9 in Scheme 1 for n=0 and X=CH when X is CH3. During hydrogenolysis, the benzyl group as X is cleaved and replaced with H; only CH3 is not cleaved under hydrogenolysis conditions.

[0330] Compound 36 can be reacted with a reducing agent to form compound 37 (compound 10 in Scheme 1 for n=0 and X=H).

[0331] Compound 37 was synthesized by the synthesis of compound 38 (n = 0 and X = CH2COOP 4 (P is a carboxylic acid protecting group, such as C-C alkyl or substituted or unsubstituted benzyl) 4 is converted to compound 10) in Scheme 1.

[0332] Compound 38 is reacted with an alcohol (or hydroxyl) group protecting agent to give compound 39 (n=0 and X=CHCOOP 4 Compound 11 in Scheme 1 can be formed having the formula:

[0333] Compound 39 can be deprotected to remove the alcohol protecting group P 1 with hydrogen to give compound 40 (n=0 and X=CHCOOP 4 Compound 12) in Scheme 1 can be formed having the formula:

[0334] Compound 40 is reacted with an alcohol (hydroxyl) protecting agent to convert the terminal hydrogen to an alcohol protecting group P 1 an alcohol protecting group P, which may be different from 6 For example, in some embodiments, P 6 can be a sulfonated alcohol, such as mesyl or tosyl chloride. The reaction with a sulfonated alcohol, such as mesyl chloride or tosyl chloride, can be carried out in one or more of the solvents discussed above. In some embodiments, the solvent can include trimethylamine, dichloromethane, or a combination thereof.

[0335] Compound 41 is an OP 6 (Sulfonated alcohol P 6 Compound 41 can be converted to compound 42 by replacing the aryl group (having the formula: ##STR00001## with a halogen, such as Br or I. Such a conversion can be carried out, for example, by reacting compound 41 with an alkali metal halogen salt, such as Na or K. For example, compound 41 can be reacted with NaI, NaBr, KI, or KBr. The reaction can be carried out in one or more of the solvents discussed above. In some embodiments, the reaction can be carried out in 2-butanone.

[0336] Compound 42 is a tricyclic alkene compound 43 (P 3 is R 1 and CH2COOP 4 is R 2

[0062] Such a conversion can be carried out, for example, by reacting compound 42 with a base, such as potassium tert-butoxide. The reaction can be carried out in one or more of the solvents discussed above. In some embodiments, the reaction can be carried out in DMF.

[0337] Compound 43 can be converted to compound 44. Such a conversion can be carried out, for example, by reacting compound 43 with an oxidizing agent, which can include, for example, 4-methylmorpholine 4-oxide (NMO), OsO, or a combination thereof. The reaction can be carried out in one or more of the solvents discussed above. In some embodiments, the reaction can be carried out in tetrahydrofuran (THF), water, or a combination thereof.

[0338] Compound 44 is a tricyclic aldehyde compound 45 (P 3 is R 1 and CH2COOP 4 is R 2

[0049] Such a conversion can be carried out, for example, by reacting compound 43 with an oxidizing agent, which can include, for example, OsO4, NaIO4, O3, or a combination of two or more thereof. The reaction can be carried out in one or more of the solvents discussed above. In some embodiments, the reaction can be carried out in 1,2-dichloroethane (DCE), water, or a combination thereof.

[0339] Although not shown in FIGS. 3A-B, in some embodiments, tricyclic alkene compound 43 can be converted to tricyclic aldehyde compound 45 via ozonolysis.

[0340] Tricyclic alkene compound 43 and tricyclic aldehyde compound 45 can be used to synthesize treprostinil, treprostinil analogs and treprostinil prodrugs.

[0341] Scheme 4 Scheme 4 in Figures 4A-B generally illustrates an exemplary route for synthesizing treprostinil from tricyclic aldehyde compound 45, which may be synthesized, for example, according to Scheme 3. Figure 4A presents a general flow for Scheme 4, while Figure 4B shows Scheme 4 with exemplary conditions.

[0342] The tricyclic aldehyde compound 45 can be converted to compound 47 via a side chain coupling reaction. The side chain coupling reaction can be a phosphonate chain coupling reaction in which the tricyclic aldehyde compound can be reacted with a phosphonate compound 46 to form compound 47. The phosphonate chain coupling reaction can be carried out in a solvent such as methyl tert-butyl ether in the presence of a base such as lithium hydroxide monohydrate, e.g., LiOH·HO.

[0343] Compound 47 can be converted to compound 48 in a reduction reaction. The reduction reaction can be, for example, a Rouche reduction reaction, which can be carried out in an alcohol, such as methanol or ethanol, in the presence of sodium borohydride (NaBH) and a lanthanide chloride, such as cerium(III) chloride (CeCl).

[0344] Compound 48 can be further converted to compound 49 in a reduction reaction. The reduction reaction can be a hydrogenation reaction carried out in the presence of a hydrogenation catalyst, such as palladium on carbon (Pd / C).

[0345] Compound 49 can be converted to treprostinil 1 via a deprotection reaction.

[0346] Scheme 5 Scheme 5 in Figures 5A-B generally illustrates an exemplary route for synthesizing treprostinil analog 55 from tricyclic aldehyde compound 45, which may be synthesized, for example, according to Scheme 3. Figure 5A presents a general flow for Scheme 5, while Figure 5B shows Scheme 5 with exemplary conditions.

[0347] The tricyclic aldehyde compound 45 can be converted to compound 52 by a side chain coupling reaction. The side chain coupling reaction can be a phosphonate chain coupling reaction in which the tricyclic aldehyde compound can be reacted with a phosphonate compound 51 to form compound 52. The phosphonate chain coupling reaction can be carried out in a solvent such as methyl tert-butyl ether in the presence of a base such as lithium hydroxide monohydrate, e.g., LiOH·HO.

[0348] Compound 52 can be converted to compound 53 via a reduction reaction. The reduction reaction can be an enantioselective reduction reaction carried out in the presence of a chiral catalyst, such as a chiral oxazaborolidine catalyst, for example, (R)-2-methyl-CBS-oxazaborolidine.

[0349] Compound 53 can be converted to compound 54 in a cyclopentyl deprotection reaction.

[0350] Compound 54 can be converted to compound 55 via a deprotection reaction, such as a base hydrolysis deprotection reaction.

[0351] FIG. 6 illustrates treprostinil analogs that may be prepared using the methods discussed above and below.

[0352] Scheme 6 Scheme 6 in Figures 7A-B generally illustrates an exemplary route for synthesizing compound 75 from compound 12, which may be synthesized, for example, according to Scheme 1. Figure 7A presents a general flow for Scheme 6, while Figure 7B shows Scheme 6 with exemplary conditions.

[0353] Compound 12 can be converted to compound 71 via a deprotection reaction, which can be a selective deprotection reaction. The deprotection reaction can be a demethylation reaction, which can be carried out in the presence of demethylating conditions, such as a combination of Ph2PH and BuLi or the reaction product of such a combination, e.g., Ph2PLi.

[0354] Compound 71 can be converted to compound 72 via reaction with a protected haloacetic acid, such as benzyl bromoacetate.

[0355] Compound 72 can be converted to the aldehyde compound 73. This reaction can be carried out in the presence of an oxidizing reagent, such as pyridinium dichromate (PDC).

[0356] Aldehyde compound 73 can be converted to compound 74 via an oxidation reaction. The oxidation reaction can be a Pinnic oxidation carried out in the presence of NaClO2.

[0357] Compound 74 can be converted to treprostinil analog 75 via a deprotection reaction.

[0358] Scheme 7 Scheme 7 in Figures 8A-B generally illustrates an exemplary route for synthesizing compound 89 from compound 12, which may be synthesized, for example, according to Scheme 1. Figure 8A presents a general flow for Scheme 7, while Figure 8B shows Scheme 7 with exemplary conditions.

[0359] Compound 12 can be converted to compound 81 by replacing the terminal hydroxy group with a halogen, such as Br or I. Such a conversion can be carried out, for example, by reacting compound 12 with mesyl chloride followed by an alkali metal halogen salt, such as Na or K. For example, compound 12 can be reacted with mesyl chloride followed by NaI, NaBr, KI, or KBr. The reaction can be carried out in one or more of the solvents discussed above. In some embodiments, the reaction can be carried out in 2-butanone.

[0360] Compound 81 can be converted to tricyclic alkene compound 82. Such a conversion can be carried out, for example, by reacting compound 81 with a base, such as potassium tert-butoxide. The reaction can be carried out in one or more of the solvents discussed above. In some embodiments, the reaction can be carried out in DMF.

[0361] Compound 82 can be converted to compound 83 via an oxidation reaction, which can be carried out in the presence of an oxidizing agent such as OsO4.

[0362] Compound 83 can be converted to compound 84 via a deprotection reaction, which can be a selective deprotection reaction. The deprotection reaction can be a demethylation reaction, which can be carried out in the presence of demethylating conditions such as a combination of Ph2PH and BuLi or the reaction product of such a combination, e.g., Ph2PLi.

[0363] Compound 84 can be converted to compound 85 via reaction with a protected haloacetic acid, such as benzyl bromoacetate.

[0364] Compound 85 can be converted to compound 86 via a deprotection reaction, which can be selective deprotection at the cyclopentyl ring. Such deprotection can be carried out in the presence of a deprotecting agent, such as pyridinium p-toluenesulfonate (PPTS).

[0365] Compound 86 can be converted to tricyclic aldehyde compound 87 via an oxidation reaction, which can be carried out in the presence of an oxidizing agent such as OsO4, NaIO4, O3, or a combination of two or more thereof.

[0366] Compound 87 can be converted to compound 88 via reaction with N2CHCO2Et.

[0367] Compound 88 can be converted to treprostinil analog 89 via a deprotection reaction, which can be carried out in the presence of a base.

[0368] Scheme 8 Scheme 8 in Figures 9A-B generally illustrates an exemplary route for synthesizing treprostinil analog 96A from compound 12, which may be synthesized, for example, according to Scheme 1. Figure 9A presents a general flow for Scheme 8, while Figure 9B shows Scheme 8 with exemplary conditions.

[0369] Compound 12 can be converted to the aldehyde compound 92. This reaction can be carried out in the presence of an oxidizing reagent, such as pyridinium dichromate (PDC).

[0370] Aldehyde compound 92 can be converted to a mixture of compounds 93 and 94, which can be further converted to a mixture of compounds 96A, 96B and 95 via a deprotection reaction.

[0371] Compound 96A can be separated from the mixture using a separation technique, such as HPLC.

[0372] Scheme 9 Scheme 9 in Figures 10A-B generally illustrates an exemplary route for synthesizing compound 108 from compound 12, which may be synthesized, for example, according to Scheme 1. Figure 10A presents a general flow for Scheme 9, while Figure 10B shows Scheme 9 with exemplary conditions.

[0373] Compound 12 can be converted to the aldehyde compound 101. This reaction can be carried out in the presence of an oxidizing reagent, such as pyridinium dichromate (PDC).

[0374] Compound 101 can then be converted to compound 102.

[0375] Compound 102 can be converted to compound 103 via a deprotection reaction, which can be a selective deprotection reaction. The deprotection reaction can be a demethylation reaction, which can be carried out in the presence of demethylating conditions such as a combination of Ph2PH and BuLi or the reaction product of such a combination, e.g., Ph2PLi.

[0376] Compound 103 can be converted to compound 104 via reaction with a protected haloacetic acid, such as benzyl bromoacetate.

[0377] Compound 104 can be converted to compound 105 by protecting the hydroxy group.

[0378] Compound 105 can be converted to compound 106 in the presence of a deprotecting agent, such as pyridinium p-toluenesulfonate (PPTS).

[0379] Compound 106 can be converted to compound 107 via an oxidation reaction. The oxidation reaction can be a Pinnic oxidation carried out in the presence of an oxidizing agent, such as NaClO.

[0380] Compound 107 can then be converted to a mixture of compound 108L and treprostinil analog 108 via a deprotection reaction. Treprostinil analog 108 can be separated from such a mixture using a separation technique, such as HPLC. Treprostinil analog 108 can be converted to its salt, such as the sodium salt.

[0381] Scheme 10 Scheme 10 in Figures 11A-B generally illustrates an exemplary route for synthesizing compound 117 from treprostinil. Figure 11A presents a general flow for Scheme 10, while Figure 11B shows Scheme 10 with exemplary conditions.

[0382] Treprostinil 1 can be converted to compound 111 by selectively protecting the carboxylic acid group.

[0383] Compound 111 can be reacted with a silyl protecting agent, such as tert-butyldimethylsilyl chloride (TBDMSCl) or tert-butyldiphenylsilyl chloride (TBDPSCl). Such a reaction can lead to a mixture of the desired compound 112, in which the silyl protecting group is on the cyclopentyl hydroxy group but not on the alkyl chain hydroxy group, the undesired compound 113, in which the silyl protecting group is on the alkyl chain hydroxy group but not on the cyclopentyl hydroxy group, and a minor product 114, in which the silyl protecting group is on both the alkyl chain hydroxy group and the cyclopentyl hydroxy group.

[0384] The desired compound 112 can be separated from the mixture using separation techniques such as column chromatography, HPLC and SFC.

[0385] Compound 112 can be converted to compound 115. Such a reaction can be carried out in the presence of an oxidizing agent such as pyridinium chlorochromate (PCC).

[0386] Compound 115 can be converted to compound 116 by deprotecting the benzyl ester of the carboxylic acid group, for example, via hydrogenolysis.

[0387] Compound 116 can be converted to treprostinil analog 117 via a deprotection reaction.

[0388] Scheme 11 Scheme 11 in Figures 12A-B generally illustrates an exemplary route for synthesizing treprostinil analogs 126 from treprostinil. Figure 12A presents a general flow for Scheme 11, while Figure 12B shows Scheme 11 with exemplary conditions.

[0389] Treprostinil 1 can be converted to compound 121 via an esterification reaction. Compound 121 can then be converted to a mixture of compounds 123, 124, and 125. This mixture can be converted to a mixture of compounds 126, 127, and 128 via base hydrolysis. Compound 126 can be separated from the mixture using a separation technique such as HPLC.

[0390] The embodiments described herein are further illustrated, but in no way limited, by the following examples. [Example]

[0391] 1. Synthesis of Treprostinil and Treprostinil Analogues 1.1. Synthesis of the tricyclic aldehyde core

[0392] [ka]

[0393] experiment: Synthesis of chiral benzylalkynol (33): To a solution of zinc trifluoromethanesulfonate (21.5 g, 0.99 mol) in toluene (50 mL), triethylamine (8.0 g, 0.0792 mol) and (1S,2R)-(+)-N-methylephedrine (10.6 g, 0.99 mol) were added and stirred at room temperature for 2 hours. To this mixture, 2-(3-butynyloxy)tetrahydro-2H-pyran (32) (12.2 g, 0.0792 mol) was added and stirred for 0.5 hours. To this mixture, a solution of 2-allyl-3-benzyloxybenzaldehyde (31) (5.0 g, 0.0198 mol) in toluene (10 mL) was added. The reaction mixture was stirred overnight at room temperature. Upon completion, the reaction was worked up to give crude product (33) (60.2 g) as a viscous liquid. The crude product was purified by column chromatography to give pure chiral benzylalkynol (33) (7.22 g).

[0394] Synthesis of benzylalkynol tert-butyldimethylsilyl ether (34): To a solution of chiral benzylalkynol 33 (7.15 g, 0.0176 mol) in dichloromethane (80 mL), 2,6-lutidine (2.45 g, 0.0229 mol) was added and stirred at ambient temperature under argon. The mixture was stirred until a clear solution was obtained. The mixture was cooled, and a solution of tert-butyldimethylsilyl trifluoromethanesulfonate (6.05 g, 0.0229 mol) in dichloromethane (40 mL) was added dropwise. After completion of the reaction, it was worked up to give crude product 34 (9.6 g) as a viscous liquid. Another 7.15 g batch was combined and purified by column chromatography to give pure benzylalkynol tert-butyldimethylsilyl ether 34 (16.93 g).

[0395] Synthesis of tricyclic enone (35): To a solution of benzylalkynol tert-butyldimethylsilyl ether 34 (6.8 g, 0.0138 mol) in toluene (70 mL) was added dicobalt octacarbonyl (4.7 g, 0.0138 mol). The mixture was then heated to reflux, which continued for 2 hours. The reaction was filtered through Celite and evaporated in vacuo to give crude compound 35 (12.8 g) as a viscous liquid. The crude product was purified by column chromatography to give tricyclic enone 35 (5.8 g).

[0396] Synthesis of tricyclic ketones (36): To a solution of tricyclic enone 35 (5.4 g, 0.0098 mol) in ethanol (80 mL) and water (2.7 mL) was added Pd / C (2.69 g). The mixture was stirred under an atmosphere of hydrogen gas. After 24 h, the reaction mixture was passed through Celite, and the filtrate was evaporated in vacuo to give crude tricyclic ketone 36 (5.1 g) as a viscous liquid. The crude product was purified by column chromatography to give tricyclic ketone 36 (3.08 g).

[0397] Synthesis of tricyclic alcohol (37): To a solution of tricyclic ketone (36) (5.1 g, 0.015 mol) in ethanol (90 mL) was added a solution of sodium hydroxide (6.2 g, 0.155 mol) in water (20 mL) at −10° C. To this mixture was added sodium borohydride (1.1 g, 0.031 mol). The reaction mixture was stirred for 2 hours, and at this stage the reaction was complete. The reaction mixture was worked up and concentrated in vacuo to give crude (37) (4.95 g). The crude product was used directly for the next step without purification.

[0398] Synthesis of tricyclic methyl ester (38): To a solution of tricyclic alcohol 37 (4.8 g, 0.0144 mol) in acetone (70 mL) were added potassium carbonate (4.0 g, 0.0288 mol) and methyl bromoacetate (2.2 g, 0.0158 mol). The reaction mixture was stirred. After 72 hours, the reaction was complete, and the reaction mixture was filtered. The filtrate was evaporated in vacuo to give crude product 38 (6.3 g) as a viscous liquid. The crude product (6.3 g) was purified by column chromatography to give tricyclic methyl ester 38 (5.5 g).

[0399] Synthesis of tricyclic tert-butyldimethylsilyl ether (39): To a solution of tricyclic methyl ester 38 (2.8 g, 0.0069 mol) in dichloromethane (30 mL) was added 2,6-lutidine (1.1 g, 0.0103 mol). The mixture was cooled, and a solution of tert-butyldimethylsilyl trifluoromethanesulfonate (2.19 g, 0.0082 mol) in dichloromethane (20 mL) was added dropwise. The reaction was stirred for 1 hour, at which point the reaction was complete. The reaction mixture was worked up to give crude product 39 (4.2 g) as a viscous liquid. Crude product from another 2.8 g batch was combined and purified by column chromatography to give tricyclic tert-butyldimethylsilyl ether 39 (6.39 g).

[0400] Synthesis of tricyclic tert-butyldimethylsilyl ether alcohol (40): To a solution of tricyclic tert-butyldimethylsilyl ether (39) (1.5 g, 0.0028 mol) in diethyl ether (30 mL) was added magnesium bromide (3.19 g, 0.0173 mol). The reaction was stirred overnight, and after 24 h, the reaction mixture was worked up to give crude product (40) (1.6 g) as a viscous liquid. The crude product (1.6 g) was purified by column chromatography to give tricyclic tert-butyldimethylsilyl ether alcohol (40) (1.1 g).

[0401] Synthesis of tricyclic mesylate (41): To a solution of tricyclic tert-butyldimethylsilyl ether alcohol (40) (1.1 g, 0.0026 mol) in dichloromethane (30 mL) was added triethylamine (0.58 g, 0.0057 mol). To the cold mixture was added methanesulfonyl chloride (0.36 g, 0.0031 mol). After the addition, the reaction mixture was stirred for 2 hours. At this stage, the reaction was complete. The reaction was worked up to give crude tricyclic mesylate (41) (1.37 g). The crude product was directly used in the next step without further purification.

[0402] Synthesis of tricyclic iodide (42): To a solution of tricyclic mesylate (41) (1.37 g, 0.0027 mol) in 2-butanone (40 mL) was added sodium iodide (2.45 g, 0.0164 mol). The reaction mixture was refluxed for 1.5 h. At this stage the reaction was complete. The reaction mixture was evaporated and worked up to give crude tricyclic iodide (42) (1.2 g) as a viscous liquid. The crude product was directly used in the next step without further purification.

[0403] Synthesis of tricyclic alkene (43): To a solution of tricyclic iodide 42 (2.34 g, 0.00429 mol) in N,N-dimethylformamide (35 mL) was added potassium tert-butoxide (2.97 g, 0.02646 mol) and stirred at room temperature for 2 hours. The reaction mixture was worked up to give crude tricyclic alkene (1.98 g). To this crude product in acetone (40 mL) was added potassium carbonate (2.72 g, excess) and methyl iodide (2.79 g, excess) and stirred at room temperature overnight. The crude reaction mixture was passed through Celite and evaporated in vacuo to give crude tricyclic alkene 43 (1.3 g). The crude product was purified by column chromatography to give tricyclic alkene 43 (0.85 g).

[0404] Synthesis of tricyclic diol (44): To a solution of tricyclic alkene (43) (0.21 g, 0.00052 mol) in a mixture of tert-butanol (10 mL), tetrahydrofuran (3 mL), and water (1 mL) (ratio = 10:3:1), osmium tetroxide (0.01 g, 0.00005 mol) and 4-methylmorpholine N-oxide (0.06 g, 0.00053 mol) were added and stirred at room temperature under argon. After 4 hours, the reaction was complete, and the reaction mixture was worked up to give crude tricyclic diol (44) (0.14 g). This crude compound was directly used in the next step without further purification.

[0405] Synthesis of tricyclic aldehyde (45): To a solution of tricyclic diol (44) (0.14 g, 0.00031 mol) in a mixture of 1,2-dichloroethane (10 mL) and water (10 mL) (ratio = 1:1) was added sodium periodate (0.12 g, 0.00077 mol) at room temperature. After two nights, the crude reaction mixture was worked up to give crude tricyclic aldehyde (45) (0.12 g). This crude compound was directly carried on to the next step without further purification.

[0406] 1.2.Synthesis of Treprostinil

[0407] [ka]

[0408] experiment: Synthesis of tricyclic enone (47): To a solution of dimethyl-2-oxoheptylphosphonate (46) (0.08 g, 0.0004 mol) in tert-butyl methyl ether (5 mL), lithium hydroxide monohydrate (0.01 g, 0.0004 mol) was added and stirred at room temperature for 1.5 hours. To this mixture, a solution of tricyclic aldehyde (45) (0.12 g, 0.0002 mol) in tert-butyl methyl ether (5 mL) was added and stirred at room temperature for 4 hours. The reaction was complete, and the mixture was worked up to give crude tricyclic α,β-unsaturated ketone (47) (0.14 g). The crude product was purified by column chromatography to give pure tricyclic enone (47) (0.1 g).

[0409] Synthesis of tricyclic alkenol (48): To a solution of tricyclic α,β-unsaturated ketone (47) (0.1 g, 0.0002 mol) in methanol (10 mL) was added cerium(III) chloride heptahydrate (0.07 g, 0.0002 mol) at room temperature. The mixture was cooled, and then sodium borohydride (0.007 g, 0.0002 mol) was added and stirred. After 1 hour, the reaction was worked up to give the crude product. This crude product was dissolved in methanol (10 mL) and 10% aq. HCl (0.3 mL) was added. The mixture was stirred at room temperature. After 1 hour, the reaction was worked up to give crude tricyclic alkenol (48) (0.07 g). This crude compound was carried on to the next step without further purification.

[0410] Synthesis of Treprostinil Methyl Ester (49): To a solution of tricyclic alkenol 48 (0.07 g) in a mixture of methanol (10 mL) and water (0.2 mL) was added Pd / C (0.1 g). This was stirred overnight under a hydrogen atmosphere. The mixture was passed through Celite and evaporated in vacuo to give crude treprostinil methyl ester 49 (0.07 g).

[0411] Synthesis of Treprostinil (1): To a solution of treprostinil methyl ester (49) (0.07 g, 0.0002 mol) in methanol (10 mL) was added a solution of potassium hydroxide (0.09 g, 0.0002 mol) in water (1 mL) and stirred overnight. The reaction mixture was worked up and evaporated in vacuo to give treprostinil (1) (45 mg) as a solid. This treprostinil was 1 It was characterized by 1 H NMR.

[0412] 1.3. Synthesis of Treprostinil Analogues

[0413] [ka]

[0414] experiment: Synthesis of tricyclic enone (52): To a solution of phosphonate side chain 51 (100 mg, 0.432 mmol) in tert-butyl methyl ether (1 mL) was added lithium hydroxide monohydrate (17 mg, 0.396 mmol) and stirred at room temperature for 2 hours. To this mixture was added a solution of tricyclic aldehyde 45 (100 mg, 0.24 mol) in tert-butyl methyl ether (2 mL) and stirred at room temperature for 4 hours. The reaction was worked up to give crude tricyclic enone 52 (132 mg). This was combined with another 301 mg batch and purified by column chromatography to give pure tricyclic enone 52 (464 mg).

[0415] Synthesis of tricyclic alkenol (53): To a solution of borane dimethyl sulfide (2.0 M, 57 μL, 0.114 mmol) in toluene (0.3 mL), (R)-(+)-2-methyl-CBS-oxazaborolidine (1.0 M, 114 μL, 0.114 mmol) in toluene was added and stirred for 1.5 hours. The mixture was cooled, and a solution of tricyclic enone 52 (30 mg, 0.057 mmol) in toluene (0.7 mL) was added, and the mixture was stirred for 1.5 hours while the temperature was brought to ambient temperature. The reaction mixture was worked up to give crude product 53 (54 mg). This was purified by column chromatography to give tricyclic alkenol 53 (30 mg).

[0416] Synthesis of methyl ester (54): To a solution of tricyclic alkenol 53 (30 mg, 0.057 mmol) in methanol (1 mL) was added 2.0 N hydrochloric acid (72 μL, 0.142 mmol), and the mixture was stirred for 2 h. The reaction mixture was worked up and evaporated in vacuo to give crude methyl ester 54 (22.6 mg). This crude compound was carried on to the next step without further purification.

[0417] Synthesis of Treprostinil Analogue (55): To a solution of the methyl ester (54) (18 mg, 0.0044 mol) in methanol (1 mL) was added a solution of sodium hydroxide (5.2 mg, 0.131 mmol) in water (0.2 mL) and stirred for 4 hours. The crude reaction mixture was worked up and evaporated in vacuo to give the treprostinil analog (55) (12.2 mg). This treprostinil analog was 1 It was characterized by 1 H NMR.

[0418] 1.3.2. Synthesis of Cyclohexyl Treprostinil Analog 60

[0419] [ka]

[0420] experiment: Synthesis of cyclohexyl tricyclic TBDMS enone (57): To a solution of tricyclic TBDMS aldehyde (45) (0.093 g, 0.221 mmol, freshly prepared from the corresponding alcohol) in anhydrous tert-butyl methyl ether (MTBE) (2 mL) was added a solution of cyclohexyl ketophosphonate side chain (56) (0.078 g, 0.333 mmol) in anhydrous tert-butyl methyl ether (MTBE) (2 mL). The clear solution was stirred at room temperature under argon for 10 minutes, and then lithium hydroxide monohydrate (0.011 g, 0.262 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight, and the reaction was complete. The mixture was quenched with water (10 mL), and the aqueous layer was separated. The aqueous layer was extracted with MTBE (2 × 15 mL). The combined MTBE extracts were washed with water (2 x 15 mL), brine (1 x 5 mL), dried (NaSO), filtered, and concentrated in vacuo to give a viscous liquid (0.147 g). The crude product was purified by chromatography to give cyclohexyl tricyclic TBDMS enone (57) (0.052 g), and 1 Characterized by 1 H NMR, MS and HPLC with 85.7% purity.

[0421] Synthesis of cyclohexyl tricyclic TBDMS alkenol (58) To a solution of (R)-(+)-2-methyl-CBS-oxazaborolidine in toluene (1.0 M) (0.20 mL, 0.20 mmol) and anhydrous toluene (1.0 mL) was added a solution of borane-methyl sulfide complex in toluene (2.0 M) (0.10 mL, 0.20 mmol) at room temperature under argon. The mixture was stirred at room temperature for 1 hour and then cooled to -40±5°C. To this cold solution was added a solution of cyclohexyl tricyclic TBDMS enone (57) (0.05 g, 0.095 mmol) in anhydrous toluene (2.0 mL). The reaction mixture was warmed to -20°C over a period of 1 hour, and the reaction was complete. The mixture was cooled to -50±5°C and then quenched by the dropwise addition of anhydrous methanol (0.5 mL). The mixture was warmed to 0°C over a period of 1 hour. The mixture was treated with saturated ammonium chloride (2.5 mL), and the mixture was stirred for 15 minutes. The mixture was filtered to remove a white solid, which was washed with MTBE (3 x 10 mL). The combined filtrate was transferred to a separatory funnel, and the aqueous layer was separated. The aqueous layer was extracted with MTBE (2 x 15 mL). The combined organic layers were washed with water (1 x 5 mL), brine (1 x 5 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the crude product as a colorless viscous liquid (0.085 g). Chromatography of the crude product gave pure cyclohexyl tricyclic TBDMS alkenol (58) (0.031 g), as well as IR, 1 H NMR, 13 It was characterized by C NMR and MS.

[0422] Synthesis of cyclohexyl tricyclic hydroxyalkenol (59) To a solution of cyclohexyl tricyclic TBDMS alkenol (58) (0.03 g, 0.057 mmol) in methanol (1.5 mL) was added a solution of hydrochloric acid (2N) (0.08 mL, 0.16 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, at which time the reaction was complete. The mixture was neutralized to pH 7-8 with saturated sodium bicarbonate (2 mL), and the methanol was evaporated in vacuo. The aqueous residue was treated with water (10 mL) and then extracted with ethyl acetate (3 × 10 mL). The combined ethyl acetate extracts were washed with water (2 × 10 mL), brine (1 × 5 mL), dried (NaSO), filtered, and concentrated in vacuo to give cyclohexyl tricyclic hydroxyalkenol (59) as a pale yellow viscous liquid (0.021 g, 87.5%), and 1 It was characterized by H NMR and purity (92.2%) by HPLC.

[0423] Synthesis of cyclohexyl tricyclic methyl ester (60) To a solution of cyclohexyl tricyclic hydroxyalkenol (59) (0.01 g, 0.024 mmol) in methanol (1.5 mL) was added palladium on carbon, 5 wt%, 50% wet (0.01 g) at room temperature. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen (filled in a balloon) for 3.5 hours. The reaction mixture was filtered through a pad of Celite (0.05 g) and the solid was washed with methanol (3 × 2 mL). The filtrate was concentrated in vacuo to give cyclohexyl tricyclic methyl ester (60) (0.011 g) as an off-white solid, as well as 1 Characterized by 1 H NMR and LSMS.

[0424] 2. Synthesis of Treprostinil Metabolites 2.1. Synthesis of Compound 89 in Figure 13

[0425] [ka]

[0426] experiment: Synthesis of racemic benzyl alkynol (4): To a solution of tetrahydro-2-(3-butynyloxy)-tetrahydro-2H-pyran (25.0 g, 162.1 mmol, 1.10 equiv.) in anhydrous tetrahydrofuran (200 mL), ethylmagnesium bromide in ether (3.0 M in ether) (54 mL, 133.3 mmol, 1.10 equiv.) was slowly added dropwise under nitrogen at ambient temperature over a 30-minute period, allowing the reagent to be added dropwise and the reaction mixture to gently reflux. After complete addition, the reaction mixture was cooled to room temperature over a 1.5-hour period and then cooled to 0 to -10°C. To this cold solution, a solution of 2-allyl-3-methoxybenzaldehyde (3) (26.7 g, 147.4 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL) was slowly added over a 30-minute period, maintaining the temperature of the reaction mixture between 0°C and 10°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. After 20 hours, the reaction was checked by TLC. The mixture was carefully quenched with saturated ammonium chloride solution (approximately 20 mL), while maintaining the temperature of the mixture below 35°C during the addition of the ammonium chloride solution. The white granular mixture was stirred for 30 minutes, diluted with ethyl acetate (200 mL), and then filtered and washed with ethyl acetate (400 mL). The filtrate was concentrated in vacuo to give a viscous liquid (51 g). The crude product was purified by silica gel column chromatography to give pure racemic benzyl alkynol (4) (42.5 g, 85%).

[0427] Synthesis of aryl alkynyl ketone (5): To a solution of racemic benzyl alkynol 4 (42.5 g, 129 mmol, 1.0 equiv.) in acetone (1,000 mL), manganese(IV) oxide (approximately 85% pure, 132.0 g, 1290 mmol, 10.0 equiv.) was added portionwise with stirring at room temperature. The reaction mixture was stirred overnight. After 22 h, the reaction was checked by TLC. The mixture was filtered through Celite (55 g) in a sintered glass funnel and washed with acetone (1500 mL). The filtrate was concentrated in vacuo to give 40 g of a viscous liquid. The crude product was purified by silica gel column chromatography to give aryl alkynyl ketone 5 as a clear, pale yellow, viscous liquid (36 g, 85%).

[0428] Synthesis of chiral benzylalkynol (6): To a solution of (R)(+)-2-methyl-CBS-oxazoborolidine (1.0 M in toluene) (130 mL, 130 mmol, 1.2 equiv.) was added a solution of aryl alkynyl ketone (5) (35 g, 107 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (300 mL) at room temperature under nitrogen. The mixture was stirred for 20 minutes, then cooled to -30°C, and then borane methyl sulfide complex (16.8 g, 21 mL, 221 mmol, 2.1 equiv.) was added slowly, maintaining the temperature of the mixture between -40°C and -30°C. The mixture was stirred at -30°C for 2 hours and then checked by TLC. The mixture was carefully quenched with methanol (22 mL) at -20 to -30°C under nitrogen with stirring over a period of 20 minutes. The mixture was allowed to warm to room temperature and then for 1 hour. The mixture was treated with saturated ammonium chloride solution (approximately 100 mL) until a white granular solid formed. The mixture was filtered and washed with ethyl acetate (500 mL). The filtrate was concentrated in vacuo to give a pale yellow viscous liquid (35 g) with some white solid residue. The crude product was purified by silica gel column chromatography to give the chiral benzylalkynol (6) as a clear, colorless viscous liquid (27.5 g, 78.1%).

[0429] Synthesis of benzylalkynyl tert-butyldimethylsilyl ether (7): To a solution of chiral benzylalkynol 6 (27.5 g, 83.2 mmol, 1.0 equiv.) in dichloromethane (300 mL) was added imidazole (8.6 g, 126 mmol, 1.5 equiv.), 4-(dimethylamino)pyridine (0.38 g, 3.1 mmol, 0.04 equiv.), tert-butyldimethylsilyl chloride (19.8 g, 131.4 mmol, 1.6 equiv.), and N,N'-dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. After 18 h, the reaction was checked by TLC. The mixture was washed with water (2 × 100 mL), brine (1 × 50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give nearly pure benzylalkynyl tert-butyldimethylsilyl ether 7 as a clear, viscous liquid (37 g, 100%). The product was used in the next step without further purification.

[0430] Synthesis of tricyclic THP-ethylenone (8): To a solution of benzylalkynyl tert-butyldimethylsilyl ether (7) (37 g, 83.4 mmol, 1.0 equiv.) in dry toluene (390 mL) under nitrogen, octacarbonyldicobalt (28.7 g, 83.9 mmol, 1.0 equiv.) was added in one portion at room temperature. The dark brown reaction mixture was stirred at room temperature. Carbon monoxide evolved slowly during stirring, and the solution turned reddish-brown after a while. The reaction was continued to stir for 2 hours and checked by TLC to confirm the formation of the complex as a single spot. The mixture was refluxed under nitrogen for 2 hours (using a preheated oil bath temperature of 120 °C) and checked by TLC to confirm the absence of any starting material. Air was bubbled through the reaction mixture overnight at room temperature. The mixture was diluted with ethyl acetate (400 mL) and then passed through Celite (50 g). The mixture was filtered and washed with ethyl acetate (250 mL). The filtrate was concentrated in vacuo to give a dark brown residue (36 g). The crude product was purified by silica gel column to give tricyclic ethyl ether enone (8) (25.3 g).

[0431] Synthesis of tricyclic THP ethyl ether ketone (9): To a solution of tricyclic ethyl ether enone (8) (0.42 g, purified and pretreated carbon, 0.89 mmol, 1.0 equiv.) in ethyl alcohol (8 mL), water (5 drops), potassium carbonate (0.021 g, 0.15 mmol, 0.17 equiv., 5% w / w), and palladium, 5% (dry basis), wet (50%), Degussa type (0.11 g, 25% w / w) on activated carbon were added. The mixture was stirred under an atmosphere of hydrogen (filled in a balloon) at room temperature for 3 hours and checked by TLC and IR to find completion. The mixture was filtered through a pad of Celite in a sintered glass funnel and washed with ethyl alcohol (20 mL). The hydrogenated product was used in the next step without isolation of tricyclic THP ethyl ether ketone (9).

[0432] Synthesis of tricyclic THP ethyl ether alcohol (10): To a solution of tricyclic THP ethyl ether ketone (9) (17.85 g, 51.83 mmol, 1.0 equiv., calculated yield from the previous step) in ethyl alcohol and water (approximately 540 mL) was added a solution of sodium hydroxide (20.73 g, 518.25 mmol, 10.0 equiv., dissolved in 180 mL of water) at −10° C. The mixture was stirred at −10° C. for 30 minutes, and then sodium borohydride (3.92 g, 103.7 mmol, 2.0 equiv.) was added portionwise. After complete addition, the mixture was stirred at −10° C. for 15 minutes and warmed to room temperature over a period of 1.5 hours, then checked by TLC. The reaction mixture was quenched with saturated ammonium chloride (100 mL until the pH changed from 14 to 9). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to remove ethyl alcohol. The residue was dissolved in water (100 mL) and dichloromethane (150 mL). The aqueous layer was separated and then extracted with dichloromethane (2 x 70 mL). The dichloromethane extract was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a viscous liquid of tricyclic THP ethyl ether alcohol (10) (17.59 g). The product (10) was sufficiently pure to be used in the next step.

[0433] Synthesis of tricyclic methoxy TBDMS THP ethyl ether (11): To a solution of tricyclic alcohol (10) (8.57 g, 24.74 mmol, 1.0 equiv.) in dichloromethane (150 mL), imidazole (2.53 g, 37.16 mmol, 1.5 equiv.), 4-(dimethylamino)pyridine (0.06 g, 0.491 mmol, 0.02 equiv.), and tert-butyldimethylsilyl chloride (4.85 g, 32.18 mmol, 1.3 equiv.) were added at room temperature. The reaction mixture was stirred overnight at room temperature. After 18 h, the reaction was checked by TLC and was complete. The mixture was washed with water (2 × 50 mL), brine (1 × 20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give nearly pure tricyclic methoxyl TBDMS THP ethyl ether (11) as a clear, viscous liquid (10.65 g, 93.40%). The pure compound (11) is 1 H and 13 The product was characterized by C NMR spectroscopy and used in the next step without further purification.

[0434] Synthesis of tricyclic methoxy TBDMS ethyl alcohol (12): To a solution of tricyclic methoxy TBDMS THP ethyl ether (11) (5.36 g, 11.63 mmol, 1.0 equiv.) in diethyl ether (200 mL) was added magnesium bromide (12.87 g, 69.90 mmol, 6.0 equiv.) at room temperature under nitrogen. The reaction mixture was stirred at room temperature overnight. After 16 h, the mixture was checked by TLC and was complete. The reaction mixture was carefully quenched with water (100 mL). The ether layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (1 x 150 mL), brine (1 x 150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give tricyclic methoxy TBDMS ethyl alcohol (12), which was purified by silica gel chromatography to give a pale yellow viscous liquid (3.48 g, 80%). Compound (12) was 1 H and 13 It was characterized by C NMR spectrum.

[0435] Synthesis of tricyclic methoxy TBDMS ethyl mesylate (81'): To a solution of tricyclic methoxy TBDMS ethyl alcohol (12) (0.18 g, 0.48 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added triethylamine (0.15 mL, 0.11 g, 1.10 mmol, 2.27 equiv.). The mixture was cooled to 0° C., and then a solution of methanesulfonyl chloride (0.07 g, 0.58 mmol, 1.2 equiv.) in dichloromethane (1 mL) was added. The reaction mixture was stirred at 0° C. and then warmed to room temperature over a period of 1.5 hours. The mixture was checked by TLC and was complete. The reaction mixture was quenched with brine (10 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (2×20 mL). The combined dichloromethane extracts were washed with brine (1 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give tricyclic methoxy TBDMS ethyl mesylate (81') as a viscous amber liquid (0.24 g, 100%). 1 H and 13 It was characterized by C NMR spectroscopy. The mesylate was used in the next step without further purification.

[0436] Synthesis of tricyclic methoxy TBDMS ethyl iodide (81): To a solution of crude mesylate (81') (0.21 g, 0.46 mmol, 1.0 equiv.) in acetone (15 mL) was added sodium iodide (0.21 g, 1.40 mmol, 3.03 equiv.) in one portion at room temperature. The reaction mixture was stirred at room temperature overnight. After 42 h, the reaction was checked by TLC. There was very little product; however, the mixture was quenched with saturated sodium bicarbonate (5 mL), and the acetone was removed in vacuo. The residue was extracted with dichloromethane (30 mL), washed with saturated sodium bicarbonate (1 x 15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the product as a viscous liquid. 1Analysis by H NMR revealed it to be a mixture (0.19 g) of tricyclic methoxy TBDMS ethyl mesylate (81′) (major) and tricyclic methoxy TBDMS ethyl iodide (81) (minor) as a viscous liquid. The recovered mesylate (81') (0.18 g, 0.39 mmol, 1.0 equiv.) was dissolved in 2-butanone (20 mL), and sodium iodide (0.35 g, 2.33 mmol, 6.0 equiv.) was added in one portion at room temperature. The reaction mixture was gently heated to reflux for 3 h. The mixture was checked by TLC (EtOAc / hexane, 3:7) and found to be complete. The mixture was cooled to room temperature, and then the 2-butanone was removed in vacuo. The residue was dissolved in water (10 mL) and then extracted with ethyl acetate (3 × 10 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate (1 x 10 mL), 10% sodium thiosulfate solution (1 x 10 mL), brine (1 x 10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give tricyclic methoxy TBDMS ethyl iodide (81) as a pale yellow viscous liquid that solidified upon standing at room temperature (0.17 g, 89%). Compound (81) was obtained by 1 H and 13 The product was characterized by C NMR spectroscopy and used in the next step without further purification.

[0437] Synthesis of tricyclic methoxy TBDMS ethylene (82): To a solution of tricyclic methoxy TBDMS ethyl iodide (81) (0.14 g, 0.29 mmol, 1.0 equiv.) in tert-butanol (15 mL) was added potassium tert-butoxide (0.07 g, 0.62 mmol, 2.14 equiv.) in one portion at room temperature (slightly exothermic!). The reaction mixture was gently heated to reflux for 1 h and then checked by TLC. The reaction appeared to be complete. The mixture was quenched with water (10 mL), and then the tert-butanol was removed in vacuo. The residue was extracted with ethyl acetate (20 mL), washed with water (2 x 10 mL), brine (1 x 10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a viscous liquid that solidified upon standing (0.13 g). 1 H NMR showed very little product, mostly starting material (iodide), along with tricyclic methoxy TBDMS ethylene (82). The tricyclic methoxy TBDMS ethyl iodide (81) (0.13 g, 0.27 mmol, 1.0 equiv.) recovered above was dissolved in N,N'-dimethylformamide (10 mL), and potassium tert-butoxide (0.16 g, 1.42 mmol, 5.26 equiv.) was added in one portion at room temperature. The reaction mixture turned brown (slightly exothermic!). The mixture was stirred at room temperature overnight. After 16 h, the reaction mixture was checked by TLC and was complete. The mixture was quenched with saturated ammonium chloride (20 mL), and the mixture was stirred for 1 h, then extracted with ethyl acetate (3 × 20 mL). The combined ethyl acetate was washed with saturated ammonium chloride (3 × 15 mL), brine (1 × 10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give tricyclic methoxy TBDMS ethyl iodide (82) as a light tan liquid (0.08 g, 82%). Compound (82) is 1 H and 13 The product was characterized by C NMR spectroscopy and used in the next step without further purification.

[0438] Synthesis of tricyclic methoxy TBDMS ethanediol (83): To a solution of tricyclic methoxyl group (82) (0.24 g, 0.67 mmol, 1.0 equiv.) in a mixture of tert-butanol (10 mL), tetrahydrofuran (3 mL), and water (1 mL) (ratio = 10:3:1) was added osmium tetroxide (0.017 g, 0.067 mmol, 0.1 equiv.), followed by 4-methylmorpholine N-oxide (0.08 g, 0.68 mmol, 1.01 equiv.). The reaction mixture was covered with aluminum foil and stirred overnight at room temperature. After 16 h, the reaction mixture was checked by TLC and found to be complete. The mixture was treated with sodium thiosulfate solution (1 M, 10 mL). The orange-red solution was stirred at room temperature for 1 h. The mixture was extracted with dichloromethane (3 × 20 mL). The combined organic extracts were washed with brine (1 x 20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give tricyclic methoxy TBDMS ethanediol (83) as a viscous liquid (0.29 g, 100%). 1 H and 13 It was characterized by C NMR spectrum. The crude product was used as is in the next step without further purification.

[0439] Synthesis of tricyclic hydroxy TBDMS ethanediol (84): To a solution of tricyclic methoxy TBDMS ethanediol (83) (0.55 g, 1.40 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (15 mL) was added n-butyllithium in hexane (2.5 M in hexane, 2.8 mL, 7.0 mmol, 5.0 equiv.) at −20° C. under nitrogen, followed by diphenylphosphine (10 wt % in hexane, 10.4 mL, 5.58 mmol, 4.0 equiv.). The reaction mixture (deep orange-red) was stirred at −20° C. for 20 minutes, and then the mixture was allowed to reach room temperature over a 1-hour period. The mixture was gently heated to reflux overnight. After 16 hours, the reaction mixture was checked by TLC and was not complete. Additional n-butyllithium in hexane (2.5 M, 2.6 mL) and diphenylphosphine (10 wt % in hexane, 8.0 mL) were added. The reaction mixture was continued to reflux overnight. After 18 hours, the reaction mixture was checked by TLC and was complete. The reaction mixture was quenched with saturated ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate layers were washed with water (1 x 30 mL), brine (1 x 10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear viscous liquid (1.07 g). The crude product was purified by silica gel column chromatography to give tricyclic hydroxy TBDMS ethanediol (84) as a viscous liquid that solidified upon standing (0.19 g, 36%). Pure compound (84) was obtained from 1 H and 13 It was characterized by C NMR spectrum.

[0440] Synthesis of tricyclic TBDMS-benzyloxycarbonyl methyl ether ethanediol (85): To a solution of tricyclic hydroxy TBDMS ethanediol (84) (1.75 g, 4.62 mmol, 1.0 equiv.) in acetone (100 mL) was added powdered potassium carbonate (1.40 g, 10.13 mmol, 2.20 equiv.) and 2-bromobenzyl acetate (1.27 g, 5.54 mmol, 1.20 equiv.). The mixture was gently heated to reflux overnight. After 18 h, the reaction mixture was checked by TLC and was complete. The mixture was cooled to room temperature, then filtered and washed with acetone. The filtrate was concentrated in vacuo to give tricyclic TBDMS-benzyloxycarbonyl methyl ether ethanediol (85) as a viscous liquid (2.47 g, 100%). Compound (85) was obtained from the following: 1 H and 13 It was characterized by C NMR spectrum. The crude product was used as it was in the next step without further purification.

[0441] Synthesis of tricyclic benzyloxycarbonyl methyl ether triol (86): To a solution of tricyclic TBDMS-benzyloxycarbonylmethyl ether ethanediol (85) (2.46 g, calculated as 2.43 g crude, 4.61 mmol, calculated as 1.0 equiv.) in acetone (100 mL) and water (5 mL) was added pyridinium p-toluenesulfonate (0.70 g, 4.63 mmol, 1.0 equiv.) at room temperature. The reaction mixture was stirred overnight at room temperature. After 68 hours, the reaction was checked by TLC. The reaction was not complete, and an additional 1 equiv. of pyridinium p-toluenesulfonate (0.70 g, 4.63 mmol, 1.0 equiv.) was added. The mixture was continued to reflux overnight. After 16 hours, the reaction mixture was checked by TLC and was complete. The reaction was concentrated in vacuo to remove acetone. The aqueous layer was extracted with ethyl acetate (3 × 40 mL). The combined ethyl acetate extracts were washed with water (1 × 40 mL), brine (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a viscous liquid (1.92 g). The crude product was purified by silica gel column chromatography to give tricyclic benzyloxycarbonyl methyl ether triol (86) as a viscous liquid / semi-solid (0.97 g, 51%).

[0442] Synthesis of tricyclic benzyloxycarbonyl methyl ether hydroxyaldehyde (87): To a solution of tricyclic benzyloxycarbonyl methyl ether triol (86) (0.96 g, 2.33 mmol, 1.0 equiv.) in 1,2-dichloroethane (40 mL) was added a solution of sodium (meta)periodate (1.0 g, 4.67 mmol, 2.0 equiv.) in water (40 mL) at room temperature. The reaction mixture was stirred overnight. After 16 h, the reaction mixture was checked by TLC and found to be complete. The reaction mixture was a white emulsion. Water (70 mL) and dichloromethane (70 mL) were added to the mixture, followed by the addition of sodium chloride until the aqueous layer was saturated. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The combined dichloromethane extracts were washed with brine (1 × 20 mL), dried over sodium sulfate, and filtered through a pad of silica gel in a sintered glass funnel. The compound was purified by silica gel column chromatography to give tricyclic benzyloxycarbonyl methyl ether hydroxyaldehyde (87) as a clear viscous liquid (0.54 g, 61%). 1 It was characterized by 1 H NMR spectrum.

[0443] Synthesis of tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88): To a solution of tricyclic benzyloxycarbonylmethyl ether hydroxyaldehyde (87) (0.53 g, 1.39 mmol, 1.0 equiv.) in dichloromethane (25 mL), ethyl diazoacetate (0.32 g, 2.80 mmol, 2.0 equiv.) and tin(II) chloride (0.06 g, 0.37 mmol, 0.27 equiv.) were added at room temperature. The reaction mixture was stirred overnight at room temperature. After 16 h, the reaction mixture was checked by TLC and found to be complete. The reaction mixture was passed directly through a silica gel column using neat dichloromethane and then a mixture of ethyl acetate in hexane (20-40%) to give pure tricyclic benzyloxycarbonylmethyl ether β-ketoethyl ester (88) as a clear viscous liquid (0.32 g) and slightly impure tricyclic benzyloxycarbonylmethyl ether β-ketoethyl ester (88) (0.19 g). Both pure and slightly impure β-ketoethyl ester (88) were 1 It was characterized by 1 H NMR spectrum.

[0444] Synthesis of Compound 89 in Figure 13 To a solution of pure tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88) (0.32 g, 0.68 mmol, 1.0 equiv.) in tetrahydrofuran (20 mL) was added 1.0 M sodium hydroxide solution (4.1 mL, 4.1 mmol, 6.03 equiv.) at room temperature. The reaction mixture was stirred overnight at room temperature. After 66 h, the reaction mixture was diluted with water (20 mL), and then the tetrahydrofuran was removed in vacuo. The aqueous layer was extracted with dichloromethane (2 × 20 mL) to remove organic impurities. The aqueous layer was carefully acidified to pH 2-3 with 10% hydrochloric acid and extracted with ethyl acetate (3 × 25 mL). The combined ethyl acetate extracts were washed with brine (1 × 15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give compound 89 as a pale yellow viscous liquid (0.24 g, 100%). Metabolite 89 was 1 Checked by 1 H NMR and confirmed by HPLC. (i) Using sodium hydroxide. Under similar conditions, tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88) (0.017 g, 0.036 mmol, 1.0 equiv.) in tetrahydrofuran (1.0 mL) was hydrolyzed with 1.0 M sodium hydroxide solution (0.22 mL, 0.22 mmol, 6.04 equiv.) at room temperature to give compound 89 as a pale yellow viscous liquid / semisolid (0.01 g, 77%). The metabolites were: 1 Checked by 1 H NMR and confirmed by HPLC. (ii) Using lithium hydroxide. Under similar conditions, tricyclic benzyloxycarbonyl methyl ether β-ketoester (88) (0.017 g, 0.036 mmol, 1.0 equiv.) in tetrahydrofuran (1.0 mL) was hydrolyzed with a 1.0 M solution of lithium hydroxide (0.22 mL, 0.22 mmol, 6.04 equiv.) at room temperature to give compound 89 as a pale yellow viscous liquid / semisolid (0.01 g, 77%). The metabolites were: 1 Checked by 1 H NMR and confirmed by HPLC. (iii) Using barium hydroxide. Under similar conditions, tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88) (0.017 g, 0.036 mmol, 1.0 equiv.) in tetrahydrofuran (1.0 mL) was hydrolyzed with a 1.0 M solution of barium hydroxide (0.04 g, 0.23 mmol, 6.41 equiv.) at room temperature to give compound 89 as a pale yellow viscous liquid / semisolid (0.01 g, 77%). The metabolites were: 1 Checked by 1 H NMR and confirmed by HPLC.

[0445] 2.2. Synthesis of Compounds 75 and 108 in Figure 13 2.2.1. Synthesis of the common intermediate (12a) for compounds 75 and 108 in Figure 13

[0446] [ka]

[0447] experiment: Synthesis of 1-pentyn-O-tetrahydropyran-2-yl-5-ol (intermediate 2a): A 500 mL three-necked round-bottom flask equipped with a mechanical stirrer and an argon inlet / outlet adapter connected to a bubbler was charged with 4-pentyn-1-ol (1a, 20 g, 0.238 mol), dichloromethane (200 mL), 3,4-dihydro-2H-pyran (21 g, 0.250 mol), and pyridinium p-toluenesulfonate (PPTS, 5.98 g, 0.024 mol) at room temperature under argon. The reaction mixture was stirred overnight at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with water (1 × 250 mL), brine (1 × 250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 2a (39 g, yield, 98%). The crude material was used directly in the next step.

[0448] Synthesis of intermediate 4a: A 1 L three-necked round-bottom flask equipped with a mechanical stirrer, an addition funnel, a thermocouple, and an argon inlet / outlet adapter connected to a bubbler was charged with 1-pentyn-O-tetrahydropyran-2-yl-5-ol (2a) (31.5 g, 0.187 mol) and anhydrous tetrahydrofuran (200-300 mL). Ethylmagnesium bromide (3 M solution in diethyl ether) (62.4 mL, 0.187 mol) was added to the solution of 2a under argon over a period of 20-30 min, maintaining the temperature below 40 °C. After complete addition, the reaction mixture was stirred between 30 °C and 45 °C for 2 h. The reaction mixture was cooled to 0 °C (ice-water bath), and a solution of 2-allyl-3-methoxybenzaldehyde (3a) (30.0 g, 0.170 mol) in anhydrous tetrahydrofuran (50 mL) was added over a period of 10 min. The reaction mixture was stirred overnight at room temperature, and the temperature of the reaction mixture was allowed to rise to ambient temperature. After 16 hours, the reaction was complete. At ambient temperature, the reaction mixture was quenched with saturated ammonium chloride, which resulted in a suspension of a granular solid. The mixture was filtered to remove the granular inorganic solid, and the filtrate was concentrated in vacuo to give crude product 4a (59 g). The crude product was purified by column chromatography to give pure 3-methoxy-2-(2-propenyl)-[5-[(tetrahydro-2H-pyran-4-yl)oxy]-1-pentonyl]benzene-methanol (Intermediate 4a) as a pale yellow, viscous liquid (46.3 g, yield, 79%).

[0449] Synthesis of intermediate 5a: A 2 L, two-necked, round-bottom flask equipped with a mechanical stirrer and thermocouple was charged with intermediate 4a (46.0 g, 0.134 mol), dichloromethane (500 mL), Celite (40 g), and sodium acetate (22 g, 0.268 mol). The stirred suspension was cooled to 0 °C, and pyridinium chlorochromate (PCC, 57.6 g, 0.238 mol) was added with stirring. The reaction mixture was allowed to warm slowly to ambient temperature and stirred for 5 h. The mixture was filtered through a pad of Celite using a Buchner funnel. The dark brown, gummy solid in the reaction flask and on the Buchner funnel was washed with ethyl acetate to recover the largest amount of product. The solvent was removed in vacuo, and the crude product was purified by column chromatography to give 1-[3-methoxy-2-(2-propenyl)phenyl]-6-[(tetrahydro-2H-pyran-4-yl)oxy]-2-hexyn-1-one (Intermediate 5a) as a pale yellow, viscous oil (30.67 g, yield, 67%).

[0450] Synthesis of intermediate 6a: A 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps was charged with aryl intermediate 5a (21 g, 0.061 mol) and anhydrous tetrahydrofuran (200-300 mL). A solution of (R)-methyloxazaborolidine (1.0 M in toluene, 73.6 mL, 0.074 mol) was added at room temperature under argon. The mixture was cooled to -30 °C (dry ice / acetone bath), and borane-methyl sulfide complex (9.32 mL, 0.122 mol) was added slowly, maintaining the temperature between -25 °C and -30 °C. After complete addition, the reaction mixture was stirred at the same temperature for 1 h. The reaction was monitored by TLC. The reaction mixture was carefully quenched by the slow addition of methanol over a 20 min period, maintaining the temperature of the exothermic reaction between -10 °C and -15 °C. The reaction mixture was allowed to warm to room temperature. 5% aqueous ammonium chloride was added with stirring (no exotherm was observed!). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate (approximately 10 g), filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give Intermediate 6a (semi-solid product) (11 g, yield, 52%).

[0451] Synthesis of intermediate 7a: A 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet trap was charged with chiral benzylalkynol (6a) (10.60 g, 30.77 mmol), dichloromethane (150 mL), imidazole (2.93 g, 43.08 mmol), and dimethylformamide (2 mL) at room temperature under argon. The mixture was stirred until a clear solution was obtained. tert-Butyldimethylsilyl chloride (6.03 g, 40.00 mmol) was added while maintaining the temperature below 20 °C. The reaction was stirred overnight. The temperature of the reaction mixture was allowed to rise to ambient temperature. After approximately 16 h, the progress of the reaction was monitored by TLC. The mixture was washed with water (3 × 150 mL) and saturated sodium chloride (1 × 150 mL). It was dried over anhydrous sodium sulfate (10 g), filtered, and concentrated in vacuo to give crude product 7a as a viscous oil, which was purified by column chromatography to give benzyl alkynyl-t-butyldimethylsilyl ether (Intermediate 7a), a colorless viscous oil (12.66 g, 90%).

[0452] Synthesis of intermediate 8a: A solution of benzyl alkynyl t-butyldimethylsilyl ether (7a, 12 g, 26.16 mmol) in dichloromethane (120-150 mL) was placed in a 1 L three-neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, and an argon inlet / outlet trap under argon. Octacarbonyl dicobalt (8.947 g, 26.16 mmol) was added at room temperature, and the reaction mixture was stirred at ambient temperature. Carbon monoxide evolved slowly, and the solution turned reddish-brown after a short time. Stirring was continued for 2 h. Dichloromethane was distilled from the reaction mixture under vacuum using a water bath (the temperature of the water bath did not exceed 30 °C). The resulting brown, viscous liquid was dissolved in acetonitrile and transferred back to a 1 L three-neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, an argon inlet / outlet trap, and a condenser. The solution was heated to reflux under argon for 2 h. The reaction mixture was cooled to room temperature, and air was bubbled through the mixture overnight. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (1 x 150 mL) and dried over anhydrous sodium sulfate (10 g). The organic phase was filtered. The filtrate was concentrated in vacuo to give crude product 8a, a brown oil. The crude product 8a was purified by column chromatography to give pure tricyclic enone (8a) as a light brown oil (12 g, yield, 94%). The crude material was dissolved in ethanol (200 mL). To the solution, activated carbon (1.2 g) was added. The suspension was heated to reflux, and the hot solution was filtered through a pad of Celite. The filtrate was used directly in the next step.

[0453] Synthesis of intermediate 9a: A 500 mL three-necked round-bottom flask equipped with a magnetic stirrer and a hydrogen-filled balloon was charged with a solution of intermediate 8a (10.9 g) in absolute ethanol (100–150 mL, from the previous step), anhydrous potassium carbonate (0.5 g), and 5% palladium on activated carbon (1.98 g, 10%, 50% wet). The air in the reaction flask was removed by vacuum, and the vacuum was replaced with hydrogen from the attached balloon. This process was repeated three times. The mixture was hydrogenated under balloon pressure at ambient temperature for 16 hours (overnight). The progress of the reaction was monitored by TLC. The reaction was not complete; for this reason, the reaction mixture was filtered through a pad of Celite, and the Celite pad was washed with more ethanol to recover the material. The volume of the reaction mixture was reduced to half by evaporation under vacuum. The reaction was repeated using the same amounts of reagents. After 16 hours, TLC indicated the absence of compound 8a (starting material). The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give crude product 9a as a colorless viscous oil. The crude product 9a was purified by column chromatography using 230-400 mesh silica gel. The product was eluted from the column using a solvent gradient of ethyl acetate in hexane (0-20%). The fractions containing the desired product were evaporated in vacuo to give the pure product, tricyclic ketone (9a), as a colorless viscous oil (6.38 g, yield, 74%).

[0454] Synthesis of intermediate 10a: A 500 mL three-necked round-bottom flask equipped with a mechanical stirrer was charged with a solution of tricyclic ketone (9a, 17.30 g, 17.3 mmol) in ethanol. The solution was cooled to -4 °C, and 20% aqueous sodium hydroxide (6.92 g, 173.00 mmol, dissolved in 30 mL of water) was added over a 10-15 min period with stirring. The reaction mixture was stirred for an additional 0.5 h, and then sodium borohydride (700 mg, 18.52 mmol) was added. Stirring was continued for 2 h at -10 °C. After 2 h, an additional equivalent of sodium borohydride (610 mg, 16.14 mmol) was added, and stirring was continued for 2 h at -10 °C. The progress of the reaction was monitored by TLC. The reaction mixture was carefully quenched by the dropwise addition of glacial acetic acid (~12 mL) until a pH of 5-6 was obtained. The mixture was allowed to reach ambient temperature. Undesired solid inorganic impurities were removed by filtration, and the filtrate was concentrated in vacuo. The residue obtained after evaporation was dissolved in ethyl acetate (300 mL), and the resulting solution was stirred for 15 minutes. The ethyl acetate solution of compound 10a was washed with sodium bicarbonate (2 × 100 mL). The aqueous layer was extracted with ethyl acetate (2 × 150 mL). The combined organic extracts were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product (tricyclic alcohol 10a) as an oil (6.3 g, yield, approximately 100%).

[0455] Synthesis of intermediate 11a: A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with a solution of crude intermediate 10a (1.250 g, 3.47 mmol), dichloromethane (20 mL), imidazole (473 mg, 6.95 mmol), and dimethylformamide (0.5 mL) at room temperature under argon. The mixture was stirred until a clear solution was obtained. tert-Butyldimethylsilyl chloride (1.045 g, 6.93 mmol) was added at room temperature. The reaction was stirred overnight. After approximately 16 hours, the progress of the reaction was monitored by TLC. The mixture was washed with water (1 × 50 mL) and saturated sodium chloride (1 × 50 mL). It was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 11a as a viscous oil. The crude product was purified by column chromatography to give intermediate 11a, a colorless viscous oil (1.45 g, 88%).

[0456] Synthesis of intermediate 12a: A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with a solution of intermediate 11a (1.40 g, 2.95 mmol), diethyl ether (50 mL), and magnesium bromide (3.26 g, 17.70 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 3-4 h. The reaction progress was monitored by TLC. The reaction mixture was slowly quenched with water (1 × 50 mL) (the quench was exothermic). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic phase was washed with saturated sodium chloride (1 × 50 mL). It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give crude product 12a as a viscous oil. The crude product was purified by column chromatography to give intermediate 12a, a colorless viscous oil (1.0 g, 87%).

[0457] 2.2.2. Synthesis of Compound 75 in Figure 13

[0458] [ka]

[0459] experiment: Synthesis of intermediate 71 A 100 mL three-necked round-bottom flask equipped with a cooling bath, a thermocouple, and an argon inlet / outlet adapter connected to a bubbler was charged with anhydrous tetrahydrofuran (10 mL) and n-butyllithium (1.31 g, 20.45 mmol) under nitrogen. The mixture was cooled to -20 to -30 °C, and diphenylphosphine (3.34 g, 17.94 mmol) was added. The resulting orange-red solution was stirred for 10 to 15 minutes. A solution of Intermediate 12a (1.00 g, 2.56 mmol) in THF (10 mL) was added to the reaction mixture at -20 °C under nitrogen. After complete addition, the dark red solution was stirred at -20 °C for 30 minutes, and then the temperature of the reaction mixture was allowed to rise to ambient temperature. The reaction mixture was heated to reflux overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature, and then water was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate (10 g), filtered, and concentrated in vacuo to give crude product 71. The crude product 71 was purified by column chromatography to give 1.3 g of product 71 (the yield was greater than 100% (964 mg) probably due to the presence of residual solvent).

[0460] Synthesis of intermediate 72 A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer, an argon inlet / outlet adapter connected to a bubbler, and a condenser was charged with Intermediate 71 (1.3 g, 3.45 mmol) and acetone. The mixture was stirred to obtain a clear solution. Benzyl bromoacetate (1.186 g, 5.18 mmol) and powdered potassium carbonate (1.431 g, 10.36 mmol) were added to the above solution. The reaction mixture was heated to reflux for 3-4 hours. The progress of the reaction was monitored by TLC. After 3.5 hours, the reaction was not complete (TLC). For this reason, additional amounts of the reagents, benzyl bromoacetate (0.5 g, 2.18 mmol) and potassium carbonate (1.0 g, 7.24 mmol), were added. The reaction mixture was again heated to reflux. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered through a pad of Celite. The Celite pad was washed with acetone, and the filtrate was concentrated in vacuo to give a viscous liquid. The crude product 72 was purified by column chromatography to give pure product 72 as a viscous liquid (1.15 g, 85% yield based on 100% yield of the previous step).

[0461] Synthesis of intermediate 73: A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with intermediate 72 (1.1 g, 2.10 mmol) and dichloromethane. The mixture was stirred to obtain a clear solution. Celite and sodium acetate (0.35 g, 4.27 mmol) were added to the above solution. After stirring the reaction mixture (5-10 min), PDC (1.58 g, 4.20 mmol) was added at ambient temperature. The progress of the reaction was monitored by TLC after 3-4 h. After 3.5 h, the reaction was complete (TLC). Product 73 was purified by column chromatography using 230-400 mesh silica gel by directly loading the reaction mixture onto the column, and the column was eluted with dichloromethane (100%). The fractions containing the desired compound 73 were evaporated in vacuo to obtain the pure product 73 as a viscous liquid (0.90 g, 83% yield).

[0462] Synthesis of intermediate 74: A 50 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with Intermediate 73 (0.82 g, 1.57 mmol), tert-butanol (15-20 mL), and water. The mixture was stirred to obtain a clear solution. Sodium dihydrogen phosphate (1.13 g, 9.42 mmol) and 2-methyl-2-butene (2.0 mL) were added. The mixture was stirred for 5-10 minutes. To the resulting suspension, sodium chlorate (1.30 g, 14.37 mmol) was added at ambient temperature. The progress of the reaction was monitored by TLC after 2-3 hours. After completion of the reaction, the solvent was evaporated in vacuo to obtain a viscous liquid. Water was added to the remaining material, and the aqueous layer was acidified to pH 3-4 and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was evaporated in vacuo to give the crude product 74. The product 74 was purified by column chromatography to give the pure product 74 as a viscous liquid (0.740 g, 88% yield).

[0463] Synthesis of Compound 75 in Figure 13 A solution of intermediate 74 (1.37 g, 1.37 mmol) in methanol was placed in a 50 mL single-neck round-bottom flask equipped with a magnetic stirrer. To the reaction mixture, HCl solution (1.3 mL, 37%, 13.18 mmol, dissolved in water (5 mL)) was added. The mixture was stirred at room temperature for 6–7 hours. After 6–7 hours, a solution of sodium hydroxide (1.1 g, 27.5 mmol, dissolved in water (2 mL)) was added. The reaction mixture was heated to reflux overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated in vacuo. Water was added to the residual material, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL) to remove impurities. The extracted ethyl acetate layer was discarded after TLC check. The aqueous layer was acidified to pH (1–2) and extracted with ethyl acetate (3 × 70 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was evaporated to give the crude product (425 mg). The crude material was triturated with dichloromethane (15 mL) followed by hexane (15 mL). The solid suspension was filtered to isolate the solid. The solid was washed with hexane, dried on the funnel, and then air-dried at room temperature in a fume hood to give the pure product 75 (385 mg, 84% yield).

[0464] 2.2.3. Synthesis of the sodium salt of compound 108 in Figure 13

[0465] [ka]

[0466] experiment: Synthesis of intermediate 101: A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with intermediate 12a (3.60 g, 9.22 mmol) and dichloromethane (60-100 mL). The mixture was stirred to obtain a clear solution. Celite (7.0 g) and sodium acetate (1.80 g, 21.94 mmol) were added to the above solution. After stirring the reaction mixture (5-10 min), PDC (6.9 g, 18.34 mmol) was added at ambient temperature. The progress of the reaction was monitored by TLC after 3-4 h. After 3.5 h, the reaction was complete (TLC). Product 101 was purified by column chromatography using 230-400 mesh silica gel by directly loading the reaction mixture onto the column, and the column was eluted with dichloromethane (100%). The fractions containing the desired compound 101 were evaporated in vacuo to give the pure product 101 as a viscous liquid (2.846 g, 80%).

[0467] Synthesis of intermediate 102: A 250 mL three-necked round-bottom flask equipped with a cooling bath, a thermocouple, and an argon inlet / outlet adapter connected to a bubbler was charged with anhydrous tetrahydrofuran (20 mL) and a 0.5 M solution of (1,3-dioxan-2-ylethyl)-magnesium bromide in THF (17.3 mL, 8.65 mmol) under nitrogen. The mixture was cooled to -20 °C, and a solution of intermediate 101 in THF (2.8 g, 7.21 mmol, dissolved in dry THF (20 mL)) was added. The temperature of the reaction mixture was allowed to rise from -20 °C to ambient temperature. The progress of the reaction was monitored by TLC after 3-4 hours. After 3.5 hours, the reaction was complete (TLC). The reaction mixture was quenched with saturated ammonium chloride solution (2 mL) while stirring. The reaction mixture converted to a suspension of a white granular solid. The resulting suspension was filtered, and the filtrate was evaporated in vacuo to give crude product 102. The product 102 was purified by column chromatography using 230-400 mesh silica gel, and the column was eluted with a gradient of ethyl acetate in hexane (15-40%). Fractions containing the desired pure compound 102 were combined and evaporated in vacuo to give the pure product 102 as a viscous liquid (3.698 g, quantitative yield).

[0468] Synthesis of intermediate 103: A 250 mL three-necked round-bottom flask equipped with a cooling bath, thermocouple, and argon inlet / outlet adapter connected to a bubbler was charged with anhydrous tetrahydrofuran (20 mL) and n-butyllithium (20.3 mL, 50.73 mmol, 2.5 M in hexanes) under nitrogen. The mixture was cooled to -20 to -30 °C, and diphenylphosphine (8.30 g, 44.58 mmol) was added. The resulting orange-red solution was stirred for 10 to 15 minutes. A solution of Intermediate 102 (3.20 g, 6.34 mmol) in THF (20 mL) was added to the reaction mixture at -20 °C under nitrogen. After complete addition, the red solution was stirred at -20 °C for 30 minutes, and then the temperature of the reaction mixture was allowed to rise to ambient temperature. The reaction mixture was heated to reflux overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature, and then water was slowly added to quench the reaction. The color of the reaction changed from red to colorless. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 103. The crude product 103 was purified by column chromatography to give product 103 (3.0 g, 96% yield).

[0469] Synthesis of intermediate 104: A 250 mL single-neck round-bottom flask equipped with a magnetic stirrer, an argon inlet / outlet adapter connected to a bubbler, and a condenser was charged with intermediate 103 (3.00 g, 6.11 mmol) and acetone (30-50 mL). The mixture was stirred to obtain a clear solution. Benzyl bromoacetate (2.10 g, 9.17 mmol) and powdered potassium carbonate (4.23 g, 30.61 mmol) were added to the above solution. The reaction mixture was heated to reflux overnight. The progress of the reaction was monitored by TLC. After completion of the reaction (checked by TLC), the reaction mixture was cooled to ambient temperature and filtered through a pad of Celite in a Buchner funnel. The Celite pad was washed with acetone, and the combined filtrate was concentrated in vacuo to obtain a viscous liquid. The crude product 104 was purified by column chromatography to obtain pure product 104 as a viscous liquid (3.75 g, 96% yield).

[0470] Synthesis of intermediate 105: A 250 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with crude intermediate 104 (3.70 g, 5.79 mmol), dichloromethane (50-100 mL), dimethylaminopyridine (DMAP, 1.77 g, 14.49 mmol), and acetic anhydride (1.30 g, 12.73 mmol) at room temperature under argon. The reaction was stirred overnight. After approximately 16 h, the progress of the reaction was monitored by TLC. For purification of product 105, the reaction mixture was loaded directly onto a silica gel-packed column. The column was eluted with a gradient of ethyl acetate in hexane. Fractions containing the desired compound were combined and evaporated in vacuo to give intermediate 105, a colorless viscous oil (3.72 g, 94%).

[0471] Synthesis of intermediate 106: A 250 mL single-neck round-bottom flask equipped with a magnetic stirrer and a condenser was charged with Intermediate 105 (3.70 g, 5.43 mmol) and acetone (100 mL). The mixture was stirred to obtain a clear solution. Pyridinium p-toluenesulfonate (PPTS) (2.50 g, 9.95 mmol) and water (50 mL) were added to the above solution. The reaction mixture was heated to reflux overnight. The progress of the reaction was monitored by TLC and 1 The reaction mixture was heated to reflux, which indicated the completion of the reaction. 1 The reaction mixture was stirred for 1 hour at 37°C for 2 hours until confirmed by H-NMR. After completion of the reaction, the reaction mixture was cooled to ambient temperature and the solvent was concentrated in vacuo to give an aqueous layer containing the product. An additional amount of water was added. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give crude product 106. The crude product was purified by column chromatography to give pure product 106 as a viscous liquid (1.693 g, 61% yield).

[0472] Synthesis of intermediate 107: A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with Intermediate 106 (0.628 g, 1.23 mmol), tert-butanol (20-30 mL), and water (10-15 mL). The mixture was stirred to obtain a clear biphasic solution. Sodium dihydrogen phosphate (0.889 g, 7.41 mmol) and 2-methyl-2-butene (5-7 mL) were added. The mixture was stirred for 5-10 minutes. To the resulting suspension, sodium chlorate (1.117 g, 12.35 mmol) was added at ambient temperature. The reaction progress was monitored by TLC after 2-3 hours. After completion of the reaction, the solvent was evaporated in vacuo to obtain a viscous liquid. Water was added to the remaining material, and the aqueous layer was acidified to pH 3-4 and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was evaporated to give the crude product. The product 107 was purified by column chromatography to give pure product 107 as a viscous liquid (600 mg, 93% yield).

[0473] Synthesis of metabolites 108L and 108. A 50 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with a solution of intermediate 107 (1.1 g, 2.10 mmol) in methanol (15-20 mL). To the reaction mixture, a solution of KOH (1.18 g, 21.03 mmol, dissolved in water (5 mL)) was added. The reaction mixture was heated to reflux for 2-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated in vacuo. Water was added to the residual material, and the aqueous layer was extracted with dichloromethane (7 × 50 mL) to remove impurities. The aqueous layer was acidified to pH (1-2) and extracted with ethyl acetate (4 × 70 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated in vacuo to give the crude product (900 mg). 1 By 1 H NMR and HPLC, the crude material was a mixture of two products, the lactone 108L and 108.

[0474] Synthesis of racemic metabolite 108Na: A solution of intermediate 108L (0.750 g, 2.00 mmol) in methanol (10 mL) was placed in a 50 mL single-neck round-bottom flask equipped with a magnetic stirrer. To the reaction mixture, NaOH solution (0.168 g, 4.20 mmol, dissolved in water (2-3 mL)) was added. The reaction mixture was heated to reflux for 3-4 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the solvent was evaporated in vacuo. The resulting material was dissolved in absolute ethanol (5-10 mL) to remove water by azeotropic evaporation in vacuo. The gummy material was evaporated to dryness. A mixture of dichloromethane and hexane (1:1) (40-60 mL) was added to the material. The mixture was stirred for 1-2 hours for trituration. The fine solid was isolated by filtration. The solid material was air-dried to give the Na salt of material 108 (800 mg, 92% yield).

[0475] 2.2.4. Synthesis of Compound 117 in Figure 13

[0476] [ka]

[0477] experiment: Synthesis of Treprostinil Benzyl Ester (111): A 100 mL round-bottom flask equipped with a magnetic stirrer was charged with a solution of treprostinil (1) (2 g, 0.0025 mol) in THF:acetone (1:4, 10:40 mL). To this clear solution, potassium carbonate (2.82 g, 0.0204 mol) was added in one portion with stirring at room temperature, followed by benzyl bromide (1.75 g, 0.0102 mol). The reaction mixture was stirred until completion (approximately 16-18 h), and the progress of the reaction was monitored by TLC. The mixture was filtered through a Buchner funnel. The filtrate was removed in vacuo, and the crude product was triturated with hexane (100 mL) to give treprostinil benzyl ester (111) as an off-white solid (2 g, 83%), which was used in the next step without further purification.

[0478] Synthesis of TBDPS ether (112): A 100 mL three-necked round-bottom flask equipped with a magnetic stirrer, a thermocouple, and an argon inlet / outlet trap was charged with a solution of treprostinil benzyl ester (111) (780 mg, 0.0016 mol), dichloromethane (15 mL), imidazole (143 mg, 0.0021 mol), and 4-(dimethylamino)pyridine (9 mg, 5 mol%) at room temperature under argon. The mixture was stirred until a clear solution was obtained. The mixture was cooled to 0°C (ice / water bath), and t-butyldiphenylsilyl chloride (535 mg, 0.0019) was added portionwise, maintaining the temperature below 20°C. The reaction mixture was stirred overnight. The temperature of the reaction mixture was allowed to rise to ambient temperature. The progress of the reaction was monitored by TLC. After approximately 16 hours, the reaction was complete. The reaction mixture was washed with water (10 mL) and saturated sodium chloride (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 112 as a viscous oil. The crude product was purified by column chromatography to give tert-butyl diphenylsilyl ether (112) (290 mg, 25%) as a colorless viscous oil.

[0479] Synthesis of ketone (115): A 100 mL round-bottom flask equipped with a magnetic stirrer was charged with monoprotected-TBDPS alcohol (112) (297 mg, 0.0004 mol) and dichloromethane (10 mL). To this suspension, pyridinium chlorochromate (PCC) (137 mg, 0.0064 mol) was added with stirring. The reaction mixture was stirred until completion (approximately 16-18 h), and the reaction progress was monitored by TLC. The mixture was filtered through a pad of Celite using a Buchner funnel. The solvent was removed in vacuo, and the crude product was purified by column chromatography to give ketone (115) as a pale yellow, viscous oil (290 mg, 95%).

[0480] Synthesis of TBDPS-protected keto acid (116): To a solution of tricyclic enone monoprotected-TBDPS ketone (115) (7.0 g, 0.0099 mol) in methanol (60 mL) was added 10% Pd / C (600 mg, 50% wet, 25% w / w), and the mixture was hydrogenated at atmospheric pressure (balloon pressure) for 15-18 h at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite and washed with ethanol. The ethanol solution was evaporated in vacuo to give keto acid (116) (7.0 g crude yield), which was used in the next step without further purification.

[0481] Synthesis of compound 117: To a stirred solution of monoprotected-TBDPS keto acid (116) (7.0 g, 0.011 mol) in tetrahydrofuran (85 mL) was added a solution of tetrabutylammonium fluoride (30.5 g, 0.117 mol) in THF (15 mL) at room temperature under argon. The reaction was stirred at room temperature until completion, as indicated by TLC. After completion of the reaction, the solvent was removed in vacuo to give a crude brown oil, which was purified by acid-base extraction to give compound 117 as a light brown solid (3.61 g, 80.2%).

[0482] 2.3 Synthesis of Compound 126 in Figure 13

[0483] [ka]

[0484] experiment: Synthesis of Treprostinil Methyl Ester (121): A 1000 mL round-bottom flask equipped with a magnetic stirrer was charged with a solution of treprostinil (1) (40 g, 0.110 mol) in methanol (400 mL). A catalytic amount of sulfuric acid (4 mL) was added to the clear solution with stirring at room temperature. The reaction mixture was heated to reflux until completion (approximately 2 hours), and the progress of the reaction was monitored by TLC. The solvent was removed in vacuo, and the crude product was purified by column chromatography to give treprostinil methyl ester (121) as a viscous oil (46.4 g, 99%).

[0485] Synthesis of protected glucuronide (123): A 100 mL round-bottom flask equipped with a magnetic stirrer was charged with a solution of treprostinil methyl ester (121) (1.0 g, 0.0024 mol) in 1,2-dichloroethane (30 mL). To the clear solution, silver oxide (1.19 g, 0.0051 mol), α-bromotriacetoxymethyl ester (122) of D-glucose, and molecular sieves (4 Å type) were added while stirring at room temperature. The reaction mixture was stirred at room temperature until completion (approximately 16-18 h), and the progress of the reaction was monitored by TLC. The reaction mixture was filtered, the solvent was removed in vacuo, and the crude product (123) was used directly for the next reaction (3.8 g, crude yield, theoretical yield 1.39 g).

[0486] Synthesis of Compound 126 A 100 mL round-bottom flask equipped with a magnetic stirrer was charged with a solution of protected glucuronide (123) (3.8 g crude from the previous step, 0.002 mol based on 100% yield) in methanol (16 mL). To the clear solution was added an aqueous solution of sodium hydroxide (1.17 g, 0.029 mol, solution in 8 mL of water) while stirring the mixture at room temperature. The reaction mixture was stirred at room temperature until hydrolysis was complete (approximately 16-18 h), and the progress of the reaction was monitored by HPLC. The reaction mixture was neutralized to pH 5-7 using 2 M HCl (10 mL). The reaction mixture was extracted with ethyl acetate (2 × 25 mL). The ethyl acetate layer, containing the crude mixture of isomeric glucuronides (126 + 127), was washed with brine (10 mL), dried over sodium sulfate, and the solvent was removed in vacuo to give crude compound 126 (12.6 g, crude). The pure metabolite 126 was collected via preparative HPLC.

[0487] 2.4 Synthesis of compound 96A

[0488] [ka]

[0489] experiment: Synthesis of intermediate 4b: A 1 L three-necked round-bottom flask equipped with a mechanical stirrer, an addition funnel, a thermocouple, and an argon inlet / outlet adapter connected to a bubbler was charged with 1-hexyne-O-tetrahydropyran-2-yl-5-ol (26.90 g, 0.148 mol) and anhydrous tetrahydrofuran (300-350 mL). Ethylmagnesium bromide (3 M solution in diethyl ether, 49.0 mL, 0.148 mol) was added to the solution under argon over a 20-30 min period, maintaining the temperature below 40 °C. After complete addition, the reaction mixture was stirred between 30 °C and 45 °C for 2 h. The reaction mixture was cooled to 0 °C (ice-water bath), and a solution of 2-allyl-3-methoxybenzaldehyde (3, 20.0 g, 0.113 mol) in anhydrous tetrahydrofuran (50 mL) was added over a 10 min period. The reaction mixture was stirred overnight at room temperature, and the temperature of the reaction mixture was allowed to rise to ambient temperature. After 16 hours, the reaction was complete (TLC). The reaction mixture was quenched with saturated ammonium chloride at ambient temperature, which resulted in the formation of a granular solid. The mixture was filtered to remove the granular inorganic solid, and the filtrate was concentrated in vacuo to give crude product 4b (45 g). The crude product was purified by column chromatography to give pure intermediate 4b as a pale yellow, viscous liquid (36 g).

[0490] Synthesis of intermediate 5b: A 2 L, two-necked round-bottom flask equipped with a mechanical stirrer and thermocouple was charged with intermediate 4b (36.0 g, 0.10 mol) and acetone (350-400 mL). Manganese dioxide (MnO2) (87.3 g, 1.00 mol) was added with stirring at ambient temperature. The reaction mixture was stirred overnight. The mixture was filtered through a pad of Celite using a Buchner funnel. The filtrate was concentrated in vacuo to give intermediate 5b as a pale yellow, viscous oil (35 g, 68%).

[0491] Synthesis of intermediate 6b: A 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps was charged with aryl intermediate 5b (35 g, 0.098 mol) and anhydrous tetrahydrofuran (300–400 mL). A solution of (R)-methyloxazaborolidine (117.8 mL, 1.0 M in toluene, 0.118 mol) was added at room temperature under argon. The mixture was cooled to −30 °C (dry ice / acetone bath), and borane-methyl sulfide complex (17 mL, 0.196 mol) was added slowly, maintaining the temperature between −25 °C and −30 °C. After complete addition, the reaction mixture was stirred at the same temperature for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was carefully quenched by the slow addition of methanol (30 mL) followed by saturated ammonium chloride (50 mL). The solid material was removed by filtration. The filtrate was evaporated in vacuo to give a sticky solid. The sticky solid was dissolved in ethyl acetate and filtered again to remove insoluble impurities. The filtrate was evaporated in vacuo to give a sticky solid. The crude product was purified by column chromatography to give Intermediate 6b (semi-solid product) (16.1 g).

[0492] Synthesis of intermediate 7b: A 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps was charged with a solution of crude chiral benzylalkynol (6b) (16.00 g), dichloromethane (160-250 mL), imidazole (4.860 g), and dimethylaminopyridine (0.273 g) at room temperature under argon. The mixture was stirred until a clear solution was obtained, and t-butyldimethylsilyl chloride (10.1 g) was added while maintaining the temperature below 20 °C. The reaction was stirred overnight. The temperature of the reaction mixture was allowed to rise to ambient temperature. After approximately 16 h, the progress of the reaction was monitored by TLC. The mixture was washed with water (3 × 150 mL) and saturated sodium chloride (1 × 150 mL), dried over anhydrous sodium sulfate (10 g), filtered, and concentrated in vacuo to give crude product 7b as a viscous oil. The crude product was purified by column chromatography to give benzyl alkynyl-t-butyldimethylsilyl ether (Intermediate 7b), a colorless viscous oil (16.1 g, 77%).

[0493] Synthesis of intermediate 8b: A 250 mL three-neck round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet trap was charged with a solution of benzyl alkynyl t-butyldimethylsilyl ether (7b, 16.10 g, 0.0341 l) in toluene (160 mL) under argon. At room temperature, dicobalt octacarbonyl (11.60 g, 0.0341 l) was added, and the reaction mixture was stirred at ambient temperature. Carbon monoxide slowly evolved from the reaction mixture, and the solution turned reddish-brown after some time. At this stage, the solution was heated to reflux under argon for 2 hours. The reaction mixture was cooled to room temperature, and air was bubbled through the mixture overnight. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (2 x 125 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give crude product 8b, a brown oil. The crude product 8b was purified by column chromatography to give pure tricyclic enone (8b) as a light brown oil (12.1 g, yield, 71%). The crude material was dissolved in ethanol (500 mL). To the solution, activated carbon (1.2 g) was added. The suspension was heated to reflux, and the hot solution was filtered through a pad of Celite. The filtrate was used directly in the next step.

[0494] Synthesis of intermediate 9b: A 1000 mL three-necked round-bottom flask equipped with a magnetic stirrer, a stirring bar, and a hydrogen-filled balloon was charged with a solution of intermediate 8b (12.1 g) in absolute ethanol (600 mL, from the previous step), anhydrous potassium carbonate (600 mg), and palladium on activated carbon (1.2 g, 10%, 50% wet). The reaction flask was evacuated by vacuum, and the vacuum was replaced with hydrogen from the attached balloon. This step was repeated three times. The mixture was hydrogenated under balloon pressure for 16 hours (overnight) at ambient temperature. The progress of the reaction was monitored by IR. After the reaction was complete (confirmed by IR), the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give a ∼200 mL solution of 9b, which was carried on to the next step for sodium borohydride reduction (theoretical yield from 8b: 8.9 g, 100%).

[0495] Synthesis of intermediate 10b: A 500 mL three-necked round-bottom flask equipped with a mechanical stirrer was charged with a solution of tricyclic ketone (9b) in ethanol. The solution was cooled to -4 °C, and aqueous sodium hydroxide (9.1 g, dissolved in 90 mL of water) was added over a 10-15 min period with stirring. The reaction mixture was stirred for an additional 0.5 h, and then sodium borohydride (1.8 g) was added. Stirring was continued at -10 °C for 2 h. The reaction progress was monitored by TLC. The reaction mixture was carefully quenched by the dropwise addition of saturated ammonium chloride solution (50 mL) until a pH of 9-10 was obtained. The mixture was allowed to warm to ambient temperature. Undesired solids were removed by filtration, and the filtrate was concentrated in vacuo to give the crude product (tricyclic alcohol 10b) as an oil (8.1 g). The crude product was purified by column chromatography to give pure tricyclic alcohol 10b (7.1 g, 80.3% over two steps).

[0496] Synthesis of intermediate 11b: A 500 mL three-necked round-bottom flask equipped with a cooling bath, a thermocouple, and an argon inlet / outlet adapter connected to a bubbler was charged with anhydrous tetrahydrofuran (100 mL) and n-butyllithium under nitrogen. The mixture was cooled to -20 to -30 °C, and diphenylphosphine was added. The resulting orange-red solution was stirred for 10 to 15 minutes. A solution of intermediate 10b in THF (100 mL) was added to the reaction mixture at -20 °C under nitrogen. After complete addition, the dark red solution was stirred at -20 °C for 30 minutes, and then the temperature of the reaction mixture was allowed to rise to ambient temperature. The reaction mixture was heated to reflux overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature, and then water was added to quench the reaction. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 11b. The crude product 11b was purified by column chromatography to give compound 11b (6.61 g, 96%).

[0497] Synthesis of intermediate 11b': A solution of intermediate 11b (6.61 g, 0.183 ml) in acetone (100 mL) was placed in a 250 mL single-neck round-bottom flask equipped with a magnetic stirrer, an argon inlet / outlet adapter connected to a bubbler, and a condenser. Benzyl bromoacetate (5.41 g, 0.023 ml) and powdered potassium carbonate (10.8 g, 0.079 ml) were added to the above solution. The reaction mixture was heated to reflux for 3-4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature and filtered through a pad of Celite. The Celite pad was washed with acetone, and the filtrate was concentrated in vacuo to give a viscous liquid. The crude product 11b' was purified by column chromatography to give pure compound 11b' (7.7 g, 82.6%) as a viscous liquid.

[0498] Synthesis of intermediate 11b": A 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, a thermocouple, and an argon inlet / outlet trap was charged with a solution of intermediate 11b' (7.7 g, 0.015 mol) and dichloromethane (110 mL). To the clear solution, 4-(dimethylamino)pyridine (2.2 g, 0.018 mol) and acetic anhydride (1.84 g, 0.0180 mol) were added at room temperature under argon. The mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After the reaction was complete, the mixture was washed with saturated ammonium chloride (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 11b" as a viscous oil. The crude product was purified by column chromatography to give the acetate ester (11b") as a colorless viscous oil (7.8 g, 92.8%).

[0499] Synthesis of intermediate 12b: A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with a solution of crude intermediate 11b″ (7.6 g, 0.014 mol), diethyl ether (110 mL), and magnesium bromide (2.59 g, 0.140) at room temperature under nitrogen. The reaction mixture was stirred for 3-4 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 12b as a viscous oil. The crude product was purified by column chromatography to give intermediate 12b, a colorless viscous oil (2.06 g, 30%).

[0500] Synthesis of intermediate 92: A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with intermediate 12b and dichloromethane (50 mL). The mixture was stirred to obtain a clear solution. To the clear solution, molecular sieves (500 mg) and PDC (2.9 g, 1.75 mol) were added, and the reaction mixture was stirred at ambient temperature. The progress of the reaction was monitored by TLC. After 16 hours, the reaction was complete. The product was purified by column chromatography to obtain the pure product 92 as a viscous liquid (1.14 g, 55.6% yield).

[0501] Synthesis of intermediates 96A and 96B (mixture): A 100 mL single-neck round-bottom flask equipped with a magnetic stirrer was charged with intermediate 92 (250 mg, 0.0005 mol) and DMF (8 mL). The mixture was stirred to obtain a clear solution. To the clear solution, monoethyl malonate (105 mg, 0.0008 mol), DMAP (22 mg, 0.00018 mol), piperidene (9 mg), and acetic acid (8 mg) were added at 5-10 °C, and the reaction mixture was stirred at ambient temperature. The reaction progress was monitored by TLC. After 1 h, the reaction was complete. At this stage, the reaction mixture was quenched by the addition of saturated ammonium chloride solution (20 mL) and stirred for 5 min. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to obtain a crude mixture of compounds 93 and 94 (270 mg). The crude mixture was dissolved in MeOH (8 mL), and aqueous sodium hydroxide (116 mg in 3 mL of water) was added to the clear solution at room temperature. The mixture was stirred at room temperature for 16 hours, and the progress of the reaction was monitored by HPLC. Once the reaction was complete, the pH of the reaction mixture was adjusted to 1-2 and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give compounds 96A and 96B (approximately 100 mg).

[0502] 3. Synthesis of Treprostinil Prodrugs 3.1. Synthesis of Treprostinil Side Chain Acetate Cyclopentyl Methyl Carbonate

[0503] [ka]

[0504] experiment: Synthesis of mono-TES treprostinil benzyl ester side chain acetate (3): To a stirred solution of mono-TES treprostinil benzyl ester (1) (3.30 g, 5.55 mmol) and DMAP (1.36 g, 11.10 mmol) in dichloromethane (DCM) at room temperature under argon, acetic anhydride (2) (787 μL, 8.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and checked by TLC. The mixture was concentrated in vacuo to give the crude product (5.28 g), which was purified by column chromatography to give mono-TES treprostinil benzyl ester side chain acetate (3) (3.47 g, 98% yield) (99.95% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0505] Synthesis of Treprostinil Benzyl Ester Side Chain Acetate (4): To a stirred solution of mono-TES treprostinil benzyl ester side chain acetate (3) (3.39 g, 5.33 mmol) in tetrahydrofuran (THF) (80 mL) and water (16 mL) at room temperature was added HCl (2N) (2.67 mL, 5.34 mmol). The reaction mixture was stirred at room temperature for 1 hour and checked by TLC. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. It was filtered, and the filtrate was concentrated in vacuo to give the crude product (3.53 g), which was purified by column chromatography to give treprostinil benzyl ester side chain acetate (4) (2.76 g, 99% yield) (99.82% HPLC purity). Compound 4 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0506] Synthesis of Treprostinil Benzyl Ester Side Chain Acetate Cyclopentyl Methyl Carbonate (5): To a stirred solution of treprostinil benzyl ester side chain acetate (4) (0.72 g, 1.38 mmol) in DCM (10 mL) and pyridine (5 mL) at 0° C. under argon was added methyl chloroformate (0.39 g, 4.14 mmol). The reaction mixture was stirred at room temperature for 2 hours and checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (1.38 g), which was purified by column chromatography to give treprostinil benzyl ester side chain acetate cyclopentylmethyl carbonate (5) (0.77 g, 96% yield) (99.90% HPLC purity). Compound 5 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0507] Synthesis of Treprostinil Side Chain Acetate Cyclopentyl Methyl Carbonate (6): To a stirred solution of treprostinil benzyl ester side chain acetate cyclopentylmethyl carbonate (5) (0.70 g, 1.20 mmol) in ethyl acetate (20 mL) and water (1 mL) was added palladium on carbon (5 wt %, 50% water) (100 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 2 hours. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil side chain acetate cyclopentylmethyl carbonate (6) (0.58 g, 98% yield) (99.73% HPLC purity). Compound 6 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0508] 3.2 Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Propionate

[0509] [ka]

[0510] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain Dibenzylphosphate Cyclopentyl Propionate (3): To a stirred solution of treprostinil benzyl ester side-chain dibenzyl phosphate (1) (0.99 g, 1.33 mmol) in DCM (20 mL) and DMAP (325 mg, 2.66 mmol) at room temperature under argon, propionic anhydride (2) (256 μL, 2.00 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (1.91 g), which was purified by column chromatography to give treprostinil benzyl ester side-chain dibenzyl phosphate cyclopentyl propionate (3) (1.02 g, 96% yield) (99.11% HPLC purity). Compound 3 was prepared as follows: 1Characterized by 1 H NMR and MS.

[0511] Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Propionate (4): To a stirred solution of treprostinil benzyl ester side chain dibenzyl phosphate cyclopentyl propionate (3) (0.94 g, 1.17 mmol) in ethyl acetate (20 mL) and water (1 mL) was added palladium on carbon (5 wt %, 50% water) (200 mg). The reaction mixture was evacuated under house vacuum and filled with hydrogen (this was repeated twice), then connected to a hydrogen balloon and stirred at room temperature for 2 hours. It was checked by TLC that the reaction was complete, and the mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil side chain phosphate cyclopentyl propionate (4) (0.60 g, 97% yield) (95.94% HPLC purity). Compound 4 was prepared as follows: 1 H NMR, 13 C NMR, 31 It was characterized by P NMR, IR and MS.

[0512] 3.3 Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Methyl Carbonate

[0513] [ka]

[0514] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain Dibenzylphosphate Cyclopentylmethyl Carbonate (3): To a stirred solution of treprostinil benzyl ester side chain dibenzyl phosphate (1) (1.03 g, 1.38 mmol) in DCM (20 mL) and DMAP (675 mg, 5.52 mmol) at room temperature under argon, methyl chloroformate (2) (260 mg, 2.76 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (2.20 g), which was purified by column chromatography to give treprostinil benzyl ester side chain dibenzyl phosphate cyclopentylmethyl carbonate (3) (1.04 g, 95% yield) (99.96% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0515] Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Methyl Carbonate (4): To a stirred solution of treprostinil benzyl ester side chain dibenzyl phosphate cyclopentyl methyl carbonate (3) (0.93 g, 1.16 mmol) in ethyl acetate (20 mL) and water (1 mL) was added palladium on carbon (5 wt %, 50% water) (250 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 3 hours. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil side chain phosphate cyclopentyl methyl carbonate (4) (0.62 g, 98% yield) (99.48% HPLC purity). Compound 4 was prepared as follows: 1 H NMR, 13 C NMR, 31 It was characterized by P NMR, IR and MS.

[0516] 3.4. Synthesis of Treprostinil Hydroxyacetate Diacetate

[0517] [ka]

[0518] experiment: Synthesis of treprostinil hydroxyacetic acid benzyl ester diacetate (3): To a stirred solution of treprostinil diacetate (1) (0.20 g, 0.43 mmol) and potassium carbonate (120 mg, 0.86 mmol) in acetone (2 mL) at room temperature was added benzyl bromoacetate (2) (150 mg, 0.65 mmol). The reaction mixture was stirred at room temperature for 2 hours and checked by TLC, and the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product (0.57 g), which was purified by column chromatography to give treprostinil hydroxyacetic acid benzyl ester diacetate (3) (0.23 g, 86% yield) (99.99% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0519] Synthesis of Treprostinil Hydroxyacetic Acid Diacetate (4): To a stirred solution of treprostinil benzyl hydroxyacetate diacetate (3) (0.22 g, 0.35 mmol) in ethyl acetate (10 mL) was added palladium on carbon (5 wt %, 50% water) (50 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil hydroxyacetate diacetate (4) (0.18 g, 99% yield) (99.78% HPLC purity). Compound 4 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0520] 3.5. Synthesis of Treprostinil Hydroxyacetate Acid Dipropionate

[0521] [ka]

[0522] experiment: Synthesis of Treprostinil Hydroxyacetic Acid Benzyl Ester Dipropionate (3): To a stirred solution of treprostinil dipropionate (1) (0.46 g, 0.91 mmol) and potassium carbonate (0.25 g, 1.82 mmol) in acetone (10 mL) was added benzyl bromoacetate (2) (0.31 g, 1.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. It was checked by TLC, and the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product (0.72 g), which was purified by column chromatography to give treprostinil hydroxyacetic acid benzyl ester dipropionate (3) (0.57 g, 97% yield) (99.06% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0523] Synthesis of Treprostinil Hydroxyacetate Acid Dipropionate (4): To a stirred solution of treprostinil hydroxyacetic acid benzyl ester dipropionate (3) (0.52 g, 0.80 mmol) in ethyl acetate (15 mL) and water (1 mL) was added palladium on carbon (5 wt %, 50% water) (100 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil hydroxyacetic acid ester acid dipropionate (4) (0.45 g, 99% yield) (99.99% HPLC purity). Compound 4 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0524] 3.6. Synthesis of Treprostinil Side Chain 2-((1,3-bisbenzyloxy)-propan-2-yloxy)acetate

[0525] [ka]

[0526] experiment: Synthesis of mono-TES treprostinil benzyl ester side chain 2-((1,3-bis(benzyloxy)propan-2-yl)oxy)acetate (3): To a solution of mono-TES treprostinil benzyl ester (1) (1.55 g, 2.61 mmol), 2-((1,3-bis(benzyloxy)propan-2-yl)oxy)acetic acid (2) (0.72 g, 2.18 mmol), DIPEA (970 μL, 5.45 mmol), and DMAP (53 mg, 0.44 mmol) in dichloromethane (DCM) (25 mL) was added EDCI.HCl (1.05 g, 5.45 mmol) at room temperature under argon. The reaction mixture was stirred overnight at room temperature and checked by TLC. Water (20 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL). The combined DCM layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the crude product (2.69 g), which was purified by column chromatography to give mono-TES treprostinil benzyl ester side chain 2-((1,3-bis(benzyloxy)propan-2-yl)oxy)acetate (3) (1.98 g) (84.38% HPLC purity). Compound 3 was 1 Characterized by 1 H NMR and MS.

[0527] Synthesis of treprostinil benzyl ester side chain 2-((1,3-bis(benzyloxy)propan-2-yl)oxy)acetate (4): To a solution of mono-TES treprostinil benzyl ester side chain 2-((1,3-bis(benzyloxy)propan-2-yl)oxy)acetic acid ester (3) (1.91 g, 2.11 mmol) in tetrahydrofuran (THF) (50 mL) and water (10 mL) at room temperature was added HCl (2N) (2.11 mL, 4.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. Water (30 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. It was filtered and the filtrate was concentrated in vacuo to give the crude product (2.20 g), which was purified by column chromatography to give treprostinil benzyl ester side chain 2-((1,3-bis(benzyloxy)propan-2-yl)oxy)acetate (4) (1.41 g, 82% yield over two steps) (99.09% HPLC purity). Compound 4 was 1 Characterized by 1 H NMR and MS.

[0528] Synthesis of Treprostinil Side Chain 2-((1,3-bishydroxy)propan-2-yl)oxy)acetate (5): To a stirred solution of treprostinil benzyl ester side chain 2-((1,3-bis(benzyloxy)propan-2-yl)oxy)acetate (4) (1.13 g, 1.42 mmol) in ethyl acetate (25 mL) and water (1.5 mL) was added palladium on carbon (5 wt %, 50% water) (350 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 5 hours. It was analyzed by TLC and 1 The reaction was checked by H NMR. The reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil side chain 2-((1,3-bishydroxy)propan-2-yl)oxy)acetate (5) (0.65 g, 88% yield) (89.62% HPLC purity). Compound 5 was 1 H NMR,13 It was characterized by C NMR, IR and MS.

[0529] 3.7. Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Trifluoroacetate

[0530] [ka]

[0531] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain Dibenzylphosphate Cyclopentyl Trifluoroacetate (3): To a stirred solution of treprostinil benzyl ester side chain dibenzyl phosphate (1) (0.74 g, 1.00 mmol) in DCM (15 mL) and DMAP (270 mg, 2.20 mmol) was added trifluoroacetic anhydride (2) (280 μL, 2.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (1.60 g), which was purified by silica gel (approximately 35 g) column chromatography to give treprostinil benzyl ester side chain dibenzyl phosphate cyclopentyl trifluoroacetate (3) (0.55 g, 65% yield) (92.42% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0532] Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Trifluoroacetate (4): To a stirred solution of treprostinil benzyl ester side chain dibenzyl phosphate cyclopentyl trifluoroacetate (3) (0.54 g, 0.64 mmol) in tetrahydrofuran (THF) (15 mL) and water (1 mL) was added palladium on carbon (160 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 5 hours. It was analyzed by TLC and 1The reaction was checked by H NMR and was complete. The mixture was filtered through a pad of Celite and washed with THF. The filtrate was concentrated in vacuo to give treprostinil side chain phosphate cyclopentyl trifluoroacetate (4) (0.37 g, 99% yield).

[0533] 3.8. Synthesis of Treprostinil Side Chain Trifluoroacetate Cyclopentyl Phosphate

[0534] [ka]

[0535] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain Trifluoroacetate Cyclopentyl Dibenzyl Phosphate (3): To a stirred solution of treprostinil benzyl ester cyclopentyl dibenzyl phosphate (1) (1.07 g, 1.44 mmol) in DCM (20 mL) and DMAP (390 mg, 3.17 mmol) at room temperature was added trifluoroacetic anhydride (2) (400 μL, 2.88 mmol). The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (2.39 g), which was purified by column chromatography to give treprostinil benzyl ester side chain trifluoroacetate cyclopentyl dibenzyl phosphate (3) (0.55 g, 65% yield) (98.64% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0536] Synthesis of Treprostinil Side Chain Trifluoroacetate Cyclopentyl Phosphate (4): To a stirred solution of treprostinil benzyl ester side chain trifluoroacetate cyclopentyl dibenzyl phosphate (3) (0.99 g, 1.18 mmol) in tetrahydrofuran (THF) (20 mL) and water (1 mL) was added palladium on carbon (5 wt %, 50% water) (300 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 4 hours. It was analyzed by TLC and 1 The reaction was checked by H NMR and was complete. The mixture was filtered through a pad of Celite and washed with THF. The filtrate was concentrated in vacuo to give treprostinil side chain trifluoroacetate cyclopentyl phosphate (4) (0.68 g, 99% yield).

[0537] 3.9. Synthesis of Treprostinil Side Chain Trifluoroacetate

[0538] [ka]

[0539] experiment: Synthesis of mono-TES treprostinil benzyl ester side chain trifluoroacetate (3): To a stirred solution of mono-TES treprostinil benzyl ester (1) (1.16 g, 1.95 mmol) in DCM (20 mL) and DMAP (596 mg, 4.88 mmol) at room temperature was added trifluoroacetic anhydride (2) (540 μL, 3.90 mmol). The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (1.91 g), which was purified by column chromatography to give mono-TES treprostinil benzyl ester side chain trifluoroacetate (3) (1.31 g, 96% yield) (99.30% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0540] Synthesis of Treprostinil Benzyl Ester Side Chain Trifluoroacetate (4): To a stirred solution of mono-TES treprostinil benzyl ester side chain trifluoroacetate (3) (1.22 g, 1.77 mmol) in tetrahydrofuran (THF) (25 mL) and water (5 mL) at room temperature, HCl (2N) (0.89 mL, 1.78 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. Water (20 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine and dried over sodium sulfate. It was filtered, and the filtrate was concentrated in vacuo to give the crude product (1.29 g), which was purified by column chromatography to give treprostinil benzyl ester side chain trifluoroacetate (4) (1.04 g, 99% yield) (99.40% HPLC purity). Compound 4 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0541] Synthesis of Treprostinil Side Chain Trifluoroacetate (5): To a stirred solution of treprostinil benzyl ester side chain trifluoroacetate (4) (0.99 g, 1.72 mmol) in ethyl acetate (20 mL) was added palladium on carbon (5 wt %, 50% water) (100 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil side chain trifluoroacetate (5) (0.95 g, 99% yield) (97.68% HPLC purity). Compound 5 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0542] 3.10. Synthesis of Treprostinil Side Chain Difluoroacetate

[0543] [ka]

[0544] experiment: Synthesis of mono-TES treprostinil benzyl ester side chain difluoroacetate (3): To a stirred solution of mono-TES treprostinil benzyl ester (1) (1.01 g, 1.70 mmol) in DCM (20 mL) and DMAP (415 mg, 3.40 mmol) at room temperature was added difluoroacetic anhydride (2) (277 μL, 2.55 mmol). The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (1.87 g), which was purified by column chromatography to give mono-TES treprostinil benzyl ester side chain difluoroacetate (3) (0.96 g, 84% yield) (99.19% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0545] Synthesis of Treprostinil Benzyl Ester Side Chain Difluoroacetate (4): To a stirred solution of mono-TES treprostinil benzyl ester side chain difluoroacetate (3) (0.94 g, 1.40 mmol) in tetrahydrofuran (THF) (20 mL) and water (4 mL) at room temperature, HCl (2N) (0.7 mL, 1.40 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. Water (20 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate in vacuo gave the crude product (0.93 g), which was purified by column chromatography to give treprostinil benzyl ester side chain difluoroacetate (4) (0.77 g, 99% yield) (98.92% HPLC purity). Compound 4 was prepared as follows: 1Characterized by 1 H NMR and MS.

[0546] Synthesis of Treprostinil Side Chain Difluoroacetate (5): To a stirred solution of treprostinil benzyl ester side-chain difluoroacetate (4) (0.72 g, 1.29 mmol) in ethyl acetate (15 mL) was added palladium on carbon (5 wt %, 50% water) (80 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil side-chain difluoroacetate (5) (0.61 g, 99% yield) (98.83% HPLC purity). Compound 5 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0547] 3.11. Synthesis of Treprostinil Di(trifluoroacetate)

[0548] [ka]

[0549] experiment: Synthesis of treprostinil benzyl ester di(trifluoroacetate) (3): To a stirred solution of treprostinil benzyl ester (1) (1.60 g, 3.33 mmol) in DCM (35 mL) and DMAP (2.03 g, 16.55 mmol) was added trifluoroacetic anhydride (2) (1.39 mL, 9.99 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (6.51 g), which was purified by column chromatography to give treprostinil benzyl ester di(trifluoroacetate) (3) (0.79 g, 35% yield) (98.79% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0550] Synthesis of treprostinil di(trifluoroacetate) (4): To a stirred solution of treprostinil benzyl ester di(trifluoroacetate) (3) (0.75 g, 1.11 mmol) in THF (15 mL) was added palladium on carbon (5 wt %, 50% water) (75 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with THF. The filtrate was concentrated in vacuo to give treprostinil di(trifluoroacetate) (4) (0.40 g, 62% yield) (92.60% HPLC purity). Compound 4 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0551] 3.12. Synthesis of Treprostinil Di(difluoroacetate)

[0552] [ka]

[0553] experiment: Synthesis of treprostinil benzyl ester di(difluoroacetate) (3): To a stirred solution of treprostinil benzyl ester (1) (1.62 g, 3.37 mmol) in DCM (35 mL) and DMAP (1.65 g, 13.48 mmol) was added difluoroacetic anhydride (2) (807 μL, 7.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (6.51 g), which was purified by column chromatography to give treprostinil benzyl ester di(difluoroacetate) (3) (1.61 g, 75% yield) (98.82% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0554] Synthesis of treprostinil di(difluoroacetate) (4): To a stirred solution of treprostinil benzyl ester di(difluoroacetate) (3) (0.73 g, 1.14 mmol) in ethyl acetate (15 mL) was added palladium on carbon (5 wt %, 50% water) (80 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (twice), connected to a hydrogen balloon, and stirred at room temperature for 1 h. It was checked by TLC, and the reaction was complete. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil di(difluoroacetate) (4) (0.65 g) as a viscous oil. Ethyl acetate (1 mL) was added to create a clear solution. This solution was added to hexane with stirring, forming a solid, which was filtered. The solid was dried in air overnight to give 0.48 g of product (77% yield) (98.44% HPLC purity) (MP: 38-40 °C). Compound 4 is 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0555] 3.13. Synthesis of Treprostinil Cyclopentyl Difluoroacetate

[0556] [ka]

[0557] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain TBDMS Cyclopentyl Difluoroacetate (3): To a stirred solution of treprostinil benzyl ester side chain TBDMS (1) (1.52 g, 2.55 mmol) in DCM (30 mL) and DMAP (623 mg, 5.10 mmol) at room temperature was added difluoroacetic anhydride (2) (420 μL, 3.83 mmol). The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (2.12 g), which was purified by column chromatography to give treprostinil benzyl ester side chain TBDMS cyclopentyl difluoroacetate (3) (1.38 g, 81% yield) (99.05% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0558] Synthesis of Treprostinil Benzyl Ester Cyclopentyl Difluoroacetate (4): To a stirred solution of treprostinil benzyl ester side-chain TBDMS cyclopentyl difluoroacetate (3) (1.35 g, 2.01 mmol) in isopropyl alcohol (IPA) (30 mL) was added 2N HCl (3.0 mL, 6.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. It was checked by TLC, and the reaction was almost complete. Water (20 mL) was added and concentrated in vacuo to remove most of the IPA. EA (20 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine and dried over sodium sulfate. It was filtered, and the filtrate was concentrated in vacuo to give the crude product (1.19 g), which was purified by column chromatography to give treprostinil benzyl ester cyclopentyl difluoroacetate (4) (0.79 g, 70% yield) (97.65% HPLC purity). Compound 4 is 1 Characterized by 1 H NMR and MS.

[0559] Synthesis of treprostinil cyclopentyl difluoroacetate (5): To a stirred solution of treprostinil benzyl ester cyclopentyl difluoroacetate (4) (0.76 g, 1.37 mmol) in ethyl acetate (15 mL) was added palladium on carbon (5 wt %, 50% water) (80 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 3 hours. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil cyclopentyl difluoroacetate (5) (0.62 g, 97% yield) (96.69% HPLC purity). Compound 5 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0560] 3.14. Synthesis of Treprostinil Side Chain Difluoroacetate Cyclopentyl Phosphate

[0561] [ka]

[0562] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain Difluoroacetate Cyclopentyl Dibenzyl Phosphate (3): To a stirred solution of treprostinil benzyl ester cyclopentyl dibenzyl phosphate (1) (1.25 g, 1.68 mmol) in DCM (25 mL) and DMAP (410 mg, 3.36 mmol) at room temperature was added difluoroacetic anhydride (2) (275 μL, 2.52 mmol). The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (2.23 g), which was purified by column chromatography to give treprostinil benzyl ester side-chain difluoroacetate cyclopentyl dibenzyl phosphate (3) (1.25 g, 90% yield) (99.60% HPLC purity). Compound 3 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0563] Synthesis of Treprostinil Side Chain Difluoroacetate Cyclopentyl Phosphate (4): To a stirred solution of treprostinil benzyl ester side chain difluoroacetate cyclopentyl dibenzyl phosphate (3) (1.21 g, 1.48 mmol) in tetrahydrofuran (THF) (25 mL) was added palladium on carbon (5 wt %, 50% water) (350 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 4 hours. It was analyzed by TLC, 1 H NMR, 31The reaction was checked by P NMR, and was complete by TLC and NMR. The mixture was filtered through a Celite pad and washed with THF. The filtrate was concentrated in vacuo to give treprostinil side chain difluoroacetate cyclopentyl phosphate (4) (0.80 g, 99% yield). The crude compound was dissolved in ethyl acetate (2 mL). This solution was added to hexane (50 mL) with stirring to form a solid. It was filtered and the solid was dried in air to give compound 4 (0.65 g, 80% yield) (97.83% HPLC purity) as a white solid (MP: 125-128 °C). Compound 4 was 1 H NMR, 13 C NMR, 31 It was characterized by P NMR, IR and MS.

[0564] 3.15. Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Difluoroacetate

[0565] [ka]

[0566] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain Dibenzylphosphate Cyclopentyl Difluoroacetate (3): To a stirred solution of treprostinil benzyl ester side chain dibenzyl phosphate (1) (1.26 g, 1.70 mmol) in DCM (25 mL) and DMAP (415 mg, 3.40 mmol) at room temperature was added difluoroacetic anhydride (2) (222 μL, 2.04 mmol). The reaction mixture was stirred at room temperature for 3 hours. It was checked by TLC, and the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product (2.34 g), which was purified by column chromatography to give treprostinil benzyl ester side chain dibenzyl phosphate cyclopentyl difluoroacetate (3) (1.13 g, 81% yield) (99.60% HPLC purity). Compound 3 was prepared as follows: 1Characterized by 1 H NMR and MS.

[0567] Synthesis of Treprostinil Side Chain Phosphate Cyclopentyl Difluoroacetate (4): To a stirred solution of treprostinil benzyl ester side chain dibenzyl phosphate cyclopentyl difluoroacetate (3) (1.11 g, 1.35 mmol) in tetrahydrofuran (THF) (25 mL) was added palladium on carbon (5 wt %, 50% water) (300 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 3 hours. It was analyzed by TLC, 1 H NMR, 31 The reaction was checked by P NMR and was complete. The mixture was filtered through a pad of Celite and washed with THF. The filtrate was concentrated in vacuo to give treprostinil side chain phosphate cyclopentyl difluoroacetate (4). Compound 4 was synthesized by the following procedure: 1 H NMR, 13 C NMR, 31 It was characterized by P NMR, IR and MS.

[0568] 3.16. Synthesis of Treprostinil Side Chain Palmitate

[0569] [ka]

[0570] experiment: Synthesis of mono-TES treprostinil benzyl ester side chain palmitate (3): To a stirred solution of mono-TES treprostinil benzyl ester (1) (3.72 g, 6.25 mmol), palmitic acid (2) (1.92 g, 7.50 mmol), DIPEA (2.72 mL, 15.63 mmol), and DMAP (153 mg, 1.25 mmol) in dichloromethane (DCM) (70 mL) was added EDCI.HCl (3.00 g, 15.63 mmol) at room temperature under argon. The reaction mixture was stirred overnight at room temperature. It was checked by TLC, and the reaction was almost complete. Water (20 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL). The combined DCM layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the crude product (6.90 g), which was purified by column chromatography to give mono-TES treprostinil benzyl ester side chain palmitate (3) (4.58 g, 88% yield). 1 Characterized by 1 H NMR and MS.

[0571] Synthesis of Treprostinil Benzyl Ester Side Chain Palmitate (4): To a stirred solution of mono-TES treprostinil benzyl ester side chain palmitate (3) (1.98 g, 2.37 mmol) in THF (50 mL) and water (10 mL) at room temperature, HCl (2N) (1.2 mL, 2.40 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. It was checked by TLC, and the reaction was complete. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. It was filtered, and the filtrate was concentrated in vacuo to give the crude product (2.23 g), which was purified by column chromatography to give treprostinil benzyl ester side chain palmitate (4) (1.72 g, 99% yield) (99.89% HPLC purity). Compound 4 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0572] Synthesis of Treprostinil Side Chain Palmitate (5): To a stirred solution of treprostinil benzyl ester side-chain palmitate (4) (1.58 g, 2.20 mmol) in ethyl acetate (30 mL) was added palladium on carbon (5 wt %, 50% water) (150 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 2 hours. It was checked by TLC, and the reaction was complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil side-chain palmitate (5) (1.38 g, 99% yield) (99.38% HPLC purity) (MP: 46-48 °C). Compound 5 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0573] 3.17. Synthesis of Treprostinil Cyclopentyl Palmitate

[0574] [ka]

[0575] experiment: Synthesis of Treprostinil Benzyl Ester Side Chain TBDMS Cyclopentyl Palmitate (3): To a stirred solution of treprostinil benzyl ester side chain TBDMS (1) (1.61 g, 2.70 mmol), palmitic acid (2) (831 mg, 3.24 mmol), DIPEA (1.2 mL, 6.75 mmol), and DMAP (66 mg, 0.54 mmol) in dichloromethane (DCM) (40 mL) at room temperature under argon, EDCI.HCl (1.29 g, 6.75 mmol) was added. The reaction mixture was stirred overnight at room temperature and checked by TLC. Water (20 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL). The combined DCM layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give the crude product (3.08 g), which was purified by column chromatography to give treprostinil benzyl ester side chain TBDMS cyclopentyl palmitate (3) (2.13 g, 95% yield) (87.03% HPLC purity). 1 Characterized by 1 H NMR and MS.

[0576] Synthesis of Treprostinil Benzyl Ester Cyclopentyl Palmitate (4): To a stirred solution of treprostinil benzyl ester side chain TBDMS cyclopentyl palmitate (3) (2.00 g, 2.40 mmol) in THF (20 mL) in a plastic tube cooled to 0° C., HF.Py (4.3 mL, 36 mmol) was added. The reaction mixture was stirred at that temperature and slowly warmed to room temperature for 5 hours. It was checked by TLC, and the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate solution to a pH of approximately 7. The reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. It was filtered, and the filtrate was concentrated in vacuo to give the crude product (1.61 g), which was purified by column chromatography to give treprostinil benzyl ester cyclopentyl palmitate (4) (1.29 g, 75% yield) (98.72% HPLC purity). Compound (4) was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0577] Synthesis of Treprostinil Cyclopentyl Palmitate (5): To a stirred solution of treprostinil benzyl ester cyclopentyl palmitate (4) (1.19 g, 1.65 mmol) in ethyl acetate (25 mL) was added palladium on carbon (5 wt %, 50% water) (120 mg). The reaction mixture was evacuated under house vacuum, filled with hydrogen (this was repeated twice), connected to a hydrogen balloon, and stirred at room temperature for 2 hours. It was checked by TLC, and the reaction was found to be complete. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated in vacuo to give treprostinil cyclopentyl palmitate (5) (1.00 g, 99% yield) (97.65% HPLC purity) (MP: 74-76 °C). Compound 5 was prepared as follows: 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0578] 3.18. Synthesis of Treprostinil Hexadecyl Ester

[0579] [ka]

[0580] experiment Synthesis of Treprostinil Hexadecyl Ester (3) To a stirred solution of treprostinil potassium salt (1) (0.50 g, 1.17 mmol) in DMF (10 mL) was added 1-bromohexadecane (2) (715 μL, 2.34 mmol) and cesium iodide (330 mg, 1.29 mmol) at room temperature. The reaction mixture was stirred in an oil bath at 60° C. for 5 hours. It was checked by TLC, and the reaction was complete. Saturated aqueous ammonium chloride (20 mL) was added, followed by ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. It was filtered and the filtrate was concentrated in vacuo to give the crude product (1.19 g), which was purified by column chromatography to give treprostinil hexadecyl ester (3) (0.73 g, 99% yield) (99.70% HPLC purity) (MP: 51-53°C). 1 H NMR, 13 It was characterized by C NMR, IR and MS.

[0581] 3.19. Synthesis of Treprostinil Glycol Phosphate

[0582] [ka]

[0583] experiment: Synthesis of di-TBDMS treprostinil benzyl glycol ester (3): To a stirred solution of di-TBDMS-treprostinil (1) (5.13 g, 8.29 mmol), benzyl glycol (2) (1.3 mL, 9.12 mmol), DIPEA (3.6 mL, 20.73 mmol), and DMAP (2.53 g, 20.73 mmol) in dichloromethane (DCM) (50 mL) was added EDCI.HCl (3.97 g, 20.73 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 2 hours and checked by TLC. Water (50 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. It was filtered and the filtrated was concentrated in vacuo to give a crude product (8.87 g), which was purified by column chromatography to give di-TBDMS treprostinil benzyl glycol ester (3) (5.13 g, 82% yield) (97.08% HPLC purity). 1 Characterized by 1 H NMR and MS.

[0584] Synthesis of di-TBDMS treprostinil glycol ester (4): To a stirred solution of di-TBDMS treprostinil benzyl glycol ester (3) (5.05 g, 6.70 mmol) in ethyl acetate (80 mL) was added palladium on carbon (0.50 g, 5 wt %, 50% water). The system was evacuated and replaced with hydrogen (from a hydrogen balloon) (repeated twice). The system was connected to a hydrogen balloon, stirred at room temperature for 6 hours, and checked by TLC. It was filtered through a Celite pad, and the filtrate was concentrated in vacuo to give the crude product (4.93 g). It was purified by column chromatography to give di-TBDMS treprostinil glycol ester (4) (4.07 g, 92% yield) (98.90% HPLC purity). Compound 4 was prepared as follows: 1 It was characterized by H and MS.

[0585] Synthesis of di-TBDMS treprostinil glycol dibenzyl phosphate (6): To a stirred solution of di-TBDMS treprostinil glycol ester (4) (1.08 g, 1.63 mmol), tetrazole (10.9 mL, 0.45 M in acetonitrile, 4.89 mmol) in DCM (40 mL) was added dibenzyl-N,N-diisopropylphosphoramidite (5) (1.13 g, 3.26 mmol) at room temperature under argon. It was stirred for 3 hours and checked by TLC, and the reaction was complete at this stage. The system was cooled to -78 °C (dry ice-acetone), and mCPBA (70-75%) (0.87 g, 5.05 mmol) was added. The reaction mixture was stirred for 3 hours and checked by TLC, and the reaction was complete. Sodium sulfite solution (10%) was added and stirred overnight. The layers were separated, and the DCM layer was checked with a Peroxide 100 Tip to confirm the absence of any peroxide. The DCM layer was washed with saturated sodium bicarbonate solution, water, brine, and dried over sodium sulfate. It was filtered, and the filtrate was concentrated in vacuo to give the crude product (2.33 g), which was purified by column chromatography to give di-TBDMS treprostinil glycol dibenzyl phosphate (6) (1.42 g, 95% yield) (86.27% HPLC purity). Compound 6 was obtained as follows: 1 Characterized by 1 H NMR and MS.

[0586] Synthesis of Treprostinil Glycol Dibenzyl Phosphate (7): To a stirred solution of di-TBDMS treprostinil glycol dibenzyl phosphate (6) (1.08 g, 1.17 mmol) in THF in a Teflon tube was added a solution of hydrogen fluoride pyridine in THF (2.5 mL). The mixture was stirred at room temperature for 4 hours and checked by TLC, and slowly quenched with sodium bicarbonate to a pH of about 8. It was extracted with EtOAc (50 mL, 2×20 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. It was filtered, and the filtrate was concentrated in vacuo to give the crude product (1.70 g), which was purified by column chromatography to give treprostinil glycol dibenzyl phosphate (7) (0.63 g, 77% yield) (99.04% HPLC purity). Compound 7 was prepared as follows: 1 Characterized by 1 H NMR and MS.

[0587] Synthesis of Treprostinil Glycol Phosphate (8): To a stirred solution of treprostinil glycol dibenzyl phosphate (7) (0.21 g, 0.30 mmol) in ethyl acetate (10 mL) was added palladium on carbon (50 mg, 5 wt %, 50% water). The system was evacuated and replaced with hydrogen from a hydrogen balloon (repeated two more times). The system was then connected to a hydrogen balloon and stirred at room temperature for 2 hours. The reaction was checked by TLC and was complete. It was filtered through a Celite pad and washed with EtOAc (2 x 10 mL). The filtrate was concentrated in vacuo to give treprostinil glycol phosphate 8 (0.12 g, 78% yield) (99.13% HPLC purity). Compound 8 was prepared as follows: 1 H NMR, 13 C NMR, 31 It was characterized by P NMR, IR and MS.

[0588] While the foregoing refers to certain preferred embodiments, it will be understood that the invention is not so limited. It will occur to those skilled in the art that various modifications can be made to the disclosed embodiments and that such modifications are intended to be within the scope of the invention.

[0589] All publications, patent applications and patents cited in this specification are hereby incorporated by reference in their entirety.

Claims

1. A compound of formula (1), its enantiomer or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R １ is H, C １ -C ３ is an alkyl group or a carboxylic acid protecting group; R ２ is H or an alcohol protecting group; and R ３ teeth, 【Chemistry 2】 (In the formula, Y １ is -C≡C-; -CH=CH-; or -(CH ２ ) ｍ － where m is an integer from 0 to 5; R ４ is H, OH or ═O; R ５ is H, OH, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted carbocyclic group; R ６ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group, where R is each H. １ and R ２ Regarding R ３ teeth, 【Transformation 3】 isn't it).

2. R １ is H or CH ３ 2. The compound of claim 1, wherein:

3. R ２ The compound of claim 1 or 2, wherein is H.

4. R ３ but 【Chemistry 4】 (In the formula, R ７ is an alkyl group, an alkenyl group, or an alkynyl group; Z is O, CH ２ , NH or S and R ８ is a heterocyclic group.

5. R ３ but 【Transformation 5】 wherein each Z is independently selected from CH, N, O, or S; n is 0 or 1; and R ９ is an alkyl group, an aryl group, an electron-withdrawing group, an electron-donating group, a heterocycle, or a carbocycle.

6. R ３ but 【Transformation 6】 (In the formula, R １０ is a cycloalkyl group having from 3 to 8 carbon atoms, wherein one or more carbon atoms in the cycloalkyl group may optionally be replaced with a heteroatom selected from O, N, and S.

7. R ３ but 【Transformation 7】 The compound of any one of claims 1 to 3, selected from:

8. A compound having the formula (2), an enantiomer thereof, or a pharmaceutically acceptable salt thereof: 【Transformation 8】 (In the formula, X １ is hydrogen, 【Chemistry 9】 or 【Chemistry 10】 (wherein q is 1, 2 or 3, p1 is an integer from 1 to 20, and R １２ is a phosphate group or COOH; X ２ and X ３ each independently represents hydrogen, 【Chemistry 11】 phosphate, or 【Chemistry 12】 (wherein p2 is an integer from 1 to 20, and R １１ is C １ -C ８ is an alkyl group, １ -C ８ One or more carbon atoms of the alkyl group may optionally be replaced by O, １ -C ８ one or more hydrogen atoms of the alkyl group may optionally be replaced by a halogen; X ２ is hydrogen, where X １ , X ２ and X ３ is not all hydrogen; X is hydrogen １ and X, which is phosphate. ２ and X ３ For one of the two, X ２ and X ３ the other is not phosphate or hydrogen; X is hydrogen １ and unsubstituted C １ -C ８ R is an alkyl group １１ have 【Chemistry 13】 is X ２ and X ３ For one of the two, X ２ and X ３ The other is not hydrogen and X ２ or X ３ are not the same).

9. X １ but 【Chemistry 14】 9. The compound of claim 8, wherein:

10. X ２ and X ３ The compound of claim 9, wherein are identical.

11. X ２ and X ３ 11. The compound of any one of claims 8 to 10, wherein each of is hydrogen.

12. X ２ and X ３ Each of 【Chemistry 15】 11. The compound of claim 9 or 10, wherein:

13. X １ The compound of claim 8, wherein is hydrogen.

14. X ２ and X ３ is a phosphate and X ２ and X ３ The other side of 【Chemistry 16】 14. The compound of claim 13, wherein:

15. X ２ and X ３ At least one of C is replaced by O １ -C ８ The C having one or more carbon atoms of an alkyl group or having one or more hydrogen atoms replaced with halogen. １ -C ８ R is an alkyl group １１ have 【Chemistry 17】 14. The compound of claim 13, wherein:

16. X ２ and X ３ at least one of which has one or more hydrogen atoms replaced with halogen; １ -C ８ R is an alkyl group １１ have [Chemistry 18] 16. The compound of claim 15, wherein:

17. X ２ and X ３ each of which has one or more hydrogen atoms replaced with halogen １ -C ８ R is an alkyl group １１ have 【Chemistry 19】 17. The compound of claim 16, wherein:

18. X ２ and X ３ 18. The compound of claim 17, wherein:

19. X ２ and X ３ At least one of the groups has p2, which is an integer from 12 to 16. 【Chemistry 20】 or X １ has p1 which is an integer between 12 and 16 【Chemistry 21】 9. The compound of claim 8, wherein:

20. (a) X ２ and X ３ are hydrogen and X １ but 【Chemistry 22】 (b) X ３ but 【Chemistry 23】 and X ２ but 【Chemistry 24】 and X １ is hydrogen; (c) X ３ but 【Chemistry 25】 and X ２ but 【Chemistry 26】 and X １ is hydrogen; (d) X ３ but 【Chemistry 27】 and X ２ but 【Chemistry 28】 and X １ is hydrogen; (e) X ２ and X ３ Each of 【Chemistry 29】 and X １ but 【Transformation 30】 (f) X ２ and X ３ Each of 【Chemistry 31】 and X １ but 【Chemistry 32】 (g) each X １ and X ２ is H and X ３ but 【Transformation 33】 (h) X ３ but 【Transformation 34】 and X ２ but 【Chemistry 35】 and X １ is hydrogen; (i) X ２ but 【Transformation 36】 and X ３ but 【Chemistry 37】 and X １ is hydrogen; (j) X １ and X ２ are hydrogen and X ３ but 【Transformation 38】 (k) X １ and X ２ are hydrogen and X ３ but 【Chemistry 39】 (l) X ２ and X ３ Each of 【Chemistry 40】 and X １ is hydrogen; (m) X ２ and X ３ Each of 【Chemistry 41】 and X １ is hydrogen; (n) X １ and X ３ are hydrogen and X ３ but 【Chemistry 42】 (o) X １ is hydrogen; X ２ but 【Chemistry 43】 and X ３ but 【Chemistry 44】 (p) X １ is hydrogen; X ２ but 【Chemistry 45】 and X ３ but 【Chemistry 46】 (q) X ２ and X ３ are hydrogen and X １ but 【Chemistry 47】 (r) X １ and X ２ are hydrogen and X ３ but 【Chemistry 48】 (s) X １ and X ３ are hydrogen and X ２ but 【Chemistry 49】 or (t) X １ but [Transformation 50] and each X ２ and X ３ but 【Chemistry 51】 9. The compound of claim 8, wherein:

21. A pharmaceutical composition comprising a compound of any one of claims 1 to 20 and a pharmaceutically acceptable carrier.

22. 21. A method of treating pulmonary hypertension, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-20.

23. Compound of formula (3): 【Chemistry 52】 (In the formula, R ２１ is a phenol protecting group or CH ２ COOR ２４ and R ２２ is an alcohol protecting group; R ２３ is a hydroxy-terminated alkyl, -C=CH ２ , —C≡CH or 【Chemistry 53】 and R ２４ is a carboxylic acid protecting group).

24. R ２３ 24. The compound of claim 23, wherein is a hydroxy-terminated alkyl.

25. Formula (31): 【Chemistry 54】 24. The compound of claim 23 having the formula:

26. Formula (32): 【Transformation 55】 24. The compound of claim 23 having the formula:

27. Formula (33): 【Transformation 56】 24. The compound of claim 23 having the formula:

28. R ２１ is C １ -C ４ Alkyl, substituted or unsubstituted benzyl or CH ２ COOR ２４ (In the formula, R ２４ is C １ -C ４ 28. The compound of any one of claims 23 to 27, wherein R is 1 or 2; R is alkyl, or substituted or unsubstituted benzyl.

29. R ２２ The compound of any one of claims 23 to 28, wherein is an acetyl group or a silyl-containing group.

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