Synthesis of dopamine D3 receptor selective antagonists / partial agonists

Abstract

A process for the synthesis of (R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl) piperazin-1-yl)-3-hydroxybutyl)-1H-indol-2-carboxamide (Compound 8) is described, as well as the intermediate compounds of formulae 5-7, 9 and 14 for use in said process, as well as a process for the synthesis of (R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl) piperazin-1-yl)-3-hydroxybutyl)-1H-indol-2-carboxamide (Compound 8). # imgabs0 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This international application claims the benefit of U.S. Provisional Patent Application No. 63 / 325,313, filed on March 30, 2022, which is incorporated herein by reference in its entirety. background Technical Field

[0002] The present disclosure relates to the synthesis of (R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide (Compound 8). Summary of the Invention

[0003] Publicly included Figure 1 Scheme 1 shows a method for synthesizing compound 8.

[0004] Publicly included Figure 2 Scheme II shows a method for synthesizing compound 8.

[0005] Publicly included Figure 3 Scheme III shows a method for synthesizing compound 8.

[0006] Disclosed is a method for preparing compound 8, The method comprises: In the presence of a coupling agent, compound 7: or its salt is coupled with 1H-indole-2-carboxylic acid, wherein compound 7 is prepared by one or both of the following methods: Compound 6 or a salt thereof with hydrochloric acid to provide compound 7 or a salt thereof; and Compound 14 or a salt thereof with one or both of a catalyst and a reducing agent to provide compound 7 or a salt thereof, and Among them, compound 6 is prepared by making compound 5: or its salt is prepared by reacting with compound 9, Boc represents tBuO(CO)- group:

[0007] Compound 7 can be prepared by: or a salt thereof with hydrochloric acid to provide compound 7 or a salt thereof; and Compound 6 is prepared by making compound 5: or its salt is prepared by reacting with compound 9, Boc represents tBuO(CO)- group:

[0008] Compound 9 can be prepared by reacting (R)-4-chloro-3-hydroxybutyronitrile with one or both of a catalyst and a reducing agent and Boc anhydride to provide Compound 9.

[0009] Reducing agents can be used to prepare compound 9.

[0010] The reducing agent may include lithium aluminum hydride, sodium borohydride, or hydrogen, or any combination thereof.

[0011] The catalyst can be used to prepare compound 9.

[0012] The catalyst may comprise Raney nickel, Raney cobalt or nickel chloride, or any combination thereof.

[0013] Compound 9 can be prepared using both a catalyst and a reducing agent.

[0014] The catalyst may be nickel chloride, and the reducing agent may be sodium borohydride.

[0015] Compound 7 can be prepared by making compound 14 or a salt thereof with one or both of a catalyst and a reducing agent to provide compound 7 or a salt thereof.

[0016] Reducing agents can be used to prepare compound 7 from compound 14.

[0017] The reducing agent may include lithium aluminum hydride, a borane complex (eg, borane-tetrahydrofuran complex, dimethyl sulfide borane, and N,N-diethylaniline borane), sodium borohydride, or hydrogen, or any combination thereof.

[0018] Reducing agents can be used to prepare compound 7 from compound 14.

[0019] The catalyst may comprise Raney nickel, Raney cobalt or nickel chloride, or any combination thereof.

[0020] Compound 14 can be prepared using both a catalyst and a reducing agent.

[0021] Compound 14 can be prepared by one or both of the following methods: Make compound 5: or its salt with (S)-epichlorohydrin and cyanide or its salt; and Make compound 5: or its salts and (R)-4-chloro-3-hydroxybutyronitrile.

[0022] Compound 14 can be prepared by making compound 5: or its salt with (S)-epichlorohydrin and cyanide or its salt to prepare the same.

[0023] Compound 14 can be prepared by making compound 5: or its salt is reacted with (R)-4-chloro-3-hydroxybutyronitrile to prepare the product.

[0024] Compound 5 can be prepared by reacting compound 4 in the presence of a base, a diphosphine and Pd(OAc)2: Reaction with piperazine affords compound 5.

[0025] Compound 4 can be prepared by reacting 2-bromo-6-chloro-4-ethylphenol (3) with iodomethane in the presence of a base.

[0026] 2-Bromo-6-chloro-4-ethylphenol (3) can be prepared by reacting 2-chloro-4-ethylphenol (2) with a brominating agent.

[0027] The brominating agent may be N-bromosuccinimide (NBS).

[0028] 2-Chloro-4-ethylphenol (2) can be prepared by reacting 4-ethylphenol (1) with a chlorinating agent.

[0029] Compound 9 is disclosed:

[0030] Disclosed is a method for preparing compound 9 by reacting (R)-4-chloro-3-hydroxybutyronitrile with one or both of a catalyst and a reducing agent and Boc anhydride to provide compound 9.

[0031] Reducing agents can be used to prepare compound 9.

[0032] The reducing agent may be lithium aluminum hydride, sodium borohydride, or hydrogen, or any combination thereof.

[0033] The catalyst can be used to prepare compound 9.

[0034] The catalyst may comprise Raney nickel, Raney cobalt or nickel chloride, or any combination thereof.

[0035] Compound 9 can be prepared using both a catalyst and a reducing agent.

[0036] The catalyst may be nickel chloride, and the reducing agent may be sodium borohydride.

[0037] Disclosed is a method for preparing a compound of formula 11, wherein the method comprises reacting a compound of formula 10 with a compound of formula NHR in the presence of BINAP and palladium acetate. 4 R 5 The amine reaction proceeds; in X is a halogen; R 2 and R 3 are independently alkyl, haloalkyl or aryl, all of which are optionally substituted with one or more R 6 replace; R 4 and R 5 are independently selected from H, alkyl, haloalkyl and aryl, all of which are optionally substituted with one or more R 6 Replacement; or R 4 and R 5 together with the nitrogen to which they are attached, form a ring containing from 2 to 12 carbon atoms, wherein the ring optionally contains one or more double or triple bonds, and wherein the ring is optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; Each R 6 are independently hydrogen, halogen, cyano, nitro, -SF5, hydroxyl, amino, -NR 9 R 10 、C(O)NR 9 R 10 , C1-C6 haloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C4 haloalkylsulfanyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, O(C1-C4 haloalkyl), -C(O)C1-C4 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, or C2-C4 alkylcarbonyl; and R 9 and R 10 are independently hydrogen, cyano, C1-C3 alkoxy or C1-C6 alkyl.

[0038] X can be chlorine or bromine.

[0039] X may be bromine.

[0040] R 4 and R 5 May contain NH or NH2 groups.

[0041] NHR 4 R 5 The compound may be piperazine.

[0042] Disclosed is a method for preparing a compound of formula 13 by reacting compound 12: Compound 12 is reacted with sodium borohydride and an organic acid anhydride (15) in the presence of nickel (II) chloride, wherein R 7 It is a C1 to C4 alkyl group.

[0043] Compound 5 is disclosed: or a salt thereof.

[0044] Compound 6 is disclosed: or a salt thereof.

[0045] Compound 7 or a salt thereof.

[0046] Disclosed is compound 7-HCl or a hydrate thereof.

[0047] Compound 14 is disclosed or a salt thereof.

[0048] Disclosed is a method for preparing compound 8, The method comprises: a) in the presence of a coupling agent, compound 7: or a salt thereof coupled with 1H-indole-2-carboxylic acid; and / or b) Compound 6 or a salt thereof with hydrochloric acid to provide compound 7 or a salt thereof; and / or c) optionally in the presence of a base, reacting compound 5: or its salt reacts with compound 9 wherein Boc represents tBuO(CO)-; and / or d) in the presence of a base, a diphosphine and Pd(OAc)2, compound 4: Reaction with piperazine to provide compound 5; and / or e) reacting 2-bromo-6-chloro-4-ethylphenol with iodomethane in the presence of a base; and / or f) reacting 2-chloro-4-ethylphenol with a brominating agent; and / or g) reacting 4-ethylphenol with a chlorinating agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] For a further understanding of the nature, objects and advantages of the present disclosure, reference should be made to the following detailed description read in conjunction with the following drawings, wherein like reference numerals represent like elements.

[0050] Figure 1 The synthetic route to compound 8 is shown (Scheme I).

[0051] Figure 2 A first synthetic route to compound 8 is shown (Scheme II).

[0052] Figure 3 A first synthetic route to compound 8 is shown (Scheme III). DETAILED DESCRIPTION

[0053] The compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0054] The terms "a / an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to").

[0055] Unless otherwise indicated herein, the recitation of numerical ranges is merely a shorthand way of referring individually to each separate value falling within the range, and each separate value is included within the specification as if it were individually recited. All endpoints of the ranges are included within the range and are independently combinable.

[0056] All methods described herein can be performed in a suitable order, unless otherwise indicated or the context clearly indicates otherwise. Unless otherwise required, the use of any and all embodiments, or exemplary language (for example, "such as") is intended only to better illustrate the present disclosure rather than to limit the scope of the present disclosure. All language in the specification should not be construed as indicating that any unclaimed element is essential for implementing the present disclosure used herein. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present disclosure belongs.

[0057] In addition, the present disclosure includes all variations, combinations, and permutations of incorporating one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other claim that is dependent on the same base claim. If elements are presented as a list, such as in the form of Markush groups, each subset of these elements is also disclosed, and any element can be removed from the group.

[0058] It is understood that all compounds include all possible isotopes of atoms present in the compound. Isotopes include atoms having the same atomic number but different mass numbers, which encompasses heavy isotopes and radioactive isotopes. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C. 13 C and 14 C. Thus, the compounds disclosed herein may include heavy isotopes or radioisotopes within the compound structure or as substituents attached to the compound structure. Examples of useful heavy isotopes or radioisotopes include 18 F. 15 N. 18 O. 76 Br, 125 I and 131 I. Formula I, its subformulae, and compounds thereof include all pharmaceutically acceptable salts of the formula I, its subformulae, and compounds thereof.

[0059] The term "substituted" means that any one or more hydrogens on a designated atom or group are replaced by a selection from an indicated group, provided that the normal valence of the designated atom is not exceeded. Combinations of substituents and / or variables are permitted, for example, if these combinations yield stable compounds or useful synthetic intermediates. A stable compound or a stable structure can be a compound having sufficient rigidity to withstand separation from a reaction mixture and subsequently formulated into an effective therapeutic agent. Unless otherwise indicated, the substituents or combinations of substituents described for a formula, subformula, or compound may also be used for any other formula, subform, or compound consistent with its valence, polarity, size, structure, and other parameters. Any substituent or combination of substituents described herein for one or more specific atoms may also be excluded as an option for replacing one or more hydrogens at the one or more specific atoms or a subset thereof.

[0060] "Substituted" means that the compound or group is substituted with at least one (e.g., 1, 2, 3 or 4) substituents other than hydrogen, said substituents being independently selected from halogen (-F, -Cl, -Br, -I), hydroxy (-OH), C1-C9 alkoxy, C1-C9 haloalkoxy, oxo (=O), nitro (-NO2), cyano (-CN), amino (-NR2, wherein each R is independently hydrogen or C1-C 10 alkyl), azido (-N3), amidino (-C(=NH)NH2), hydrazine (-NHNH2), hydrazono (-C(=NNH2)-), carbonyl (-C(=O)-), carbamoyl (-C(O)NH2), sulfonyl (-S(=O)2-), mercapto (-SH), thiocyanato (-SCN), tosyl (CH3C6H4SO2-), carboxylic acid (-C(=O)OH), C1-C6 carboxylic acid alkyl ester (-C(=O)OR, wherein R is C1-C 10 alkyl), carboxylate (-C(=O)OM), wherein M is an organic or inorganic anion, sulfonic acid (-SO3H2), sulfonic acid monosalt or disalt (-SO3MH or -SO3M2, wherein M is an organic or inorganic anion), phosphoric acid (-PO3H2), phosphoric acid monosalt or disalt (-PO3MH or -PO3M2, wherein M is an organic or inorganic anion), C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C2-C 12 Alkenyl, C5-C 12 Cycloalkenyl, C2-C 12 Alkynyl, C6-C 12 Aryl, C7-C 13 Arylalkylene, C4-C 12 Heterocycloalkyl and C3-C 12 Heteroaryl groups, provided that the normal valence of the substituted atom is not exceeded.

[0061] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.

[0062] "Alkyl" refers to a radical derived from a straight or branched chain saturated aliphatic hydrocarbon having the specified number of carbon atoms and a valence of 1, which, where indicated, is optionally substituted with one or more substituents, provided that the valence of the alkyl group is not exceeded.

[0063] "Cycloalkyl" refers to a group containing one or more saturated and / or partially saturated rings, wherein all ring members are carbon and the group has the specified number of carbon atoms. Cycloalkyl groups do not include aromatic or heterocyclic rings.

[0064] "Alkanoyl" refers to a group having the formula "alkyl-C(=O)-", wherein "alkyl" has the same meaning as above.

[0065] "Cycloalkanoyl" refers to a group having the formula "cycloalkyl-C(=O)-", wherein "cycloalkyl" is as defined above.

[0066] "Aryl" refers to a cyclic group in which all ring members are carbon and all rings are aromatic, the group having the specified number of carbon atoms and a valence of 1, which, where indicated, is optionally substituted with one or more substituents, provided that the valence of the aryl group is not exceeded. More than one ring may be present, and any additional rings may be fused, pendant, spirocyclic, or a combination thereof.

[0067] "Heteroaryl" means a monovalent carbocyclic group comprising one or more aromatic rings, wherein at least one ring member (e.g., one, two, or three ring members) is a heteroatom selected from nitrogen (N), oxygen (O), sulfur (S), and phosphorus (P), and the group has the specified number of carbon atoms.

[0068] "Halogen" means fluorine, chlorine, bromine, or iodine, and is defined herein to include all isotopes thereof, including heavy isotopes and radioactive isotopes. Examples of useful halogen isotopes include 18 F. 76 Br and 131 I. Additional isotopes will be readily appreciated by those skilled in the art.

[0069] The compound of formula can contain one or more asymmetric elements, such as stereocenters, stereoaxes, etc., such as asymmetric carbon atoms, so that the compound can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can also be mixtures of diastereomers. For compounds with an asymmetric center, all optical isomers and mixtures thereof in pure form are included. In these cases, a single enantiomer, i.e., an optically active form, can be synthesized by asymmetric synthesis, from optically pure precursors, or obtained by the resolution of a racemate. The resolution of a racemate can, for example, also be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, such as using a chiral HPLC column. All forms are contemplated herein, regardless of the method used to obtain these forms.

[0070] All forms of the active agents (eg, hydrates, optical isomers, enantiomeric forms, polymorphs, free compounds, and salts) can be used alone or in combination.

[0071] The term "chiral" refers to a molecule that has the property of being non-superimposable on its mirror image partner.

[0072] "Stereoisomers" are compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0073] "Diastereoisomers" are stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, e.g., melting points, boiling points, spectroscopic properties, and reactivity. Mixtures of diastereoisomers can be separated by high-resolution analytical procedures, such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, e.g., using a chiral HPLC column.

[0074] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. A 50:50 mixture of enantiomers refers to a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselectivity or stereospecificity.

[0075] Stereochemical definitions and conventions used herein generally follow those of S. P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign with which the compound rotates plane-polarized light, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory.

[0076] A "racemic mixture" or "racemate" is an equimolar (or 50:50) mixture of two enantiomers that is optically inactive. A racemic mixture can occur in a chemical reaction or process without stereoselectivity or stereospecificity. The present disclosure also provides combinations of the two enantiomers other than a 50:50 racemic mixture, such as 1:10,000, 1:1,000, 1:100, 1:10, 1:9, 1:7.5, 1:5, 1:3, 1:2.5, 1:2, or 1:1.5, or any reverse ratio, or any intermediate ratio.

[0077] "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its inorganic and organic, non-toxic, acid or base addition salts. The salts of the disclosed compounds can be synthesized from the parent compound containing an alkaline or acidic portion by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions can be carried out in water or in an organic solvent or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used where feasible. The salts of the disclosed compounds also include solvates of the compounds and compound salts.

[0078] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts and quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic acid salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n -COOH (wherein n is 0-4), etc. Any suitable pharmaceutically acceptable salt may be used.

[0079] like Figure 1 As shown, 4-ethylphenol 1 can be chlorinated under conditions known to those of ordinary skill in the art, for example, with sulfuryl chloride, thereby providing 2-chloro-4-ethylphenol 2. The reaction conditions can be varied according to methods known to those of ordinary skill in the art.

[0080] Compound 2 can be brominated using N-bromosuccinimide to provide 2-bromo-6-chloro-4-ethylphenol 3. Compound 3 can then be methylated using iodomethane to provide anisole 4, optionally with a base to neutralize the hydrogen iodide.

[0081] The C-Br bond of compound 4 can react selectively with piperazine in the presence of a palladium catalyst to provide anisole 5.

[0082] Anisole 5 can be reacted with chiral chlorohydrin 9 under basic conditions to provide alcohol 6, where Boc represents tert-butyloxycarbonyl.

[0083] The tert-butyl carbonate (Boc) protecting group of compound 6 can be removed under acidic conditions, for example, using hydrogen chloride, thereby generating amine 7 or its acid salt.

[0084] Amine 7 can be condensed with 1H-indole-2-carboxylic acid using a coupling agent to produce compound 8 or a salt thereof. Coupling agents include, for example, carbonyldiimidazole, dialkylcarbodiimide, or a salt thereof.

[0085] Compound 9 is disclosed:

[0086] Disclosed is a method for preparing compound 9, which is carried out by reacting (R)-4-chloro-3-hydroxybutyronitrile with one or both of a catalyst and a reducing agent and Boc anhydride to provide compound 9. The reducing agent can be used to prepare compound 9. The reducing agent can be, for example, lithium aluminum hydride, sodium borohydride or hydrogen, or any combination thereof. The hydrogen can be hydrogen gas. The catalyst can be used to prepare compound 9. Compound 9 can be prepared using both a catalyst and a reducing agent. The catalyst can be, for example, nickel chloride, and the reducing agent can be, for example, sodium borohydride. The reducing agent, catalyst, etc. described for producing compound 9 can be used to produce compound 7 from compound 14, and vice versa. The choice of reducing agent, catalyst, etc. can affect the yield. Compound 9 can be used to synthesize pharmaceutical compounds and salts thereof, for example, dopamine receptor targeting compounds, such as compound 8. Compound 9 can also be used to synthesize other classes of drugs, such as statins, such as atorvastatin, pravastatin, rosuvastatin, fluvastatin or cerivastatin, or any combination thereof.

[0087] Disclosed is a method for synthesizing a compound of Formula 11 from a compound of Formula 10: in: X is a halogen; R 2 and R 3 are independently alkyl, haloalkyl or aryl, all of which are optionally substituted with one or more R 6 replace; R 4 and R 5 are independently selected from H, alkyl, haloalkyl and aryl, all of which are optionally substituted with one or more R 6 Replacement; or R 4 and R 5 Together with the nitrogen to which they are attached they form a ring containing 2 to 12 carbon atoms, wherein the ring optionally contains one or more double or triple bonds and the ring is optionally interrupted by one or more oxygen, nitrogen or sulfur atoms. Each R 6 are independently hydrogen, halogen, cyano, nitro, -SF5, hydroxyl, amino, -NR 9 R 10 、C(O)NR 9 R 10, C1-C6 haloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C4 haloalkylsulfanyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, O(C1-C4 haloalkyl), -C(O)C1-C4 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, or C2-C4 alkylcarbonyl. R 9 and R 10 are independently hydrogen, cyano, C1-C3 alkoxy or C1-C6 alkyl.

[0088] R 4 and R 5 It may be substituted with NH or NH2 groups.

[0089] The reaction can be carried out in a solvent, such as a non-polar solvent. Typical solvents include alkanes or aromatic solvents. For example, some non-halogenated solvents, such as aromatic solvents, can be used. Such solvents include, for example, benzene, toluene, o-xylene, m-xylene, p-xylene or chlorobenzene, or a combination thereof.

[0090] Amine HNR 4 R 5 The molar ratio to compound 10 can be 10:1 to 2:1, 9:1 to 2:1, 8:1 to 2:1, 7:1 to 2:1, 6:1 to 2:1, 5:1 to 2:1, 4:1 to 2:1, 3:1 to 2:1, 8:1 to 3:1, or 6:1 to 5:1.

[0091] The reaction can be carried out in the presence of a base, for example, a tertiary amine base (e.g., triethylamine), or an alkoxide base, for example, tert-butoxide, isopropoxide, ethanolate, etc. In one embodiment, the molar ratio of the base to compound 10 can be 10:1 to 1:1, 9:1 to 1:1, 8:1 to 1:1, 7:1 to 1:1, 6:1 to 1:1, 5:1 to 1:1, 4:1 to 1:1, 3:1 to 1:1, or 2:1 to 1:1.

[0092] A ligand called BINAP can be used in this reaction. BINAP is an acronym or abbreviation of ([1,1′-binaphthyl]-2,2′-diyl)bis(diphenylphosphine). Other phosphorus ligands may also be used, such as those known to those of ordinary skill in the art, including, but not limited to: 1,1-bis(diphenylphosphino)methane (dppm); 1,2-bis(dimethylphosphino)ethane (dmpe); 1,2-bis(diisopropylphosphino)ethane (dippe); 1,2-bis(diphenylphosphino)benzene (dppbz); 1,2-bis(diphenylphosphino)ethane (dppe); a derivative of phenylanisylmethylphosphine (DIPAMP); bis(dicyclohexylphosphino)ethane (dcpe); 1,3-bis(diphenylphosphino)propane (dppp); 1,4-bis(diphenylphosphino)butane (dppb); (S,S)-DIOP (O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane) (DIOP); 2,3-bis(diphenylphosphino)butane (Chir aphos); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (Xantphos); bis[(2-diphenylphosphino)phenyl]ether (DPEphos); 4,4,4',4',6,6'-hexamethyl-2,2'-spiroditryptamine-8,8'-diylbis(diphenylphosphine) (SPANphos); 4,4'-bis-1,3-benzodioxole-5,5'- Dimethylbis(diphenylphosphine) (SEGPHOS); 1,1'-bis(diphenylphosphino)ferrocene (dppf); 1,2-bis(2,5-dimethylphosphino)benzene (Me-DuPhos); (diphenylphosphino)ferrocenylethyldicyclohexylphosphine 1,5-diaza-3,7-diphosphacyclooctane (Josiphos); and 1,5-diaza-3,7-diphosphacyclooctane (P2N2).

[0093] Acetate palladium (II) and diphosphine ligand (for example BINAP) can be used in catalytic amount, for example, 0.0001 to 0.01 molar equivalent, and every kind of amount is selected independently of one another.In one embodiment, the amount of acetate palladium (II) and diphosphine ligand is 0.0001,0.0005,0.001,0.0015,0.002,0.0025,0.003,0.0035,0.004,0.0045,0.005,0.0055,0.006,0.0065,0.007,0.0075,0.008,0.0085,0.009,0.0095 or 0.01 molar equivalent independently.

[0094] Disclosed is a method for synthesizing a compound of Formula 13 from a compound of Formula 12:

[0095] R7 Can be C1 to C4 alkyl, for example, tert-butyl, isobutyl, sec-butyl, n-butyl, n-propyl, isopropyl, ethyl or methyl.Compound 12, i.e., (R)-4-chloro-3-hydroxybutyronitrile can be reacted with Lewis acid and borohydride in the presence of dialkyl dicarbonate, for example di-tert-butyl dicarbonate (also known as Boc anhydride).

[0096] The borohydride acts as a reducing agent for the nitrile associated with the Lewis acid and can be a conventional borohydride such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride, tetrabutylammonium borohydride, or another borohydride known to those of ordinary skill in the art. In one embodiment, the molar ratio of borohydride to nitrile is from about 3:1 to about 1.1:1, from about 2.9:1 to about 1.1:1, from about 2.8:1 to about 1.1:1, from about 2.7:1 to about 1.1:1, from about 2.6:1 to about 1.1:1, from about 2.5:1 to about 1.1:1, from about 2.4:1 to about 1.1:1, from about 2.3:1 to about 1.1:1, from about 2.2:1 to about 1.1:1. 1, about 2.1:1 to about 1.1:1, about 2:1 to about 1.1:1, about 1.9:1 to about 1.1:1, about 1.8:1 to about 1.1:1, about 1.7:1 to about 1.1:1, about 1.6:1 to about 1.1:1, about 1.5:1 to about 1.1:1, about 1.4:1 to about 1.1:1, about 1.3:1 to about 1.1:1, or about 1.2:1 to about 1.1:1.

[0097] The Lewis acid associated with the borohydride may comprise a Group I (alkali) metal ion, a Group II (alkaline earth) metal ion, a Group III non-metal or metal atom, molecule or ion, and / or a third row transition metal ion, for example, Ti, V, Cr, Mn, Fe, Co, Ni, Cu and / or Zn. For example, such molecules comprising third row metal ions include TiCl4, FeCl3, CuCl2, CuCl, NiCl2, ZnCl2, etc., as known to those of ordinary skill in the art. In one embodiment, the molar ratio of Lewis acid to nitrile is from about 0.01:1 to about 0.9:1, from about 0.05:1 to about 0.9:1, from about 0.1:1 to about 0.9:1, from about 0.15:1 to about 0.9:1, from about 0.2:1 to about 0.9:1, from about 0.25:1 to about 0.9:1, from about 0.3:1 to about 0.9:1, from about 0.35:1 to about 0.9:1, from about 0.4:1 to about 0.9:1, from about 0.45:1 to about 0.9:1, from about 0.5:1 to about 0.9:1, from about 0.55:1 to about 0.9:1, from about 0.6:1 to about 0.9:1 1, about 0.65:1 to about 0.9:1, about 0.7:1 to about 0.9:1, about 0.75:1 to about 0.9:1, about 0.8:1 to about 0.9:1, or about 0.85:1 to about 0.9:1, about 0.1:1 to about 0.5:1, about 0.15:1 to about 0.5:1, about 0.2:1 to about 0.5:1, about 0.25:1 to about 0.5:1, about 0.3:1 to about 0.5:1, about 0.35:1 to about 0.5:1, about 0.4:1 to about 0.5:1, or about 0.45:1 to about 0.5:1, or about 0.1:1 to about 0.5:1.

[0098] The reaction can be carried out in a solvent, such as a hydroxyl solvent (e.g., alcohol). Typical solvents include alkyl alcohols, such as propanol, isopropanol, ethanol, and methanol. The reaction can be carried out under anhydrous conditions.

[0099] The present disclosure also provides a second route to compound 8, wherein the intermediate between compounds 5 and 7 is compound 14 instead of compound 6. This second route (Scheme II) is shown in Figure 2 .

[0100] The present disclosure also provides a third route to compound 8, wherein, as in Scheme II, the intermediate is compound 14 instead of compound 6, but different reagents are used to form compound 14. This third route (Scheme III) is shown in Figure 3For Schemes II and III, alternative or additional reducing agents and / or catalysts may be used, for example, those described in Scheme I, and one or more borane complexes, for example, borane-tetrahydrofuran complex, dimethyl sulfide borane, or N,N-diethylaniline borane, or any combination thereof. Example Example 1:

[0101] This example illustrates the reaction conditions for the first step in Schemes I-III, wherein compound 2 is formed from compound 2.

[0102] At 70 ° C, over 30 minutes, sulfonyl chloride (146 mL, 1.801 mol) in 600 mL of toluene was added dropwise to a toluene (1.2 L) solution of 4-ethylphenol (Compound 1, 200 g, 1.64 mol) and diisobutylamine (28.6 mL, 0.164 mol). The reaction mixture was heated at 70 ° C for 1 hour and cooled to room temperature, then diluted with 2 L of methyl tert-butyl ether. The mixture was transferred to 1 kg of ice and 1 L in a 12 L post-processing reactor. The resulting mixture was stirred at room temperature for 30 minutes. When GC-MS indicated that there was no product left, the aqueous layer was discarded. The combined organic phase was washed with brine (2x500 mL) and dried over Na2SO4. The solvent was removed under reduced pressure (15 Torr / 40 ° C) to obtain Compound 2 as a yellow oil, i.e., 2-chloro-4-ethylphenol (260 g, 93% pure / GC, 94% yield). Example 2

[0103] This example illustrates the reaction conditions for the second step of Schemes I-III, wherein compound 3 is formed from compound 2.

[0104] Under water cooling and below 35 ℃, to the acetonitrile (1.56L) solution of compound 2 (2-chloro-4-ethylphenol, 260g, 1.544mol) was added N-bromosuccinimide (275g, 1.544mol) in batches. A slight exotherm was observed. The mixture was stirred at room temperature overnight (20 hours) and then diluted with water (1000mL). The resulting mixture was extracted with 5x500mL hexane. The combined organic phase was first washed with 500mL brine, then with Na2S2O3 (saturated aqueous solution) 2x200mL and brine 3x500mL. The combined organic layer was dried over Na2SO4 (50g). The solvent was evaporated under reduced pressure (15 torr / 40℃) to obtain 2-bromo-6-chloro-4-ethylphenol 3 (320g, 88%) as a crude brown oil, which was used without further purification. Example 3

[0105] This example illustrates the reaction conditions for the third step of Schemes I-III, wherein compound 4 is formed from compound 3.

[0106] To a solution of 2-bromo-6-chloro-4-ethylphenol (compound 3, 320 g, 1.359 mol) in N,N-dimethylformamide (1440 mL) was added potassium carbonate (282 g, 2.038 mol) and iodomethane (127 mL, 2.038 mol) at room temperature under N2. The mixture was heated to 70°C for 4 hours. The reaction was cooled to room temperature and diluted with 3 L of water. The mixture was extracted with hexane (4 x 500 mL), the combined organic phases were washed with brine (3 x 500 mL) and dried over Na2SO4 (50 g), and the solvent was removed under reduced pressure (15 Torr / 40°C) to obtain 2-bromo-6-chloro-4-ethylanisole 4 (336 g, 99% yield). 1 H NMR (400MHz, CDCl3) δ7.28 (dd, J=2.1, 0.7Hz, 1H), 7.16 (dd, J=2.0, 0.7Hz, 1H), 3.87 (s, 3H), 2.57 (q, J=7.5Hz, 2H); 1.21 (t, J=7.6Hz, 3H) 13 C NMR (101MHz, CDCl3) δ151.22,142.43,131.34,129.19,128.83,118.20,60.78,28.00,15.38. Example 4

[0107] This example illustrates the reaction conditions for the fourth step of Schemes I-III, wherein compound 5 is formed from compound 4.

[0108] To a solution of 2-bromo-6-chloro-4-ethylanisole (200 g, 0.802 mol, 1 eq) in 1000 mL of toluene at room temperature with N inlet and mechanical stirring was added piperazine (414 g, 4.809 mol, 6 eq) and sodium tert-butoxide (139 g, 1.443 mol, 1.8 eq). The mixture was degassed for 10 minutes by bubbling N. 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (2.99 g, 4.81 mmol, 0.6% eq) and Pd(OAc) (0.344 g, 1.603 mmol, 0.2% eq) were added, and the resulting mixture was degassed for an additional five minutes. The mixture was heated to 90°C overnight, with a small stream of N bubbling throughout to exclude O. The reaction mixture was cooled to room temperature and subsequently diluted with toluene (1 L) and methyl tert-butyl ether (1 L). The mixture is filtered through diatomite and washed with methyl tert-butyl ether (3x500mL).The organic phase merging is washed with 4x500mL salt water and through Na SO Dry three hours.The organic phase of drying is transferred in 5L reactor and at room temperature drips the 3M HCl (267mL, 0.802mol, 1 equivalent) in cyclopentyl methyl ether.The mixture stirred at room temperature 1 hour.Filter precipitate and wash with methyl tert-butyl ether (3x500mL) and dry under high vacuum to obtain the pale solid (88% yield) of 205g compound 5. 1 H NMR(400MHz, CDCl3)δ9.94(s,2H),6.94(d,J=1.9Hz,1H),6.70(d,J=2.0Hz,1H), 3.83(s,3H),3.47(q,J=5.7Hz,9H),2.53(q,J=7.6Hz,2H),1.18(t,J=7.6Hz,3H); 13 C NMR (101MHz, CDCl3) δ146.85,144.21,141.53,128.80,124.70,117.47,60.02,47.85,43.96,28.54,15.48. Example 5

[0109] This example illustrates the reaction conditions for forming compound 9 from compound 12, which is used as the reactant in step 5 of Scheme 1. Sodium borohydride (27.7 g, 2.0 eq) was added portionwise to a mixture of (R)-4-chloro-3-hydroxybutyronitrile 12 (43 g, 41.8 mmol), Boc-anhydride (1.2 eq), and NiCl2 (0.1 eq) in MeOH (800 mL). The mixture was cooled with an ice-salt bath (-10 to -15°C, external temperature) to maintain the internal reaction temperature below 17°C. The reaction was stirred at room temperature overnight. GCMS analysis of the reaction mixture showed approximately 6-7% of compound 12 remaining. The mixture was cooled again with an ice-water bath and more NaBH4 (3.8 g) was added. The reaction was stirred at room temperature for an additional 6 hours until GC-MS showed no starting material. The reaction was cooled to 5°C and 1N HCl (~850 mL) was added to reach pH 3. The mixture was extracted with methyl tert-butyl ether, washed with 0.3N HCl, water, and salt water, dried and concentrated to obtain (R)-(4-chloro-3-hydroxybutyl) tert-butyl carbamate (57g, 255mmol, 70.8% yield), which was a light yellow oil. The crude product was processed with imidazoles (0.4eq) in ethanol, diluted with water and extracted with MTBE. After removing the solvent, (R)-(4-chloro-3-hydroxybutyl) tert-butyl carbamate 9 was isolated, 96.4% by weight being pure. 1 H NMR (400 MHz, chloroform-d) δ 4.90 (s, 1H), 3.87 (dq, J = 10.0, 5.0, 4.1 Hz, 1H), 3.62–3.39 (m, 3H), 3.18 (dq, J = 14.6, 5.4 Hz, 1H), 1.84–1.68 (m, 1H), 1.66–1.54 (m, 1H), 1.44 (s, 9H), 13 C NMR (101 MHz, chloroform-d) δ 156.90, 79.75, 69.04, 49.56, 37.07, 34.78, 28.36. Alternative Example 5

[0110] To a 12 L four-necked flask equipped with a mechanical stirrer and a reflux condenser was added (R)-4-chloro-3-hydroxybutyronitrile (200 g, 1.673 mol, 1.0 eq), followed by methanol (4000 ml), Boc anhydride (548 ml, 2.51 mol, 1.5 eq), and nickel(II) chloride (19.51 g, 151 mmol, 0.09 eq). The reaction mixture was cooled to 0°C (-10 to -15°C, external temperature), and then NaBH4 (190 g, 5.019 mol, 3.0 eq) was added portionwise to maintain the internal temperature below 5°C (typically, this process was performed by observing the evolution of H2 gas; 7-8 g of NaBH4 constituted a portion; after each portion was added, 10-15 minutes were allowed until the internal temperature cooled back to 0°C). The entire amount of NaBH4 was added over 3.5 hours. The reaction was allowed to warm to room temperature and stirred at 22°C over the weekend; the reaction progress was monitored by GCMS. The reaction mixture was cooled to 0°C with an ice bath and diluted with 1.5L methyl tert-butyl ether; 20% citric acid solution (1000mL) was added until pH=4.05. Methyl tert-butyl ether (850mL) was added to the mixture, which was transferred to a 12L separation reactor, followed by addition of water (2L). The organic layer was separated and the aqueous layer was extracted with methyl tert-butyl ether (800mL×2). The combined organic layers were washed with 20% citric acid (500mL), water (500mL), saturated NaHCO3 aqueous solution (500mL), brine (500mL), dried over Na2SO4, filtered, and concentrated under reduced pressure at 40°C to obtain crude (R)-(4-chloro-3-hydroxybutyl)carbamic acid tert-butyl ester as a light yellow oil. The crude product was treated with imidazole (45.6g, 0.669mol, 0.4 equivalents) in methyl tert-butyl ether (2L) containing 10% ethanol and stirred at room temperature for 3 hours. The reaction mixture was washed with brine (3 x 300 mL).The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to give tert-butyl (R)-(4-chloro-3-hydroxybutyl)carbamate 9, 96.4 wt% pure (195 g, 52.1%). Example 6

[0111] This example illustrates the reaction conditions of the fifth step of Scheme 1, wherein compound 6 is formed from compound 5.

[0112] Under N₂ at room temperature, potassium carbonate (350 g, 2532 mmol, 2.5 eq) was added portionwise to a mixture of 1-(3-chloro-5-ethyl-2-methoxyphenyl)-piperazine 5 hydrochloride (295 g, 1013 mmol, 1 eq) in 90% EtOH / 10% aqueous solution (3000 mL). The mixture was stirred at room temperature for 30 minutes. Then, tert-butyl (R)-(4-chloro-3-hydroxybutyl)carbamate 9 (378 g, 1519 mmol, 1.5 eq, 90 wt%) was added. The mixture was heated to reflux overnight. The reaction vessel was cooled to room temperature and diluted with 6 L of methyl tert-butyl ether and 6 L of water. The organic layer was washed with brine 3×1000 mL, dried over Na 2 SO 4 , and all solvents were removed by reduced pressure (40° C., 15 Torr) and the remaining brown oil was placed under high vacuum (0.5 Torr) overnight to give 578.89 g of brown oil containing crude compound 6 (129%). Example 7

[0113] This example illustrates the reaction conditions for forming the hydrochloride salt of compound 6 as the reactant in step 6 of Scheme 1.

[0114] To a solution of (R)-tert-butyl(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)-piperazin-1-yl)-3-hydroxybutyl)carbamate 6 (crude, 579 g, 1310 mmol, 1 eq) in methyl tert-butyl ether (5800 mL) was added 3N HCl in cyclopentyl methyl ether (437 mL, 1310 mmol, 1 eq) dropwise over 42 minutes at 2-5°C. The reaction was stirred at this temperature for 30 minutes. The resulting precipitate was filtered under N2, the solid washed with 3 x 1000 mL of methyl tert-butyl ether, and the collected solid slurried in 4000 mL of methyl tert-butyl ether for 3 hours, filtered again under N2, and dried under high vacuum to afford 435 g (69.4%) of 6-HCl as an off-white solid. Example 8

[0115] This example illustrates the reaction conditions of the sixth step of Scheme 1, wherein compound 7 is formed from the hydrochloride salt of compound 6.

[0116] The HCl salt of tert-butyl (R)-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)-piperazin-1-yl)-3-hydroxybutyl)carbamate, 6-HCl (427 g, 171 mmol, 1 eq) was dissolved in 4270 mL of 10% MeOH in toluene (10 volumes), and 3M HCl in cyclopentyl methyl ether (744 mL, 2231 mmol, 2.5 eq) was added dropwise over 40 minutes at room temperature. The mixture was stirred at room temperature overnight. After LCMS showed the disappearance of tert-butyl (R)-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)carbamate, 6-HCl, the precipitate was filtered under N2. The solid was washed with 10% MeOH in toluene (2 x 1000 mL) and then with tert-butyl methyl ether (3 x 1000 mL). The crude solid was then slurried in methyl tert-butyl ether (4 L) containing 10% MeOH overnight. The precipitate was filtered and washed with 2x1000 mL of methyl tert-butyl ether containing 10% methanol and 3x1000 mL of methyl tert-butyl ether. The solid was filtered overnight under N2. The gray solid was dried under high vacuum to obtain 373 g of 7-HCl, i.e., (R)-4-amino-1-(4-(3-chloro-5-ethyl-2-methoxyphenyl)-piperazine-1-yl)-2-butanol, 3-HCl (93%). 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.19(d,J=5.9Hz,3H),6.94(d,J=1.8Hz,1H),6.77(d,J=2.0Hz,1H),4.21(q,J=8.7Hz,1H),3.58(q,J =12.5,11.2Hz,5H),3.34–3.11(m,6H),3.14–3.02(m,1H),2.96–2.78(m,3H),2.57–2.45(m,3H),1.80–1.60(m,2H),1.13(t,J=7.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ146.12,144.92,141.51,127.72,122.97,117.81,62 .52,61.24,59.42,53.03,51.43,46.87,46.80,36.05,32.83,28.07,15.89. Example 9

[0117] This example illustrates the reaction conditions for the seventh step of Schemes I-III, wherein compound 8 is formed from compound 7.

[0118] A mixture of carbonyldiimidazole (CDI, 154 g, 951 mmol, 1.15 eq) and 1H-indole-2-carboxylic acid (1-2COOH, 153 g, 951 mmol, 1.15 eq) in 1800 mL of anhydrous N,N-dimethylformamide (9 L) was stirred at room temperature for 3 hours. Diisopropylethylamine (DIPEA, 589 mL, 3306 mmol, 4 eq) was added to the mixture under N₂ at room temperature, followed by the addition of (R)-4-amino-1-(4-(3-chloro-5-ethyl-2-methoxyphenyl)-piperazin-1-yl)-butan-2-ol and 3-HCl (7-HCl, 373 g, 827 mmol, 1 eq) in portions over 5 minutes. A slight exotherm was observed. The reaction mixture was stirred at room temperature overnight. Water (1800 mL) was added dropwise over 45 minutes to precipitate a solid, which was then stirred for an additional 30 minutes before being filtered. The precipitate was washed with 2 x 1000 mL of water containing 50% N,N-dimethylformamide and 4 x 1000 mL of water. The crude wet solid was added to 3600 mL of MeOH and treated with 276 mL of 3NNaOH (827 mmol, 1 eq). The resulting mixture was stirred at room temperature for 3 hours. Water (3600 mL) was added dropwise over 50 minutes, and the mixture was stirred for an additional 30 minutes. The resulting precipitate was then filtered and washed with water containing 50% MeOH (2 x 1000 mL) and water (4 x 1000 mL). The precipitate was filtered and dried overnight under N2 using a Buchner filtration system. The solid was then dried under high vacuum overnight to afford (R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)-piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide 8 (322 g, 80%) as a grey solid with a purity of 98.87% (290 nm). 1H NMR (400MHz, DMSO-d6) δ11.52(d,J=2.2Hz,1H),8.43(t,J=5.7Hz,1H),7.58(d,J=8.0Hz,1H),7.40(d,J=8.2Hz,1H),7.18–7. 10(m,1H),7.10–7.05(m,1H),7.00(dd,J=7.9,6.7Hz,1H),6.85(d,J=1.9Hz,1H),6.67(d,J=2.0Hz,1H),4.48(d,J=4.5Hz,1H ),3.78–3.71(m,1H),3.71(s,3H),3.39(ddq,J=37.9,12.7,7.1,6.2Hz,2H),3.01(t,J=4.9Hz,4H),2.57(t,J=4.7Hz,4H),2. 54–2.43(m,3H),2.34(qd,J=12.5,6.2Hz,2H),1.79(dtd,J=16.0,7.7,3.3Hz,1H),1.59–1.46(m,1H),1.11(t,J=7.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ161.57,146.14,144.92,141.49,136.83,132.28,127.72,127.49,123.64,122.96,121.8 5,120.11,117.81,112.70,103.29,62.88,61.38,59.42,53.12,51.38,46.93,46.84,35.56,35.31,28.08,15.88. Example 10

[0119] This example illustrates the reaction conditions for the fifth step of Scheme II, wherein compound 14 is formed from compound 5.

[0120] Under stirring at room temperature, (S)-epichlorohydrin (46 mL, 589 mmol, 1.5 eq) was added to a mixture of 1-(3-chloro-5-ethyl-2-methoxyphenyl)piperazine 5 (100 g, 393 mmol, 1 eq) and NaHCO (99 g, 1178 mmol, 3 eq) in 1000 mL of EtOH. The reaction mixture was stirred at room temperature overnight until all starting material disappeared by LCMS. Sodium cyanide (57.7 g, 1178 mmol, 3 eq) in 500 mL of water was added in one go. The mixture was heated to 40 ° C and kept overnight. The reaction mixture was cooled to room temperature and the total volume was diluted to 3000 mL by adding water (1500 mL). The mixture was extracted with ethyl acetate (2 x 1000 mL). The combined organic phases were washed with brine (3 x 500 mL) and dried over Na SO. The solvent was evaporated under reduced pressure to obtain 140 g (106%) of a brown oil. After flash column, 113.9 g (86%) of a clear oil was obtained. 1 H NMR (400MHz, chloroform-d) δ6.86(d,J=2.0Hz,1H),6.61(d,J=2.1Hz,1H),4.07–3.96(m,1H),3.83(s,3H),3.68(s,1H),3.15(td,J=1 9.2,18.1,8.5Hz,4H),2.82(dt,J=10.2,4.7Hz,2H),2.62(dd,J=16.7,5.7Hz,2H),2.60–2.47(m,5H),1.20(t,J=7.6Hz,3H). 13 CNMR (101 MHz, chloroform-d) δ 146.56, 146.02, 141.05, 128.44, 122.66, 117.14, 116.86, 62.78, 62.55, 59.25, 50.45, 28.60, 23.42, 15.56. Example 11

[0121] This example illustrates the reaction conditions for the fifth step of Scheme III, wherein compound 15 is formed from compound 5.

[0122] Sodium bicarbonate (33 mg, 0.393 mmol, 2 eq) was added to a 3 mL ethanol solution of 1-(3-chloro-5-ethyl-2-methoxyphenyl)-piperazine (50 mg, 0.196 mmol, 1 eq) and (R)-4-chloro-3-hydroxybutyronitrile (235 mg, 1.96 mmol, 10 eq). The mixture was heated to 75 ° C and maintained for 36 hours. The reaction was tracked by LCMS. When compound 5 was completely consumed, the mixture was cooled to room temperature and 6 mL of water was added. It was extracted with MTBE (3x5 mL). The combined organic phases were washed with brine (3x5 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by ISCO to obtain 53 mg (80%) of brown oil. 1 H NMR (400MHz, chloroform-d) δ6.86(d,J=2.0Hz,1H),6.61(d,J=2.1Hz,1H),4.07–3.96(m,1H),3.83(s,3H),3.68(s,1H),3.15(td,J=1 9.2,18.1,8.5Hz,4H),2.82(dt,J=10.2,4.7Hz,2H),2.62(dd,J=16.7,5.7Hz,2H),2.60–2.47(m,5H),1.20(t,J=7.6Hz,3H). 13 CNMR (101 MHz, chloroform-d) δ 146.56, 146.02, 141.05, 128.44, 122.66, 117.14, 116.86, 62.78, 62.55, 59.25, 50.45, 28.60, 23.42, 15.56. Example 12

[0123] This example illustrates the reaction conditions for the sixth step of Schemes II and III, wherein compound 7 is formed from compound 14.

[0124] Compound 14 (8.1 g, 24 mmol) was dissolved in 100 mL of 7N NH3 methanol and Raney Ni (1 g, wet) was added. The mixture was hydrogenated at 50 psi at room temperature overnight. LCMS analysis revealed only 15% conversion. The mixture was hydrogenated continuously at 50 psi at 40°C for 48 hours. The solvent was removed under reduced pressure. The crude oil was purified by ISCO to obtain 4.5 g (55%) of a light-colored oil. Alternative Example 12

[0125] This example illustrates the reaction conditions for the sixth step of Schemes II and III, wherein compound 7 is formed from compound 14.

[0126] Over 15 minutes, (R)-4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyronitrile 14 (1 g, 2.96 mmol, 1 eq) in 10 mL of THF was added to a solution of LiAlH4 (5.92 mL, 5.92 mmol, 1 M in THF, 2 eq) in 15 mL of THF via a syringe pump. The reaction temperature was slightly shifted to -5°C. After checking by LCMS, the reaction mixture still contained approximately 20% of compound 14, at which point another equivalent of LAH in THF was added. After 30 minutes, the mixture was quenched with 5 N NaOH, the solid residue was washed with 2 x 15 mL of MeOH, and the filtrate was evaporated under reduced pressure to give a brown oil (1.012 g). This was used directly in the next reaction.

[0127] Any combination of the disclosed features herein is considered part of the present disclosure. Each element described herein, or two or more together, is also within the scope of the present disclosure. All references cited in this specification are incorporated herein by reference as if each reference was specifically and individually indicated to be incorporated herein by reference.

Claims

1. A method for preparing compound 8, The method comprises: In the presence of a coupling agent, compound 7: or its salt is coupled with 1H-indole-2-carboxylic acid, wherein compound 7 is prepared by one or both of the following methods: Compound 6 or a salt thereof with hydrochloric acid to provide compound 7 or a salt thereof; and Compound 14 or a salt thereof with one or both of a catalyst and a reducing agent to provide compound 7 or a salt thereof, and Among them, compound 6 is prepared by making compound 5: or its salt is prepared by reacting with compound 9, Boc represents tBuO(CO)- group:

2. The method according to claim 1, wherein Compound 7 is prepared by making compound 6: or a salt thereof with hydrochloric acid to provide compound 7 or a salt thereof; and Compound 6 is prepared by making compound 5: or its salt is prepared by reacting with compound 9, Boc represents tBuO(CO)- group:

3. The method according to claim 1 or 2, wherein Compound 9 is prepared by reacting (R)-4-chloro-3-hydroxybutyronitrile with one or both of a catalyst and a reducing agent and Boc anhydride to provide Compound 9.

4. The method of claim 3, wherein a reducing agent is used to prepare compound 9.

5. The method according to claim 4, wherein: The reducing agent includes lithium aluminum hydride, sodium borohydride or hydrogen, or any combination thereof.

6. The method according to claim 3, wherein: The catalyst was used to prepare compound 9.

7. The method according to claim 6, wherein: The catalyst comprises Raney nickel, Raney cobalt or nickel chloride, or any combination thereof.

8. The method of claim 3, wherein: Both the catalyst and the reducing agent were used to prepare compound 9.

9. The method of claim 1, wherein: Compound 7 is prepared by making compound 14 or a salt thereof with one or both of a catalyst and a reducing agent to provide compound 7 or a salt thereof.

10. The method of claim 9, wherein: A reducing agent was used to prepare compound 7 from compound 14.

11. The method according to claim 10, wherein: Reducing agents include lithium aluminum hydride, borane complexes, sodium borohydride, or hydrogen, or any combination thereof.

12. The method of claim 9, wherein: The catalyst was used to prepare compound 7 from compound 14.

13. The method of claim 12, wherein: The catalyst comprises Raney nickel, Raney cobalt or nickel chloride, or any combination thereof.

14. The method of claim 9, wherein: Compound 14 was prepared by one or both of the following methods: Make compound 5: or its salt with (S)-epichlorohydrin and cyanide or its salt; and Make compound 5: or its salts and (R)-4-chloro-3-hydroxybutyronitrile.

15. The method of claim 14, wherein: Compound 14 is prepared by making compound 5: or its salt with (S)-epichlorohydrin and cyanide or its salt to prepare the same.

16. The method of claim 14, wherein: Compound 14 is prepared by making compound 5: or its salt is reacted with (R)-4-chloro-3-hydroxybutyronitrile to prepare the product.

17. A method as claimed in any preceding claim, wherein: Compound 5 is prepared by reacting compound 4 in the presence of a base, a diphosphine and Pd(OAc)2: Prepared by reaction with piperazine to provide compound 5.

18. A method as claimed in any preceding claim, wherein Compound 5 is prepared by reacting 2-bromo-6-chloro-4-ethylphenol with iodomethane in the presence of a base.

19. The method of claim 18, wherein: 2-Bromo-6-chloro-4-ethylphenol is prepared by reacting 2-chloro-4-ethylphenol with a brominating agent.

20. The method of claim 19, wherein: The brominating agent was N-bromosuccinimide (NBS).

21. The method of any one of claims 19 or 20, wherein 2-Chloro-4-ethylphenol is prepared by reacting 4-ethylphenol with a chlorinating agent.

22. Compound 9 23. A method for preparing compound 9, the method being carried out by reacting (R)-4-chloro-3-hydroxybutyronitrile with one or both of a catalyst and a reducing agent and Boc anhydride to provide compound 9.

24. The method of claim 23, wherein: A reducing agent was used to prepare compound 9.

25. The method of claim 24, wherein: The reducing agent includes lithium aluminum hydride, sodium borohydride or hydrogen, or any combination thereof.

26. The method of claim 23, wherein: The catalyst was used to prepare compound 9.

27. The method of claim 23, wherein: The catalyst comprises Raney nickel, Raney cobalt or nickel chloride, or any combination thereof.

28. The method of claim 23, wherein: Both the catalyst and the reducing agent were used to prepare compound 9.

29. A method for preparing a compound of formula 11, said method comprising reacting a compound of formula 10 with a compound of formula NHR in the presence of BINAP and palladium acetate. 4 R 5 The amine reaction proceeds: in: X is a halogen; R 2 and R 3 are independently alkyl, haloalkyl or aryl, all of which are optionally substituted with one or more R 6 replace; R 4 and R 5 are independently selected from H, alkyl, haloalkyl and aryl, all of which are optionally substituted with one or more R 6 Replacement; or R 4 and R 5 together with the nitrogen to which they are attached, form a ring containing from 2 to 12 carbon atoms, wherein the ring optionally contains one or more double or triple bonds, and wherein the ring is optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; Each R 6 are independently hydrogen, halogen, cyano, nitro, -SF5, hydroxyl, amino, -NR 9 R 10 、C(O)NR 9 R 10 , C1-C6 haloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C4 haloalkylsulfanyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, O(C1-C4 haloalkyl), -C(O)C1-C4 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, or C2-C4 alkylcarbonyl; and R 9 and R 10 are independently hydrogen, cyano, C1-C3 alkoxy or C1-C6 alkyl.

30. The method of claim 29, wherein: X is chlorine or bromine.

31. The method of claim 29, wherein: X is bromine.

32. The method of claim 29, wherein: R 4 and R 5 Contains NH or NH2 groups.

33. The method of claim 29, wherein: NHR 4 R 5 The compound is piperazine.

34. A method for preparing a compound of formula 13 by reacting compound 12: in, Compound 12 reacts with sodium borohydride and anhydride in the presence of nickel(II) chloride, wherein R 7 It is a C1 to C4 alkyl group.

35. Compound 5 or a salt thereof.

36. Compound 6 or a salt thereof.

37. Compound 7 or a salt thereof.

38. Compounds or a hydrate thereof.

39. Compound 14 or a salt thereof.

40. A method for preparing compound 8 The method comprises: a) in the presence of a coupling agent, compound 7: or a salt thereof coupled with 1H-indole-2-carboxylic acid; and / or b) Compound 6 or a salt thereof with hydrochloric acid to provide compound 7 or a salt thereof; and / or c) optionally in the presence of a base, reacting compound 5: or its salt reacts with compound 9 wherein Boc represents tBuO(CO)-; and / or d) in the presence of a base, a diphosphine and Pd(OAc)2, compound 4: Reaction with piperazine to provide compound 5; and / or e) reacting 2-bromo-6-chloro-4-ethylphenol with iodomethane in the presence of a base; and / or f) reacting 2-chloro-4-ethylphenol with a brominating agent; and / or g) reacting 4-ethylphenol with a chlorinating agent.

Images