Method for synthesis of diazabicyclo[6.2.0]decane related compounds

Abstract

To provide a method for synthesis of diazabicyclo[6.2.0]decane compounds.SOLUTION: The synthesis proceeds by stereoselective synthesis of a chiral lactone followed by azetidine formation via a series of chemoselective reactions. Bicyclization results with the formation of diazobicyclo[6.2.0]decane related compounds.SELECTED DRAWING: None

Description

Government support statement

[0001] This invention was made with Government support under Award No. W81XWH-16-1-0719 awarded by the United States Department of Defense under the Peer Reviewed Medical Research Program. The Government has certain rights in this invention. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 790,340, filed January 9, 2019, which is incorporated herein by reference. [Technical field]

[0003] The present invention relates to a stereochemically defined synthesis for producing 1,6-diazabicyclo[6.2.0]decane. [Background technology]

[0004] Malaria is an infectious disease caused by parasitic protozoa of the genus Plasmodium. Eradication of malaria has been difficult due to the complex life cycle of Plasmodium and the emergence of parasite resistance. Diversity-directed synthesis (DOS) has been used to identify antimalarial compounds. For example, the phenylalanyl-tRNA synthetase inhibitor BRD7929 has been identified. BRD7929 exhibits activity in all stages of the parasite life cycle.

[0005] BRD7929, which has the chemical name (8R,9S,10S)-10-[(dimethylamino)methyl]-N-(4-methoxyphenyl)-9-[4-(2-phenylethynyl)phenyl]-1,6-diazabicyclo[6.2.0]decane-6-carboxamide, has been reported in U.S. Patent Application Publication No. 2016 / 0289235, which is incorporated herein by reference. BRD7929 has the following structure: [ka]

[0006] Similarly, a compound represented by the following structure (Formula XIV, or compound 22) has also been identified as useful in the treatment and / or prevention of diseases transmitted by parasites, including malaria and cryptosporidiosis: [ka] See WO 2018 / 175385, which is relied upon and incorporated in its entirety herein.

[0007] Moreover, additional related compounds and their syntheses described as useful in therapies to combat parasitic diseases, including, for example, malaria and cryptosporidiosis, are described in WO 2018 / 175385; Lowe, J. T. et al., Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries, J. Org. Chem. 77, 7187-7211 (2012); Maetani, M. et al., Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp 3 )-H Arylation, JACS139, 11300-11306 (2017); and Kato, N. et al., Diversity-oriented synthesis yields novel multistage antimalarial inhibitors, Nature 538, 344-349 (2016), all of which are incorporated herein by reference in their entireties.

[0008] Additional references related to the preparation and treatment of compounds for parasitic diseases include the following: WO2015070204, WO2015002755, WO2016172631, and U.S. Patent Application Publication No. 2018 / 0194768, all of which are relied upon herein and incorporated by reference in their entireties.

[0009] However, long, low-yielding and / or costly synthetic routes limit the usefulness of these compounds. While BRD7929, Formula XIV and related compounds are known to have therapeutic value, improved synthetic routes to their production could simultaneously provide for further medicinal chemistry exploration of this class of compounds and reduce their cost of production, thereby making the development and / or widespread delivery of these therapeutics more feasible. Thus, there is a need for improved syntheses to make these potential antimalarial compounds. Summary of the Invention

[0010] One embodiment is a compound of formula I: [ka] The present invention is directed to a method for forming a solid compound represented by the formula:

[0011] In formula I, R1 is -I, -Cl, -Br, or [ka] R2 is C(O)R3; R3 is -O - a positive counterion is ionically bonded to formula I; P1 is a nitrogen protecting group. [ka] with a base and resolving the racemic mixture by crystallization with a chiral reagent.

[0012] In one embodiment, R is [ka] It is.

[0013] In another embodiment, P1 is selected from the group consisting of -C(O)CF3, -C(O)OC(CH3)3, and -C(O)OCH2Ph.

[0014] In another embodiment, P1 is -C(O)CF3.

[0015] In another embodiment, the step of reacting with a base is lithium diisopropylamine in the presence of ZnCl 2 .

[0016] In another embodiment, the chiral reagent is (R)-(+)-1-phenylethylamine.

[0017] In another embodiment of forming a compound represented by Formula I, R1 is -I, -Cl, -Br, or [ka] R2 is C(O)R3; R3 is -Oalkyl; P1 is a nitrogen protecting group. The method comprises the steps of: [ka] (wherein X1 is a halogen atom). with a chiral sulfinyl imine.

[0018] In one embodiment, R1 and X1 are each -Br, and the chiral sulfinyl imine is [ka] and R4 and R5 are linear or branched alkyl.

[0019] In another embodiment, R4 is -C(CH3)3 and R5 is -CH2CH3.

[0020] In another embodiment, the reacting is in the presence of Zn.

[0021] Another embodiment is a compound of formula IV: [ka] The present invention can be directed to a method of forming a compound represented by the formula:

[0022] In formula IV, R1 is -I, -Cl, -Br, or [ka] and P1 and P2 are the same or different and represent a nitrogen protecting group. The method comprises reacting a compound of formula V: [ka] The lactone of formula I [ka] (wherein R2 is C(O)R3; R3 is -OH, -Oalkyl, -O - and R3 is -O - where a positive counterion is ionically bonded to formula I; P1 is a nitrogen protecting group. forming a lactone of formula V from a compound of formula VI: [ka] and converting the alcoholic group covalently attached to the unsaturated carbon of formula VI to a leaving group to form an intermediate which reacts with a nitrogen nucleophile to generate a compound of formula IV.

[0023] In one embodiment, the nitrogen nucleophile is a phthalimide.

[0024] In another embodiment, R1 is [ka] and R2 is -C(O)O - and P1 is -C(O)CF3.

[0025] In another embodiment, the lactone of formula V is formed by reacting a compound of formula I with an electropositive source of halogen in a polar solvent.

[0026] In another embodiment, the electropositive source of halogen is I2 and the polar solvent is an aqueous mixture of CH3CN. One of skill in the art will readily recognize a variety of polar solvents that can be used, including, without limitation, water, an aqueous solution of THF, DMF, or other polar protic or polar aprotic water-miscible solvents.

[0027] In another embodiment, the lactone of formula V is formed by reacting a compound of formula I with I2 in a polar solvent to form a first product, and reacting the first product with NaN3 to form a compound of formula V.

[0028] In another embodiment, the reducing is performed with NaBH4.

[0029] In another embodiment, the leaving group is a mesylate group and the intermediate has the following structure: [ka] is indicated by one or both of the following:

[0030] In another embodiment, P1 is selected from the group consisting of -C(O)CF3 and the following structure: [ka] is converted to

[0031] In another embodiment, R1 is -Br, R2 is -C(O)OCH2CH3, and P1 is -S(O)C(CH3)3.

[0032] In another embodiment, P1 is selected from the group consisting of -S(O)C(CH3)3 and the structure: [ka] is converted to

[0033] In another embodiment, the lactone of formula V is formed by reacting a compound of formula I with an electropositive source of halide in a polar solvent to form a first product, and reacting the first product with NaN3 to form a compound of formula V.

[0034] In another embodiment, the lactone of formula V is reduced with NaBH4 to give the following compound: [ka] Form.

[0035] In another embodiment, the leaving group is a mesylate group and the intermediate has the following structure: [ka] is indicated by one or both of the following:

[0036] Another embodiment is a compound of formula VIII: [ka] The present invention is directed to a method of making a compound represented by the structure:

[0037] In formula VIII, R1 is -I, -Cl, -Br, or [ka] R6 and R7 are independently the same or different and are selected from -H, alkyl, -Oalkyl, or R6 and R7 together with the atom to which they are attached form a ring; R8 and R9 are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system; R 10 is -H, linear or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl; alkyl, aryl, and heteroaryl are optionally substituted with one or more halogen, oxygen, nitrogen, or sulfur atoms. The method comprises reacting a compound of formula IV: [ka] with a substituted γ-hydroxyaldehyde and carrying out bicyclization.

[0038] In one embodiment, the γ-hydroxyaldehyde has the following structure: [ka] (In the formula, R 11 is -H or an oxygen protecting group; R 12 is -H or -CHOH) As shown by:

[0039] In another embodiment, the γ-hydroxyaldehyde is [ka] and the compound of formula VIII can be prepared by the following intermediate: [ka] It is produced through the process.

[0040] In another embodiment, the method further comprises oxidizing to produce the compound of formula VIII as follows: [ka] It is produced through the process.

[0041] In another embodiment, the method further comprises reduction and bicyclization to produce the compound of formula VIII as the following intermediate: [ka] It is produced through the process.

[0042] In another embodiment, the method includes further reduction to produce the compound of formula VIII as the following intermediate: [ka] It is produced through the process.

[0043] In another embodiment, the compound of formula XIII is reacted with 4-methoxyphenylisocyanate and the compound of formula VIII has the following structure: [ka] As shown by:

[0044] Another object of the present invention is to provide a compound of formula IV [ka] The present invention is directed to a method of forming a compound represented by the formula:

[0045] In formula IV, R1 is -I, -Cl, -Br, or [ka] and P1 and P2 are the same or different and represent nitrogen protecting groups. [ka] by converting an alcoholic group covalently bonded to the unsaturated carbon of formula (IV) into a leaving group to form an intermediate which reacts with a nitrogen nucleophile to generate a compound of formula IV.

[0046] In one embodiment, the leaving group is a mesylate group and the intermediate has the following structure: [ka] is indicated by one or both of the following:

[0047] In another embodiment, the nitrogen nucleophile is a phthalimide.

[0048] One beneficial discovery of the present invention is the chemoselective tandem process for preparing substituted azetidines. This may be the first or one of the first examples of custom-made nucleophilic aziridines that open preferentially to oxygen leaving group displacement, highlighting the importance of ring strain energy relief in tuning chemical reactivity. Another beneficial discovery of the present invention is the application of the aza-Wittig / reduction sequence to construct 8-membered rings directly from azide-aldehydes.

[0049] Another embodiment is a compound of formula I: [ka] In the present invention, in formula I, R1 is [ka] R2 is C(O)R3; R3 is -O - where a positive counterion is ionically bonded to Formula I or R3 is -OH; P1 is a nitrogen protecting group or -H.

[0050] Another embodiment is a compound of formula IV: [ka] The present invention relates to a compound represented by the formula:

[0051] In formula IV, R1 is -I, -Cl, -Br, or [ka] P1 and P2 are the same or different and represent a nitrogen protecting group or -H.

[0052] Another embodiment is a compound of formula V: [ka] The present invention relates to a compound represented by the formula:

[0053] In formula V, R1 is -I, -Cl, -Br, or [ka] and P1 is a nitrogen protecting group or -H.

[0054] Another embodiment is a compound of formula VI: [ka] The present invention relates to a compound represented by the formula:

[0055] In formula VI, R1 is -I, -Cl, -Br, or [ka] and P1 is a nitrogen protecting group or -H.

[0056] Another embodiment is a compound of formula VII: [ka] The present invention relates to a compound represented by the formula:

[0057] In formula VII, R1 is -I, -Cl, -Br, or [ka] and P1 is a nitrogen protecting group or -H.

[0058] Another embodiment is of formula VIIb: [ka] The present invention relates to a compound represented by the formula:

[0059] In formula VIIb, R1 is -I, -Cl, -Br, or [ka] and P1 is a nitrogen protecting group or -H.

[0060] Another embodiment is a compound of formula VIII: [ka] The present invention relates to a compound represented by the formula:

[0061] In formula VIII, R1 is -I, -Cl, -Br, or [ka] R6 and R7 are independently the same or different and are selected from -H, alkyl, -Oalkyl, or R6 and R7 together with the atom to which they are attached form a ring; R8 and R9 are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system; R 10 is -H, straight chain or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, wherein alkyl, aryl, and heteroaryl are substituted by one or more hydrogen, halogen, oxygen, nitrogen, or sulfur atoms.

[0062] Another embodiment is a compound of formula X: [ka] The present invention relates to a compound represented by the formula:

[0063] In formula X, R1 is -I, -Cl, -Br, or [ka] R and R are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)alkyl, or R and R together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is substituted by one or more hydrogen, halogen, oxygen, nitrogen or sulfur atoms.

[0064] Another embodiment is a compound of formula XI: [ka] The present invention relates to a compound represented by the formula:

[0065] In formula XI, R1 is -I, -Cl, -Br, or [ka] R and R are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)alkyl, or R and R together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is substituted by one or more hydrogen, halogen, oxygen, nitrogen or sulfur atoms.

[0066] Another embodiment is a compound of formula XII: [ka] The present invention relates to a compound represented by the formula:

[0067] In formula XII, R1 is -I, -Cl, -Br, or [ka] R8 and R9 are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms.

[0068] Another embodiment is a compound of formula XIII: [ka] The present invention relates to a compound represented by the formula:

[0069] For formula XIII, R1 is -I, -Cl, -Br, or [ka] R8 and R9 are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms.

[0070] Another embodiment is a compound of formula XV: [ka] The present invention relates to a compound represented by the formula:

[0071] For formula XV, R1 is -I, -Cl, -Br, or [ka] and Z is a 4-membered nitrogen-containing heterocycle selected from one of the following: [ka] (P1 and P2 are the same or different and are a nitrogen protecting group or -H); [ka] (R6 and R7 are independently the same or different and are selected from -H, alkyl, -Oalkyl, or R6 and R7 together with the atom to which they are attached form a ring; R8 and R9 are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system; R 10 is -H, straight chain or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, wherein alkyl, aryl and heteroaryl are substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms; [ka] (R8 and R9 are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms; [ka] (R8 and R9 are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms; [ka] wherein R and R are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O)alkyl, or R and R together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms; and [ka] (R8 and R9 are independently the same or different and selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9 together with the N to which they are attached form a monocyclic or bicyclic ring system, wherein the alkyl is optionally substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms).

[0072] Another embodiment is a compound represented by formula XV: [ka] [In the formula, R1 is -I, -Cl, -Br, or [ka] and In formula XV, Z is [ka] (R2 is C(O)R3; R3 is -O - where a positive counterion is ionically bonded to formula XVI or R3 is -OH; P1 is a nitrogen protecting group or -H); [ka] (P1 is a nitrogen protecting group or -H); [ka] (P1 is a nitrogen protecting group or -H); [ka] (P1 is a nitrogen protecting group or -H); and [ka] (P1 is a nitrogen protecting group or -H) or a pharma- ceutically acceptable salt thereof.

[0073] The compounds provided herein, including but not limited to those of formula I, IV, V, VI, VII, VIIb, VIII, X, XI, XII, XIII and XV, can be provided as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" as used herein refers to acid or base addition salts of the compounds in the present disclosure. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any undue harmful or undesirable effects to the subject to which it is administered and in the context in which it is administered. Pharmaceutically acceptable salts include but are not limited to metal complexes and salts of both inorganic acids and carboxylic acids. Pharmaceutically acceptable salts also include metal salts, such as aluminum salts, calcium salts, iron salts, magnesium salts, manganese salts and complex salts. In addition, pharma- ceutically acceptable salts include, but are not limited to, acid salts, such as acetate, aspartate, alkylsulfonate, arylsulfonate, axetil, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, butyrate, calcium edetate, camsylate, carbonate, chlorobenzoate, citrate, edetate, edisylate, estolate, esylate, esylenate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsanilate, hexamate, hexylresorcinolate, hydrabamate, hydrobromide, hydrochloride, iodide, and the like. Examples of suitable salts include hydrochloride, hydroxynaphthoate, isethionate, lactate, lactobionate, maleate, malate, malonate, mandelate, methanesulfonate, methyl nitrate, methyl sulfate, mucate, muconate, napsylate, nitrate, oxalate, p-nitromethanesulfonate, pamoate, pantothenate, phosphate, monohydrogen phosphate, dihydrogen phosphate, phthalate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfonate, sulfate, tannate, tartrate, teoclate, toluenesulfonate, etc. Pharmaceutically acceptable salts can be derived from amino acids, including, but not limited to, cysteine.Methods for producing compounds as salts are known to those of skill in the art (see, e.g., Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; Verlag Helvetica Chimica Acta, Zurich, 2002; Berge et al., J. Pharm. Sci. 66:1, 1977).

[0074] Other aspects and advantages of the present invention will be apparent from the following description, drawings and appended claims. [Brief description of the drawings]

[0075] [Figure 1] FIG. 1 shows the ORTEP projection for compound 5. [Diagram 2] FIG. 1 shows the ORTEP projection for compound 32. Detailed Description of the Invention

[0076] While the terms used herein are believed to be well understood by those of ordinary skill in the art, definitions are set forth herein to facilitate description of the subject matter disclosed herein.

[0077] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are described herein.

[0078] As used herein, all combinations of method or process steps can be performed in any order unless otherwise specified or clearly implied to be contradictory by the context in which the referenced combination is made.

[0079] The methods and apparatuses of the present disclosure can include, consist of, or consist essentially of the essential elements and limitations of the embodiments described herein, including their components, as well as any additional or optional elements or limitations described herein or otherwise useful.

[0080] Unless otherwise indicated, all numbers expressing quantities of components, physical dimensions, reaction conditions, and the like properties used in the specification and claims are to be understood as being modified in all instances by the term "about" and, thus, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[0081] The term "alkyl" includes branched, straight chain, and cyclic substituted or unsubstituted saturated aliphatic hydrocarbon groups. An alkyl group can contain from about 1 to about 24 carbon atoms ("C1-C24"), from about 7 to about 24 carbon atoms ("C7-C24"), from about 8 to about 24 carbon atoms ("C8-C24"), or from about 9 to about 24 carbon atoms ("C9-C24"). An alkyl group can also contain from about 1 to about 8 carbon atoms ("C1-C8"), from about 1 to about 6 carbon atoms ("C1-C6"), or from about 1 to about 3 carbon atoms ("C1-C3"). Examples of C1-C6 alkyl groups include, but are not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, an isohexyl group, a cyclohexyl group, a cyclohexylmethyl group, a cyclopropylmethyl group, and a neohexyl group.

[0082] The term "aryl" includes 6- to 14-membered monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring systems. Examples of aryl groups include phenyl and naphthyl.

[0083] The term "heteroaryl" includes aromatic heterocycles containing 5 to 14 members and at least one carbon atom, including monocyclic, bicyclic and tricyclic ring systems, and having at least one heteroatom selected from nitrogen, oxygen and sulfur. Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl.

[0084] Oxygen protecting groups include, for example and without limitation, benzyl or substituted benzyl groups, silyl or substituted silyl groups, acetyl or other ester protecting groups, methoxymethyl ethers or other methoxy ethers. Those of skill in the art will recognize other acceptable protecting groups, such as those identified in Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter GMWuts, John Wiley & Sons, Inc. (2014), which is incorporated herein by reference in its entirety.

[0085] Those skilled in the art will recognize a wide variety of nitrogen protecting groups that can be used in accordance with embodiments of the present invention. See also Greene's Protective Groups in Organic Synthesis, 5th Edition, which is fully incorporated herein by reference. Useful nitrogen protecting groups can include, for example, but are not limited to, 9-fluorenylmethylcarbamate; t-butylcarbamate; 2-nitrobenzenesulfonyl; 4-nitrobenzenesulfonyl; benzyl carbamate; acetamide; trifluoroacetamide; phthalimide; benzylamine; triphenylmethylamine; benzylideneamine; and p-toluenesulfonamide.

[0086] Abbreviations. XPhos-Pd-G3 (XPhosG3) is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate, XPhos-G3-Palladacycle (Sigma-Aldrich). Dess-Martin periodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Sigma-Aldrich). MTBE is methyl tertiary-butyl ether. As used herein, "Ns" or "nosyl" refers to the 2-nitrophenylsulfonyl group; "Ms" or "mesyl" refers to the methanesulfonyl group; and "TFA" refers to the trifluoroacetyl group.

[0087] While only a certain stereoisomer may be represented in any given claim, those skilled in the art will recognize that enantiomers or other stereoisomers may be produced through preparation of the appropriate corresponding chiral starting materials or intermediates.

[0088] If there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure controls. In addition, if the stereochemistry of a structure or portion of a structure is not shown, for example, with bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers thereof. EXAMPLES

[0089] Route A synthesis Esterification of 4-bromocinnamic acid to give (methyl (E)-3-(4-bromophenyl)acrylate) 1 [ka]

[0090] Thionyl chloride (176 mL, 2422 mmol) was added dropwise to a white suspension of 4-bromocinnamic acid (500 g, 2202 mmol) in methanol (3000 mL) over 20 min, during which the reaction temperature remained below 40° C. The mixture was then heated to reflux for 1 h, during which time the mixture became homogeneous. The solution was allowed to slowly come to room temperature, giving a white suspension. The suspension was filtered and the filter cake was washed twice with cold methanol to give 1 as a white solid. The filtrate was concentrated to half the original volume, filtered again, and the filter cake was washed with cold methanol. The procedure was repeated two more times to give additional 1 (523 g combined, 98% yield). 1 H NMR(400 MHz, CDCl3) δ 7.62 (d, J = 16.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H), 6.43 (d, J = 16.0 Hz,1 H), 3.81 (s, 3 H); 13 C NMR (75 MHz, CDCl3) δ 167.1, 143.4, 133.2, 132.1, 129.4, 124.5, 118.5, 51.8.

[0091] Sonogashira reaction of 1 to give (methyl (E)-3-(4-(phenylethynyl)phenyl)acrylate) 2 [ka]

[0092] Dissolving 1 (285 g, 1180 mmol) in diisopropylamine (2500 ml) gave a clear homogeneous solution. The solution was sparged with nitrogen gas for 30 min before copper(I) iodide (0.169 g, 0.885 mmol), bis(benzonitrile)palladium(II) chloride (0.453 g, 1.18 mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.685 g, 2.36 mmol) were added. The mixture was heated to 80° C. before adding phenylacetylene (136 mL, 1239 mmol) in small portions to first initiate the reaction as indicated by an increase in internal temperature to reflux and the formation of a precipitate, then to maintain reflux of the exothermic reaction. After the addition was complete, the mixture was stirred at 80° C. for an additional hour, then slowly brought to 50° C. and the reaction was quenched with water (2000 mL). The mixture was allowed to reach room temperature with stirring and then filtered. The filter cake was washed with water (200 mL x 3) and then dried under vacuum at 40°C to give 2 (296 g, 96%) as a white solid that was pure based on NMR spectrum. 1 H NMR(400 MHz, CDCl3) δ 7.69 (d, J = 16.0 Hz, 1H), 7.56 - 7.50 (m, 6 H), 7.38 - 7.35 (m, 3 H), 6.46 (d, J = 16.0 Hz, 1 H),3.83 (s, 3 H); 13 C NMR (75 MHz, CDCl3) δ 167.2, 143.9, 134.1, 132.0, 131.6, 128.5, 128.4, 128.0, 125.2,122.9, 118.4, 91.6, 89.0, 51.7.

[0093] Reduction of 2 to give ((E)-3-(4-(phenylethynyl)phenyl)prop-2-en-1-ol) 3 [ka]

[0094] A clear, colorless solution of 2 (210 g, 801 mmol) in dichloromethane (3150 mmol) was cooled to −78° C. in a dry ice-acetone bath during which the solution turned into a white suspension. A solution of diisobutylaluminum hydride (25 wt.% in toluene, 934 g, 1641 mmol) was slowly added and the mixture was then slowly brought to −20° C. over 12 h. The reaction was carefully quenched with a solution of potassium sodium tartrate tetrahydrate (926 g, 3282 mmol) in water (4200 mL) and the mixture was stirred at room temperature for 12 h. The two phases were separated and the aqueous phase was extracted with dichloromethane (1700 mL×4). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give 3 (184 g, 98%) as a white solid that was pure based on NMR spectrum. 1 H NMR(400 MHz, CDCl3) δ 7.55 - 7.48 (m, 4 H),7.39 - 7.34 (m, 5 H), 6.63 (d, J = 16.1 Hz, 1 H), 6.41 (dt, J = 16.0, 5.4 Hz, 1H), 4.36 (dd, J = 5.5, 1.6 Hz, 2H); 13 C NMR (75 MHz, CDCl3)δ 136.6, 131.8, 131.6, 130.4, 129.5, 128.3, 128.3,126.4, 123.2, 122.4, 90.1, 89.4, 63.6.

[0095] Esterification of 3 with N-(trifluoroacetyl)glycine to give ((E)-3-(4-(phenylethynyl)phenyl)allyl(2,2,2-trifluoroacetyl)glycinate) 4 [ka]

[0096] A mixture of 3 (184 g, 785 mmol), N-(trifluoroacetyl)glycine (136 g, 793 mmol) and 4-(dimethylamino)pyridine (9.59 g, 78.5 mmol) in dichloromethane (1840 mL) gave a yellow suspension. The suspension was cooled to 10 °C in an ice bath, at which time N,N'-diisopropylcarbodiimide (128 mL, 825 mmol) was added in small portions while maintaining the internal temperature below 15 °C. The mixture was slowly brought to room temperature and stirred overnight. The mixture was filtered and the filter cake was washed with methylene chloride (50 mL x 3). The filtrate was taken up in a mixture of ethyl acetate / methyl tert-butyl ether (1:1, 3680 mL) and washed with aqueous sodium bicarbonate (400 mL x 2) and brine (400 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was crystallized in isopropanol to give 4 (240 g, 79%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.56 - 7.50 (m, 4 H),7.40 - 7.34 (m, 5 H), 6.90 (br s, 1 H), 6. 6.69 (d, J = 15.6 Hz, 1 H), 6.31(dt, J = 16.0, 6.6 Hz, 1 H), 4.88 (dd, J = 6.6, 1.1 Hz, 2 H), 4.19 (d, J = 5.0Hz, 1 H); 13 C NMR (75 MHz, CDCl3) δ 168.0, 135.5, 134.9, 131.9, 131.6, 128.4, 126.6, 123.3,123.1,122.5, 90.5, 89.1, 66.6, 41.4.

[0097] Claisen rearrangement of 4 and chiral resolution using (R)-(+)-1-phenylethylamine to give ((R)-1-phenylethan-1-aminium (2S,3S)-3-(4-(phenylethynyl)phenyl)-2-(2,2,2-trifluoroacetamido)pent-4-enoic acid) 5 [ka]

[0098] Preparation of lithium diisopropylamide (LDA): A solution of diisopropylamine (22.8 mL, 160 mmol) in tetrahydrofuran (130 mL) was cooled in an ice bath and slowly treated with a solution of n-butyllithium (2.5 M in hexanes, 62.0 mL, 155 mmol) while maintaining the internal temperature below 20° C. The ice bath was removed and the mixture was stirred at room temperature for 30 min.

[0099] In a separate vessel, a solution of 4 (20.0 g, 51.6 mmol) in tetrahydrofuran (140 mL) was cooled in a dry ice-acetone bath to give a yellow suspension. The suspension was treated with a solution of zinc chloride (1.9 M in 2-methyltetrahydrofuran, 40.8 mL, 77.4 mmol) while maintaining the internal temperature below -60 degrees. To this mixture, the LDA solution was added slowly while maintaining the internal temperature below -65°C, during which the mixture became a dark blue homogeneous solution toward the end of the addition. The reaction mixture was maintained at this temperature for 60 min. The cooling bath was removed and the reaction mixture was slowly brought to room temperature during which the mixture became dark orange. The reaction was quenched with hydrochloric acid (1 M, 336 mL, 336 mmol), during which the internal temperature rose to 35°C. The two phases were separated and the aqueous phase was extracted with methyl tert-butyl ether (160 mL x 2). The combined organic phase was concentrated and the residue was taken up in methyl tert-butyl ether (160 mL). The mixture was heated to reflux temperature to give a nearly clear solution. The solution was treated with (R)-(+)-1-phenylethylamine (12.5 g, 103 mmol) to give a clear solution from which a precipitate immediately began to form. With stirring, the mixture was slowly brought to room temperature and then cooled in an ice bath. The product was filtered, washed with methyl tert-butyl ether (20 mL x 2) and dried under vacuum to give 5 (10.7 g, 40.8% yield, er = 16.8:1) as a white solid. 1 H NMR(400 MHz, MeOH-d4) δ 7.52 - 7.49 (m, 2 H),7.46 - 7.39 (m, 7 H), 7.39 - 7.34 (m, 3 H), 7.28 (d, J = 8.2 Hz, 2 H), 6.24 -6.14 (m, 1 H), 5.13 - 5.09 (m, 2 H), 4.70 (d, 8.2 Hz, 1 H), 4.44 (q, J = 7.0Hz, 1 H), 3.86 (t, J = 8.2 Hz, 1 H), 1.63 (d, J = 7.0 Hz, 3 H); 13CNMR (75 MHz, MeOH-d4) δ 175.5, 142.2, 140.1,139.1, 132.7, 132.6, 130.5, 130.3, 130.0, 129.7, 129.5, 127.7, 124.9, 123.2,117.4, 90.2, 90.1, 61.0, 54.3, 52.5, 21.0.

[0100] Iodolactonization of 5 and displacement with sodium azide to give (N-((3S,4S,5S)-5-(azidomethyl)-2-oxo-4-(4-(phenylethynyl)phenyl)tetrahydrofuran-3-yl)-2,2,2-trifluoroacetamide) 7 [ka]

[0101] A white milky suspension of 5 (30.9 g, 60.8 mmol) in acetonitrile (494 mL) and water (124 mL) was cooled to 0° C. and treated with iodine (30.8 g) to give a dark red solution, which was stirred at this temperature for 1 h. The reaction was quenched by treating the mixture with sodium thiosulfate (28.8 g, 182 mmol) and stirring for 10 min, during which time the reaction turned pale yellow. The mixture was poured into methyl tert-butyl ether (500 mL) and the two phases were separated. The organic phase was washed with 1 M hydrochloric acid (150 mL) and brine (150 mL). The aqueous phase was back-extracted with methyl tert-butyl ether. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give crude (2,2,2-trifluoro-N-((3S,4S,5S)-5-(iodomethyl)-2-oxo-4-(4-(phenylethynyl)phenyl)tetrahydrofuran-3-yl)acetamide) 6 as a red gum.

[0102] The crude 6 from above was taken up in N,N-dimethylformamide (185 mL) and treated with sodium azide (15.8 g, 243 mmol). The mixture was stirred at room temperature for 12 h, then heated to 45° C. and stirred for an additional 12 h. The mixture was taken up in methyl tert-butyl ether (400 mL) and washed with water (300 mL) and brine (300 mL). The aqueous phase was back-extracted with methyl tert-butyl ether (300 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude was passed through a short pad of silica gel (130 g) eluted with 50% ethyl acetate in heptane (100 mL). The filtrate was concentrated to give 7 as a light yellow foamy solid, which was used without purification.

[0103] Preparation of aminodiol 9 from azidolactone ((2S,3S,4S)-2-amino-5-azido-3-(4-(phenylethynyl)phenyl)pentane-1,4-diol) 7 [ka]

[0104] The crude 7 from above (26.0 g, 60.8 mmol) was taken up in ethanol (260 mL) to give a colorless solution. The solution was cooled in an ice bath and treated with sodium borohydride (2.76 g, 73.0 mmol). The mixture was stirred at this temperature for 2 h to give a white suspension. The ice bath was removed and the mixture was then brought to room temperature and the mixture was then brought to 45° C., at which point bubbles ceased to form and the mixture became homogeneous. The solution was treated with potassium carbonate (25.2 g, 182 mmol) and water (13 mL) and stirred at this temperature for 24 h. The mixture was concentrated and the residue was taken up in methylene chloride (390 mL). The mixture was treated with celite (26 g) and filtered through a pad of celite, rinsing with methylene chloride (260 mL×2). The filtrate was concentrated to give an orange solid, which was filtered through a pad of silica gel (160 g) eluting with 20% methanol in dichloromethane (conditioned with 1% aqueous ammonia, 2000 mL). The filtrate was concentrated and the residue was crystallized (isopropyl acetate / isopropanol = 3:1, concentrated mother liquor, further crystallized acetonitrile, then in ethyl acetate) to give 9 as a white solid (7.01 g). Another fraction of 9 was obtained crude in the mother liquor (7.84 g, 5-73% combined yield based on 9.8 g of concentrate with 80% purity as shown by ELSD). 1 H NMR(400 MHz, MeOH-d4) δ 7.53 - 7.49 (m, 4 H),7.40 - 7.36 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 4.31 (ddd, J = 9.8, 6.2, 2.7Hz, 1 H), 3.49 - 3.45 (m, 1 H), 3.40 (dd, J = 10.6, 6.3 Hz, 1 H), 3.33 - 3.32(m, 1 H), 3.29 (dd, J = 10.5, 7.4 Hz, 1 H), 3.15 (dd, J = 12.7, 3.0 Hz, 1 H),3.03 (dd, J = 12.5, 6.6 Hz, 1 H), 3.00 (dd, J = 9.7, 3.5 Hz, 1 H); 13CNMR (75 MHz, MeOH-d4) δ 138.4, 131.2, 131.1,129.4, 128.1, 128.0, 123.1, 122.0, 88.9, 88.4, 70.8, 64.4,55.6, 52.4, 50.1.

[0105] One-pot N-nosylation and bis-O-mesylation of 9 to give azetidine (2-(((2S,3S,4R)-4-(azidomethyl)-1-((2-nitrophenyl)sulfonyl)-3-(4-(phenylethynyl)phenyl)azetidin-2-yl)methyl)isoindoline-1,3-dione) 12; tandem N-nucleophilic substitution [ka]

[0106] A suspension of 9 (2.00 g, 5.95 mmol) and triethylamine (4.97 mL, 35.7 mmol) in dichloromethane (20 mL) was cooled in an ice bath and treated with a solution of 2-nitrobenzenesulfonyl chloride (1.98 g, 8.92 mmol) in dichloromethane (10 mL) while maintaining the internal temperature below 6° C. The mixture was stirred at this temperature for 30 min, during which time it became homogeneous. The solution was then treated with methanesulfonyl chloride (1.39 mL, 17.8 mmol) and stirred at this temperature for 30 min. The reaction was quenched with aqueous sodium hydroxide (1 M, 100 mL) and the mixture was poured into ethyl acetate (300 mL). The organic phase was separated, washed with brine (50 mL) and concentrated to give the crude product consisting of the bis-mesylate 11 and the aziridine intermediate.

[0107] The crude material from above was taken up in N,N-dimethylformamide (20 mL) and treated with potassium carbonate (2.47 g, 17.8 mmol), potassium phthalimide (1.65 g, 8.92 mmol) and stirred at room temperature for 60 h. The reaction mixture was taken up in ethyl acetate (400 mL), washed with water (100 mL), brine (100 mL) and concentrated. The residue was taken up in isopropanol (30 mL) and boiled to give a homogenous solution which was allowed to warm slowly to room temperature with stirring during which the product precipitated. The product was filtered, washed with isopropanol (10 mL x 2) and dried under vacuum to give 12 (3.14 g, 83% yield) as an off-white solid. 1 H NMR(400 MHz, CDCl3) δ 8.15 (dd, J = 7.8, 1.5Hz, 1 H), 7.85 - 7.75 (m, 4 H), 7.72 - 7.69 (m, 3 H), 7.61 (d, J = 8.6 Hz, 2H), 7.57 - 7.54 (m, 2 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.39 - 7.35 (m, 3 H), 4.93(dt, J = 8.2, 6.7 Hz, 1 H), 4.55 (dt, J = 9.3, 3.9 Hz, 1 H), 4.23 (dd, J =14.4, 6.2 Hz, 1 H), 3.79 (t, J = 8.6 Hz, 1 H), 3.75 (dd, J = 14.4, 6.6 Hz, 1H), 3.71 (dd, J = 12.9, 5.1 Hz, 1 H), 3.60 (dd, J = 12.8, 9.3 Hz, 1 H); 13 CNMR (75 MHz, CDCl3) δ 167.6, 149.3, 134.8,134.0, 132.6, 132.2, 132.0, 131.8, 131.7, 131.6, 130.5, 128.4, 128.3, 127.4,124.3, 123.5, 123.3, 123.1, 90.4, 88.8, 62.5, 61.9, 48.7, 42.4, 37.5.

[0108] Deprotection and reductive amination of 12 to give (2-(((2S,3S,4R)-4-(azidomethyl)-1-(((4S,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(4-(phenylethynyl)phenyl)azetidin-2-yl)methyl)isoindoline-1,3-dione) 15 [ka]

[0109] A clear, colorless solution of 12 (5.84 g, 9.23 mmol) and 1-dodecanethiol (2.65 mL, 11.1 mmol) in tetrahydrofuran (70 mL) was cooled in an ice bath to an internal temperature of 4 °C. A solution of potassium tert-butoxide (1 M in THF, 11.1 mL, 11.1 mmol) was added dropwise while maintaining the internal temperature below 10 °C, during which the mixture turned dark red. The ice bath was removed and the mixture was allowed to reach room temperature. The mixture was stirred at this temperature for 1 h, then quenched with aqueous sodium bicarbonate (100 mL) and taken up in ethyl acetate (200 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and then concentrated to give crude 13 as a yellow gum.

[0110] Crude 13 was combined with 14 (2.11 g, 11.1 mmol) and taken up in methanol (70 mL) to give a yellow solution which was treated with acetic acid (2.64 mL, 46.2 mmol) and sodium cyanoborohydride (0.696 g, 11.1 mmol). The solution was stirred at room temperature for 24 h before being treated with additional acetic acid (2.64 mL, 46.2 mmol) and sodium cyanoborohydride (0.300 g, 4.78 mmol). After 12 h, a third portion of sodium cyanoborohydride (0.300 g, 4.78 mmol) was added and the mixture was stirred for an additional 6 h. The reaction mixture was taken up in ethyl acetate (200 mL) and washed with 1 M sodium hydroxide (100 mL). The aqueous phase was separated and back extracted with ethyl acetate (200 mL). The combined organic phase was washed with brine (100 mL) and concentrated. The residue was filtered through a silica gel (140 g) column, rinsing with methylene chloride (700 mL) and then ethyl acetate (700 mL). The ethyl acetate filtrate was concentrated to give 15 (5.34 g, 93%) as a pale yellow foamy solid, which was used without further purification.

[0111] Oxidative cleavage of the 1,2-diol of 15 to give ((4S,5S)-5-(((2R,3S,4S)-2-(azidomethyl)-4-((1,3-dioxoisoindolin-2-yl)methyl)-3-(4-(phenylethynyl)phenyl)azetidin-1-yl)methyl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde) 16 [ka]

[0112] A clear, colorless solution of 15 (5.34 g, 8.59 mmol) in tetrahydrofuran (64 mL) and water (6.4 mL) was treated with sodium periodate (2.76 g, 12.9 mmol). The mixture was stirred at room temperature for 2 h, during which time it became a white milky suspension. The suspension was taken up in ethyl acetate (500 mL) and washed successively with aqueous sodium thiosulfate (50 mL) and brine (50 mL). The organic phase was separated and dried over anhydrous sodium sulfate. The organic phase was concentrated to give 16 as a white foamy solid, which was used without purification.

[0113] Conversion of 16 to (2-(((3aR,6aR,7R,8S,10aS)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazocin-8-yl)methyl)isoindoline-1,3-dione) 18 using the aza-Wittig reaction followed by reduction [ka]

[0114] Crude 16 from above was taken up in methanol (30 mL) to give a clear, colorless solution. The solution was slowly added to a stirred white suspension of triphenylphosphine (2.70 g, 10.3 mmol) in methanol (50 mL) at room temperature over 8 h, during which the mixture became a colorless homogeneous solution. After the solution was further stirred at this temperature for 6 h, acetic acid (2.46 mL, 43.0 mmol) and sodium cyanoborohydride (0.648 g, 10.3 mmol) were added. The mixture was stirred at this temperature for 4 h and then concentrated. The residue was taken up in ethyl acetate (400 mL) and washed with 1 M sodium hydroxide (40 mL) and brine (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude 18 as a colorless gum.

[0115] Conversion of 18 to ((3aR,6aR,7S,8S,10aS)-8-((1,3-dioxoisoindolin-2-yl)methyl)-N-(4-methoxyphenyl)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazocine-5-carboxamide) 19 [ka]

[0116] The crude 18 from above was taken up in dichloromethane (57 mL) and treated with 4-methoxyphenyl isocyanate (1.34 mL, 10.3 mmol). The mixture was kept at room temperature for 30 min and then concentrated. The residue was crystallized in a mixed solvent of isopropanol / acetonitrile (1:1, 100 mL) to give 19 (1.60 g) as a white solid. The mother liquor was concentrated and purified using silica gel column chromatography eluting with 50%-60% ethyl acetate in heptane to give additional 19 (1.0 g, 12-43% combined yield). 1 H NMR(400 MHz, DMF-d7) δ 8.44 (s, 1H), 7.88 (s,4H), 7.74 (d, J = 8.2 Hz, 2H), 7.64 - 7.61 (m, 4 H), 7.51 - 7.44 (m, 3 H), 7.37- 7.33 (m, 2 H), 6.87 - 6.83 (m, 2 H), 4.50 - 4.47 (m, 1 H), 4.34 - 4.29 (m, 1H), 4.08 (br dd, J = 16.0, 5.0 Hz, 1 H), 3.97 (br dd, J = 16.0, 2.8 Hz, 1 H),3.87 - 3.65 (m, 6 H), 3.75 (s, 3 H), 3.52 (dd, J = 14.0, 4.6 Hz, 1 H), 3.48 (s,1 H), 3.10 (br t, J = 2.1 Hz, 1 H), 1.39 (s, 3 H), 1.37 (s, 3 H); 13CNMR (75 MHz, DMF-d7) δ 168.9, 163.3, 157.5,156.1, 138.5, 135.5, 135.0, 133.1, 132.6, 132.4, 132.3, 129.9, 129.8, 124.1,124.1, 122.4, 122.1, 114.8, 108.1, 90.5, 90.5, 78.9, 77.4, 68.0, 66.5, 59.0,56.1, 50.7, 47.4, 45.0, 39.7, 28.9, 26.3.

[0117] Hydrolysis of the phthalimide 19 to give ((3aR,6aR,7S,8S,10aS)-8-(aminomethyl)-N-(4-methoxyphenyl)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazocine-5-carboxamide) 20 [ka]

[0118] A white suspension of 19 (2.30 g, 3.30 mmol) in methanol (23 mL) was treated with ethanolamine (2.00 mL, 33.0 mmol). The mixture was stirred at 55° C. for 12 h and then refluxed for 12 h, during which time the mixture became a homogeneous solution. The solution was treated with ethanolamine (1.50 mL, 24.8 mmol) and refluxed for 24 h. The solution was concentrated to give a colorless gum, which was taken up in dichloromethane (300 mL), washed with water (50 mL×2), brine (50 mL), and dried over anhydrous sodium sulfate. The gum was concentrated to give crude 20 as a white waxy solid, which was used without purification.

[0119] Reductive amination of 20 and acetonide removal to give ((3S,4R,8R,9S,10S)-10-((dimethylamino)methyl)-3,4-dihydroxy-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide) 22 [ka]

[0120] The above crude 20 was taken up in methanol (18.7 mL) to give a suspension which was treated with formaldehyde (37%, 3.69 mmol, 49.5 mmol), acetic acid (1.13 mL, 19.8 mmol) and sodium cyanoborohydride (0.622 g, 9.90 mmol). After the mixture was stirred at room temperature for 2 h, the mixture was taken up in ethyl acetate (150 mL) and washed with aqueous sodium bicarbonate (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was passed through a pad of silica gel eluting with 15% methanol in dichloromethane and concentrated to give crude ((3aR,6aR,7S,8S,10aS)-8-((dimethylamino)methyl)-N-(4-methoxyphenyl)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazocine-5-carboxamide) 21 as a colorless gum which was used without further purification.

[0121] The crude 21 from above was taken up in a mixture of tetrahydrofuran (14 mL) and 1 M hydrochloric acid (14 mL, 14 mmol) to give a colorless solution, which was stirred at 50° C. for 12 h. The solution was taken up in ethyl acetate (300 mL), washed with 1 M sodium hydroxide (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (conditioned with 0.1% 7 M ammonia in methanol) eluting with 20-30% methanol in dichloromethane to give 22 (0.86 g, 52%) as a white waxy solid. 1 H NMR(400 MHz, MeOH-d4) δ 7.56 -7.51 (m, 6 H),7.42 - 7.36 (m, 3 H), 7.16 (d, J = 9.0 Hz, 2 H), 6.84 (d, J = 8.9 Hz, 2 H),4.19 (dd, J = 15.6, 6.6 Hz, 1 H), 4.14 - 4.10 (m, 1 H),3.83 - 3.78 (m, 2 H),3.76 (s, 3 H), 3.65 (dd, J = 14.4, 7.6 Hz, 1 H), 3.60 (br t, J = 7.1 Hz, 1 H),3.40 (br t, J = 8.8 Hz, 1 H), 3.30 (d, J = 10.5 Hz, 1 H), 2.84 (dd, J = 13.5,9.2 Hz, 1 H), 2.75 (dt, J = 15.2, 3.0 Hz, 1 H), 2.55 (dd, J = 13.3, 8.6 Hz, 1H), 2.45 (dd, J = 13.3, 2.4 Hz, 1 H), 2.05 (s, 6 H); 13 C NMR (75MHz, MeOH-d4) δ 160.2, 157.3, 138.7, 134.2,132.7, 132.5, 132.3, 129.7, 129.6, 124.8, 123.5, 123.3, 115.1, 90.5, 90.2,77.0, 74.0, 71.3, 66.8, 58.2, 57.7, 56.0, 53.0, 52.1, 46.9, 46.0

[0122] Route B synthesis Reduction of methyl 4-bromocinnamate 1 to give 4-bromocinnamyl alcohol 23 [ka]

[0123] A 3 L three-neck round bottom flask was charged with methyl 4-bromocinnamate (1, 100 g, 414 mmol) and dichloromethane (1.1 L) to give a clear solution. The solution was cooled in a dry ice-acetone bath to give a milky mixture. The mixture was treated with a solution of diisobutylaluminum hydride (25 wt% in toluene, 586 mL, 871 mmol) to give a light greenish solution. The mixture was slowly brought to -5°C and carefully quenched in an ice bath with a solution of potassium sodium tartrate tetrahydrate (351 g, 1.24 mol) in water (800 mL). The mixture was stirred at room temperature overnight, treated with water (2 L) and extracted with methyl tert-butyl ether (1 L x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give 4-bromocinnamyl alcohol (23, 87.5 g, 99%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.46 - 7.44 (m, 2 H),7.27 - 7. 25 (m, 2 H), 6.58 (d, J = 16.0 Hz, 1 H), 6.37 (dt, J = 15.6, 5.5 Hz,1 H), 4.33 (dd, J = 5.8, 1.5Hz, 2H)

[0124] Bromination of 4-bromocinnamyl alcohol 23 to give 4-bromocinnamyl bromide 24 [ka]

[0125] A 5 L three-neck round bottom flask was charged with 4-bromocinnamyl alcohol (23, 329 g, 1.54 mol) and diethyl ether (3 L). An ice bath was used to cool the mixture to 5° C. during which the solution became slightly cloudy. A solution of tribromophosphane (72.6 mL, 772 mmol) in diethyl ether (200 mL) was added dropwise to the mixture while maintaining the internal temperature below 12° C., resulting in a nearly clear solution at the end of the addition. After stirring the mixture in the ice bath for 1 h, the mixture was quenched by slow addition of a solution of sodium bicarbonate (133 g, 1.57 mol) in water (1.5 L). The organic phase was separated and washed with brine (300 mL). The aqueous phase was extracted with methyl tert-butyl ether (1 L×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give pure 24 (404 g, 95%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.48 - 7. 45 (m, 2 H),7.25 - 7.24 (m, 2 H), 6.59 (d, J = 15.6 Hz, 1 H), 6.40 (dt, J = 15.6, 7.4 Hz, 1H), 4.15 (dt, J = 7.8, 0.7Hz, 2H)

[0126] Preparation of (ethyl (S,E)-2-((tert-butylsulfinyl)imino)acetate) 25 [ka]

[0127] Zinc-mediated crotylation of 25 to give (ethyl (2S,3S)-3-(4-bromophenyl)-2-(((S)-tert-butylsulfinyl)amino)pent-4-enoate) 26 [ka]

[0128] A 5 L three-neck round bottom flask was charged with 4-bromocinnamyl bromide (24, 175 g, 6363 mmol), 25 (87 g, 424 mmol) and N,N-dimethylformamide (1.3 L). The solution was stirred for 30 min and sparged with nitrogen gas. Zinc dust (55.4 g, 848 mmol) was added in small portions while maintaining the internal temperature below 48°C. The mixture initially turned green and then brown towards the end of the addition. After stirring the mixture at ambient temperature for 2 h, the reaction was quenched with water (1.3 L). The mixture was filtered through a pad of Celite and rinsed with methyl tert-butyl ether. The filtrate was taken up in water (1.3 L) and the aqueous phase was extracted with methyl tert-butyl ether (870 mL x 2). The combined organic phase was concentrated and the concentrate was filtered through a pad of Celite and rinsed with a small amount of methyl tert-butyl ether. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with ethyl acetate in heptane to give 26 (111 g, 65.2%) as a pale yellow oil. 1 H NMR(400 MHz, CDCl3) δ 7.44 - 7.40 (m, 2 H),7.05 - 7.03 (m, 2 H), 6.05 - 5.96 (m, 1 H), 5.17 - 5.11 (m, 2 H), 4.20 - 4.12(m, 3 H), 3.91 (d, J = 9.4 Hz, 1 H), 3.67 (t, J = 7.8 Hz, 1 H), 1.25 (s, 3 H)

[0129] Conversion of sulfinamide 26 to (ethyl (2S,3S)-3-(4-bromophenyl)-2-((2-nitrophenyl)sulfonamido)pent-4-enoate) 27 [ka]

[0130] A solution of 26 (2.48 g, 5.30 mmol) in tetrahydrofuran (21 mL) was treated with concentrated hydrogen chloride (37%, 2.18 mL, 26.5 mmol) and stirred at room temperature for 2 h. The reaction was quenched with aqueous sodium bicarbonate (20 mL) followed by solid sodium bicarbonate, and the mixture was no longer acidic. The mixture was extracted with methyl tert-butyl ether (200 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give a thick yellow oil.

[0131] The oil was taken up in dichloromethane (16 mL) and treated with 2-nitrobenzenesulfonyl chloride (1.29 g, 5.83 mmol) and triethylamine (1.11 mL, 7.95 mmol) to give an orange solution that was stirred at room temperature overnight. The mixture was taken up in methyl tert-butyl ether (200 mL) and washed with 1 M sodium hydroxide (30 mL). The aqueous phase was extracted with methyl tert-butyl ether (50 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with 15-40% ethyl acetate in heptane to give 27 (2.29 g, 89%) as a pale yellow gum. 1 H NMR(400 MHz, MeOH-d4) δ 7.50 - 7.32 (m, 3 H),7.23 - 7.19 (m, 2 H), 7.10 - 7.07 (m, 2 H), 5.97 - 5.88 (m, 1 H), 5.01 (dd, J =17.0, 1.0 Hz, 1 H), 4.95 (dd, J = 10.1, 1.3 Hz, 1 H), 4.06 (d, J = 10.5 Hz, 1H), 4.03 - 3.92 (m, 2 H), 3.58 (t, J = 9.8 Hz, 1 H), 1.76 (t, J = 7.0 Hz, 3 H)

[0132] Iodolactonization and azide substitution of 27 to give (N-((3S,4S,5S)-5-(azidomethyl)-4-(4-bromophenyl)-2-oxotetrahydrofuran-3-yl)-2-nitrobenzenesulfonamide) 29 [ka]

[0133] A solution of 27 (10.0 g, 20.7 mmol) in acetonitrile (80 mL) and water (3.2 mL) was treated with iodine (10.5 g, 41.3 mmol) to give a dark red solution which was stirred at room temperature after which all starting material had been consumed. The reaction was quenched with excess aqueous sodium thiosulfate and stirred at room temperature, turning the mixture pale yellow. The mixture was taken up in methyl tert-butyl ether, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude (N-((3S,4S,5S)-4-(4-bromophenyl)-5-(iodomethyl)-2-oxotetrahydrofuran-3-yl)-2-nitrobenzenesulfonamide) 28 (12 g) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.89 (dd, J = 8.1, 1.4Hz, 1 H), 7.81 (dd, J = 8.0, 1.4 Hz, 1 H), 7.72 (dt, J = 7.8, 1.5 Hz, 1 H),7.62 (dt, J = 7.8, 1.2 Hz, 1 H), 7.44 - 7.41 (m, 2 H), 7.15 - 7.12 (m, 2 H),6.25 (d, 9.0 Hz, 1 H), 4.81 (dd, J = 12.1, 9.0 Hz, 1 H), 4.27 - 4.22 (m, 1 H),3.48 - 3.41 (m, 2 H), 3.24 (dd, J = 11.9, 4.9 Hz, 1 H)

[0134] The crude 28 was taken up in N,N-dimethylformamide (65 mL) and treated with sodium azide (2.02 g, 31.0 mmol) to give a yellow suspension, which was stirred at room temperature overnight. The mixture was taken up in methyl tert-butyl ether, washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in heptane to give 29 (7.90 g, 77%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 0.9Hz, 1 H), 7.75 (dd, J = 7.8, 1.2 Hz, 1 H), 7.69 (dt, J = 7.6, 1.3 Hz, 1 H),7.57 (dt, J = 7.6, 1.2 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 2 H), 7.09 (d, J = 8.6Hz, 2 H), 6.46 (d, J = 9.0 Hz, 1 H), 4.79 (dd, J = 12.1, 9.0 Hz, 1 H), 4.58 -4.53 (m, 1 H), 3.63 - 3.53 (m, 2 H), 3.38 (dd, J = 13.9, 4.9 Hz, 1H)

[0135] Reduction of 29 to give (N-((2S,3S,4S)-5-azido-3-(4-bromophenyl)-1,4-dihydroxypentan-2-yl)-2-nitrobenzenesulfonamide) 30 [ka]

[0136] A yellow solution of 29 (9.10 g, 18.3 mmol) in ethanol (80 mL) was treated with sodium borohydride (1.04 g, 27.5 mmol) in small portions during which the mixture turned dark purple. After stirring the reaction at room temperature for 1 h, the reaction was quenched with 1 M HCl. The mixture was taken up in methyl tert-butyl ether, washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography eluting with 50-80% ethyl acetate in heptane to give 30 (8.20 g, 89%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 8.17 - 8.15 (m, 1 H),7.92 - 7.89 (m, 1 H), 7.80 - 7.75 (m, 2 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.10 (d,J = 8.2 Hz, 2 H), 5.45 (d, J = 9.0 Hz, 1 H), 4.41 - 4.37 (m, 1 H), 4.16 - 4.11(m, 1 H), 3.72 (brs, 1 H), 3.44 (dd, J = 11.4, 5.5 Hz, 1 H), 3.30 (dd, J =11.3, 7.0 Hz, 1 H), 3.23 (dd, J = 12.9, 2.7 Hz, 1 H), 3.00 - 2.91 (m, 2 H)

[0137] Bis-mesylation and tandem N-nucleophilic substitution to convert 30 to the azetidine (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)-1-((2-nitrophenyl)sulfonyl)azetidin-2-yl)methyl)isoindoline-1,3-dione) 32 [ka]

[0138] A solution of 30 (5.37 g, 10.7 mmol) and triethylamine (5.98 mL, 42.9 mmol) in dichloromethane (50 mL) was cooled to 0° C. and treated dropwise with methanesulfonyl chloride (2.08 mL, 26.8 mmol). After stirring the pale yellow cloudy mixture at this temperature for 2 h, the reaction was quenched with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product consisting of 31 and the aziridine intermediate.

[0139] The residue was taken up in N,N-dimethylformamide (35 mL) and treated with potassium carbonate (4.45 g, 32.2 mmol), potassium phthalimide (2.39 g, 12.9 mmol) and stirred at room temperature for 84 h. The mixture was taken up in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in heptane to give 32 (4.92 g, 75%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 8.14 (dd, J = 7.9, 1.6Hz, 1 H), 7.83 - 7.70 (m, 7 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.33 (d, J = 8.2 Hz,2 H), 4.91 (dd, J = 14.9, 6.7 Hz, 1 H), 4.56 - 4.50 (m, 1 H), 4.18 (dd, J =17.7, 6.0 Hz, 1 H), 3.77 - 3.68 (m, 3 H), 3.55 (dd, J = 12.7, 9.6 Hz, 1 H)

[0140] Deprotection and reductive amination to convert 32 to (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)-1-(((4S,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)azetidin-2-yl)methyl)isoindoline-1,3-dione) 35. [ka]

[0141] A solution of 32 (1.35 g, 2.21 mmol) and 1-dodecanethiol (0.635 mL, 2.65 mmol) in tetrahydrofuran (10 mL) was treated dropwise with a solution of potassium tert-butoxide (1 M in tetrahydrofuran, 2.65 mL, 2.65 mmol) at room temperature and then stirred for 5 h. The mixture was taken up in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)azetidin-2-yl)methyl)isoindoline-1,3-dione) 33 as a yellow gum.

[0142] A mixture of crude 33 (0.469 g, 1.10 mmol) and ((3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol) 34 (0.29 g, 1.53 mmol) in methanol (5 mL) was treated with acetic acid (0.315 mL, 5.50 mmol), sodium cyanoborohydride (0.104 g, 1.65 mmol) and stirred at room temperature, whereupon the reaction was complete. The mixture was taken up in ethyl acetate, washed with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified using silica gel column chromatography eluting with methanol in dichloromethane to give 35 (365 mg, 55%) as a colorless oil. 1H NMR(400 MHz, CDCl3) δ 7.77 - 7.74 (m, 2 H),7.71 - 7.67 (m, 2 H), 7.52 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 8.6 Hz, 2 H),6.11 (brs, 1 H), 4.53 - 4.48 (m, 1 H), 4.31 (dd, J = 9.3, 6.2 Hz, 1 H), 3.93 -3.75 (m, 7 H), 3.58 (dd, J = 13.9, 7.3 Hz, 1 H), 3.51 -3.46 (m, 1 H), 3.32 -3.24 (m, 2 H), 2.77 (dd, J = 12.5, 3.9Hz, 1H), 2.49 (brs, 1H), 1.41 (s, 3H), 1.33 (s, 3H)

[0143] Reductive amination of 33 with ((3aR,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol) 36 to give (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)-1-(((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)azetidin-2-yl)methyl)isoindoline-1,3-dione) 37 [ka]

[0144] Crude 35 (2.72 g, 6.38 mmol) and 36 (1.53 g, 9.57 mmol) were taken up in methanol (40 mL), acetic acid (1.83 mL, 31.9 mmol) and treated with sodium cyanoborohydride (0.601 g, 9.57 mmol). The mixture was stirred at room temperature and the reaction was complete. The mixture was taken up in methyl tert-butyl ether (500 mL) and washed with 1 M sodium hydroxide (50 mL) and brine (50 mL). The aqueous phase was back-extracted with methyl tert-butyl ether (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (conditioned with 70 mM ammonia) eluting with methanol in dichloromethane to give 37 (2.34 g, 64%) as a white foamy solid. 1 H NMR(400 MHz, CDCl3) δ 7.75 - 7.71 (m, 2 H),7.68 - 7.64 (m, 2 H), 7.48 - 7.45 (m, 2 H), 7.23 - 7.21 (m, 2 H), 4.43 - 4.34(m, 2 H), 4.01 (brs, 1 H), 3.81 - 3.66 (m, 6 H), 3.50 (dd, J = 13.7, 6.6 Hz, 1H), 3.42 (dd, J = 12.7, 6.5 Hz, 1 H), 3.21 (dd, 12.7, 6.5 Hz, 1 H), 3.08 (dd,12.9, 7.8Hz, 1H), 2.76 (dd, J = 12.9, 5.1 Hz, 1 H), 1.41 (s, 3 H), 1.31 (s, 3H)

[0145] Oxidative cleavage of 35 to give ((4S,5S)-5-(((2R,3S,4S)-2-(azidomethyl)-3-(4-bromophenyl)-4-((1,3-dioxoisoindolin-2-yl)methyl)azetidin-1-yl)methyl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde) 38 [ka]

[0146] A solution of 35 (2.73 g, 4.55 mmol) in tetrahydrofuran (33 mL) and water (3.6 mL) was treated with sodium periodate (1.46 g, 6.82 mmol) and stirred at room temperature for 2 h to give a white suspension. The mixture was taken up in methyl tert-butyl ether (500 mL) and washed with aqueous sodium thiosulfate (100 mL) and aqueous sodium bicarbonate (100 mL). The combined aqueous phases were back-extracted with methyl tert-butyl ether (150 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 38 as a colorless gum which was used without purification. 1 H NMR(400 MHz, CDCl3) δ 9.79 (d, J = 2.7 Hz, 1H), 7.78 - 7.75 (m, 2 H), 7.71 - 7.68 (m, 2 H), 7.52 - 7.49 (m, 2 H), 7.31 -7.29 (m, 2 H), 4.54 - 4.51 (m, 1 H), 4.47 - 4.44 (m, 2 H), 3.79 - 3.3.61 (m, 4H), 3.46 - 3.40 (m, 2 H), 3.21 - 3.19 (m, 1 H), 2.96 (dd, J = 13.7, 4.7 Hz, 1H), 2.80 (dd, J = 13.7, 5.5Hz, 1H), 1.60 (s, 3H), 1.41 (s, 3H)

[0147] Oxidation of 37 to give 38 [ka]

[0148] A solution of 37 (900 mg, 1.58 mmol) in dichloromethane (10 mL) was treated with Dess-Martin periodinane (803 mg, 1.89 mmol) and stirred at room temperature for 3 h. The mixture was taken up in ethyl acetate, washed with aqueous sodium thiosulfate, 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, and concentrated to give 38 as a colorless gum which was used without purification.

[0149] Aza-Wittig reaction of 38 and subsequent reduction to give (2-(((3aR,6aR,7R,8S,10aS)-7-(4-bromophenyl)-2,2-dimethyloctahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazocin-8-yl)methyl)isoindoline-1,3-dione) 40 [ka]

[0150] To a suspension of triphenylphosphane (1.79 g, 6.82 mmol) in methanol (13 mL) was added slowly a solution of crude 38 in methanol (39 mL) and tetrahydrofuran (7.8 mL) over 12 h to give a clear solution. After an additional 3 h, the solution was treated with acetic acid (0.78 mL, 13.6 mmol) and sodium cyanoborohydride (0.343 g, 5.46 mmol) and stirred for 3 h. The mixture was taken up in methyl tert-butyl ether, washed with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give 40 (1.88 g, 79%) as a white solid. 1H NMR(400 MHz, CDCl3) δ 7.81 - 7.77 (m, 2 H),7.71 - 7.64 (m, 2 H), 7.46 - 7.44 (m, 2 H), 7.40 - 7.38 (m, 2 H), 4.87 (brs, 3H), 4.39 - 4.34 (m, 1 H), 4.28 - 4.24 (m, 1 H), 3.75 (dd, J = 14.0, 5.5 Hz, 1H), 3.70 - 3.65 (m, 1 H), 3.60 - 3.55 (m, 2 H), 3.47 (dd, J = 14.2, 5. 3 Hz, 1H), 3.28 (dd, J = Hz, 1H), 3.27 (dd, J = 14.6, 9.8 Hz, 1 H), 3.08 (dd, J =14.7, 2.2 Hz, 1 H), 2.90 (dd, J = 13.2, 4.3 Hz, 1 H), 2.79 (dd, J = 13.6, 8.6Hz, 1 H), 2.71 - 2.60 (m, 2 H), 1.36 (s, 3 H), 1.32 (s, 3 H)

[0151] Conversion of 40 to ((3aR,6aR,7S,8S,10aS)-7-(4-bromophenyl)-8-((1,3-dioxoisoindolin-2-yl)methyl)-N-(4-methoxyphenyl)-2,2-dimethyloctahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazocine-5-carboxamide) 41 [ka]

[0152] A solution of 40 (70 mg, 0.133 mmol) in dichloromethane (1.5 mL) was treated with 4-methoxyphenyl isocyanate (0.026 mL, 0.199 mmol), triethylamine (0.028 mL, 0.199 mL) and maintained at room temperature for 2 h. The mixture was concentrated and the residue was purified using silica gel column chromatography eluting with approximately 60% ethyl acetate in heptane to give 41 (67 mg, 75%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 8.35 (s, 1 H), 7.85 -7.80 (m, 2 H), 7.73 - 7.69 (m, 2 H), 7.51 - 7.45 (m, 4 H), 7.23 - 7.19 (m, 2H), 6.85 - 6.80 (m, 2 H), 4.38 (d, J = 16.8 Hz, 1 H), 4.29 (brs, 2 H), 4.16 -4.10 (m, 1 H), 3.86 - 3.77 (m, 2 H), 3.77 (s, 3 H), 3.65 - 3.47 (m, 4 H), 2.79- 2.73 (m, 1H), 2.64 - 2.61 (m, 2 H), 1.44 (s, 3 H), 1.41 (s, 3 H)

[0153] Hydrolysis of acetonide 41 to give ((3S,4R,8R,9S,10S)-9-(4-bromophenyl)-10-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroxy-N-(4-methoxyphenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide) 42 [ka]

[0154] A solution of 41 (5.0 mg, 0.0074 mmol) in tetrahydrofuran (1 mL) and 1 M HCl (1 mL) was stirred for 3 h at 50° C. The solution was concentrated and the residue was purified by reverse-phase preparative HPLC to give 42 (3.8 mg, 81%) as a white solid. 1H NMR(400 MHz, CD3OD) δ 7.79 - 7.73 (m, 4 H),7.52 - 7.46 (m, 4 H), 7.11 - 7.07 (m, 2 H), 6.80 - 6.76 (m, 2 H), 4.14 (dd, J =15.5, 6.5 Hz, 1 H), 4.08 - 4.07 (m, 1 H), 3.82 - 3.68 (m, 4 H), 3.71 (s, 3 H),3.33 - 3.27 (m, 2 H), 2.82 - 2.73 (m, 2 H), 2.82 - 2.73 (m, 2 H), 2.67 - 2.63(m, 1H)

[0155] 42 can be converted to compound 22 following procedures previously described. See, for example, pages 53-55 of WO 2018 / 175385, which is incorporated by reference in its entirety. This process is shown in concise form as follows: [ka]

[0156] The structures for compounds 5 and 32 were confirmed by X-ray crystallography. ORTEP projections for compounds 5 and 32 are provided in Figures 1 and 2, respectively. ORTEP is an acronym for Oak Ridge Thermal Ellipsoid Plot, which is a representation of a molecular structure as determined by X-ray diffraction.

[0157] Further procedures that can be combined with the above procedures or used independently are set out below.

[0158] Hydrolysis of the o-nitrophenylsulfonamide of 12 using thioglycolic acid to give 13 [ka]

[0159] A reactor is charged with 12 (1.0 w / w, 1.0 equiv.), methanol (12 v / w) and tetrahydrofuran (4 v / w) at room temperature. Thioglycolic acid (0.221 v / w, 0.291 w / w, 2.0 equiv.) and potassium carbonate (0.874 w / w, 4.0 equiv.) are added in one portion each. The mixture is heated to an internal temperature of 50° C. and stirred for 3 h. An aliquot of the reaction is monitored for complete consumption of 12 using LCMS / UV. The reaction mixture is poured into a separate vessel with ethyl acetate (25 v / w) and water (18 v / w) for extraction. The aqueous phase is back-extracted twice with ethyl acetate (12 v / w). The organic phases are combined and washed with aqueous sodium bicarbonate (12 v / w) and then with 50% brine (12 v / w). The organic phase is dried over anhydrous sodium sulfate. The organic phase is filtered and concentrated under house vacuum (T bath Concentration using a rotary evaporator (° C.=37° C.) affords crude 13 (approximately 0.8 v / w, quantitative) as a yellow gum. Reaction volume: 17v / w Aftertreatment volume: 65v / w Expected Yield (%): Quantitative Maximum scale: 12 at 20g 1 H NMR(400 MHz, CDCl3) δ 7.84 - 7.82 (m, 2 H),7.72 - 7.67 (m, 2 H), 7.62 - 7.52 (m, 6 H), 7.39 - 7.32 (m, 3 H), 4.50 (dt, J =7.6, 4.5 Hz, 1 H), 4.25 (dd, J = 14.1, 7.0 Hz, 1 H), 3.91 (dd, J = 14.3, 7.8Hz, 1 H), 3.79 (t, J = 7.6 Hz, 1 H), 3.53 (dd, J = 14.2, 4.4 Hz, 1 H), 3.35(dd, J = 12.6, 7.1Hz, 1H), 3.20 (dd, J = 12.6, 6.6 Hz, 1 H); 13CNMR (75 MHz, CDCl3) δ168.2, 135.6, 134.3,134.0, 132.0, 131.6, 131.6, 130.6, 128.4, 128.3, 123.3, 122.5, 89.9, 89.2,57.5, 57.2, 52.0, 46.7, 40.2

[0160] Reductive amination of 13 with 14 to give 15-HCl (HCl salt of 15) [ka]

[0161] A reactor is charged with crude 13 (prepared as above, 1.0 w / w, 1.0 equiv.), 14 (0.850 w / w, 2.0 equiv.) and ethanol (10 v / w). To this mixture is added acidic acid (0.640 v / w, 0.671 w / w, 5.0 equiv.) and then sodium cyanoborohydride (0.281 w / w, 2.0 equiv.), all at once at room temperature. 1 The mixture is stirred at room temperature for 12-18 h. An aliquot of the reaction is monitored for complete consumption of 13 using LCMS / UV. Saturated aqueous sodium bicarbonate (18 v / w), 2 The reaction is then quenched using ethyl acetate (35 v / w) and the mixture is stirred at room temperature for 10 min. Using a separatory vessel, the two phases are separated and the aqueous phase is back-extracted twice with ethyl acetate (15 v / w). The organic phases are combined, washed with brine (18 v / w) and dried over anhydrous sodium sulfate. Filter and then evaporate under house vacuum (T bath The organic phase is concentrated using a rotary evaporator (pH = 37 °C). The residue is taken up in ethyl acetate (35 v / w) and filtered through a plug of silica gel to remove insoluble material. The clear filtrate is cooled on an ice bath and 3 4M HCl-dioxane solution (0.071 v / w, 1.05 eq.) is added slowly over 10 min. The white suspension is stirred in an ice bath for 10 min, then stirring is stopped and the mixture is maintained for another 20 min to allow precipitation of a white solid. 4The mixture is filtered to first obtain a clear supernatant and then a suspension of a white solid. The filter cake is washed with ethyl acetate. The filter cake is dried in a house vacuum drying oven at 40° C. to obtain 15-HCl (0.813 w / w, 55%) as a white solid. Expected Yield(%):>55% Maximum scale: 12 at 20g 1 H NMR(400 MHz, MeOH-d4) δ7.83 - 7.78 (m, 4 H),7.57 - 7.51 (m, 6 H), 7.40 - 7.38 (m, 3 H), 5.4208 (dt, J = 9.7, 6.6 Hz, 1 H),4.93 - 4. 85 (m, 1 H), 4.59 (dd, 8.5, 6.5 Hz, 1 H), 4.45 - 4.34 (m, 2 H), 4.21(dd, J = 8.7, 6.4 Hz, 1 H), 4.14 - 3.94 (m, 3 H), 3.76 (d, J = 9.0 Hz, 1 H),3.69 - 3.58 (m, 4 H), 1.48 (s, 3H), 1.08 (s, 3H); 13 C NMR (75 MHz,MeOH-d4) δ168.9, 135.7, 133.1, 133.1, 132.6,132.5, 131.9, 131.8, 129.8, 129. 6, 125.2, 124.4, 124.2, 111.6, 91.5, 89.2,77.5, 74.4, 71.0, 69.2, 68.9, 65.0, 59.3, 43.7, 37.5, 28.1, 25.2

[0162] Oxidative cleavage of 1,2-diol 15-HCl using sodium periodate [ka]

[0163] A reactor is charged with compound 15-HCl (1.0 w / w, 1.0 equiv.), tetrahydrofuran (15 v / w, 13.2 w / w) and water (5 v / w, 5 w / w). Sodium periodate (0.650 w / w, 2.0 equiv.) is added in one portion. The mixture is stirred at room temperature for 1-2 h. An aliquot of the reaction mixture is monitored for complete consumption of 15 using LCMS / UV. The mixture is poured into ethyl acetate (36 v / w, 32.4 w / w) and washed with aqueous sodium bicarbonate (12 v / w) and then 50% brine (12 v / w). The organic phase is dried over anhydrous sodium sulfate and filtered. The mixture is stirred under house vacuum (T bath = 37 °C) Rotavap evaporator to give crude 16 (ca. 0.9 w / w, quantitative) as a colorless oil. Expected Yield(%): 100% Maximum scale: 8.3 g of 15·HCl 1 H NMR(400 MHz, CDCl3) δ9.82 (d, J = 2.8 Hz, 1 H),7.79 - 7.76 (m, 2 H), 7.71 - 7.67 (m, 2 H), 7.58 - 7.53 (m, 4 H), 7.44 - 7.42(m, 2 H), 7.39 - 7.35 (m, 3 H), 4.55 (dd, J = 11.9, 5.8 Hz, 1 H), 4.48 (dd, J =7.2, 2.8 Hz, 1 H), 3.82 - 3.67 (m, 3 H), 3.50 - 3.41 (m, 2 H), 3.27 - 3.22 (m,1 H), 2.98 (dd, J = 13.6, 4.7 Hz, 1 H), 2.82 (dd, J = 13.6, 5.7 Hz, 1 H), 1.61(s, 3 H), 1.42 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ199.9, 167.8, 135.3, 134.0, 131.8, 131.7, 131.6, 130.6, 128.3,128.2, 123.3, 123.2, 122.4, 110.9, 89.8, 89.2, 81.4, 66.7, 66.4, 56.9, 50.2,44.2, 38.1, 27.3, 22.7

[0164] Tandem Staudinger / Aza-Wittig / reduction to convert 16 to 18·HCl [ka]

[0165] The reactor is charged with triphenylphosphine (0.128 w / w, 1.2 eq.) and ethanol (7 v / w, 5.52 w / w). To this mixture is added slowly a solution of crude 16 (prepared as above, 1.0 w / w, 1.0 eq.) in ethanol (10 v / w, 7.89 w / w) and tetrahydrofuran (5 v / w, 4.40 w / w) over 1.5 h at room temperature. The reaction mixture is further stirred at room temperature for 12 h and monitored for complete consumption of 16 using LCMS / UV of an aliquot of the reaction mixture. Sodium cyanoborohydride (0.128 w / w, 1.2 eq.) and acetic acid (0.291 v / w, 0.306 w / w, 3.0 eq.) are added in one portion each. 1 The mixture is stirred at this temperature for 0.5-1 h and monitored for complete consumption of the imine intermediate (not shown) using LCMS / UV of an aliquot of the reaction mixture. The reaction is quenched with aqueous sodium bicarbonate (30 v / w) and extracted with ethyl acetate (30 v / w). The aqueous phase is further extracted twice with ethyl acetate (12 v / w). The organic phases are combined, washed with brine (12 v / w) and dried over anhydrous sodium sulfate. The organic phase is filtered and concentrated under house vacuum (T bathConcentrate using a rotary evaporator (at 37° C.). Take up the residue in ethyl acetate (35 v / w) and filter to remove insoluble material. Cool the solution in an ice bath. Slowly add 4M HCl in dioxane (0.054 v / w, 0.065 w / w, 1.05 equiv.) over 10 min with stirring. Stir the resulting white suspension further in the ice bath for 10 min, then stop stirring and hold the mixture for another 20 min to allow precipitation of a white solid. 2 The mixture is filtered, the filter cake is washed with ethyl acetate, and the filter cake is dried in a house vacuum drying oven at 40° C. to give 18-HCl (0.81 w / w, 82%) as a white solid. Expected Yield(%): 80% Maximum scale: 8.3g of 18-HCl 1) Additional Spectral Data [ka] Compound 18: 1 HNMR (400 MHz, CDCl3) δ7.82 - 7.78 (m, 2 H),7.71 - 7.65 (m, 2 H), 7.55 - 7.49 (m, 6 H), 7.38 - 7.31 (m, 3 H), 4.40 - 4.35(m, 1 H), 4.23 - 4.19 (m, 1 H), 3.79 (dd, J = 14.2, 5.5 Hz, 1 H), 3.70 (dd, J =11.7, 6.0 Hz, 1 H), 3.51 (dd, J = 14.2, 5.2 Hz, 1 H), 3.28 (dd, J = 14.6, 8.5Hz, 1 H), 3.09 (dd, J = 14.6, 2.4 Hz, 1 H), 2.87 - 2.68 (m, 3 H), 2.59 (brd, J= 13.3 Hz, 1 H), 1.74 (brs, 1 H), 1.39 (s, 3 H), 1.33 (s, 3 H); 13CNMR (75 MHz, CDCl3) δ167.9, 136.6, 133.9,131.9, 131.5, 131.2, 130.8, 128.3, 128.1, 123.3, 123.2, 121.8, 106.8, 89.5,89.3, 77.7, 68.2, 65.1, 57.7, 48.7, 45.5, 44.7, 38.5, 27.8, 25.1

Chem.

[0166] Although embodiments of the present invention have been described with reference to certain illustrative embodiments and examples, it will be appreciated that the embodiments disclosed herein are for illustrative purposes only and that various modifications and changes can be made by those skilled in the art without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 2】 and R ２ is C(O)R ３ and R ３ Is -O － wherein a positive counterion is ionically bonded to formula I; P １ is a nitrogen protecting group) A method for forming a solid compound represented by formula II 【Chemistry 3】 with a base, and resolving the racemic mixture by crystallization with a chiral reagent.

2. R １ but, 【Chemistry 4】 The method of claim 1, wherein

3. P １ is -C(O)CF ３ , -C(O)OC(CH ３ ) ３ , and -C(O)OCH ２ 3. The method of claim 2, wherein the cation exchanger is selected from the group consisting of phosphate phosphate (Pt), phosphate phosphate (Pb), phosphate phosphate (Pt ...

4. P １ is -C(O)CF ３ The method according to claim 3, wherein

5. The step of reacting with a base is lithium diisopropylamine, ZnCl ２ The method of claim 4, wherein the method is in the presence of

6. The method of claim 5, wherein the chiral reagent is (R)-(+)-1-phenylethylamine.

7. Formula I: 【Chemistry 5】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 6】 and R ２ is C(O)R ３ and R ３ is -Oalkyl; P １ is a nitrogen protecting group) A method of forming a compound represented by formula III 【Chemistry 7】 (In the formula, X １ is a halogen atom) reacting the reactant of with a chiral sulfinyl imine.

8. R １ and X １ are each -Br, The chiral sulfinyl imine is 【Chemistry 8】 (In the formula, R ４ and R ５ is linear or branched alkyl That is, The method according to claim 7.

9. R ４ But -C(CH ３ ) ３ and R ５ But -CH ２ CH ３ The method according to claim 8, wherein

10. 10. The method of claim 9, wherein the reacting step is in the presence of Zn.

11. Formula IV 【Chemistry 9】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 10】 and P １ and P ２ are the same or different and represent a nitrogen protecting group) A method for forming a compound represented by formula V 【Chemistry 11】 The lactone of formula I 【Chemistry 12】 (In the formula, R ２ is C(O)R ３ and R ３ is -OH, -Oalkyl, -O － and R ３ Ga-O － A positive counterion is ionically bonded to Formula I when P １ is a nitrogen protecting group) forming from a compound of Reacting said lactone of formula V with a compound of formula VI 【Chemistry 13】 and A method comprising converting an alcoholic group covalently attached to the unsaturated carbon of formula VI to a leaving group to form an intermediate which reacts with a nitrogen nucleophile to generate a compound of formula IV.

12. The method of claim 11 , wherein the nitrogen nucleophile is a phthalimide.

13. R １ but, 【Chemistry 14】 and R ２ -C(O)O － And P １ is -C(O)CF ３ The method of claim 12, wherein

14. 14. The method of claim 13, wherein the lactone of formula V is formed by reacting a compound of formula I with an electropositive source of halogen in a polar solvent.

15. The electropositive source of halogen is I ２ and the polar solvent is CH ３ 15. The method of claim 14, wherein the aqueous mixture of CN is CN.

16. The lactone of formula V is a compound of formula I ２ in a polar solvent to form a first product, and reacting the first product with NaN ３ to form a compound of formula V.

17. The reducing step comprises reducing with NaBH ４ The method of claim 16, wherein the method is carried out using

18. The leaving group is a mesylate group and the intermediate has the following structure: 【Chemistry 15】 The method of claim 17, wherein the method is represented by one or both of the following:

19. P １ is -C(O)CF ３ to the following structure: 【Chemistry 16】 The method of claim 18, wherein

20. R １ is -Br, and R ２ is -C(O)OCH ２ CH ３ And P １ But -S(O)C(CH ３ ) ３ The method of claim 11, wherein

21. P １ But -S(O)C(CH ３ ) ３ to the following structure: 【Chemistry 17】 The method of claim 20, wherein

22. The lactone of formula V is prepared by reacting a compound of formula I with an electropositive source of halide in a polar solvent to form a first product, and reacting the first product with NaN ３ to form a compound of formula V.

23. The lactone of formula V is NaBH ４ to give the following compound: 【Chemistry 18】 23. The method of claim 22, further comprising forming

24. The leaving group is a mesylate group and the intermediate has the following structure: 【Chemistry 19】 24. The method of claim 23, wherein the method is represented by one or both of the following:

25. The following structure: 【Chemistry 20】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 21】 and R ６ and R ７ are independently the same or different and are selected from -H, alkyl, -Oalkyl, or R ６ and R ７ form a ring together with the atoms to which they are attached; R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ together with the N to which they are attached form a monocyclic or bicyclic ring system; R １０ is —H, straight chain or branched alkyl, —C(O)alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —C(O)aryl, —C(O)O-aryl, —C(O)NH-aryl, —C(O)heteroaryl, —C(O)O-heteroaryl, and —C(O)N-heteroaryl; The alkyl, aryl and heteroaryl are optionally substituted with one or more halogen, oxygen, nitrogen or sulfur atoms. A method for making a compound represented by formula IV 【Chemical 22】 with a substituted γ-hydroxyaldehyde and effecting bicyclization.

26. The γ-hydroxyaldehyde has the following structure: 【Chemistry 23】 (In the formula, R １１ is —H or an oxygen protecting group; R １２ is -H or -CH ２ OH) 26. The method of claim 25, wherein the

27. The γ-hydroxyaldehyde is 【Chemistry 24】 and the compound of formula VIII is prepared by the following intermediate: 【Chemistry 25】 The method of claim 26, wherein the polymer is prepared via

28. It comprises an oxidation step, and the compound of formula VIII is obtained by the following intermediate: 【Chemistry 26】 The method of claim 27, wherein the polymer is produced via

29. The compound of formula VIII is obtained by the following intermediate: 【Chemical 27】 The method of claim 28, wherein the polymer is prepared via

30. A further reduction step is included to afford the compound of formula VIII as the following intermediate: 【Chemistry 28】 The method of claim 29, wherein the polymer is prepared via

31. The compound of formula XIII is reacted with 4-methoxyphenylisocyanate to give a compound of formula VIII having the following structure: 【Chemical 29】 The method of claim 30, wherein the

32. Formula IV 【Chemistry 30】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 31】 and P １ and P ２ are the same or different and represent a nitrogen protecting group) A method for forming a compound represented by formula VI 【Chemistry 32】 by converting an alcoholic group covalently bonded to the unsaturated carbon of formula (IV) into a leaving group to form an intermediate which reacts with a nitrogen nucleophile to generate a compound of formula (IV).

33. The leaving group is a mesylate group and the intermediate has the following structure: 【Chemical 33】 33. The method of claim 32, wherein the method is represented by one or both of the following:

34. 34. The method of claim 33, wherein the nitrogen nucleophile is a phthalimide.

35. Compound of formula XV: 【Chemical 34】 [In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 35】 and Z is, 【Chemical 36】 (In the formula, P １ and P ２ are the same or different and are a nitrogen protecting group or -H), or a pharma- ceutically acceptable salt thereof; 【Chemical 37】 (In the formula, R ６ and R ７ are independently the same or different and are selected from -H, alkyl, -Oalkyl, or R ６ and R ７ form a ring together with the atoms to which they are attached; R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form, together with the N to which they are attached, a monocyclic or bicyclic ring system; R １０ is -H, straight chain or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, wherein alkyl, aryl, and heteroaryl are substituted by one or more halogen, hydrogen, oxygen, nitrogen, or sulfur atoms, or a pharma- ceutically acceptable salt thereof; 【Chemical Formula 38】 (In the formula, R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form together with the N to which they are attached a monocyclic or bicyclic ring system, and the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms, or a pharma- ceutically acceptable salt thereof; 【Chemical Formula 39】 (In the formula, R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form together with the N to which they are attached a monocyclic or bicyclic ring system, and the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms, or a pharma- ceutically acceptable salt thereof; 【Chemistry 40】 (In the formula, R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form, together with the N to which they are attached, a monocyclic or bicyclic ring system, and the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms, or a pharma- ceutically acceptable salt thereof; and 【Chemistry 41】 (In the formula, R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form a monocyclic or bicyclic ring system together with the N to which they are attached, and the alkyl is optionally substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms, or a pharma- ceutically acceptable salt thereof. and wherein R is a substituted 4-membered nitrogen-containing heterocycle selected from the group consisting of:

36. Formula IV: 【Chemistry 42】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 43】 and P １ and P ２ are the same or different and are a nitrogen protecting group or -H. or a pharma- ceutically acceptable salt thereof.

37. Formula VIII: 【Chemistry 44】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 45】 and R ６ and R ７ are independently the same or different and are selected from -H, alkyl, -Oalkyl, or R ６ and R ７ form a ring together with the atoms to which they are attached; R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form, together with the N to which they are attached, a monocyclic or bicyclic ring system; R １０ is -H, straight chain or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, wherein alkyl, aryl, and heteroaryl are substituted by one or more halogen, hydrogen, oxygen, nitrogen, or sulfur atoms. or a pharma- ceutically acceptable salt thereof.

38. Formula X: 【Chemistry 46】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 47】 and R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form a monocyclic or bicyclic ring system together with the N to which they are attached, and the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms. or a pharma- ceutically acceptable salt thereof.

39. Formula XI: 【Chemistry 48】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 49】 and R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form a monocyclic or bicyclic ring system together with the N to which they are attached, and the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms. or a pharma- ceutically acceptable salt thereof.

40. Formula XII: 【Chemistry 50】 (In formula XII, R １ is -I, -Cl, -Br, or 【Chemistry 51】 and R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ form a monocyclic or bicyclic ring system together with the N to which they are attached, and the alkyl is substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms. or a pharma- ceutically acceptable salt thereof.

41. Formula XIII: 【Chemistry 52】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 53】 and R ８ and R ９ are independently the same or different and are -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ together with the N to which they are attached form a monocyclic or bicyclic ring system, and the alkyl is optionally substituted by one or more halogen, hydrogen, oxygen, nitrogen or sulfur atoms. or a pharma- ceutically acceptable salt thereof.

42. Formula XV: 【Chemical Formula 54】 [In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 55】 and Z is, 【Chemistry 56】 (In the formula, R ２ is C(O)R ３ and R ３ Is -O － and a positive counterion is ionically bonded to formula XVI or R ３ is —OH; P １ is a nitrogen protecting group or -H; 【Chemistry 57】 (In the formula, P １ is a nitrogen protecting group or -H; 【Chemistry 58】 (In the formula, P １ is a nitrogen protecting group or -H; 【Chemistry 59】 (In the formula, P １ is a nitrogen protecting group or -H; and 【Chemistry 60】 (In the formula, P １ is a nitrogen protecting group or -H), or a pharma- ceutically acceptable salt thereof. selected from the group consisting of or a pharma- ceutically acceptable salt thereof.

43. Formula I: 【Chemistry 61】 (In the formula, R １ teeth, 【Chemistry 62】 and R ２ is C(O)R ３ and R ３ Is -O － and a positive counterion is ionically bonded to formula I or R ３ is —OH; P １ is a nitrogen protecting group or -H.

43. The compound or pharma- ceutically acceptable salt thereof of claim 42, which is a compound of the formula:

44. Formula V: 【Chemistry 63】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 64】 and P １ is a nitrogen protecting group or -H.

43. The compound or pharma- ceutically acceptable salt thereof of claim 42, which is a compound of the formula:

45. Formula VI: 【Chemistry 65】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 66】 and P １ is a nitrogen protecting group or -H.

43. The compound or pharma- ceutically acceptable salt thereof of claim 42, which is a compound of the formula:

46. Formula VII: 【Chemistry 67】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 68】 and P １ is a nitrogen protecting group or -H.

43. The compound or pharma- ceutically acceptable salt thereof of claim 42, which is a compound of the formula:

47. Formula VIIb: 【Chemistry 69】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 70】 and P １ is a nitrogen protecting group or -H.

43. The compound or pharma- ceutically acceptable salt thereof of claim 42, which is a compound of the formula:

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