Methods for Producing Macrocyclic Compounds with ENT1 Inhibitory Activity - Patent application

Abstract

The present disclosure relates in particular to compound (R)-11: [Formula 1] The present invention also includes a method for producing TIFF2024535501000104.tif65102 or a pharma- ceutically acceptable salt thereof. Compound (R)-11 is useful for treating or reducing the severity of cancer.

Description

[Technical field]

[0001] Field The present disclosure relates to the synthesis of macrocyclic diamines. More particularly, the present disclosure relates to the production of inhibitors of ENT family transporters, particularly ENT1, that are useful as therapeutic compounds, particularly in the treatment of cancer. [Background technology]

[0002] background The equilibrative nucleoside transporter (ENT) family (also known as SLC29) is a group of plasma membrane transport proteins that transport nucleoside substrates into cells. There are four known ENTs, designated ENT1, ENT2, ENT3, and ENT4.

[0003] One of the endogenous substrates of ENT is adenosine, which is a potent physiological and pharmacological regulator of many functions. Cell signaling by adenosine occurs through four known G protein-coupled adenosine receptors A1, A2A, A2B, and A3. By influencing the concentration of adenosine available to these receptors, ENT plays an important regulatory role in various physiological processes such as regulation of coronary blood flow, inflammation, and neurotransmission (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3).

[0004] Adenosine is also a potent immunosuppressive metabolite that is frequently found elevated in the extracellular tumor microenvironment (TME) (Non-Patent Document 4). Extracellular adenosine is mainly generated by the conversion of ATP by the ectonucleotidases CD39 and CD73 (Non-Patent Document 5). Adenosine activates four G protein-coupled receptor subtypes (A1, A2A, A2B, and A3). In particular, activation of the A2A receptor is thought to be a major driver of innate and adaptive immune cell suppression that leads to the suppression of antitumor immune responses (Non-Patent Document 6) (Non-Patent Document 7) (Non-Patent Document 8) (Non-Patent Document 9) (Non-Patent Document 10) (Non-Patent Document 11).

[0005] The applicant previously demonstrated in Patent Document 1 that both adenosine and ATP greatly inhibit T cell proliferation and cytokine secretion (IL-2) and strongly reduce T cell viability. The adenosine-mediated and ATP-mediated inhibition of T cell viability and proliferation was successfully restored by using an ENT inhibitor. Furthermore, the use of an ENT inhibitor in combination with an adenosine receptor antagonist not only allowed the adenosine-mediated and ATP-mediated inhibition of T cell survival and proliferation to be restored, but also restored T cell cytokine secretion. These results indicated that ENT inhibitors, either alone or in combination with an adenosine receptor antagonist, may be useful in the treatment of cancer.

[0006] Various drugs such as dilazep, dipyridamole, and draflazine interact with ENT and alter adenosine levels and have been developed for their cardioprotective or vasodilatory effects. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] PCT / EP2019 / 076244 [Non-patent literature]

[0008] [Non-Patent Document 1] Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181 [Non-Patent Document 2] Shryock JC and Belardinelli L, Am J Cardiol, 1997, 79(12A), 2-10 [Non-Patent Document 3] Anderson CM et al., J Neurochem, 1999, 73, 867-873 [Non-Patent Document 4] Blay J et al., Cancer Res, 1997, 57, 2602-2605 [Non-Patent Document 5] Stagg J and Smyth MJ, Oncogene, 2010, 2, 5346-5358 [Non-Patent Document 6] Ohta and Sitkovsky, Nature, 2001, 414, 916-920 [Non-Patent Document 7] Stagg and Smyth, Oncogene, 2010, 2, 5346-5358 [Non-Patent Document 8] Antonioli L et al., Nature Reviews Cancer, 2013, 13, 842-857 [Non-Patent Document 9] Cekic C and Linden J, Nature Reviews, Immunology, 2016, 16, 177-192 [Non-Patent Document 10] Allard B et al., Curr Op Pharmacol, 2016, 29, 7-16 [Non-Patent Document 11] Vijayan D et al., Nature Reviews Cancer, 2017, 17, 709-724 [Non-Patent Document 12] Vlachodimou et al., Bio-Chemical Pharmacology, 2020, 172, 113747 Summary of the Invention [Problem to be solved by the invention]

[0009] At present, two non-selective ENT1 inhibitors (dilazep and dipyridamole) are on the market (Non-Patent Document 12). However, their binding kinetics are unknown; in addition, there is still a need for more potent ENT inhibitors, and especially for ENT1 inhibitors for use in the treatment of cancer, either alone or in combination with adenosine receptor antagonists.

[0010] As a result, there remains a need for efficient and cost-effective methods for producing ENT1 inhibitors in high yields. The present disclosure provides a viable method for producing high-value key intermediates for ENT1 inhibitors. [Means for solving the problem]

[0011] Abstract The present disclosure relates to compound (R)-11: [ka] or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description The present disclosure relates to the synthesis of key intermediates useful in the synthesis of ENT1 inhibitors.

[0013] Generally, the synthetic route for any individual compound of the present disclosure depends on the specific substituents of each molecule and the ready availability of the necessary intermediates; such factors are further understood by those skilled in the art. According to further general methods, the compounds of the present disclosure can be converted to alternative compounds of the present disclosure using suitable interconversion techniques well known to those skilled in the art. Of course, any process disclosed herein can be made enantioselective by using suitable reagents. Furthermore, the present disclosure contemplates the use of enantioenriched starting materials. In some embodiments, the reactions disclosed herein that result in chiral products can be produced using separation methods known in the art for separating one enantiomer from another.

[0014] In some embodiments, the synthesis of compound (R)-11 can be accomplished by a method including any of steps 1-10 summarized in Scheme 1.

[0015] Scheme 1 [ka]

[0016] Scheme 2 [ka]

[0017] Scheme 3 [ka]

[0018] In some embodiments, PG 1 are suitable hydroxyl protecting groups. The term "hydroxyl protecting group" is likewise known in general terms and relates to groups which are suitable for protecting hydroxyl groups against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, but also alkyl groups. The nature and size of the hydroxyl protecting group is not very critical, since it is removed again after the desired chemical reaction or series of reactions; groups having 1 to 20, in particular 1 to 10, carbon atoms are preferred. Examples of hydroxyl protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.

[0019] In some embodiments, PG 1is selected from the group consisting of acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT), methoxymethyl ether (MOM), methoxytrityl[(4-methoxyphenyl)diphenylmethyl] (MMT), p-methoxybenzyl ether (PMB), p-methoxyphenyl ether (PMP), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), trityl (triphenylmethyl, Tr), and silyl ether. In some embodiments, PG is 1 is a silyl ether. In some embodiments, PG 1 is selected from the group consisting of trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers. In some embodiments, PG 1 is tert-butyldimethylsilyl (TBS).

[0020] In some embodiments, PG 2 is selected from the group consisting of acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT), methoxymethyl ether (MOM), methoxytrityl[(4-methoxyphenyl)diphenylmethyl] (MMT), p-methoxybenzyl ether (PMB), p-methoxyphenyl ether (PMP), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), trityl (triphenylmethyl, Tr), and silyl ether. In some embodiments, PG is 2 is a C1-C6 aliphatic. In some embodiments, PG 2 is t-Bu.

[0021] In some embodiments, PG 3is an amino-protecting group. The term "amino-protecting group" is known in general terms and relates to groups suitable for protecting (blocking) an amino group against chemical reaction, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since amino-protecting groups are removed after the desired reaction (or series of reactions), their type and size are even less critical; however, those having 1 to 20, in particular 1 to 8, carbon atoms are preferred. The term "acyl group" is to be understood in the broadest sense in connection with the method of the present disclosure. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxy-carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-carbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protecting groups are BOC and Mtr, as well as CBZ, Fmoc, benzyl and acetyl.

[0022] BOC, OtBu and Mtr groups can be cleaved, for example, preferably using TFA in dichloromethane or about 3-5N HCl in dioxane at 15-30° C., and FMOC groups can be cleaved using about a 5-50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30° C.

[0023] Protecting groups which can be removed by hydrogenolysis (e.g. liberation of an amidino group from CBZ, benzyl or its oxadiazole derivatives) can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst, e.g. palladium, advantageously on a support such as carbon).

[0024] Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0° C. and 100° C. and pressures between about 1 bar and 200 bar, preferably at 20-30° C. and 1-10 bar. The hydrogenolysis of the CBZ group is well-successful at 20-30° C., for example, with 5-10% Pd / C in methanol, or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF.

[0025] It is also possible that several identical or different protected amino and / or hydroxyl groups are present in the starting molecule. When the protecting groups present are different from one another, they can often be selectively cleaved.

[0026] The compounds described herein are liberated from their functional derivatives, depending on the protecting group used, for example from strong inorganic acids such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid, TFA, or sulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary.

[0027] In some embodiments, the oxidation of compound 1_1 can be achieved using methods known to those skilled in the art. For example, the oxidation of compound 1_1 can be achieved using an oxidizing agent that is Py.SO3. In some embodiments, the oxidation of compound 1_1 can be achieved using Py.SO3, TEA, and DMSO. In some embodiments, the oxidation of compound 1_1 can be achieved using Py.SO3, TEA, and DMSO in DCM.

[0028] In some embodiments, esterification of compound 3A can be achieved by treating compound 3 with an azodicarboxylate. In some embodiments, the azodicarboxylate is DEAD or DIAD. In some embodiments, the azodicarboxylate is DEAD.

[0029] In some embodiments, hydroboration-oxidation of compound 4 can be achieved by treating compound 4 with BH3, followed by an oxidative post-treatment, such as NaBO3.

[0030] In some embodiments, compound 6 can be prepared by treating compound 5 with an azodicarboxylate and compound 5A. In some embodiments, the azodicarboxylate is DEAD or DIAD. In some embodiments, the azodicarboxylate is DEAD.

[0031] In some embodiments, LG is selected from the group consisting of halogen, -OTf, -OMs, and -OTs. In some embodiments, LG is selected from the group consisting of -OMs.

[0032] Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, as well as alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the aforementioned solvents are furthermore suitable. TFA is preferably used in excess without adding further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction temperature for the cleavage is advantageously between about 0 and about 50° C., preferably between 15 and 30° C. (room temperature).

[0033] Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyl-formamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the abovementioned solvents.

[0034] Esters can be hydrolyzed, for example, using HC1, H2SO4, or using LiOH, NaOH or KOH, for example, in water, water / THF, water / THF / ethanol or water / dioxane at temperatures between 0°C and 100°C.

[0035] The free amino groups may further be acylated using acyl chlorides or acyl anhydrides or alkylated using unsubstituted or substituted alkyl halides in conventional manner, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60°C and +30°C.

[0036] For all protection and deprotection methods see Philip J. Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, and Theodora W. Greene and Peter GM Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999.

[0037] The reaction schemes depicted in the Examples section are illustrative only and should not be construed as limiting the disclosure in any way.

[0038] In some embodiments, compound (R)-11 is at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.9% enantiomerically pure.

[0039] Enumerated embodiments The present disclosure includes the following embodiments 1-84:

[0040] 1. Compound (R)-11 [ka] or a pharma- ceutically acceptable salt or solvate thereof, comprising reacting compound 11: [ka] The above method further comprises a step of separating compound (R)-11 from a racemic mixture of

[0041] 2. The method of embodiment 1, wherein the step of separating compound (R)-11 is accomplished using chiral supercritical fluid chromatography (chiral SFC).

[0042] 3. Reacting compound 10 with a peptide coupling reagent to produce compound 11: [ka] 3. The method of any one of embodiments 1 to 2, further comprising:

[0043] 4. The method of embodiment 3, wherein the peptide coupling reagent is selected from the group consisting of BOP, PyBOP, HATU, and HBTU.

[0044] 5. The method of any one of embodiments 3 to 4, wherein the peptide coupling reagent is PyBOP.

[0045] 6. Deprotecting compound 9 by reacting compound 9 with an acid to produce compound 10: [ka] 6. The method of any one of embodiments 3 to 5, further comprising:

[0046] 7. The method of embodiment 6, wherein the acid is HCl.

[0047] 8. Reacting compound 8 with compound 8A to produce compound 9: [ka] 7. The method according to any one of embodiments 5 to 6, further comprising:

[0048] 9. The method of embodiment 8, wherein the step of reacting compound 8 with compound 8A comprises adding a suitable base.

[0049] 10. The method of embodiment 9, wherein the suitable base is selected from the group consisting of K2CO3, Na2CO3, and Ca2CO3.

[0050] 11. The method of embodiment 10, wherein the suitable base is K2CO3.

[0051] 12. Reacting compound 7 with a mesylating agent to produce compound 8: [ka] 12. The method of any one of embodiments 8 to 11, further comprising:

[0052] 13. The method of embodiment 12, wherein the mesylating agent is MsCl.

[0053] 14. The method of any one of embodiments 12-13, wherein the step of reacting compound 7 with a mesylating agent comprises adding a suitable base.

[0054] 15. The method of embodiment 14, wherein the suitable base is selected from the group consisting of TEA, DEA, DIPA, and pyridine.

[0055] 16. The method of embodiment 15, wherein the suitable base is TEA.

[0056] 17. Reacting compound 6 with a suitable deprotecting agent to produce compound 7: [ka] 17. The method of any one of embodiments 12 to 16, further comprising:

[0057] 18. The method of embodiment 17, wherein the suitable deprotecting agent is a fluoride source.

[0058] 19. The method of embodiment 18, wherein the fluoride source is selected from HF-pyridine, TBAF, KF, and TBAT.

[0059] 20. The method of embodiment 19, wherein the fluoride source is HF-pyridine.

[0060] 21. Reacting compound 5 with compound 5A to produce compound 6 [ka] 21. The method of any one of embodiments 17 to 20, further comprising:

[0061] 22. The method of embodiment 21, wherein the step of reacting compound 5 with compound 5A further comprises adding DEAD and PPh3.

[0062] 23. Process for synthesis of compound 5 from compound 4: [ka] 23. The method of any one of embodiments 21-22, further comprising:

[0063] 24. The method of embodiment 23, wherein the process from compound 4 to compound 5 comprises a series of hydroboration-oxidation reactions.

[0064] 25. The method of embodiment 24, wherein the hydroboration-oxidation sequence comprises: (a) adding BH3 / THF; (b) quenching with H2O; and (c) adding NaBO3.

[0065] 26. Reacting compound 3 with compound 3A to produce compound 4: [ka] 26. The method of any one of embodiments 23 to 25, further comprising:

[0066] 27. The method of embodiment 26, wherein the step of reacting compound 3 with compound 3A comprises adding an ester coupling reagent.

[0067] 28. The method of embodiment 27, wherein the ester coupling reagent is DCC.

[0068] 29. A process for producing compound 3 by reacting compound 1 with compound 2: [ka] 29. The method of any one of embodiments 26 to 28, further comprising:

[0069] 30. A process for producing compound 1 by oxidizing compound 1_1: [ka] 30. The method of embodiment 29, further comprising:

[0070] 31. The method of embodiment 30, wherein the step of oxidizing compound 1_1 comprises adding an oxidizing agent.

[0071] 32. The method of embodiment 31, wherein the oxidizing agent is Py.SO3.

[0072] 33. Reacting compound 18 with compound 3A: [ka] The method for producing compound (R)-11, comprising:

[0073] 34. The method of embodiment 33, wherein the step of reacting compound 18 with compound 3A comprises adding an azodicarboxylic acid ester.

[0074] 35. The method of embodiment 34, wherein the azodicarboxylate ester is DEAD or DIAD.

[0075] 36. The method of embodiment 35, wherein the azodicarboxylate ester is DEAD.

[0076] 37. The method of any one of embodiments 34-36, wherein the step of reacting compound 18 with compound 3A further comprises adding PPh3.

[0077] 38. Compound (R)-11 [ka] or a pharma- ceutically acceptable salt or solvate thereof, comprising the steps of reacting compound (R)-10 with a peptide coupling reagent: [ka] The above method.

[0078] 39. The method of embodiment 38, wherein the peptide coupling reagent is selected from the group consisting of BOP, PyBOP, HATU, and HBTU.

[0079] 40. The method of any one of embodiments 38 to 39, wherein the peptide coupling reagent is PyBOP.

[0080] 41. A process for producing compound (R)-10 by deprotecting compound (9) by reacting compound (R)-9 with an acid: [ka] The method of any one of embodiments 38 to 40, further comprising:

[0081] 42. The method of embodiment 41, wherein the acid is HCl.

[0082] 43. Reacting compound (R)-17 with 3A to produce compound (R)-9: [ka] 43. The method of any one of embodiments 38 to 42, further comprising:

[0083] 44. The method of embodiment 43, wherein the step of reacting compound (R)-17 with compound 3A comprises adding a carbodiimide.

[0084] 45. The method of embodiment 44, wherein the carbodiimide is selected from the group consisting of DIC and DCC.

[0085] 46. ​​The method of embodiment 45, wherein the carbodiimide is DIC.

[0086] 47. The method of any one of embodiments 43-46, further comprising the preliminary step of increasing the enantiomeric purity of compound 17 using a resolving agent.

[0087] 48. A splitting agent is [ka] 48. The method of embodiment 47, wherein

[0088] 49. Reacting compound 15 with a suitable reducing agent to produce compound 17: [ka] 49. The method of any one of embodiments 43 to 48, further comprising:

[0089] 50. The method of embodiment 49, wherein the suitable reducing agent is an enantiomeric reducing agent.

[0090] 51. The method of embodiment 50, wherein the enantiomeric reducing agent is (S,S)-Ms-DENEB.

[0091] 52. Reacting compound 14 with compound 8A to produce compound 15: [ka] 52. The method of any one of embodiments 49 to 51, further comprising:

[0092] 53. The method of embodiment 52, wherein the step of reacting compound 14 with compound 8A comprises adding a suitable base.

[0093] 54. The method of embodiment 53, wherein the suitable base is triethylamine.

[0094] 55. A process for preparing compound 14 from compound 13: [ka] 55. The method of any one of embodiments 53 to 54, further comprising:

[0095] 56. Reacting compound 12 with compound 5A to produce compound 13: [ka] 56. The method of embodiment 55, further comprising:

[0096] 57. The method of embodiment 56, wherein the step of reacting compound 12 with compound 5A comprises adding an azodicarboxylic acid ester.

[0097] 58. The method of embodiment 57, wherein the azodicarboxylate ester is DEAD.

[0098] 59. Reacting compound 12B with compound 12A to produce compound 12: [ka] 59. The method of any one of embodiments 56 to 58, further comprising:

[0099] 60. The method of embodiment 59, wherein the step of reacting compound 11 with compound 11A includes adding a reducing agent.

[0100] 61. The method of embodiment 60, wherein the reducing agent is DIBAL-H.

[0101] 62. Compound (R)-11 [ka] or a pharma- ceutically acceptable salt or solvate thereof, comprising reacting compound (R)-10 with a peptide coupling reagent: [ka] The above method.

[0102] 63. The method of embodiment 62, wherein the peptide coupling reagent is selected from the group consisting of BOP, PyBOP, HATU, and HBTU.

[0103] 64. The method of any one of embodiments 62-63, wherein the peptide coupling reagent is PyBOP.

[0104] 65. A process for producing compound (R)-10 by deprotecting compound (R)-17 by reacting compound (R)-17 with an acid: [ka] 65. The method of any one of embodiments 62 to 64, further comprising:

[0105] 66. The method of embodiment 65, wherein the acid is HCl.

[0106] 67. Reacting compound 24 with compound 25A to produce compound (R)-17: [ka] 67. The method of any one of embodiments 62 to 66, further comprising:

[0107] 68. The method of embodiment 67, wherein the step of reacting compound 24 with compound 25A comprises adding an azodicarboxylic acid ester.

[0108] 69. The method of embodiment 68, wherein the azodicarboxylate ester is selected from the group consisting of DEAD and DIAD.

[0109] 70. The method of embodiment 69, wherein the azodicarboxylic acid ester is DEAD.

[0110] 71. Reacting compound 23 with a reducing agent to produce compound 24: [ka] The method of any one of embodiments 67 to 70, further comprising:

[0111] 72. The method of embodiment 71, wherein the reducing agent is NaBH4.

[0112] 73. Reacting compound 22 with a catalyst to produce compound 23: [ka] 73. The method of any one of embodiments 71-72, further comprising:

[0113] 74. The method of embodiment 73, wherein the catalyst is RhCl(PPh3)3.

[0114] 75. Reacting compound 21 with compound 3A to produce compound 22: [ka] 75. The method of any one of embodiments 73-74, further comprising:

[0115] 76. The method of embodiment 75, wherein the step of reacting compound 21 with compound 3A comprises adding an ester coupling reagent.

[0116] 77. The method of embodiment 76, wherein the ester coupling reagent is DCC.

[0117] 78. Reacting compound 20 with compound 8A to produce compound 21: [ka] 78. The method of any one of embodiments 75 to 77, further comprising:

[0118] 79. The method of embodiment 78, wherein the step of reacting compound 20 with compound 8A comprises adding a suitable reducing agent.

[0119] 80. The method of embodiment 79, wherein the reducing agent is NaBH4.

[0120] 81. A process for producing compound 20 from compound 19: [ka] The method of any one of embodiments 78 to 80, further comprising:

[0121] 82. The method of embodiment 81, wherein the step of producing compound 20 comprises adding PPh3, I2, and imidazole.

[0122] 83. A process for producing compound 19 from compound 18: [ka] 83. The method of any one of embodiments 81-82, further comprising:

[0123] 84. Reacting compound 18 with compound 3A: [ka] The method for producing compound (R)-11, comprising: EXAMPLES

[0124] Example The present invention will be better understood with reference to the following examples, which are intended to represent certain embodiments of the invention and are not intended to limit the scope of the invention.

[0125] The following abbreviations are used: MeOH: Methanol THF: tetrahydrofuran; DCM: dichloromethane; EtOAC: ethyl acetate; ACN: acetonitrile; Et3N: triethylamine; DIPEA: N,N-diisopropylethylamine; N2: nitrogen gas; min: minutes hr: time; Na2SO4: Sodium sulfate; MgSO4: Magnesium sulfate prep-HPLC: preparative high pressure liquid chromatography; HPLC: High Pressure Liquid Chromatography; SiO2: Silica gel; K2CO3: Potassium carbonate; LiOH: Lithium hydroxide; DEAD: Diethyl azodicarboxylate PPh3: Triphenylphosphine OPPh3: Triphenylphosphine oxide TFA: Trifluoroacetic acid PE / EA: Petroleum ether / Ethyl acetate CHCl3: Chloroform DCM: dichloromethane MPLC: Medium Pressure Liquid Chromatography Pd / C: Palladium on carbon DMSO: Dimethyl sulfoxide Py.SO3: Sulfur trioxide pyridine complex DiBAl-H: Diisobutylaluminum hydride NaHCO3: Sodium bicarbonate BH3.THF: Borane-tetrahydrofuran complex NaBO3: Sodium perborate HCOOH: Formic acid MEK: Methyl ethyl ketone DIC: N,N'-diisopropylcarbodiimide (S,S)-Ms-DENEB: Chloro[(S,S)-N-[2-(4-methylbenzyloxy)ethyl]-N'-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium(II) BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate PyBOP: Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU: (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate MsCl: methanesulfonyl chloride TEA: Triethylamine DEA: Diethylamine DIPA: Diisopropylamine TBAF: Tetrabutylammonium fluoride TBAT: Tetrabutylammonium difluorotriphenylsilicate DIAD: Diisopropyl azodicarboxylate DCC: dicyclohexylcarbodiimide

[0126] I. Chemical Examples LCMS: Method 1: Instrument: Agilent 1200 HPLC MSD:6120 Single Quadrupole MSD Column: Luna C18, 2.0*50mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) 0.04% TFA in HO Mobile phase B (MPB) 0.02% TFA in ACN Flow rate: 1.0ml / min [Table 1] Detection: 220nm.

[0127] Method 2: Equipment: Shimadzu LC-20AD MSD:LCMS-2020 Column: Kinetex 5um EVO C18 30*2.1mm Column temperature: 40 Mobile phase: A: 0.04% TFA in H2O Mobile phase: B: 0.02% TFA in ACN Flow rate: 1.5ml / min Time B% Flow rate (ml / min) 0.01 5 1.5 0.70 95 1.5 1.16 95 1.5 1.50 5 1.5.

[0128] Chiral HPLC: Method 1: Instrument: CAS-TJ-Chiral HPLC-K (Waters Arc with PDA detector) Processing channel description (Proc. Chnl. Descr.): 2998 PDA 254.0nm (2998 (190-300)nm) Column: Chiralpak IC-3, 50×4.6mm, ID, 3um Mobile phase: A: Heptane B: EtOH (0.05% DEA, vol / vol) Gradient: A:B=20:80 Flow rate: 1mL / min Column temperature: 35°C.

[0129] Method 2 Equipment: CAS-TJ-ANA-Chiral HPLC-K (Waters Arc with 2998) Processing channel description: 2998 PDA 254.0nm (2998(190-300)nm) Column: Chiralpak IF-3, 150×4.6mmI.D., 3um Mobile phase: A: Hexane B: EtOH+ACN (4:1) (0.05% IPAm, vol / vol) Gradient: A:B=92:8 Flow rate: 1mL / min Column temperature: 30°C.

[0130] NMR analysis The NMR data presented in the Examples described below was obtained as follows: 1H-NMR: Bruker DPX 400MHz. Abbreviations for multiplicities observed in NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Solvents, reagents and starting materials were purchased from commercial sources and used as received unless otherwise specified.

[0131] Intermediate compound 5A: [ka]

[0132] THF (4.80 L), MeOH (1.60 L, 1.00 vol), H2O (1.60 L, 1.00 vol), 2_1 (1.60 kg, 7.56 mol, 1.0 equiv) were charged into the reaction vessel at 15-25 °C. Then LiOH.H2O (1.58 kg, 37.7 mol, 5.0 equiv) was charged into the reaction vessel in five portions. The reaction mixture was kept stirring at 30-35 °C for 16 h. Aqueous HCl (3 M) was added dropwise to the mixture at 15-25 °C until pH = 3-4. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2.00 L x 2). The combined organic phase was washed with brine (2.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product. Compound 2_2 (1.30 kg, yield 69.6%, purity 98.9%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.7 (brs, 1H), 9.52 (brs, 1H), 7.10 (s, 1H), 7.03 (s, 1H), 3.80 (s, 3H), 3.72 (s, 3H).

[0133] At 20-25°C, toluene (7.00L), compound 2_2 (1.00kg, 4.94mol, 1.00eq) were placed in a reaction vessel and heated to 80-85°C. Compound 2-2A (3.59kg, 17.6mol, 3.50eq) was placed in five portions in the reaction vessel at 80-85°C. The reaction mixture was stirred at 80-85°C for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, n-hexane / ethyl acetate=40 / 1-20 / 1) to obtain compound 5A (1.00kg, yield 60.2%, purity 99.5%) as a colorless oil. 1H NMR (400 MHz, CDCl3-d) δ 7.18 (s, 1H), 7.09 (s, 1H), 5.81 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 1.50 (s, 9H).

[0134] Intermediate compound 4A: [ka]

[0135] Acetonitrile (2.83 L, 10.0 vol), compound 3-1A (373 g, 1.57 mol, 1.30 eq), KI (40.0 g, 0.23 mol, 0.20 eq), DIPEA (311 g, 2.41 mol, 2.0 eq), and compound 3-1 (283 g, 1.21 mol, 1.00 eq) were added to a reaction vessel at 15-25 °C. The reaction mixture was stirred at 70-80 °C for 12 h. The reaction mixture was concentrated at 40-45 °C. H2O (1.00 L) and EtOAc (1.00 L) were added to the mixture and stirred at 15-25 °C for 10 min. The organic phase was separated and washed with brine (1.00 L), dried over Na2SO4, and concentrated to give the residue as a yellow oil. The residue was purified by reverse-phase MPLC (0.10% NH4OH and ACN in water) to give compound 3-2 (890 g, 76.0% yield, 96.5% purity) as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ 7.28-7.38 (m, 5H), 5.42-5.47 (m, 1H), 5.14 (s, 2H), 3.51-3.58 (m, 4H), 3.18 (brs, 2H), 2.49-2.67 (m, 6H), 1.79-2.04 (m, 2H), 1.59-1.63 (m, 2H), 1.43 (s, 9H).

[0136] At 15-25 °C, Pd / C (5.04 g, 10 wt%), MeOH (350 mL, 7.00 vol), and compound 3-2 (50.4 g, 0.12 mol, 1.00 equiv) were charged under argon. The reaction mixture was degassed with H2 three times and then stirred at 35 °C for 16 h under H2 (45 Psi). The reaction mixture was filtered. The filter cake was washed with MeOH (500 mL). The filtrate was concentrated to give the residue as a yellow oil. The residue was triturated with ACN (1.00 L) at 15-25 °C for 30 min. The mixture was filtered to remove insoluble solids, and the filtrate was collected. The filtrate was concentrated to give compound 4A (705 g, 85.8% yield, 81.1% purity) as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ 5.79 (s, 1H), 3.18-3.19 (m, 3H), 2.92- 2.97 (m, 3H), 2.50-2.69 (m, 6H), 1.75-1.81 (m, 2H), 1.57-1.64 (m, 2H), 1.42 (s, 9H).

[0137] Synthesis of the final compound Example 1. Synthesis of compound (R)-11

[0138] Scheme 4: [ka]

[0139] Step 1: [ka]

[0140] Compound 1_1 (3.50 kg, 18.41 mol, 1.00 equiv), DCM (21.0 L) and DMSO (3.50 L) were charged into a reaction vessel at 0-5°C. Then TEA (5.58 kg, 55.1 mol, 3.00 equiv), Py.SO3 (4.39 kg, 27.5 mol, 1.50 equiv) were charged into the mixture at 0-20°C. The reaction mixture was stirred at 20-25°C for 12 h. 0.5 M aqueous citric acid solution (20.0 L) was slowly added to the mixture at 0-20°C and stirred for 10 min. The organic phase was separated, washed with 10% aqueous NaHCO3 solution (20.0 L) and brine (20.0 L), dried over Na2SO4, filtered and concentrated to give compound 1 (3.60 kg, crude) as a brown oil. Purity determined by quantitative NMR: 66.8% 1H NMR (400 MHz, CDCl3-d) δ 9.79 (d, J=2.0 Hz, 1H), 3.97 (t, J=2.0 Hz, 2H), 2.57 (t, J=6.0 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H).

[0141] Step 2: [ka]

[0142] THF (28.8 L), compound 2 (1M, 22.9 L, 1.20 equiv.) were charged to a reaction vessel at 20°C, then cooled to -60 to -50°C. Compound 1 (3.60 kg, 19.12 mol, 1.00 equiv.) in THF (7.20 L) was added to this mixture at -60 to -50°C. The reaction mixture was stirred at -50 to -40°C for 3 h, then slowly warmed to 0 to 10°C. The reaction was quenched by adding 0.5N aqueous HCl (20.0 L) between 0 and 10°C. The organic phase was separated, washed with brine (20.0 L), dried over Na2SO4, filtered, and concentrated to give a brown oil. This oil was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 1 / 0 to 50 / 1) to obtain compound 3 (2.10 kg, 9.11 mol, yield 48.0%) as a yellow oil. Note: When the order was changed by adding the aldehyde to the Grignard reagent, the yield increased from 40% to 48%. 1H NMR (400 MHz, CDCl3-d) δ 5.72 - 5.94 (m, 1H), 4.97-5.18 (m, 2H), 3.75-3.94 (m, 3H), 3.37 (d, J=6.4 Hz, 1H), 2.17-2.31 (m, 2H), 1.60-1.71 (m, 2H), 0.88 (s, 9H), 0.03 (s, 6H).

[0143] Step 3: [ka]

[0144] At 20-25°C, THF (14.70L), compound 3 (2.10kg, 9.11mol, 1.00eq), compound 3A (1.93kg, 9.11mol, 1.00eq), DCC (2.82kg, 13.69mol, 487mL, 1.50eq), and DMAP (1.67kg, 13.69mol, 1.50eq) were added to a reaction vessel. The reaction mixture was stirred at 20-25°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (n-hexane / ethyl acetate = 100 / 0-90 / 10) to obtain compound 4 (2.70kg, 6.36mol, yield 70%, purity 95.1%) as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ 7.28 (s, 2H), 5.74-5.92 (m, 1H), 5.22-5.33 (m, 1H), 5.02-5.17 (m, 2H), 3.90 (s, 9H), 3.67-3.76 (m, 2H), 2.41-2.57 (m, 2H), 1.87-2.00 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H).

[0145] Step 4: [ka]

[0146] Compound 4 (2.40 kg, 5.66 mol, 1.00 equiv) and THF (16.80 L) were placed in a 50.0 L reaction vessel at 10-20 °C. BH3.THF (1 M, 8.48 L, 1.50 equiv) was added dropwise to the mixture at 0-10 °C. The reaction was quenched by adding a mixture of H2O (10.8 L) and THF (10.8 L) between 0-10 °C. (Caution: H2 evolution and exotherm were observed). NaBO3.4H2O (2.61 kg, 16.9 mol, 3.00 equiv) was added portionwise to the mixture at 0-10 °C, and then the reaction mixture was stirred at 10-25 °C for 4 h. The reaction was quenched by slowly adding 10% Na2S2O3 aqueous solution (20.0 L) at 0-10 °C. Ethyl acetate (7.50 L) was charged into the reaction vessel at 10-20°C and stirred for 10 min. The organic phase was separated, washed with brine (5.00 L), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=10:1-1:1) to give compound 5 (1.40 kg, 3.38 mol, yield 60%, purity 91.6%) as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ 7.26 (s, 2H), 5.16-5.33 (m, 1H), 3.88 (s, 9H), 3.55-3.78 (m, 4H), 1.56-2.01 (m, 6H), 0.87 (s, 9H), 0.02 (s, 6H).

[0147] Step 5: [ka]

[0148] Compound 5 (1.48 kg, 3.34 mol, 1.00 equiv.) and toluene (10.3 L), compound 5A (0.85 kg, 3.34 mol, 1.00 equiv.), and PPh3 (0.91 kg, 3.51 mol, 1.05 equiv.) were added to a reaction vessel at 20° C. DEAD (0.58 kg, 3.34 mol, 1.00 equiv.) was added dropwise (an exothermic phenomenon was observed during the dropping process). After the dropwise addition, the reaction mixture was stirred at 25° C. for 6 hours, and then the reaction mixture was stirred at −20° C. for 1 hour to precipitate a part of OPPh3. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (n-hexane / ethyl acetate=5 / 1) to obtain compound 6 (1.38 kg, 2.03 mol, purity 81.2%) as a colorless oil. 1H NMR (400 MHz, CDCl3-d) δ 7.29 (s, 2H), 7.22 (d, J=1.6 Hz, 2H) 5.27 - 5.37 (m, 1H), 4.06 (s, 2H), 3.84-3.95 (m, 15H), 3.67 - 3.78 (m, 2H), 1.87-2.06 (m, 6H), 1.65 (s, 9H), 0.89 (s, 9H), 0.02 (s, 6H).

[0149] Step 6: [ka]

[0150] At 20°C, compound 6 (1.35 kg, 1.98 mol, 1.00 equiv.) and THF (9.45 L) were added to the reaction solution. Pyridine (0.78 kg, 9.95 mol, 5.00 equiv.), HF-pyridine (1.40 kg, 9.95 mol, 70% purity, 5.00 equiv.) were added to the reaction mixture at 0-10°C. The reaction mixture was stirred at 60-65°C for 6 h. 1M aqueous citric acid solution (ca. 16.00 L) was added to the reaction mixture at 0-20°C and stirred for 10 min. The pH of the organic layer was adjusted to pH ca. 8 by adding 10% aqueous NaHCO3 solution (ca. 16.00 L). The organic layer was washed with brine (16.0 L), dried over Na2SO4, filtered, and concentrated to give compound 7 (1.09 kg, 81.0% purity) as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ 7.30 (s, 2H), 7.21-7.25 (m, 2H), 5.33-5.45 (m, 1H), 4.05-4.12 (m, 2H), 3.86-3.94 (m, 15H), 3.58-3.77 (m, 2H), 1.88-2.04 (m, 6H), 1.58 (s, 9H).

[0151] Step 7: [ka]

[0152] Compound 7 (1.03 kg, 1.82 mol, 1.00 equiv) and DCM (7.21 L) were placed in a 20.0 L reaction vessel at 0°C, and then TEA (0.37 kg, 3.64 mol, 2.00 equiv) was added. MsCl (0.33 kg, 2.88 mol, 1.58 equiv) was added dropwise to the reaction mixture at 0-5°C. The reaction mixture was stirred at 15-25°C for 3 h. The reaction was quenched at 0-20°C by slow addition of 1 M aqueous citric acid (6.00 L) and stirred for 10 min. The aqueous phase was separated. The organic layer was adjusted to pH=8 with 10% aqueous NaHCO3 (6.00 L). The organic phase was separated, washed with brine (6.00 L), dried over Na2SO4, filtered, and concentrated to give compound 8 (1.14 kg, 1.77 mol, crude, 82% purity) as a brown oil. Purity determined by quantitative NMR: 87.3% 1H NMR (400 MHz, CDCl3-d) δ 7.28 (s, 2H), 7.19-7.25 (m, 2H), 5.3 -5.43 (m, 1H), 4.26-4.40 (m, 2H), 4.04 - 4.12 (m, 2H), 3.84-3.93 (m, 15H), 2.98 (s, 3H), 2.21 (q, J=6.0 Hz, 2H), 1.87-2.00 (m, 4H), 1.58 (s, 9H).

[0153] Step 8: [ka]

[0154] Compound 8 (1190 g, 1.85 mol, 1.00 equiv) and ACN (9.52 L) were added to a 20.0 L reaction vessel at 25° C. Then compound 8A (548 g, 2.13 mol, 1.05 equiv), K2CO3 (1279 g, 9.26 mol, 5.00 equiv) and KI (307 g, 1.85 mol, 1.00 equiv) were added. The reaction mixture was stirred at 65° C. for 18 h. The solvent was removed under reduced pressure to give a residue. H2O (3.00 L) was added to the residue and extracted with EtOAc (3.00 L×3). The organic phase was separated, washed with brine (3.00 L), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 50 / 1 to 5 / 1) to obtain compound 9 (1116 g, 1.39 mol, yield 75.0%) as a yellow oil. Purity determined by quantitative NMR: 91.8% 1H NMR (400 MHz, CDCl3-d) δ 7.30 (s, 2H), 7.21 (s, 2H), 5. 23-5.36 (m, 1H), 4.04-4.17 (m, 2H), 3.73-3.94 (m, 15H), 3.06 (t, J=6.8 Hz, 2H), 2.65-2.80 (m, 8H), 2.60 (t, J=7.6 Hz, 2H), 2.49 (t, J=7.6 Hz, 2H), 1.86-2.03 (m, 6H), 1.76-1.85 (m, 2H), 1.61-1.68 (m, 2H), 1.58 (s, 9H), 1.43 (s, 9H).

[0155] Step 9: [ka]

[0156] A solution of HCl in dioxane (4 mol, 7.60 L) and compound 9 (1086 g, 1.35 mol, 1.00 equiv) were charged into a 20.0 L reaction vessel at 0-5° C. The reaction mixture was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure to give compound 10 (1050 g, as the HCl salt) as a yellow solid. Purity determined by quantitative NMR: 75.2% 1H NMR (400 MHz, MeOD-d4) δ 7.29 (s, 2H), 7.26 (s, 2H) 5.2 -5.37 (m, 1H), 4.11 (s, 2H), 3.94 (brs, 4H), 3.78-3.90 (m, 15H), 3.33-3.45 (m, 4H), 3.08 (t, J=7.6 Hz, 2H), 2.12-2.49 (m, 6H), 1.90-2.09 (m, 4H).

[0157] Step 10: [ka]

[0158] Compound 10 (1050 g, 1.53 mol, 1.00 equiv, HCl) and DCM (210 L) were charged to a reaction vessel at 20° C. Then, DIEA (793 g, 6.13 mol, 4.00 equiv) and PyBOP (38.4 g, 2.29 mol, 1.50 equiv) were added to the reaction vessel at 20° C. The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated at 35-40° C. to give a residue. The residue was triturated with MeOH (4.2 L, 4.00 vol) at 20° C. for 60 min. The mixture was filtered and the cake was collected to give compound 11 (470 g, 34.94 mmol, 48.6% yield) as a white solid. Purity determined by quantitative NMR: 75.2% 1H NMR (400 MHz, MeOD-d4) δ 7.31 (s, 2H), 7.20 (d, J =1.8 Hz, 1H), 7.13 (d, J =1.8 Hz, 1H), 5.49 (s, 1H), 4.31 (br d, J =8.3 Hz, 1H), 4.18 (br s, 1H), 3.85-3.89 (m, 9H), 3.81 (d, J =7.3 Hz, 6H), 3.56-3.66 (m, 1H), 3.38-3.49 (m, 1H), 2.97 (td, J=3.2, 10.3 Hz, 1H), 2.84-2.91 (m, 2H), 2.74-2.84 (m, 3H), 2.61-2.73 (m, 4H), 2.56 (br t, J =6.5 Hz, 2H), 1.86-1.95 (m, 5H), 1.73-1.85 (m, 5H).

[0159] SFC chiral separation of compound 11: [ka]

[0160] The enantiomers of racemic compound 11 (470 g) were separated by chiral SFC (Supercritical Fluid Chromatography - Column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); Mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 60%-60%, 10 min) to give compounds (S)-11 (170 g) and (R)-11 (165 g) as white solids. Compound (S)-11: LCMS (Method 1) (ESI position ion) m / z: 630.2 (M+H)+ (calculated: 630.3), purity >99% Chiral HPLC (Method 1): retention time = 3.836 min, ee > 99% 1H NMR (400 MHz, MeOD-d4) δ 7.31 (s, 2H), 7.20 (d, J =1.8 Hz, 1H), 7.13 (d, J =1.8 Hz, 1H), 5.49 (s, 1H), 4.31 (br d, J =8.3 Hz, 1H), 4.18 (br s, 1H), 3.85-3.89 (m, 9H), 3.81 (d, J =7.3 Hz, 6H), 3.56-3.66 (m, 1H), 3.38-3.49 (m, 1H), 2.97 (td, J=3.2, 10.3 Hz, 1H), 2.84-2.91 (m, 2H), 2.74-2.84 (m, 3H), 2.61-2.73 (m, 4H), 2.56 (br t, J =6.5 Hz, 2H), 1.86-1.95 (m, 5H), 1.73-1.85 (m, 5H). Compound (R)-11: LCMS (Method 1) (ESI position ion) m / z: 630.2 (M+H)+ (calculated: 630.3), purity >99% Chiral SFC (Method 1): retention time = 6,560 min, ee > 99% 1H NMR (400 MHz, MeOD-d4) δ 7.31 (s, 2H), 7.20 (d, J =1.8 Hz, 1H), 7.13 (d, J =1.8 Hz, 1H), 5.49 (s, 1H), 4.31 (br d, J =8.3 Hz, 1H), 4.18 (br s, 1H), 3.85-3.89 (m, 9H), 3.81 (d, J =7.3 Hz, 6H), 3.56-3.66 (m, 1H), 3.38-3.49 (m, 1H), 2.97 (td, J=3.2, 10.3 Hz, 1H), 2.84-2.91 (m, 2H), 2.74-2.84 (m, 3H), 2.61-2.73 (m, 4H), 2.56 (br t, J =6.5 Hz, 2H), 1.86-1.95 (m, 5H), 1.73-1.85 (m, 5H).

[0161] Step 1 for conversion of (S)-11 to (R)-11: [ka]

[0162] To a solution of compound (S)-11 (150 g, 238.19 mmol, 1 equiv.) in MeOH (800 mL) and H2O (400 mL), NaOH (28.58 g, 714.58 mmol, 3 equiv.) was added. The mixture was stirred at 20 °C for 5 h. The solvent MeOH was removed under reduced pressure at 25 °C. The mixture was diluted with H2O (1500 mL) and extracted with DCM (500 mL x 3). The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated to give compound 18 (116.5 g, crude) as a yellow solid. LCMS (Method 1) (ESI position ion) m / z: 436.2 (M+H)+ (calculated value: 436.3) 1H NMR (400 MHz, MeOD-d4) δ 7.15 (dd, J=1.8, 7.6 Hz, 2H), 4.30 - 4.13 (m, 2H), 3.99 - 3.90 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.57 - 3.40 (m, 2H), 2.88 - 2.52 (m, 12H), 2.05 - 1.92 (m, 1H), 1.91 - 1.71 (m, 5H), 1.71 - 1.51 (m, 4H).

[0163] Step 2 for conversion of (S)-11 to (R)-11: [ka]

[0164] A mixture of compound 18 (10.00g, 22.96 mmol, 1 equiv.), compound 3A (14.62g, 68.88mmol, 3 equiv.) and PPh3 (30.11g, 114.80mmol, 5 equiv.) in toluene (250mL) was added dropwise to DEAD (19.99g, 114.80mmol, 20.87mL, 5 equiv.) at 0°C. The mixture was stirred at 0°C for 2 hours under nitrogen atmosphere. The reaction mixture was filtered by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0-0 / 1 and DCM / MeOH=10 / 1-1 / 1) to obtain the crude product. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 250*50mm*10um; mobile phase: [water (FA)-ACN]; B%: 2%-32%, 15min). The purified solution was concentrated and the pH was adjusted to 7-8 with NaHCO3 at 0 °C. The solution was extracted with DCM (500 mL x 2). The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated to give compound (R)-11 (4.7 g, 33% yield) as a white solid. The reaction was carried out in 12 batches and gave (R)-11 in total with 50 g ee = 60%. The compound was further purified by chiral SFC under the following conditions to give compound (R)-11 (35.5 g) as a white solid. LCMS (Method 1) (ESI position ion) m / z: 630.2 (M+H)+ (calculated: 630.3), purity >99% Chiral SFC (Method 1): retention time = 6,560 min, ee > 99% 1H NMR (400 MHz, MeOD-d4) δ 7.31 (s, 2H), 7.20 (d, J =1.8 Hz, 1H), 7.13 (d, J =1.8 Hz, 1H), 5.49 (s, 1H), 4.31 (br d, J =8.3 Hz, 1H), 4.18 (br s, 1H), 3.85-3.89 (m, 9H), 3.81 (d, J =7.3 Hz, 6H), 3.56-3.66 (m, 1H), 3.38-3.49 (m, 1H), 2.97 (td, J=3.2, 10.3 Hz, 1H), 2.84-2.91 (m, 2H), 2.74-2.84 (m, 3H), 2.61-2.73 (m, 4H), 2.56 (br t, J =6.5 Hz, 2H), 1.86-1.95 (m, 5H), 1.73-1.85 (m, 5H). 5H), 1.83 - 1.72 (m, 5H). Column: Chiralpak AD-3 50×4.6mm ID, 3um Mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); Gradient elution: 5% to 40% B in A Flow rate: 3mL / min; Detector: PDA Column temperature: 35C; Back pressure: 100Bar SFC: tR = 9.658 min, 100% ee value.

[0165] Example 2. Synthesis of compound (R)-11

[0166] Scheme 5 [ka]

[0167] Step 1: [ka]

[0168] Compound 12A (210 g, 1.50 equiv, 1.57 mol) was dissolved in THF (450 mL, 5.00 vol) at 15-25 °C. DIBAL-H (1.57 L, 1.50 equiv, 1.57 mol) was added dropwise to the reaction mixture at 0-10 °C. The reaction mixture was stirred at 15-25 °C for 2 h. Compound 12B (90.0, 1.00 equiv, 1.05 mol) was added dropwise to the reaction mixture at 0-10 °C. The reaction mixture was stirred at 15-25 °C for 5 h. H2O (63.0 mL) was added dropwise at 0-10 °C, then an aqueous solution of NaOH (15%, 63.0 mL) was added slowly, followed by more H2O (157 mL) slowly added at 0-10 °C. The reaction mixture was stirred at 15-25 °C for 15 min, then dried over MgSO4. The solvent was removed under reduced pressure to give compound 12 (70.0 g, 0.48 mol, 45.5% yield) as a yellow oil.

[0169] Step 2: [ka]

[0170] Compound 12 (30.0 g, 1.00 equiv.), compound 5A (51.8 g, 1.00 equiv.), PPh3 (56.1 g, 1.05 equiv.) and toluene (150 mL, 5.00 vol.) were added to a reaction vessel at 15-25 °C. DEAD (37.2 g, 1.05 equiv.) was added dropwise to the reaction mixture at 0-10 °C. The reaction mixture was stirred at 15-25 °C for 24 h. The solvent was removed under reduced pressure, and the residue was purified by silica column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain compound 13 (50.0 g, 0.13 mol) as a yellow solid. 1H NMR (400 MHz, CDCl3-d) δ 7.24 (s, 2 H) 4.08 - 4.16 (m, 2 H) 3.84 - 3.94 (m, 6 H) 3.62 - 3.76 (m, 3 H) 3.13 - 3.26 (m, 3 H) 2.59 - 2.74 (m, 2 H)2.12 - 2.32 (m, 2 H)1.52 - 1.63 (m, 9 H).

[0171] Step 3: [ka]

[0172] Compound 13 (45.0 g, 1.00 equiv) was dissolved in THF (225 mL, 5.00 vol) at 15-25 °C. Compound 13A (293 mL, 1.00 equiv, 1 M) was added dropwise to the reaction mixture at -30 °C. The reaction mixture was stirred at -30 °C for 2 h. HCl (1.35 L, 1 M in H2O, 30.0 vol) was added slowly at -30 °C. Ethyl acetate (225 mL, 5.00 vol) was added. The organic phase was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound 14 (27.0 g, 75.5 mmol, yield 64.3%, purity 98.3%) as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ 7.21 - 7.25 (m, 2 H) 6.20 - 6.53 (m, 2 H) 5.80 - 5.89 (m, 1 H) 4.03 - 4.14 (m, 2 H) 3.81 - 3.92 (m, 6 H) 2.77 - 2.94 (m, 2 H) 2.06 - 2.25 (m, 2 H) 1.46 - 1.67 (m, 10 H)

[0173] Step 4: [ka]

[0174] Compound 14 (27.0 g, 1.00 equiv) was dissolved in DCM (135 mL, 5.00 vol) at 15-25° C. Compound 8A (24.7 g, 1.00 equiv) and Et3N (15.6 g, 2.00 equiv) were added and the reaction mixture was stirred for 12 h. The reaction mixture was concentrated to give crude compound 15 (42.0 g, 69.1 mmol) as a yellow oil. 1H NMR (400 MHz, MeOD-d4) δ 7.21 - 7.28 (m, 2 H) 4.01 - 4.13 (m, 2 H) 3.75 - 3.91 (m, 6 H) 2.99 - 3.16 (m, 3 H) 2.63 - 2.85 (m, 13 H) 2.44 - 2.58 (m, 3 H) 2.02 - 2.12 (m, 2 H) 1.75 - 1.86 (m, 2 H) 1.61 - 1.66 (m, 2 H) 1.59 (s, 9 H) 1.43 (s, 9 H).

[0175] Step 5: [ka]

[0176] To a solution of compound 15 (3.00 g, 1.00 equiv.), HCOOH / Et3N (9.00 mL, 1:1, 3.00 vol.) in THF (15.0 mL, 5.00 vol.) at 15-25 °C, (S,S)-Ms-DENEB catalyst (0.11 g, 0.04 equiv.) was added. The reaction mixture was stirred at 15-25 °C for 12 h. H2O (9.00 mL, 3.00 vol.) and DCM (9.00 mL, 3.00 vol.) were added to the reaction mixture. The organic phase was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound 16 (1.80 g, 2.89 mmol, purity 98.1%) as a yellow oil. LCMS (Method 2) (ESI position ion) m / z: 630.2 (M+H)+ (calculated value: 630.3) Chiral HPLC (Method 2): retention times = 21.398 and 23.972 min, ee = 85.9%.

[0177] Step 6: [ka]

[0178] Compound 16 (1.00 equiv.) was placed in butanone (MEK) (5.00 vol.) at 15-25° C., and the mixture was then stirred for 2 h at 55-60° C. Di-p-toluoyl-l-tartaric acid (2.00 equiv.) was added, and the mixture was stirred for 12 h at 10-20° C.

[0179] The mixture was concentrated to give the crude product. (red-brown solid). The solid was triturated with butanone (10.0 vol) at 25° C. for 30 min (white solid). The mixture was filtered and the filter cake was washed twice with butanone (1.00 vol). The solid was dissolved in water (3.00 vol). Saturated sodium carbonate solution was added to the mixture to adjust pH=11. DCM (3.00 vol) was added to the mixture and the organic phase was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give compound 17 as a red-brown oil. Chiral HPLC (Method 2): retention times = 18.335 and 20.673 min, ee = 95.9%

[0180] Step 7: [ka]

[0181] To a solution of compound 17 (1.00 g, 1.00 equiv.), compound 6A (1.20 equiv.) in DCM (5.00 vol.) at 15-25°C, DIC (2.20 equiv.) and DMAP (1.50 equiv.) were added. The reaction mixture was stirred at 15-25°C for 16 h. H2O (3.00 vol.) and DCM (3.00 vol.) were added, and the organic phase was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound (R)-9 (600 mg, 45% yield). LCMS (Method 2) (ESI position ion) m / z: 804.4 (M+H)+ (calculated: 804.5).

[0182] Step 8: [ka]

[0183] A solution of HCl in dioxane (4 mol, 7.60 L) and compound (R)-9 (1086 g, 1.35 mol, 1.00 equiv.) were charged into a 20.0 L reaction vessel at 0-5° C. The reaction mixture was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure to give compound (R)-10 (1050 g, as the HCl salt) as a yellow solid. Purity determined by quantitative NMR: 75.2% 1H NMR (400 MHz, MeOD-d4) δ 7.29 (s, 2H), 7.26 (s, 2H) 5.2 -5.37 (m, 1H), 4.11 (s, 2H), 3.94 (brs, 4H), 3.78-3.90 (m, 15H), 3.33-3.45 (m, 4H), 3.08 (t, J=7.6 Hz, 2H), 2.12-2.49 (m, 6H), 1.90-2.09 (m, 4H).

[0184] Step 9: [ka]

[0185] Compound (R)-10 (1050 g, 1.53 mol, 1.00 equiv, HCl) and DCM (210 L) were charged to a reaction vessel at 20 °C. Then, DIEA (793 g, 6.13 mol, 4.00 equiv) and PyBOP (38.4 g, 2.29 mol, 1.50 equiv) were added to the reaction vessel at 20 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated at 35-40 °C to give a residue. The residue was triturated with MeOH (4.2 L, 4.00 vol) at 20 °C for 60 min. The mixture was filtered and concentrated in vacuo to give compound (R)-11 (470 g, 34.94 mmol, 48.6% yield) as a white solid. Purity determined by quantitative NMR: 75.2% 1H NMR (400 MHz, MeOD-d4) δ 7.31 (s, 2H), 7.20 (d, J =1.8 Hz, 1H), 7.13 (d, J =1.8 Hz, 1H), 5.49 (s, 1H), 4.31 (br d, J =8.3 Hz, 1H), 4.18 (br s, 1H), 3.85-3.89 (m, 9H), 3.81 (d, J =7.3 Hz, 6H), 3.56-3.66 (m, 1H), 3.38-3.49 (m, 1H), 2.97 (td, J=3.2, 10.3 Hz, 1H), 2.84-2.91 (m, 2H), 2.74-2.84 (m, 3H), 2.61-2.73 (m, 4H), 2.56 (br t, J =6.5 Hz, 2H), 1.86-1.95 (m, 5H), 1.73-1.85 (m, 5H).

[0186] Example 3. Synthesis of compound (R)-11

[0187] Scheme 6 [ka]

[0188] [ka]

[0189] Step 1: Compound 12A (1.70 kg, 1.50 equiv) was dissolved in THF (5.00 L, 5.00 vol). DIBAL-H (17.4 L, 1 M in toluene, 1.50 equiv) was added dropwise to the reaction mixture at 0-10 °C. The reaction mixture was stirred at 20-30 °C for 2 h. Compound 12B (1.00 kg, 1.00 equiv) was added dropwise to the reaction mixture at 0-10 °C. The reaction mixture was stirred at 20-30 °C for 12 h. HO (700 mL, 0.04 mL) was added dropwise at 0-10 °C, followed by slow addition of aqueous NaOH (700 mL, 0.04 mL, 15%), followed by slow addition of more HO (1.74 L, 0.1 mL) at 0-10 °C. The reaction mixture was stirred at 20-30 °C for 15 min and then dried over MgSO4 (500 g). The solvent was removed under reduced pressure to give compound 12 (7.80 kg, 65% yield) as a yellow oil. 1 H NMR: (400 MHz, CDCl3) δ ppm 1.75 - 1.95 (m, 2 H), 2.53 - 2.63 (m, 2 H), 3.13 - 3.24 (m, 3 H), 3.61 - 3.72 (m, 5 H).

[0190] Step 2: Compound 12 (7.80 kg, 1.00 equiv.), compound 5A (8.30 kg, 1.00 equiv.), PPh3 (9.00 kg, 1.05 equiv.) and toluene (35 L) were charged to a reaction vessel at 15-25 °C. DEAD (13.0 kg, 1.05 equiv.) was added slowly to the reaction mixture at 0-10 °C. The reaction mixture was stirred at 15-25 °C for 12 h. The reaction was filtered and the filter cake was washed with MTBE. Water (0.3 L) was added to the filtrate followed by MgCl2 (5.64 kg) and the mixture was stirred at 20-30 °C for 2 h. The reaction was filtered and the filter cake was washed with MTBE. The filtrate was washed with 10% aqueous citric acid solution (25.0 L, 3.00X volume). The organic phase was washed with 5% brine and dried over Na2SO4 (4.15 kg, 0.50X mass). The organic phase was concentrated at 45-55°C to a volume of 12-20 L. n-Heptane (12.5 L, 1.50X volume) was added and the reaction was reduced to 12-20 L; this was repeated. n-Heptane (41.5 L, 5.00X volume) was added and the reaction was heated with stirring at 50-60°C for 2 hours. The reaction was cooled, filtered, and the cake was washed with n-heptane. The filter cake was dried under vacuum at 40-50°C to give compound 13 (6.50 kg, 98% purity by HPLC, 65% yield). 1 H NMR (400 MHz, CDCl3-d) δ ppm 7.22 - 7.26 (m, 2 H), 4.08 - 4.15 (m, 2 H), 3.86 - 3.92 (m, 6 H), 3.67 - 3.71 (m, 3 H), 3.16 - 3.24 (m, 3 H), 2.63 - 2.73 (m, 2 H), 2.13 - 2.25 (m, 2 H), 1.57 - 1.60 (m, 9 H).

[0191] Step 3: Compound 13 (6.00 kg, 1.00 equiv) was dissolved in THF (30.0 L, 5.00 vol) at 15-25 °C. Compound 13A (39.0 L, 1 M in THF, 6.52X vol) was added slowly to the reaction mixture at -20 °C. The reaction mixture was stirred at -10-0 °C for 2 h. HCl (30.0 L, 1 M, 5.00X vol) was added slowly at 0-20 °C to control the pH to 1-3. MTBE (18.0 L, 3.00X vol) was added. The organic phase was separated and washed twice with 0.5 N HCl (18.0 L, 3.00X vol). The organic phase was washed with 5% aqueous NaHCO3 (18.0 L, 3.00X volume), 5% brine (18.0 L, 3.00X volume), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 14 (4.50 kg, 75% yield, 92.3% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ ppm 7.20 - 7.26 (m, 2 H), 6.20 - 6.51 (m, 2 H), 5.78 - 5.93 (m, 1 H), 4.03 - 4.17 (m, 2 H), 2.80 - 2.91 (m, 2 H), 2.11 - 2.23 (m, 2 H), 1.53 - 1.64 (m, 9 H).

[0192] Step 4: Compound 14 (5.20 kg, 1.00 equiv) was dissolved in DCM (26.0 L, 5.00X volume) at 15-25° C. Compound 8A (4.57 kg, 1.00 equiv) and Et3N (3.0 kg, 2.00 equiv) were added and the reaction mixture was stirred for 12 h. The reaction mixture was concentrated to give crude compound 15 (7.30 kg, 90.7% purity, 85% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.17 - 7.24 (m, 2 H), 5.63 - 5.79 (m, 1 H), 4.00 - 4.07 (m, 2 H), 3.81 - 3.89 (m, 6 H), 3.11 - 3.21 (m, 2 H), 2.76 - 2.84 (m, 2 H), 2.44 - 2.70 (m, 15 H), 2.04 - 2.14 (m, 2 H), 1.71 - 1.79 (m, 2 H), 1.57 (s, 9 H), 1.41 (s, 9 H).

[0193] Step 5: To a solution of compound 15 (5.00 kg, 1.00 equiv.), HCOOH (7.50 L, 1.50X vol.), Et3N (7.50 L, 1.50X vol.) in THF (25.0 L, 5.00X vol.) at 15-25°C was added (S,S)-Ms-DENEB catalyst (360 g, 0.04 equiv.). The reaction mixture was stirred at 10-15°C for 12 hours. The reaction mixture was cooled to 5-10°C and the pH of the reaction was adjusted to 11-12 with saturated aqueous Na2CO3 (approximately 15.0 L). DCM (15.0 L, 3.00 vol.) was added to the reaction mixture. The organic phase was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give compound 16 (4.50 kg, 83.4% purity, 84.9% ee, 85% yield) as a brown oil.

[0194] [Table 2]

[0195] Step 6: Compound 17 (62.0 kg, 1.00X mass) was dissolved in acetone (ACE) (434 L, 7.00X volume) and EtOH (434 L, 7.00X volume) at 10-20° C., the mixture was stirred at 50-55° C. for 1 hour, then allowed to cool to 25-30° C., acetone (186 L, 3.00X volume), ethanol (186 L, 3.00X volume) and compound 6A (78.5 kg, 1.26X mass) were added, and the mixture was stirred at 50-55° C. for 1 hour. The reaction was cooled to 25-30° C. at a rate of 3-5° C. per hour. The mixture was filtered and the filter cake was washed with ACE:EtOH=1:1 (4.50 L, 1.00X volume) and dried under N2 in a blast drying oven at 45-55°C to give the product 17-tartrate salt (5.10 kg, 98.0% purity, 97.5% ee).

[0196] Step 7: Compound 6 (1.50 kg, 1.0 equiv.) was dissolved in 2-MeTHF (20.2 L). The solution was cooled to 10-15 °C under N2. A solution of 2,3,4 trimethoxybenzoyl chloride (624.0 g, 1.10 equiv.) in 2-MeTHF (3.00 L) was added dropwise to the solution. The reaction mixture was stirred at 15-20 °C for 16 h. At this point, aqueous Na2CO3 (10%, 4.5 L) was added to adjust the pH to 11-12 at 10-20 °C. The organic phase was separated, washed with 10% NaCl (4.5 L), dried over Na2SO4, and filtered. The solvent of the filtrate was removed under reduced pressure to give compound (R)-9 (1.70 kg, 94.4% purity, 97.7% ee, 86% yield).

[0197] Step 8: Compound (R)-9 (200 g, 1.00 equiv.) was dissolved in DCM (1.00 L) under N2. 4 M HCl in MTBE (600 mL) was added at 15-20 °C. The reaction mixture was stirred at 15-20 °C for 16 h. MTBE (2.00 L) was added dropwise over 20 min. A white precipitate formed. Stirring was stopped and the mixture was allowed to stand for 30 min. The supernatant liquid was removed using a peristaltic pump to reduce the volume of the solution to approximately 1.0 L. The mixture was filtered and the filter cake was dried under vacuum at 40-45 °C to give compound (R)-10 (150 g, purity 98.6, yield 86%).

[0198] Step 9: PyBOP (913 g, 1.5 equiv) was dissolved in DCM (40.0 L, 30.0 vol) under N2 at 15-25 °C and DIEA (600 g, 4.00 equiv) was added followed by a solution of (R)-10 (800 g, 1.00 equiv) in DCM (1.60 L, 20.0 vol) over approximately 1.5 h. The mixture was stirred for an additional 20 min at 15-25 °C. At this point, the reaction mixture was concentrated to approximately 2.00 vol at 40-45 °C. The solution was washed three times with water (2.40 L, 3.00 vol). The organic phase was washed with 10% NaCl (2.40 L, 3.00 vol). The organic phase was dried over Na2SO4 (200 g, 0.25X wt) and filtered. The filter cake was washed with MeOH. MeOH (2.40 L, 3.00 vol) was added to the filtrate and then the mixture was concentrated to about 2.00 vol. The addition and concentration of MeOH was repeated two more times to remove residual DCM. MeOH (2.40 L, 3.00 vol) was added to the mixture and stirred at 15-25 °C for 12 h. The reaction was filtered and the resulting cake was washed with MeOH (0.80 L, 1.00 vol). The filter cake was dried under vacuum at 45-50 °C and gave 6550 g of (R)-11-HPF with a purity of 98.8% (yield 66%).

[0199] The reaction vessel was charged with MeOH (4.00 L, 5.00 vol) and 6550 g of (R)-11 HPF. 30% NH3.H2O (1375 mL, 2.50 vol) was then slowly added to the reaction vessel at 15-25 °C for 20 min until the reaction gradually became clear. The reaction was extracted with DCM three times (2750 mL, (5.00 vol) x 3). The combined organic layers were washed once with 10% Na2CO3 (1.50 L, 3.00 vol) and with 10% NaCl (1.50 L, 3.00 vol). The organic layers were dried with Na2SO4 (125 g, 0.25 x wt), filtered (washing the filter cake with DCM (250 mL, 0.50 vol)), and the solvent was removed under vacuum to give 410 g of crude (R)-11.

[0200] Example 4 Synthesis of Compound (R)-11

[0201] Scheme 7 [ka]

[0202] Step 1: Methanol (1.2 L) was charged to the reaction vessel and stirred for 10-15 min and cooled to 0-5 °C, then acetyl chloride (2.34 g, 29.8 mmol, 0.05 equiv.) was added and the mixture was stirred at 0-5 °C for 10-15 min. The resulting methanolic hydrogen chloride was transferred to another vessel. Methanol (400 mL) was charged to a clean vessel and stirred at 25-35 °C for 10-15 min. 2-Deoxy-D-ribose (80.0 g, 596.43 mmol, 1.00 equiv.) was charged to the reaction vessel and the mixture was stirred at 25-35 °C for 10-15 min. The whole was cooled to 0-5 °C and the above prepared methanolic hydrogen chloride was charged to the reaction vessel at the same temperature. The resulting whole was kept at 0-5 °C for 2-3 h. Sodium bicarbonate (3.0 g, 35.78 mmol, 0.06 equiv) was added to the whole at 0-5 °C and the cake was filtered. The filtrate was collected in a separate vessel and the filter bed was washed with methanol (100 mL). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with PE / THF (5:1) to give (2R,3S)-2-(hydroxymethyl)-5-methoxyoxolan-3-ol (19) (83 g, 94% yield) as a white solid.

[0203] Step 2: To a stirred solution of (2R,3S)-2-(hydroxymethyl)-5-methoxyoxolan-3-ol (80 g, 539.96 mmol, 1.00 equiv.) and PPh3 (212.44 g, 0.81 mol, 1.50 equiv.) in THF (1.6 L) was added imidazole (73.52 g, 1.08 mol, 2.00 equiv.) and I2 (205.57 g, 0.81 mol, 1.50 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched at room temperature with a saturated solution of NaHSO3. The organic phase was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (5:1) to give (2S,3S)-2-(iodomethyl)-5-methoxyoxolan-3-ol (98 g, 70% yield) as a light oil.

[0204] Step 3: To a stirred solution of (2S,3S)-2-(iodomethyl)-5-methoxyoxolan-3-ol (6.1 g, 23.63 mmol, 1.00 equiv) and zinc (15.46 g, 236.38 mmol, 10.00 equiv) in EtOH (120 mL) and AcOH (1.7 g, 28.36 mmol, 1.20 equiv) was added tert-butyl 1,4-diazepane-1-carboxylate (4.73 g, 23.63 mmol, 1.00 equiv) and NaBH3CN (4.46 g, 70.91 mmol, 3.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with DCM (20 mL). The resulting mixture was filtered; the filter cake was washed with DCM (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:THF (1:2) to give tert-butyl 4-[(3S)-3-hydroxypent-4-en-1-yl]-1,4-diazepane-1-carboxylate (2.8 g, 42% yield) as a colorless oil. LC-MS(ES+) m / z: 285.2(M+H)+(calculated: 285.2).

[0205] Step 4: To a solution of tert-butyl 4-[(3S)-3-hydroxypent-4-enyl]-1,4-diazepane-1-carboxylate (1, 996.47 mg, 3.50 mmol, 1 equiv.) and 3,4,5-trimethoxybenzoic acid (3A) (2, 891.24 mg, 4.20 mmol, 1.2 equiv.) in THF (10 mL) was added DCC (1.08 g, 5.25 mmol, 1.06 mL, 1.5 equiv.) and DMAP (641.38 mg, 5.25 mmol, 1.5 equiv.) The mixture was stirred at 30° C. for 16 h. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1), TLC (petroleum ether / ethyl acetate = 2:1, Rf = 0.42) to give tert-butyl 4-[(3S)-3-(3,4,5-trimethoxybenzoyl)oxypent-4-enyl]-1,4-diazepane-1-carboxylate ((3, 1.3 g, 2.53 mmol, 72.18% yield)) as a white solid. LC-MS(ES+) m / z: 479.0(M+H)+(calculated value: 479.3) 1H NMR (400 MHz, CDCl3-d) δ 7.31 (s, 2H), 5.91 (ddd, J=6.4, 10.4, 17.1 Hz, 1H), 5.56 (q, J=6.5 Hz, 1H), 5.34 (br d, J=17.4 Hz, 1H), 5.23 (br d. (s, 12H).

[0206] Step 5: To a solution of tert-butyl 4-[(3S)-3-(3,4,5-trimethoxybenzoyl)oxypent-4-enyl]-1,4-diazepane-1-carboxylate (3, 100 mg, 208.95 μmol, 1 equiv.) in toluene (5 mL), chlororhodium; triphenylphosphane (19.33 mg, 20.90 μmol, 0.1 equiv.) was added under N2 atmosphere. The mixture was stirred at 80° C. under H2 (75 Psi) and CO (75 Psi) for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-[(3R)-6-oxo-3-(3,4,5-trimethoxybenzoyl)oxy-hexyl]-1,4-diazepane-1-carboxylate (100 mg, crude) as a brown oil. The residue was used in the next step without purification. LC-MS(ES+) m / z: 509.2(M+H)+(calculated: 509.3).

[0207] Step 6: To a solution of tert-butyl 4-[(3R)-3-benzyloxy-6-oxo-hexyl]-1,4-diazepane-1-carboxylate (4, 100 mg, 247.19 μmol, 1 equiv.) in toluene (2 mL) was added NaBH4 (14.03 mg, 370.79 μmol, 1.5 equiv.) at 0° C. The mixture was stirred at 20° C. for 1 h. The residue was purified by preparative HPLC (column: PhenomenexLuna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 12%~42%, 10min) to give tert-butyl 4-[(3R)-6-hydroxy-3-(3,4,5-trimethoxybenzoyl)oxy-hexyl]-1,4-diazepane-1-carboxylate (10mg, yield 9.26%) as a white solid. LC-MS(ES+) m / z: 511.1(M+H)+(calculated value: 511.3) 1H NMR (400 MHz, CDCl3-d) δ 8.40 (br s, 1H), 7.28 (s, 2H), 5.22 (quin, J=6.1 Hz, 1H), 3.94 - 3.91 (m, 9H), 3.72 - 3.65 (m, 3H), 3.62 (br s, 1H), 3.53 - 3.44 (m, 2H), 2.97 (br s, 3H), 2.88 (br d, J=7.4 Hz, 3H), 2.13 (br s, 4H), 1.91 - 1.77 (m, 2H), 1.73 - 1.59 (m, 2H), 1.46 (s, 9H).

[0208] Step 7: Compound 8 (1.00 eq.) and toluene, compound 5A (0.85 kg, 3.34 mol, 1.00 eq.), PPh3 (1.05 eq.) were added to the reaction mixture at 20° C. DEAD (1.00 eq.) was added dropwise (an exothermic phenomenon was observed during the addition process). After the addition, the reaction mixture was stirred at 25° C. for 6 hours, and then the reaction mixture was stirred at −20° C. for 1 hour to precipitate a part of OPPh3. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography. 1H NMR (400 MHz, CDCl3-d) δ 7.30 (s, 2H), 7.21 (s, 2H), 5. 23-5.36 (m, 1H), 4.04-4.17 (m, 2H), 3.73-3.94 (m, 15H), 3.06 (t, J=6.8 Hz, 2H), 2.65-2.80 (m, 8H), 2.60 (t, J=7.6 Hz, 2H), 2.49 (t, J=7.6 Hz, 2H), 1.86-2.03 (m, 6H), 1.76-1.85 (m, 2H), 1.61-1.68 (m, 2H), 1.58 (s, 9H), 1.43 (s, 9H).

[0209] Step 8: A solution of HCl in dioxane (4 mol, 7.60 L) and compound 9 (1086 g, 1.35 mol, 1.00 equiv) were charged into a 20.0 L reaction vessel at 0-5° C. The reaction mixture was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure to give compound 10 (1050 g, as the HCl salt) as a yellow solid. Purity determined by quantitative NMR: 75.2% 1H NMR (400 MHz, MeOD-d4) δ 7.29 (s, 2H), 7.26 (s, 2H) 5.2 -5.37 (m, 1H), 4.11 (s, 2H), 3.94 (brs, 4H), 3.78-3.90 (m, 15H), 3.33-3.45 (m, 4H), 3.08 (t, J=7.6 Hz, 2H), 2.12-2.49 (m, 6H), 1.90-2.09 (m, 4H).

[0210] Step 9: Compound 10 (1050 g, 1.53 mol, 1.00 equiv, HCl) and DCM (210 L) were charged to a reaction vessel at 20 °C. Then, DIEA (793 g, 6.13 mol, 4.00 equiv) and PyBOP (38.4 g, 2.29 mol, 1.50 equiv) were added to the reaction vessel at 20 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated at 35-40 °C to give a residue. The residue was triturated with MeOH (4.2 L, 4.00 vol) at 20 °C for 60 min. The mixture was filtered and the cake was collected to give compound (R)-11 470 g, 34.94 mmol, 48.6% yield) as a white solid. Purity determined by quantitative NMR: 75.2% 1H NMR (400 MHz, MeOD-d4) δ 7.31 (s, 2H), 7.20 (d, J =1.8 Hz, 1H), 7.13 (d, J =1.8 Hz, 1H), 5.49 (s, 1H), 4.31 (br d, J =8.3 Hz, 1H), 4.18 (br s, 1H), 3.85-3.89 (m, 9H), 3.81 (d, J =7.3 Hz, 6H), 3.56-3.66 (m, 1H), 3.38-3.49 (m, 1H), 2.97 (td, J=3.2, 10.3 Hz, 1H), 2.84-2.91 (m, 2H), 2.74-2.84 (m, 3H), 2.61-2.73 (m, 4H), 2.56 (br t, J =6.5 Hz, 2H), 1.86-1.95 (m, 5H), 1.73-1.85 (m, 5H).

Claims

1. Compound (R)-11 【Chemical 1】 or a pharmaceutically acceptable salt or solvate thereof, comprising reacting compound 11: 【Chemistry 2】 separating compound (R)-11 from a racemic mixture of The step of separating compound (R)-11 is accomplished using chiral supercritical fluid chromatography (chiral SFC), Reacting compound 10 with a peptide coupling reagent to produce compound 11: 【Chemistry 3】 further comprising The method wherein the peptide coupling reagent is selected from the group consisting of BOP, PyBOP, HATU, and HBTU.

2. 2. The method of claim 1, wherein the peptide coupling reagent is PyBOP.

3. Deprotecting compound 9 by reacting compound 9 with an acid to produce compound 10: 【Chemistry 4】 The method of claim 1 or 2, further comprising:

4. 4. The method of claim 3, wherein the acid is HCl.

5. Reacting compound 8 with compound 8A to prepare compound 9: 【Chemistry 5】 The method of claim 3 further comprising:

6. 6. The method of claim 5, wherein the step of reacting compound 8 with compound 8A comprises adding a suitable base.

7. Suitable bases include K 2 CO 3 , Na 2 CO 3 , and Ca 2 CO 3 7. The method of claim 6, wherein the compound is selected from the group consisting of:

8. Reacting compound 7 with a mesylating agent to produce compound 8: 【Chemistry 6】 The method of claim 5 further comprising:

9. 9. The method of claim 8, wherein the mesylating agent is MsCl.

10. 9. The method of claim 8, wherein the step of reacting compound 7 with a mesylating agent comprises adding a suitable base.

11. 11. The method of claim 10, wherein the suitable base is selected from the group consisting of TEA, DEA, DIPA, and pyridine.

12. Reacting compound 6 with a suitable deprotecting agent to produce compound 7: 【Chemistry 7】 The method of claim 8 further comprising:

13. 13. The method of claim 12, wherein the suitable deprotecting agent is a fluoride source.

14. 14. The method of claim 13, wherein the fluoride source is selected from HF-pyridine, TBAF, KF, and TBAT.

15. reacting compound 5 with compound 5A to produce compound 6 【Chemistry 8】 The method of claim 12 further comprising:

16. The step of reacting compound 5 with compound 5A comprises reacting DEAD and PPh 3 16. The method of claim 15, further comprising adding:

17. Steps for preparing compound 5 from compound 4: 【Chemistry 9】 16. The method of claim 15, further comprising:

18. The method according to claim 17, wherein the step of producing compound 5 from compound 4 comprises a series of hydroboration-oxidation reactions.

19. The hydroboration-oxidation sequence is: (a) BH 3 (b) adding H 2 (c) quenching with NaBO; 3 20. The method of claim 18, comprising adding:

20. Reacting compound 3 with compound 3A to prepare compound 4: 【Chemistry 10】 20. The method of claim 17, further comprising:

21. 21. The method of claim 20, wherein the step of reacting compound 3 with compound 3A comprises adding an ester coupling reagent.

22. 22. The method of claim 21, wherein the ester coupling reagent is DCC.

23. Reacting compound 1 with compound 2 to produce compound 3: 【Chemistry 11】 21. The method of claim 20, further comprising:

24. A process for preparing compound 1 by oxidizing compound 1_1: 【Chemistry 12】 24. The method of claim 23, further comprising:

25. 25. The method of claim 24, wherein the step of oxidizing compound 1_1 comprises adding an oxidizing agent.

26. The oxidizing agent is Py.SO 3 26. The method of claim 25, wherein:

27. Reacting compound 18 with compound 3A: 【Chemistry 13】 A method for producing compound (R)-11, comprising:

28. 28. The method of claim 27, wherein the step of reacting compound 18 with compound 3A comprises adding an azodicarboxylic acid ester.

29. 29. The method of claim 28, wherein the azodicarboxylic acid ester is DEAD or DIAD.

30. The step of reacting compound 18 with compound 3A is carried out by PPh 3 30. The method of any one of claims 27 to 29, further comprising adding:

31. Compound (R)-11 【Chemistry 14】 or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of reacting compound (R)-10 with a peptide coupling reagent: 【Chemistry 15】 The above method, comprising:

32. 32. The method of claim 31 , wherein the peptide coupling reagent is selected from the group consisting of BOP, PyBOP, HATU, and HBTU.

33. A step of reacting compound (R)-9 with an acid to deprotect compound (9) to produce compound (R)-10: 【Chemistry 16】 33. The method of claim 31 or 32, further comprising:

34. 34. The method of claim 33, wherein the acid is HCl.

35. A step of reacting compound (R)-17 with 3,4,5-trimethoxybenzoic acid (compound 3A) or 3,4,5-trimethoxybenzoyl chloride to produce compound (R)-9: 【Chemistry 17】 34. The method of claim 33, further comprising:

36. 36. The method of claim 35, wherein the step of reacting compound (R)-17 with compound 3A comprises adding a carbodiimide.

37. 37. The method of claim 36, wherein the carbodiimide is selected from the group consisting of DIC and DCC. Law.

38. 36. The method of claim 35, further comprising the preliminary step of increasing the enantiomeric purity of compound (R)-17 using a resolving agent.

39. The splitting agent is 【Chemistry 18】 39. The method of claim 38, wherein:

40. Reacting compound 15 with a suitable reducing agent to produce compound (R)-17: 【Chemistry 19】 36. The method of claim 35, further comprising:

41. 41. The method of claim 40, wherein the suitable reducing agent is an enantiomeric reducing agent.

42. 42. The method of claim 41, wherein the enantiomeric reducing agent is (S,S)-Ms-DENEB.

43. Reacting compound 14 with compound 8A to prepare compound 15: 【Chemistry 20】 41. The method of claim 40, further comprising:

44. 44. The method of claim 43, wherein the step of reacting compound 14 with compound 8A comprises adding a suitable base.

45. 45. The method of claim 44, wherein the suitable base is triethylamine.

46. Preparation of Compound 14 from Compound 13: 【Chemical 21】 44. The method of claim 43, further comprising:

47. Reacting compound 12 with compound 5A to prepare compound 13: 【Chemical 22】 47. The method of claim 46, further comprising:

48. 48. The method of claim 47, wherein the step of reacting compound 12 with compound 5A comprises adding an azodicarboxylic acid ester.

49. 49. The method of claim 48, wherein the azodicarboxylic acid ester is DEAD.

50. Reacting compound 12B with compound 12A to prepare compound 12: 【Chemical 23】 48. The method of claim 47, further comprising:

51. 51. The method of claim 50, wherein the step of reacting compound 12B with compound 12A comprises adding a reducing agent.

52. 52. The method of claim 51, wherein the reducing agent is DIBAL-H.

53. Reacting compound 24 with compound 25A to prepare compound (R)-9: 【Chemical 27】 34. The method of claim 33, further comprising:

54. 54. The method of claim 53, wherein the step of reacting compound 24 with compound 25A comprises adding an azodicarboxylic acid ester.

55. 55. The method of claim 54, wherein the azodicarboxylic acid ester is selected from the group consisting of DEAD and DIAD.

56. Reacting compound 23 with a reducing agent to produce compound 24: 【Chemical 28】 54. The method of claim 53, further comprising:

57. The reducing agent is NaBH 4 57. The method of claim 56, wherein:

58. Reacting compound 22 with a catalyst to produce compound 23: 【Chemical 29】 57. The method of claim 56, further comprising:

59. The catalyst was RhCl(PPh 3 ) 3 59. The method of claim 58, wherein:

60. Reacting compound 21 with compound 3A to prepare compound 22: 【Chemistry 30】 59. The method of claim 58, further comprising:

61. 61. The method of claim 60, wherein the step of reacting compound 21 with compound 3A comprises adding an ester coupling reagent.

62. 62. The method of claim 61, wherein the ester coupling reagent is DCC.

63. Reacting compound 20 with compound 8A to prepare compound 21: 【Chemical 31】 61. The method of claim 60, further comprising:

64. 64. The method of claim 63, wherein the step of reacting compound 20 with compound 8A comprises adding a suitable reducing agent.

65. The reducing agent is NaBH 4 65. The method of claim 64, wherein:

66. Preparation of Compound 20 from Compound 19: 【Chemical 32】 64. The method of claim 63, further comprising:

67. The process for producing compound 19 is 3 , I 2 and adding imidazole.

68. Steps for preparing compound 19 from compound 18: 【Chemical 33】 67. The method of claim 66, further comprising:

Images