Novel synthesis method for the production of (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(methano)pyrazolo[4,3-B][1,7]diazacyclotetradecine-5(6H)-one

Abstract

To provide a highly efficient method for manufacturing XIa inhibitors useful for the treatment of thromboembolic disorders.SOLUTION: Highly efficient methods are provided for preparing key intermediates in the synthesis of Compound (I), which are broadly applicable and can provide selected components having a variety of substituents.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to several improved methods for producing (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(methano)pyrazolo[4,3-b][1,7]diazacyclotetradecine-5(6H)-one, which is a factor XIa inhibitor useful for the treatment of thromboembolic disorders (e.g., venous thrombosis and deep vein thrombosis). [Background technology]

[0002] Factor XIa is a plasma serine protease involved in regulating blood coagulation. In vivo, tissue factor (TF) initiates binding to factor VII (FVII), producing factor VIIa (FVIIa). The resulting TF:FVIIa complex contributes to the activation of factor IX (FIX) and factor X (FX), leading to the production of factor Xa (FXa). The produced FXa acts as a catalyst, converting prothrombin to a small amount of thrombin, after which this pathway is inhibited by tissue factor pathway inhibitors (TFPIs). The catalytic amount of thrombin then triggers feedback activity to factors V, VIII, and XI, further propagating the coagulation process (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007)). Increased thrombin levels lead to the polymerization of fibrinogen into fibrin, forming the framework of a thrombus and activating platelets, which are essential cellular coagulation components (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIa plays a crucial role in the propagation of this amplification loop and is an attractive target in antithrombotic therapy.

[0003] U.S. Patent No. 9,453,018 discloses macrocyclic compounds as factor XIa inhibitors useful for the treatment of thromboembolic disorders. One of these compounds has the following structure. [ka]

[0004] The aforementioned U.S. patent discloses a multi-step synthesis method for producing macrocyclic compounds. This method includes a step of coupling a pyridine-containing macrocyclic compound with pyrimidinol to form compound (I). The disclosed method also includes a step of ring-closing metathesis using a catalyst (e.g., Grubbs(II)).

[0005] Applying the multi-step synthesis disclosed in U.S. Patent No. 9,453,018 to larger-scale synthesis (e.g., production in a pilot plant or on a manufacturing scale) presents various challenges. One is that the high cost of the Grubbs(II) reagent makes it difficult to apply to industrial-scale synthesis. Furthermore, there is a need to continuously seek methods that yield higher results in order to reduce manufacturing costs and / or unreacted material. Preferably, inexpensive starting materials are selected in the new process.

[0006] There is a need for a method suitable for producing larger quantities of compound (I) than those typically produced by laboratory-scale methods. Furthermore, there is a need for a method that yields compound (I) in higher quantities than previously disclosed methods.

[0007] The present invention relates to one or both of these embodiments, as well as other important embodiments. [Overview of the project]

[0008] In one embodiment, the present invention provides a method for producing compound (I), characterized by the following steps. [ka] 1) Formula [Chemical formula] Compound 1 with the structure of is reacted with the formula [Chemical formula] [wherein, X is selected from Cl, Br, and I; Y is OR , 3 , , , 1 , 3 , , 1-6 , , , NHOC 1-3 alkyl, Cl, Br, and I; and R 9 is selected from C 1-3 alkyl, C 1-3 hydroxyalkyl, substituted phenyl and substituted benzyl], Compound 2 in a suitable solvent to obtain compound 3a or 3b of the formula [Chemical formula] to obtain. 2) Compound 3a or 3b is converted to the compound of the formula [Chemical formula] in the presence of an acid. 3) Next, compound 4 is reacted with trialkyl orthoformate in an alcohol solvent to give a compound of the formula [Chemical formula] [wherein, R 1 is C 1-6 alkyl; and R 3 ' is selected from C 1-6 alkyl, optionally substituted phenyl and benzyl]. 4) The ester of compound 5 is hydrolyzed under basic conditions or undergoes hydrogenolysis when R 3 ' is substituted benzyl, [Chemical formula] wherein R 1And X becomes compound 6 as defined above. 5) Next, the carboxyl portion of compound 6 is activated and reacted with the chiral additive, and the formula [ka] [In the formula, Xa is an asymmetric additive, R 1 And we obtain compound 6a of [X is defined as above]. 6) Next, compound 6a is reacted with a base in the presence of a methyl donor (e.g., an alkyl halide) and an asymmetric additive. [ka] In the formula, R 1 We obtain compound 6b in which X and Xa are defined as described above. 7) Remove the chirality enhancer Xa, [ka] In the formula, R 1 And we obtain compound 7 in which X is defined as described above. 8) Next, compound 7 is subjected to the following structure in the presence of a metal catalyst. [ka] Compound 8 is reacted with compound 9 [ka] To obtain. 9) Reduce the nitro group of compound 9 to obtain the following formula [ka] Compound 10 is obtained. 10) Compound 10 is cyclized with a suitable coupling agent, and compound 11 [ka] To obtain. 11) Deprotect the ketone group in the presence of an acid, and compound 12 [ka] To obtain. 12a) Reduce compound 12 with an equivalent amount of ammonia in the presence of a reducing agent, or 12b) Compound 12 is reduced by an aminotransferase in the presence of an amine donor, a different recyclization system, and a cofactor to obtain compound 13. [ka] The amine stereocenter shown is obtained. 13) Compound 13 followed by Compound 14 [ka] It couples with compound (I) [ka] To obtain.

[0009] In yet another embodiment, the present invention relates to formula (II): [ka] [In the formula, The dashed line (----) represents any combination; R 1 C 1-6 Alkyl, preferably Me; R 2 C 1-3 Alkyl, preferably Me; R 3 OH, OC 1-4 Alkyl, [ka] Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I. Provides the compound or free base form or salt of the compound.

[0010] In some embodiments of the compound of formula (II), R 1 C 1-6 It is alkyl; R 2 C 1-3 It is alkyl; R 3 OH, OC 1-6 Alkyl, [ka] Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3 Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I.

[0011] In some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R 1 It is methyl; R 2 It is methyl; R 3 is OH; and X is Cl.

[0012] In some embodiments of the compound of formula (II), R 1 It is methyl; R 2 It is methyl; R 3 is OH; and X is Cl, The compound is in the form of its free base or as a (1S,2R)-2-amino-1,2-diphenylethane-1-ol salt or dicyclohexylamine salt.

[0013] In yet another embodiment, the present invention relates to formula (IIa): [ka] [In the formula, The dashed line (----) represents any combination; R 1 C 1-6 Alkyl, preferably Me; R 2 C 1-3 Alkyl or C 1-3 An alkenyl, preferably Me or CH2; R 3 OH, OC 1-4 Alkyl, [ka] Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3 Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I. Provides the compound or free base form or salt of the compound.

[0014] In some embodiments, formula (II) has the following structure: [ka] [In the formula, R 1 It is methyl; R 2 It is methyl; R 3 is OH; and X is Cl. The method for producing the compound is characterized by the following steps. a) Formula [ka] Compound 22 of formula [ka] Compound 2 [In the formula, X is selected from Cl, Br, and I; Y is OR 9 NHOC 1-3 Selected from alkyl, Cl, Br, and I; and R 9 C 1-3 Alkyl, C 1-3 [Selected from hydroxyalkyl, substituted phenyl, and substituted benzyl] React with the appropriate solvent, [ka] Compound 23 is obtained. b) Compound 23a or 23b under the presence of an acid, formula [ka] Convert to compound 24. c) Next, compound 24 is reacted with trimethyl orthoformate or triethyl orthoformate, and the formula is obtained. [ka] [In the formula, R 1 [where is methyl or ethyl, and X is as defined above] to obtain compound 25. d) Compound 25 by enzyme [ka] In the formula, R 1And X is converted to compound 26 as defined above. e) Hydrolyze compound 26, [ka] In the formula, R 1 And X is converted to compound 27 as defined above.

[0015] In some embodiments of the method for producing the compound of formula (II), the enzyme is lipase.

[0016] In some embodiments, the structure of compound 21 [ka] A method for producing a compound of formula (II) or (IIa) having the following steps: 1) Formula [ka] R is C 1-6 A cyclopentane ester derivative, which is alkyl, is reacted with a dialkylamine, and the formula [ka] Alk is C 1-6 A compound 40, which is an alkyl compound, is obtained. 2) When compound 40 is combined with the first base, the following structure is formed. [ka] It forms compound 41. 3) Compound 41 with acid and alcohol R 3 'React with OH, formula [ka] R 3 ' is C 1-6 It forms compound 42, which is alkyl. 4) Compound 42 has the following structure [ka] Compound 2a is reacted with the second base, and the formula [ka] Compound 18b is obtained. 5) Compound 18b has the following structure [ka] Convert to compound 20b. 6) Next, compound 20b is hydrogenated to form the following structure [ka] A compound of formula (II) having the following characteristics is obtained.

[0017] In some embodiments of the method for producing a compound of formula (II) or (IIa) having the structure of compound 21, the hydrogenation in step (6) includes a chiral ruthenium catalyst.

[0018] formula [ka] [In the formula, R1 is C 1-6 It is alkyl; R 10 C 1-6 It is alkyl. In some embodiments of a method for producing a compound of formula (II) or (IIa) having compound 19, the following steps are characterized: 1) Formula: [ka] Compound 37 was reacted with pyruvate ester phosphonium ylide, and the formula was: [ka] R 3 'But, independently C 1-6 Compound 38, which is alkyl, is obtained. 2) Compound 38 has the following structure [ka] Compound 2a having the formula is reacted with a base, [ka] It forms compound 39. 3) Compound 39 is reacted with the first acid to obtain the following structure [ka] It forms compound 18a. 4) Compound 18a is C 1-6 The alkyl alcohol, the second acid, and a drying agent as needed are added and reacted to form compound 19.

[0019] In yet another embodiment, the present invention relates to formula (III): [ka] [In the formula, R 1 C 1-6 It is alkyl; R 2 C 1-3 It is alkyl; R 4 It is selected from NO2, N=O, NHOH, and NH2; and R 5 [Selected from CHF2, CD3, and CH3] The compound is provided.

[0020] In some embodiments of the compound of formula (III), R 1 It is methyl; R 2 It is methyl; R 4 It is selected from NO2 and NH2; and R 5 It is CHF2.

[0021] In yet another aspect, the present invention provides a compound of formula (IV):

Chemical formula

[0022] In some embodiments of the compound of formula (IV), R 1 is methyl; R 2 is methyl; and R 5 is CHF2.

[0023] In yet another aspect, the present invention provides a compound of formula (V):

Chemical formula

[0024] In some embodiments of the compound of formula (V), R 2 is methyl, and R 5 is CHF2.

[0025] In yet another aspect, the present invention provides a compound of formula (VI):

Chemical formula

[0026] In some embodiments of the compound of formula (VI), R 2 C 1-3 It is alkyl; R 3 OH, OC 1-4 Alkyl, [ka] Selected from; and X is selected from F, Cl, Br, and I.

[0027] In some embodiments, the compound of formula (VI) is compound 34 [ka] It has the structure of [the object].

[0028] In another embodiment, the present invention provides a method for treating thromboembolic disorders, characterized by administering a therapeutically effective amount of compound (I), which is produced using the novel synthesis method of the present invention, to a mammal in need of treatment, preferably a human. [Modes for carrying out the invention]

[0029] definition As used herein, the term "alkyl" refers to a linear or branched saturated aliphatic molecule containing 1 to 10 carbon atoms. Unless otherwise specified, examples of alkyls include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. The term "lower alkyl" refers to an alkyl group having 1 to 4 carbon atoms.

[0030] The term "alkoxy" refers to a group having the formula -O-alkyl, in which the alkyl group defined above is connected to the parent molecule via an oxygen atom. The alkyl portion of the alkoxy group consists of 1 to 10 carbon atoms (i.e., C1-C1). 10 It may be an alkoxy group, or a group of 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -OtBu).

[0031] The term "aryl" refers to a monocyclic or bicyclic fused ring containing 6 to 10 ring carbon atoms, where each ring is aromatic (e.g., phenyl or naphthyl).

[0032] The term "substituent" refers to an additional substituent selected from halogens (preferably fluoro, chloro, or bromo), hydroxy, amino, mercapto, and the like. In groups such as substituted lower alkyls or substituted alkyls as described herein, preferred substituents are halogens, particularly fluoro groups.

[0033] The term "reducing agent" refers to any reagent that reduces the oxidation state of carbon atoms in a starting material by adding hydrogen atoms or electrons. These reagents are well known to those in the field. Examples of "reducing agents" include, but are not limited to, borane-dimethyl sulfide complexes, 9-borabicyclo[3.3.1]nonane (9-BBN), catecholborane, lithium borohydride, sodium borohydride, sodium borohydride-methanol complex, potassium borohydride, sodium hydroxyborohydride, lithium triethylborohydride, lithium n-butylborohydride, sodium cyanoborohydride, calcium(II) borohydride, lithium aluminum hydride, diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodium bis-methoxyethoxyaluminum hydride, triethoxysilane, diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen Ni / B, etc. Certain acidic reagents and Lewis acid reagents enhance the activity of reducing agents. Examples of such acidic reagents include acetic acid, methanesulfonic acid, and hydrochloric acid. Examples of such Lewis acid reagents include trimethoxyborane, triethoxyborane, aluminum chloride, lithium chloride, vanadium(III) chloride, bis(cyclopentadienyl)titanium dichloride, cesium fluoride, potassium fluoride, zinc(II) chloride, zinc(II) bromide, and zinc(II) iodide.

[0034] The term "removable protecting group" or "protecting group" refers to any group that binds to a functional site (e.g., the oxygen atom of a hydroxyl or carboxyl group, or the nitrogen atom of an amino group), preventing a reaction from occurring at these functional sites, and which can be removed by conventional chemical or enzymatic steps to reconstruct the original functional site. The type of removable protecting group used is not important.

[0035] As used herein, the term "ligand" refers to a palladium-binding phosphine derivative, such as an arylphosphine or alkylphosphine, which can form a complex with a palladium atom and coordinate one or two atoms. This term is well known to those skilled in the art.

[0036] As used herein, the term "silylation" refers to the process of introducing a silyl or silicon-containing group. Examples of silyl groups include, but are not limited to, tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl-oxymethyl (TOM), and di-tert-butylsilylbis(trifluoromethanesulfonate).

[0037] As used herein, the term "desilylation" refers to the process of removing a silyl or silicon-containing group.

[0038] Embodiments of the present invention The present invention relates to a number of synthetic intermediates and methods for producing these intermediates and compound (I).

[0039] General aspects of these example methods are shown in the scheme and examples. Each product used in the following process is separated, isolated, and / or purified as appropriate before use.

[0040] Generally, the reaction conditions used for a particular reaction (e.g., temperature, reaction time, solvent, work-up method, etc.) are common to those skilled in the art. Typically, the temperature is between -100°C and 200°C, the solvent is aprotic or protic, and the reaction time is between 10 seconds and 10 days. Generally, the work-up consists of quenching any unreacted reagents, followed by partitioning (extracting) into the water / organic layer, and separating the layer containing the product.

[0041] Generally, oxidation and reduction reactions take place at around room temperature (approximately 20°C), although metal hydride reduction often requires temperatures ranging from 0°C to -100°C. Generally, the solvent is aprotic in reduction reactions, while it can be either protic or aprotic in oxidation reactions. The reaction time is adjusted to achieve the desired conversion rate.

[0042] In one embodiment, the present invention provides a method for producing compound (I). Typical general production methods for derivatives are outlined in Schemes 1 and 2 below. [ka] [ka]

[0043] The details of each step in the manufacturing method shown in the above scheme are described below.

[0044] Step 1

[0045] The starting materials for this process are compound 1 and compound 2. In embodiments where the starting materials are prepared according to the method described in the literature, the starting materials are preferably purified before the reaction. Compounds 1 and 2 react in a suitable solvent under basic conditions to form compound 3. Suitable bases include, for example, Li + na + , and K + There are alkoxide bases that use as a countercation (e.g., methoxide, ethoxide, tert-butoxide, amylate, tert-amylate).

[0046] Examples of suitable solvents include, but are not limited to, polar aprotic solvents (e.g., dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidinone); ether solvents (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl t-butyl ether (MTBE), diethoxymethane, and CPME); hydrocarbon solvents (e.g., benzene, toluene, hexane, and heptane); halogen solvents (e.g., dichloromethane and 1,2-dichloroethane); acetate ester solvents (e.g., ethyl acetate, isopropyl acetate, and butyl acetate); and other solvents (e.g., acetonitrile, methyl vinyl ketone, N,N-dimethylacetamide); polar aprotic solvents and mixtures thereof. Preferred solvents include ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, and diethoxymethane).

[0047] This reaction can take place at approximately -78°C to approximately 0°C. Preferably, the reaction takes place at approximately -50°C to approximately -20°C.

[0048] Step 2

[0049] Next, compound 3 is subjected to a reverse Claisen reaction under acidic conditions or in an acidic aqueous solution to obtain compound 4. Suitable acids include, but are not limited to, formic acid, acetic acid, benzenesulfonic acid (BSA), nitric acid, perchloric acid, methanesulfonic acid (MSA), trifluoroacetic acid (TFA), citric acid, hydrochloric acid (HCl), sulfuric acid (H2SO4), and phosphoric acid (H3PO4). Preferably, the acid is MSA.

[0050] This reaction can be carried out over a relatively wide temperature range. The reaction generally takes place at temperatures between 0°C and 80°C. Preferably, the reaction takes place between approximately 20°C and 65°C.

[0051] Step 3

[0052] Compound 4 is then converted to the ester and ketal corresponding to Compound 4 using an alcoholic solvent, an acid catalyst, and optionally a drying agent, in the presence of trialkyl orthoformate. In some embodiments, the alcoholic solvent is C 1-6 The solvent is an alcohol (e.g., methanol, ethanol, propanol, butanol, pentanol, and hexanol). The acid catalyst may be selected from HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), and p-toluenesulfonic acid (PTSA), and if a drying agent is required, it may be selected from Na2SO4 and MgSO4, and the trialkyl orthoformate may be selected from, but is not limited to, trimethyl orthoformate (TMOF) and triethyl orthoformate (TEOF).

[0053] Step 4

[0054] The ester of compound 5 is then hydrolyzed under basic conditions in the presence of water and a suitable organic solvent (e.g., toluene, NMP) that is stable under basic conditions. The suitable base is Li + na + , K + , Cs + or NH4 + This is a hydroxide with a countercation. Examples of countercation-associated hydroxides include KOH, NaOH, and LiOH, although they are not limited to the following.

[0055] Step 5

[0056] The carboxylic acid of compound 6 is further reacted with an activator to form an active species that reacts directly with a chiral auxiliary, yielding compound 6a in the presence of a base. Typical activators include reagents such as acyl chloride (e.g., pivaloyl chloride), isopropyl chloride, acid anhydrides (e.g., pivalic anhydride, isopropyl anhydride), or oxalyl chloride and sulfonyl chloride.

[0057] Examples of chirality enhancers include, but are not limited to, oxazolidinone, 8-phenylmenthol, trans-phenylcyclohexanone, camphorsultam, pseudoephedrine (R,R) or (S,S), or pseudoefenamide (R,R) or (S,S), alkylthiazolidinedione-2-thione derivatives, or N-(-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)-N-phenylbenzenesulfonamide. In one embodiment, the chirality enhancer is [ka] It is an oxazolidinone selected from the following.

[0058] The base can be selected from, for example, DIPEA, TEA, LDA, n-BuLi, sec-BuLi, or tert-BuLi, potassium tert-butoxide, in a suitable solvent, regardless of the presence of an inorganic salt (e.g., LiCl).

[0059] Step 6

[0060] Compound 6a is alkylated using an alkylating agent and a strong base to obtain compound 6b. Examples of activators include, but are not limited to, alkyl halides, dialkyl sulfates, and trialkyloxonium tetrafluoroborates. Preferably, the alkylating agent is methyl halide (e.g., MeI). Suitable bases are NaHMDS, LiHMDS, KHMDS, and LDA. The solvent can be selected from ether solvents (THF, 2-Me-THF, MTBE, CPME), aromatic solvents (toluene), or polar aprotic solvents, or a combination thereof. The chiral additive is then removed under basic conditions using hydroxide bases (e.g., LiOH, NaOH, and KOH) to obtain compound 7.

[0061] Step 7

[0062] Compound 7 is isolated in a desired solvent as an amine base or an alkali salt of Na or K. Suitable bases are dibenzylamine, DABCO, dicyclohexylamine, ethanolamine, diethanolamine, imidazole, arginine, lysine, tromethamine, alanine, NaOH, KOH, and LiOH. Suitable solvents are ether solvents (THF, 2-Me-THF, MTBE, CPME), aromatic solvents (toluene), ketone solvents (acetone, MIBK, MEK), or ester solvents (RINKAN, PrOAc), acetonitrile, and alcohol solvents (MeOH, EtOH, IPA). Alternatively, compound 7 may be isolated as a free acid.

[0063] Step 8

[0064] Compound 7 is then reacted with compound 8 in the presence of a metal catalyst and a base to obtain compound 9. The metal catalyst is derived from Pd, Pt, Rh, Ru, Ir, Fe, Ni, or Cu. Ligands (e.g., phosphines, i.e., CX-A, XPhos, SPhos, Xantphos, DCEPhos) or N-heterocyclic carbenes (i.e., IMes, Ipr) can assist in this reaction. Suitable bases include organic bases (i.e., Et3N, DIPEA), inorganic bases (i.e., KOPiv, KOAc, K2CO3), or bases derived from inorganic bases and carboxylic acids (i.e., K2CO3 / PivOH, Cs2CO3 / PivOH, K2CO3 / PhCO2H). Suitable solvents are ether solvents (i.e., THF, 2-Me-THF, MTBE, CPME), aromatic solvents (i.e., toluene, benzene), or polar aprotic solvents (i.e., DMF, DMAc, NMP).

[0065] Step 9

[0066] The nitro group of compound 9 is reduced using a metal catalyst (e.g., Pd, Pt, Rh supported on carbon, aluminum oxide) in an ether solvent or an alcohol solvent in the presence of hydrogen gas or a hydrogen substitution reagent (e.g., ammonium formate or sodium formate) to form compound 10. Compound 9 can also react with HSiCl3 / DIPEA, SnCl2 or Na2S2O4 to give compound 10.

[0067] Step 10

[0068] Compound 10 is then subjected to macrocyclic lactamization using a suitable carboxyl activating agent and a base in a suitable solvent. Suitable coupling agents are any of the well-known coupling agents that couple an amine with an acid to form an amide. Examples of coupling agents include, but are not limited to, PyBOP, HATU / HOBt, EDAC, oxalyl chloride, acid anhydrides (e.g., pivalic anhydride), acid chlorides (e.g., pivaloyl chloride), or activators (e.g., DPPCL, DMC or TCFH). Suitable solvents typically include ether solvents (THF, 2-Me-THF, MTBE, CPME), aromatic solvents (toluene).

[0069] Step 11

[0070] In step 11, the ketone group of compound 11 is deprotected under acidic aqueous conditions to give compound 12. Examples of acids include, but are not limited to, HCl, HBr, and TFA.

[0071] Step 12

[0072] A reductive amination step is then performed on compound 12 to give compound 13. This transformation can be carried out using a reducing agent (e.g., BH3, NaBH3CN, Pd / C, Pt / C) in the presence of an amine donor (e.g., ammonia or an ammonium salt such as ammonium chloride), a hydrogen substitution salt (e.g., ammonium formate, or hydrogen gas if Pd / C or Pt / C is used).

[0073] Furthermore, reductive amination can also be obtained using aminotransferases in the presence of amine donors (e.g., isopropylamine, alanine, 3-aminobutyric acid, and methylbenzylamine) and cofactors (e.g., PLP). In the latter case, the preferred solvent is aqueous DMSO. Different recyclation systems (e.g., aminotransferase / lactate dehydrogenase / glucose dehydrogenase and aminotransferase / amino acid dehydrogenase / formate dehydrogenase) can be used. Examples of aminotransferases include, but are not limited to, ATA-113, ATA-200, ATA-237, ATA-251, ATA-254, ATA-256, and ATA-260.

[0074] The aminotransferases used in the processes of this disclosure generally contain amino acid sequences that are at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to a reference amino acid sequence selected from one of ATA-113, ATA-200, ATA-237, ATA-251, ATA-254, ATA-256, and ATA-260. In some embodiments, the aminotransferase is a recombinant aminotransferase polypeptide having an amino acid sequence in which one or more amino acid residues differ from the reference sequence (e.g., ATA-113, ATA-200, ATA-237, ATA-251, ATA-254, ATA-256, and ATA-260). In some embodiments, the polynucleotides that can be hybridized under very harsh conditions match the reference sequence (e.g., ATA-113, ATA-200, ATA-237, ATA-251, ATA-254, ATA-256, and ATA-260) in the proportions described above, with one or more residues encoding different aminotransferase polypeptides.

[0075] In the process described herein, an aminotransferase uses an amine donor to form the product compound. In some embodiments, the amine donor in the reaction conditions includes isopropylamine (also referred to herein as "IPM") or a compound selected from any other suitable amine donor used in the reaction of interest. In some embodiments, the amine donor is IPM.

[0076] Furthermore, appropriate reaction conditions for this process generally involve the presence of a cofactor in the reaction mixture. Since aminotransferases generally use members of the vitamin B6 family, the reaction conditions include a cofactor selected from pyridoxal-5'-phosphate (also known as pyridoxal phosphate, PLP, or P5P), pyridoxine (PN), pyridoxal (PL), pyridoxamine (PM), and their phosphorylated forms; pyridoxine phosphate (PNP), and pyridoxamine phosphate (PMP). In some embodiments, appropriate reaction conditions may include a cofactor selected from PLP, PN, PL, PM, PNP, and PMP. In some embodiments, the cofactor is PLP.

[0077] Step 13

[0078] Compound 13 ultimately couples with compound 14 to obtain compound (I), as shown in WO 2015 / 116886.

[0079] In the process described above, additional steps may be taken between steps 1-13. Furthermore, in schemes 1 and 2, different synthetic routes may also be used to produce key intermediates. Scheme 3 shows an alternative method for producing a specific example of compound 7 (scheme 1) as compound 21. [ka]

[0080] Compound 15 can be coupled with 3-chloro-1,1-dimethoxypropane, 3-bromo-1,1-dimethoxypropane, or 3-iodo-1,1-dimethoxypropane in a suitable solvent (e.g., THF) in the presence of a metal (e.g., Mg) and an initiator (e.g., I2) to form compound 16. Subsequently, compound 17 can be obtained by ketal hydrolysis using an organic acid (e.g., TFA, MSA, BSA, PTSA, PPTS) or an inorganic acid (e.g., HCl, HBr) in the presence of water and a suitable solvent. Next, the aldehyde of compound 17 is reacted with a triphenylphosphonium ylide (e.g., methyl 2-(triphenylphosphoranylidene)propanoate or ethyl 2-(triphenylphosphoranylidene)propanoate), or in a suitable solvent in the presence of a base (e.g., NaH or KOtBu), with a phosphonate derivative (e.g., methyl 2-(diethoxyphosphoryl)propanoate or ethyl 2-(diethoxyphosphoryl)propanoate) to obtain compound 18. Then, the ketone of compound 18 is reacted with an alcoholic solvent (e.g., C 1-6 The compounds are protected with an alcohol, an acid as a catalyst (e.g., HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and a drying agent as appropriate (e.g., Na2SO4, MgSO4, trimethyl orthoformate (TMOF), or triethyl orthoformate (TEOF)) to convert them to the corresponding ketal compound 19. The ester is then hydrolyzed under basic conditions in the presence of water to obtain compound 20. Suitable bases include Li + na + , K + , Cs + NH4 + There are hydroxides that use as a countercation. Finally, the olefin of compound 20 is reduced using a metal catalyst in the presence of H2 to obtain compound 21. The metal is preferably Ru or Rh. Chirality at the methyl carbon center is introduced by the use of a suitable chiral ligand. Alternatively, compound 19 can be reduced by treatment with an enreductase enzyme and ester hydrolysis under basic conditions.

[0081] Compound 19 can be prepared by another condensation (Scheme 4). [ka]

[0082] Compound 38 may be formed by coupling aldehyde 37 with a triphenylphosphonium ylide (e.g., methyl 2-(triphenylphosphoranylidene)propanoate or ethyl 2-(triphenylphosphoranylidene)propanoate), or by reacting it with a phosphonate derivative (e.g., methyl 2-(diethoxyphosphoryl)propanoate or ethyl 2-(diethoxyphosphoryl)propanoate) in a suitable solvent in the presence of a base (e.g., NaH or KOtBu) to obtain compound 38. The obtained bisester 38 is reacted with compound 2 having the structure of compound 2a in a suitable solvent in the presence of a base (e.g., LiHMDS, LDA, tBuOK) to obtain compound 39. This compound is further decarboxylated in a suitable solvent in the presence of an acid (e.g., HCl, MSA, H3PO4) to obtain compound 18a, which is then converted to compound 19 by the method described above.

[0083] In another embodiment, compound 21 may be obtained starting from a cyclopentane ester derivative (Scheme 5). [ka]

[0084] Compound 40 is formed by coupling a cyclopentane ester derivative with formaldehyde and a dialkylamine. Further treatment under basic conditions yields compound 41, a diacid derivative. After esterification to form compound 42, it is coupled with compound 2a and treated with acid to obtain compound 18b, an acrylic acid derivative. The ketone of compound 18b is then treated with an alcoholic solvent (e.g., C 1-6Alcohol), an acid catalyst (e.g., HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and optionally a drying agent (e.g., Na2SO4, MgSO4, trimethyl orthoformate (TMOF) or triethyl orthoformate (TEOF)) are used for protection to obtain the corresponding ketal. Next, the ester is hydrolyzed under basic conditions in the presence of water to obtain Compound 20b. Suitable bases include hydroxides or free carboxylic acids having Li + 、Na + 、K + 、Cs + 、NH4 + as the counter cation. Finally, the olefin of Compound 20b is reduced using a metal catalyst in the presence of H2 to give Compound 21. The metal is preferably Ru or Rh. The chirality at the methyl carbon center is introduced by the use of a suitable chiral ligand. Alternatively, the desired enantiomer may be obtained by treating with an ene reductase enzyme.

[0085] In another embodiment, Compounds 7 (Scheme 1) and 27 (Scheme 7) of specific examples that can be produced by enzymatic resolution are shown in Reaction Schemes 6 and 7.

Chemical formula

[0086] Compound 22 and 2 are reacted under basic conditions in a suitable solvent to obtain Compound 23. Li + 、Na + 、K +A base such as an alkoxide (methoxide, ethoxide, tert-butoxide, amylate, tert-amylate) with the countercation is suitable as a solvent (e.g., ether solvents (THF, 2-MeTHF, MTBE, CPME), aromatic solvents (toluene), or dipolar aprotic solvents). Compound 24 is obtained by the reverse Claisen reaction of compound 23 under acidic conditions or in an acidic aqueous solution. Suitable acids include, but are not limited to, H2SO4, MSA, BSA, nitric acid, TFA, or perchloric acid.

[0087] Next, compound 24 is dissolved in an alcohol-based solvent (C 1-6 The corresponding ester and ketal compounds 25 are converted using an alcohol, an acid catalyst (for example, but not limited to, HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and, as appropriate, a drying agent (for example, Na2SO4, MgSO4, and trialkyl orthoformate (for example, trimethyl orthoformate (TMOF) or triethyl orthoformate (TEOF))).

[0088] Next, compound 25 is divided using an enzyme as shown in Scheme 7. [ka]

[0089] The racemic compound 25 is divided using an enzyme. The unwanted enantiomer in compound 25 of the racemic mixture is hydrolyzed while the desired enantiomer compound 26 remains unreacted. Compound 26 is then hydrolyzed with a basic aqueous solution (e.g., NaOH) to obtain compound 27. Preferably, the hydrolytic enzyme is lipase MH Amano 10 SD, which exhibits high selectivity (enantiomer excess >90%).

[0090] In method B, the racemic compound 25 is resolved using an enzyme. With some of the unwanted enantiomers remaining unreacted, the desired enantiomer in the racemic mixture compound 25 is hydrolyzed to obtain compound 27.

[0091] In method C, the unreacted and unwanted enantiomer compound S-26 produced in method B is racemized in the presence of a base to form compound 25, which is used as a starting material in either method A or method B.

[0092] In another embodiment, intermediate compound 10 is produced by the method shown in Scheme 8, which is different from Scheme 1. [ka]

[0093] Step 1

[0094] Compound 28 is coupled with silyl-protected acetylene in a strong base and a suitable solvent to obtain compound 29. The base may be a strong lithium base (e.g., an alkyllithium base or an aryllithium base). Examples of alkyllithium bases and aryllithium bases include, but are not limited to, methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium. The solvent may be an ether-based solvent (e.g., THF).

[0095] Step 2 Next, the ketone portion is treated with an alcohol-based solvent (C 1-6 The compounds are protected as corresponding ketals using an alcohol, an acid catalyst (e.g., HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and a suitable drying agent (e.g., Na2SO4, MgSO4), and a trialkyl orthoformate (e.g., trimethyl orthoformate (TMOF) or triethyl orthoformate (TEOF)). The protected silyl groups are then deprotected in a suitable solvent (e.g., THF, 2-MeTHF) using a fluorine source (e.g., TBAF, HF·TEA, HF) to obtain compound 30.

[0096] Step 3

[0097] Next, the triple bond of compound 30 is converted to the corresponding vinyl halide compound 31 in a two-step process using LiAl(OtBu)3H / Cp2ZrCl2 followed by a halide donor (e.g., N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide).

[0098] Step 4

[0099] Next, compound 31 is cross-coupled with commercially available (S)-(-)-3-methoxy-2-methyl-3-oxopropylzinc bromide using a metal catalyst to obtain compound 32. Examples of metal catalysts include, but are not limited to, Pd(II) salts (e.g., PdCl2, Pd(OAc)2) or coordination metals (e.g., 1,1'-bis(di-tert-butylphosphin)ferrocenedichloropalladium).

[0100] Step 5

[0101] Compound 32 is then reacted with compound 8 in the presence of a metal catalyst and a base to obtain compound 33. The metal catalyst can be derived from Pd, Pt, Rh, Ru, Ir, Fe, Ni, or Cu. Ligands (e.g., phosphines, i.e., CX-A, XPhos, SPhos, Xantphos, DCEPhos) or N-heterocyclic carbenes (i.e., IMes, Ipr) can assist in this reaction. Suitable bases include organic bases (i.e., Et3N, DIPEA), inorganic bases (i.e., KOPiv, KOAc, K2CO3), or bases derived from inorganic bases and carboxylic acids (i.e., K2CO3 / PivOH, Cs2CO3 / PivOH, K2CO3 / PhCO2H). Suitable solvents are ether-based solvents (i.e., THF, 2-Me-THF, MTBE, CPME), aromatic solvents (i.e., toluene, benzene), or polar aprotic solvents (i.e., DMF, DMAc, NMP).

[0102] Step 6

[0103] Next, compound 33 is reduced under reducing conditions to remove the double bond and nitro group, and then the methyl ester is hydrolyzed to obtain compound 10. Reduction is effective when using a metal (e.g., Pd or Pt) in the presence of hydrogen gas in a protic solvent (e.g., MeOH, EtOH, IPA). Ester hydrolysis occurs by treating the methyl ester with a hydroxide base (e.g., LiOH, NaOH, KOH) in the presence of water or water and a miscible organic solvent. [ka]

[0104] Step 1

[0105] Compound 45 can be synthesized from compounds 43 and 44 under appropriate Suzuki coupling conditions, for example, in a suitable solvent (e.g., methanol, DMF, or acetonitrile) in the presence of an appropriate level of palladium catalyst (e.g., Pd(PPh3)4, Pd(OAc)2, or Pd(dppf)Cl2-DCM complex).

[0106] Steps 2 and 3

[0107] Compound 46 is obtained by azidation followed by a click reaction with a suitable acetylene compound. Compound 45 is treated under azidation conditions (e.g., TMSN3 / tBuONO) to obtain an intermediate azide, which is then reacted with trimethylsilylacetylene in the presence of a copper(I) catalyst (e.g., CuOAc or copper(I) iodide) to obtain triazole compound 46.

[0108] Step 4

[0109] Compound 47 is obtained by reacting silyl compound 46 with 1,3-dichloro-5,5-dimethylhydantoin in a suitable solvent. Suitable solvents include polar aprotic solvents (e.g., THF or DMF).

[0110] Step 5

[0111] Compound 14 is obtained by reacting compound 47 in hydrochloric acid (e.g., concentrated hydrochloric acid).

[0112] In another embodiment, the present invention is given by formula (II): [ka] [In the formula, The dashed line (----) represents any combination; R 1 C 1-6 It is alkyl; R 2 C 1-3 Alkyl and alkenyl; R 3 OH, OC 1-6 Alkyl, [ka] Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3 Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I. The compound is provided in the form of a base or salt.

[0113] In another embodiment, the present invention is [ka] We provide compounds selected from the group consisting of the following.

[0114] In another embodiment, the present invention is [ka] The present invention provides compounds having a structure selected from the group consisting of the following.

[0115] In another embodiment, the present invention is [ka] We provide compounds selected from the group consisting of the following.

[0116] In another embodiment, the present invention is given by formula (III): [ka] [In the formula, R 1 C 1-6 It is alkyl; R 2 C 1-3 It is alkyl; R 4 It is selected from NO2, N=O, NHOH, and NH2; and R 5 [Selected from CHF2, CD3, and CH3] The compound is provided.

[0117] In another embodiment, the present invention is [ka] We provide compounds selected from the group consisting of the following.

[0118] In another embodiment, the present invention relates to formula (IV): [ka] [In the formula, R 1 C 1-6 It is alkyl; R 2 C 1-3 Alkyl and R 5 [Selected from CHF2, CD3, and CH3] The compound is provided.

[0119] In another embodiment, the present invention is [ka] We provide compounds selected from the group consisting of the following.

[0120] In another embodiment, the present invention is given by formula (V): [ka] [In the formula, R 2 C 1-3 Alkyl and R 5 The selected type is CHF2, CD3, and CH3. The compound is provided.

[0121] In another embodiment, the present invention is [ka] The compound is provided.

[0122] In another embodiment, the present invention is given by formula (VI): [ka] [In the formula, R 2 C 1-3 It is alkyl; R 3 OH, OC 1-6 Alkyl, [ka] Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3 Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I. The compound is provided.

[0123] In another embodiment, the present invention has the following structure [ka] The present invention provides compounds having the following properties. [Examples]

[0124] To make the present invention easier to understand, the following examples are described. Unless otherwise specified, all reactions were carried out under nitrogen atmosphere and anhydrous conditions. Unless otherwise specified, reagents were used in the condition as received from the distributor. The yields stated are for isolated substances and have not been corrected for water content. The reactions were monitored using a normal-phase or reverse-phase HPLC system (Shimadzu) with CH3CN / H2O / MeOH (containing either 0.05% TFA or 0.1% NH4OAc) as the mobile phase.

[0125] Method A

[0126] chromatography conditions [Table 1]

[0127] gradient [Table 2]

[0128] Method B

[0129] chromatography conditions [Table 3]

[0130] gradient [Table 4]

[0131] Method C

[0132] chromatography conditions [Table 5]

[0133] gradient [Table 6]

[0134] Method D

[0135] chromatography conditions [Table 7]

[0136] gradient [Table 8]

[0137] Method E

[0138] chromatography conditions [Table 9]

[0139] gradient [Table 10]

[0140] Method F

[0141] chromatography conditions [Table 11]

[0142] gradient [Table 12]

[0143] Method G

[0144] chromatography conditions [Table 13]

[0145] gradient [Table 14]

[0146] Method H

[0147] chromatography conditions [Table 15]

[0148] gradient [Table 16]

[0149] Method I

[0150] chromatography conditions [Table 17]

[0151] Gradient: [Table 18]

[0152] Method J

[0153] chromatography conditions [Table 19]

[0154] gradient [Table 20]

[0155] Method K

[0156] chromatography conditions [Table 21]

[0157] gradient [Table 22]

[0158] Method L

[0159] chromatography conditions [Table 23]

[0160] gradient [Table 24]

[0161] NMR spectra were recorded using a Bruker DRX-600, DRX-500, or DRX-400, with residual protons in the deuterated solvent referenced. Low-resolution mass spectrometry (LRMS) was recorded using a Waters ZQ ES.

[0162] The abbreviations used in this specification are defined as follows: "1x" means once, "2x" means twice, "3x" means three times, "℃" means degrees Celsius, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means normality, "M" means molar, "mmol" means millimoles, "min" means minutes, "h" means hours, "rt" means room temperature, "RT" means retention time, "atm" means atmospheric pressure, "psi" means pounds per square inch, "conc." means concentrated, "sat" or "sat'd" means saturated, "MW" means molecular weight, "mp" means melting point, "ee" means enantiomer excess, "MS" or "Mass Spec" means mass spectrometry, "ESI" means electrospray ionization mass spectrometry, "HR" means high resolution, "HRMS" means high-resolution mass spectrometry, "LCMS" means liquid chromatography-mass spectrometry, "HPLC" means high-performance liquid chromatography, "RP" means high-resolution "HPLC" is reversed-phase HPLC, "TLC" or "tlc" is thin-layer chromatography, "NMR" is nuclear magnetic resonance spectroscopy, "nOe" is nuclear Overhauser effect spectroscopy, 1 "H" is a proton, "δ" is a delta, "s" is a singlet, "d" is a doublet, "t" is a triplet, "q" is a quartet, "m" is a multiplet, "br" is a broad, "Hz" is Hertz, and "α", "β", "R", "S", "E", and "Z" are symbols used in stereochemistry that are well known to those skilled in the art. [Table 25] [Table 26] [Table 27]

[0163] The preparation of intermediate compounds 3a-Cl, 4a, 5a, 6a, 7a, 35, and 36 is described in Scheme 10 (an embodiment of General Scheme 1 described above) and Examples 1-4. An embodiment of General Scheme 2 that forms compound (I) is described in Examples 5-12 below. [ka] Example 1 Synthesis of compound 3a-Cl [ka]

[0164] Compound 2a (540 g, 3053 mmol, limiting reagent) was added to a 20 L reaction vessel fitted with a nitrogen inlet, temperature probe, and overhead stirrer, followed by THF (4500 mL), and the mixture was stirred to dissolve compound 2a. Compound 1 (287.4 g, 3382 mmol, 1.2 equivalents) was then added, followed by rinsing with THF (50 mL).

[0165] This solution was cooled to -35°C in a condenser. Then, potassium tert-butoxide / THF solution (1M, 3650 mL, 1.3 equivalents) was slowly added, ensuring that the temperature did not exceed -30°C.

[0166] The reaction mixture was kept at -35 to -30°C for 1 hour until the reaction was complete. Water (3635 mL) was added to another 20 L reaction vessel, followed by concentrated sulfuric acid (193.3 g, 0.69 equivalents). The temperature of the reaction vessel was set to 10°C, and the reaction mixture was cooled to 12°C. The cooling solution from the aforementioned cold container (-35 to -30°C) was added to the 20 L reaction vessel containing the cold H2SO4 aqueous solution using a transport tube, while maintaining the temperature below 10°C. After the transfer was complete, the THF was then distilled under vacuum at 20 to 25°C until the volume was reduced to ~7.5 L. At this point, a solid was formed. The slurry was filtered and washed with water (2000 mL, 3.7 V). Compound 3a-Cl[1,061 g] was obtained as a yellowish-brown solid.

[0167] 1H NMR(500MHz, DMSO-d6)δ 14.97 (br s, 0.5H), 8.73 (t, J=5.1Hz, 1H), 8.02-7.98 (d, J= 24.1Hz, 1H), 7.85-7.75 (dd, J= 32, 5.1Hz, 1H), 4.70 (t, J=9.5Hz, 0.5H), 2.93 (t, J=7.2Hz, 1H), 2.61-2.53 (m, 1H), 2.44-2.21 (m, 2H), 2.08 (ddd, J=12.3, 8.2, 4.0Hz, 1H), 2.01-1.81 (m, 1H)

[0168] C 11 H 11 ClNO2 + LRMS calculation value: [M+H] + 224.05, Observed value: 224.28

[0169] Example 2 Synthesis of compound 4a In a 20 L cold container, 1074 g (7823 mmol, 2.83 equivalents) of 70 wt% MSA solution was added, followed by 4900 mL of water. The reaction mixture was heated at 65°C. Next, a moist cake of compound 3a-Cl was added to the container, and the mixture was heated at 65°C for 3 hours until the reaction was complete. The reaction mixture was then cooled to 20-25°C, and 489 g (3907 mmol, 1.41 equivalents) of 28 wt% NH4OH aqueous solution was added. The pH was adjusted to 5.06 using a pH probe. The resulting slurry was heated at 44°C and maintained at 44°C overnight. The reaction mixture was cooled to 20-25°C, the slurry was filtered, and the resulting cake was washed with 3000 mL of water (6V). The moist cake was dried in a vacuum oven (50°C, 100 mmHg) for 2 days to obtain compound 4a (590 g) as a white solid.

[0170] 1H NMR (500MHz, DMSO-d6): δ 12.01 (br s, 1H), 8.75-8.67 (m, 1H), 7.94 (br s, 1H), 7.86-7.78 (m, 1H), 3.16 (br t, J=6.8Hz, 2H), 2.25 (br t, J=6.6Hz, 2H), 1.70-1.60 (m, 2H), 1.60-1.50 (m, 2H)

[0171] C 11 H 13 ClNO3 + LRMS calculation value: [M+H] + 242.06, Observed value: 242.24

[0172] Example 3 Synthesis of compounds 5a and 6-Cl TIFF0007885383000108.tif4316420L reaction vessel was filled with MeOH (4L) and compound 4a (367.3g, 1500mmol, 98.9% by mass). This was followed by the addition of 3L of MeOH. Next, trimethyl orthoformate (734mL, 6700mmol, 100% by mass, 4.5 equivalents) was added, followed by rinsing with MeOH (400mL). Chlorotrimethylsilane (367mL, 2880mmol, 100% by mass, 1.92 equivalents) was added, followed by the addition of MeOH (200mL). The resulting reaction mixture was heated at an internal temperature of 49°C for 12 hours.

[0173] In a separate 20 L reaction vessel, NaOH (10 N, 1220 mL) was added, followed by H2O (1620 mL), and the resulting reaction mixture was cooled to 0°C. The reaction mixture containing compound 5a was transferred to the reaction mixture containing the NaOH aqueous solution. The internal temperature rose to 5°C to 22°C. The reaction vessel was rinsed with MeOH (700 mL), and the solution was transferred to a quenching vessel. The reaction mixture was stirred for 4 hours. The temperature of the reaction vessel was raised to 20°C, and the mixture was stirred. MTBE (2570 mL) was then added. Stirring was stopped, and the aqueous layer with a high product content was collected and used next. 20% by weight citric acid (2985 mL) was then added to the stirred aqueous layer. When the pH reached 5.3, a slurry was formed, which was filtered to obtain compound 6-Cl as a solid (387.1 g, 89.6% yield).

[0174] 1 H NMR(400MHz, DMSO-d6)δ 11.98 (br s, 1H), (8.61 (d, J=4.8Hz, 1H), 7.60 (d, J=1.8Hz, 1H), 7.51 (dd, J=5.2, 2.1Hz, 1H), 3.03 (s, 6H), 2.08 (t, J=7.5Hz, 2H), 2.02 (br d, J=16.9Hz, 2H), 1.42-1.30 (m, 2H), 0.90-0.78 (m, 2H)

[0175] C 12 H 15 ClNO3 + LRMS calculated value: [M-CH3O] + 256.07, Observed value: 256.24 Example 4 Synthesis of compound 7a-DCHA [ka]

[0176] Compound 6a (87.88 g, 305 mmol, limiting reagent) was added to a reaction vessel (2 L, chem-glass), followed by the addition of anhydrous THF (1760 mL). The THF was distilled until it reached 10 Vol. The KF of the solution was less than 200 ppm. Further addition of THF (880 mL) was added with triethylamine (CAS: 121-44-8, 106.4 mL, 2.5 equivalents). The solution was cooled to 0°C, and pivaloyl chloride (CAS: 3282-30-2, 44.13 g, 1.2 equivalents) was added via a dropping funnel at a rate that did not exceed 5°C. After 30 minutes, lithium chloride (16.16 g, 1.2 equivalents) was added. After aging for 15 minutes, the chiral additive (CAS: 102049-44-7, 64.86 g, 1.2 equivalents) was added all at once in solid form. The slurry was heated to 20°C over 3 hours and left overnight. The THF was then distilled under reduced pressure until the final volume was 800 mL. Toluene (530 mL) was added, followed by saturated NH4Cl aqueous solution (270 mL) and water (270 mL). After mixing for 15 minutes, the two phases separated, and the lower aqueous layer was removed. The organic layer was washed with 7 wt% NaHCO3 (270 mL) and water (270 mL). After phase separation, the lower aqueous layer was removed. The organic layer was distilled until the volume was 220 mL. Anhydrous THF (1860 mL) was then added. This solution was passed through a 0.45 micropolish and filtered.

[0177] The solution containing compound 35 was then cooled to -45°C, methyl iodide (95.4 g, 2.2 equivalents) was added, followed by 1N NaHMDS / THF (458 mL, 1.5 equivalents) at a rate such that the temperature did not exceed -39°C. The reaction was continued for 6 hours. The resulting reaction mixture was then neutralized in one step with a solution of acetic acid (29.30 g, 1.6 equivalents) / anhydrous THF (88 mL). The organic reaction mixture was washed with a 14 wt% NaCl solution (530 mL), followed by a 7.0 wt% NaHCO3 solution (530 mL). After washing, the organic solution containing compound 36 was concentrated to 220 mL.

[0178] THF (880 mL) was added, and the solution was cooled to 0°C. A 30 wt% H2O2 solution (64.18 g, 1.82 equivalents) was then added, followed by a lithium hydroxide solution (12.42 g / 110 mL of water) over 10 minutes. After 6 hours of reaction, a 10 wt% sodium bisulfite solution (63.48 g, 2.0 equivalents / 580 mL of water) was added. The mixture was aged for 1 hour. The THF was then removed by distillation until the volume was reduced to ~700 mL, and the solution was recovered.

[0179] The pH was then adjusted to approximately 9.5 using NaOH (10N). Toluene (540 mL) was added. The two-phase mixture was mixed for 15 minutes and then allowed to stand. The separated organic layer was further extracted with saturated NaHCO3 (360 mL). The combined aqueous layer was returned to the reaction vessel and extracted with MTBE (720 mL). The organic layer was removed.

[0180] The aqueous layer containing a large amount of product, including compound 7a, was returned to the reaction vessel, and MTBE (900 mL) was added. The pH was adjusted to 4.4 using citric acid.

[0181] MTBE was removed by distillation and replaced with MeCN / MTBE (4:1, 6 vol) based on the amount of compound 7a added (corrected effective amount). The resulting solution was filtered by polish filtration. Dicyclohexylamine (up to 1.5 equivalents relative to compound 7a) was then added all at once. The slurry was heated to 55°C and reacted for 30 minutes. The reaction mixture was then cooled to 0°C. The slurry was filtered using a Buchner funnel under N2 protection, washed with cold MeCN (2.0 vol) at 0°C, vacuum dried, and then dried in a vacuum oven at 50°C for 24 hours. Compound 7a-DCHA was obtained as 61 g of white solid (yield 88.2% in the salt formation step, and 61.6% in the total yield obtained from compound 6a over all 4 steps). Compound 7 is a complex of compound 7:dicyclohexylamine in a 1:1.5 ratio.

[0182] 1H NMR (400MHz, MeOH-d4): 8.52 (d, J=5.3Hz, 1H), 7.72 (d, J=2.0Hz, 1H), 7.44 (dd, J=5.3, 2.0Hz, 1H), 3.16 (d, J=3.0Hz, 6H), 3.07-2.97 (m, 3H), 2.20-2.06 (m, 3H), 2.05-1.99 (m, 6H), 1.90-1.80 (m, 6H), 1.76-1.67 (m, 3H), 1.60-1.47 (m, 1H), 1.33-1.10 (m, 16H), 1.00 (d, J=6.8Hz, 3H), 0.97-0.87 (m, 2H)

[0183] C 13 H 17 ClNO3 + LRMS calculated value: [M-CH3O] + 270.09, Observed value: 270.24 Example 5 Synthesis of compound 9a [ka]

[0184] In a clean 2 L reaction vessel fitted with an overhead stirrer, temperature probe, and nitrogen inlet, 2 MeTHF (500 mL), catalyst [Pd(allyl)Cl]2 (1.57 g, 0.05 equivalents), and Xphos (4.48 g, 0.055 equivalents) were added sequentially at 20°C to obtain a nearly homogeneous pale yellow solution. The salt compound 7a-DCHA (98.2 g, 1.0 equivalent) and pyrrole compound 8 (32.3 g, 1.15 equivalents) were added gradually to the reaction vessel to obtain a white suspension. After 30 minutes, KOPiv (32.3 g, 1.3 equivalents) was added to the solution all at once, and the reaction vessel was rinsed with 2-MeTHF (500 mL) that had been bubbling with N2 for 30 minutes. This solution was refluxed under N2 for 10 hours to obtain a black suspension. The obtained crude product was cooled to 20°C and quenched with K3PO4 (550 mL, 20% aqueous solution) to a pH of 10.0–10.5. The aqueous layer was separated, and the organic layer was washed with K3PO4-K2HPO4 buffer solution (800 mL, pH 10.2 aqueous solution). The aqueous layers were combined and filtered to obtain a dark-colored solution. 2-MeTHF (1300 mL) and activated carbon (13.9 g, Darco G-60) were added to the aqueous solution, and citric acid (254 g, 3.4 equivalents) was gradually added to the solution over 30 minutes to acidify the pH to 5–6. This suspension was stirred at 20°C for 30 minutes. The suspension was filtered, and the organic layer was concentrated under reduced pressure to 300 mL, then concentrated under reduced pressure at 80°C (150 mbar), and the solvent was replaced with nBuOH (1000 mL). The concentration of the obtained solution was adjusted to 170-180 mg / mL (less than 5% by mass of 2-MeTHF in 500 mL of solution). This solution was gradually cooled to 0°C over 10 hours and maintained at 0°C for another 10 hours to obtain a white slurry. The slurry was filtered through a Nutsche filter, the reaction vessel was rinsed with nBuOH (100 mL), and a cake was obtained from the resulting suspension. The cake was rinsed with heptane (100 mL) and dried in an oven (vacuum, 50°C for 24 hours). Isolated compound 9a (73.2 g, 95% by mass) was obtained in 83% yield.

[0185] 1H NMR (400MHz, DMSO-d6): δ 8.89-8.80 (m, 1H), 8.72-8.65 (m, 1H), 7.88-7.52 (m, 3H), 3.10-3.00 (m, 6H), 2.50 (dt, J=3.5, 1.8Hz, 1H), 2.52-2.44 (m, 1H), 2.22-2.13 (m, 1H), 2.11-1.99 (m, 2H), 1.51-1.35 (m, 1H), 1.27-1.14 (m, 1H), 1.00-0.84 (m, 5H). 13 C NMR (101MHz, DMSO-d6) δ 177.3, 158.9, 149.5, 139.3, 138.3, 135.0, 132.8, 123.5, 123.0, 110.5 (t, J=253.9Hz, 1C), 103.0, 48.2, 48.2, 38.4, 34.0, 32.9, 20.4, 16.6

[0186] LRMS [M-OMe] + C 17 H 19 F2N4O5 + : 397.36, 397.13 Example 6 Synthesis of compound 10a [ka]

[0187] In a pressure-resistant reaction vessel fitted with an overhead stirrer, temperature probe, and nitrogen inlet, THF (900 mL), Pd / C (4.6 g, 10% by mass, 0.1 equivalent), and compound 9a (46.0 g, 1.0 equivalent) were added sequentially at 20°C to obtain a suspension. The reaction vessel was purged three times each with N2 and H2. The solution was vigorously stirred under H2 (40 psi) for 18 hours. The resulting crude product was removed from the reaction vessel and filtered through a Nutsche filter. The THF solution was concentrated until a clear oily substance was obtained, yielding compound 10a (101 g, 40% by mass) in 95% yield. A small sample was taken, thoroughly concentrated, and used for spectral analysis.

[0188] 1 H NMR (500MHz, CDCl3): δ 8.77 (1H, s, br), 7.75 (1H, s. br), 7.39 (1H, s. br), 7.33 (1H, s. br), 7.11 (1H, t, J=59.1Hz), 5.75 (3H, s, br), 3.17 (6H, s), 2.35-2.25 (1H, m), 2.20-1.98 (2H, m), 1.55-1.43 (1H, m), 1.30-1.13 (1H, m), 0.80-1.09 (5H, m)

[0189] LRMS [M+H] + C 18 H 25 F2N4O4 + : 399.18 Example 7 Synthesis of compound 11a-FUM [ka]

[0190] 600 mL of THF was added to a 1 L reaction vessel, followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH, 17.1 g, 59.7 mmol, 98.0% by mass, 1.52 equivalents). The mixture was then rinsed with 200 mL of THF to add all of the TCFH to the reaction vessel. N,N-diisopropylethylamine (14.6 mL, 83.7 mmol, 100% by mass, 2.13 equivalents) was added to this suspension and stirred at room temperature. A solution of compound 10a / THF (44.9 g, 39.2 mmol, 34.8% by mass, 1.00 equivalent) was added to a 50 mL syringe and added to the reaction vessel via syringe over 10 hours (rate: approximately 5 mL / hour).

[0191] The solvent in the resulting reaction mixture (approximately 50 mL per 1 g of added compound 11a) was changed from THF to MIBK (approximately 20 mL). The organic layer was washed with 15% aqueous K2HPO4 solution (15 mL), followed by the addition of 1.2 equivalents of solid fumaric acid (relative to the amount of added compound 11a (mol)). The mixture was then concentrated under reduced pressure to approximately 8 mL. A yellowish-brown slurry product was formed, which was filtered, and the cake was washed with MIBK (2 mL), then heptane (2 mL), and vacuum-dried. Yield = 1.01 g (75.3% of the corrected effective amount of added compound 11a); effective amount = 74.2% by weight; ee = 97.3%

[0192] 1 H NMR(400MHz, DMSO-d6)δ 13.31-13.02 (m, 1H), 9.30 (s, 1H), 8.76 (d, J=5.1Hz, 1H), 7.94 (s, 1H), 7.87-7.79 (m, 1H), 7.66-7.60 (m, 1H), 7.41-7.35 (m, 2H), 6.64 (s, 2H), 3.22 (s, 3H), 3.15 (s, 3H), 2.41-2.28 (m, 1H), 1.85-1.60 (m, 3H), 1.55-1.41 (m, 1H), 0.88 (br d, J=7.1Hz, 4H), 0.46 (br s, 1H)

[0193] C 17 H 19 F2N4O2 + LRMS calculated value: 349.15 [M-CH3O] + Observed value: 349.08 Example 8 Synthesis of compound 12 [ka]

[0194] To a slurry of compound 11a-FUM (0.50 g, 67% by mass, 96% ee) / water (5 mL), cyclopentyl methyl ether (2.5 mL) was added, followed by trifluoroacetic acid (0.23 mL, 3.5 equivalents). The resulting mixture was heated at 45 °C for 5 hours. The mixture was then cooled to ambient temperature and filtered. The reaction vessel was rinsed with water (2.5 mL) and used to wash the filter cake. The filtrates were combined and the phases were separated. The resulting organic layer was extracted with aqueous HCl solution (0.5 N, 2.0 mL). The extracted acidic aqueous solution was combined with the acidic aqueous layer obtained from the reaction mixture. The pH of the combined aqueous solution was adjusted to 9-10 by adding solid K3PO4 (~2 g). The resulting mixture was stirred for 2 hours and filtered. The filtered cake was washed with water (5 mL x 2) and MTBE (5 mL x 2), dried under reduced pressure, and compound 12 (0.25 g, 78%, 97.2% ee) was obtained.

[0195] 1 H NMR (500MHz, CDCl3): δ 8.89 (s, 1H), 7.97 (s, 1H), 7.68 (s, 2H), 7.46 (s, 1H), 7.34 (t, J=59.7Hz, 1H), 6.85 (br s, 1H), 3.14 (br s, 1H), 2.82 (br d, J=8.9Hz, 1H), 2.46-2.37 (m, 1H), 2.05 (br s, 1H), 1.68 (br d, J=7.0Hz, 1H), 1.41 (br s, 1H), 1.21 (br s, 3H)

[0196] LRMS [M+H] + C 16 H 17 F2N4O2 + : 335.18 Example 9 Alternative synthesis method for compound 12 [ka]

[0197] Compound 9a (75.0 g, 169 mmol), THF (525 mL), and Pt / V / C (~50% wet, 10% by weight, 7.5 g) were added to a pressure vessel (1 L). The reaction vessel was replaced three times each with N2 and H2. The solution was vigorously stirred under H2 (1.5 bar) at 20°C for 1 hour and then heated at 40°C for 16 hours. The mixture was removed from the reaction vessel, filtered, and the resulting solution was concentrated. THF was distilled, followed by azeotropic distillation of the water. In a separate reaction vessel, THF (1.2 L), followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH, 70 g, 1.52 equivalents) and N,N-diisopropylamine (103 mL, 3.5 equivalents) were added. The mixture was vigorously stirred and heated at 55°C. To this mixture, a solution of compound 10a / THF was added over 20 hours (~50 mL / hour). The mixture was then concentrated, and the solvent was replaced with acetonitrile until compound 11a / acetonitrile was approximately 4 L / kg. Next, aqueous hydrochloric acid (3N, 23 mL) was added, and the resulting reaction mixture was heated at 55°C for 15 hours to obtain crude compound 12. This reaction mixture was cooled to 10°C, and dichloromethane (270 mL), water (540 mL), and hydrochloric acid (10.8N, 71 mL) were added. After stirring for 1 hour, the layers were separated, and the lower organic layer was removed. Potassium hydroxide (22.5% by mass, ~169 mL) was added to the aqueous layer at 10°C to adjust the pH to 3.0. After stirring at pH 3 for 1 hour, potassium hydroxide (22.5% by mass, ~17 mL) was added to adjust the pH of the reaction mixture to 9.5. Compound 12 was isolated by filtration, rinsed with water (169 mL) and EtOH (114 mL), and then dried. Example 10 Synthesis of compound 13 [ka]

[0198] A reaction vessel (125 mL) equipped with a water circulator was used to maintain the reaction temperature at 35°C throughout the series of reactions. When adding the 4 M isopropylamine aqueous solution to the reaction vessel, the pH was controlled to 7.5 using a calibrated pH meter. Ketone compound 12 (5.0 g, 50 g / L), DMSO (30 mL, 30%), and pyridoxal-5'-phosphate monohydrate (53 mg, final concentration 2.0 mM) were added to the reaction vessel. A 1 M isopropylamine hydrochloride aqueous solution was prepared and 63 mL was added to the reaction vessel (final concentration 0.7 M). The reaction mixture was stirred for 2.0 minutes. The resulting reaction solution was heterogeneous. Aminotransferase: ATA-237 (0.5 g) was dissolved in 1 M isopropylamine hydrochloride solution (4.0 mL) and added to the reaction vessel. Furthermore, the container that held the enzyme was rinsed with 1 M isopropylamine hydrochloride solution (3.0 mL) and added to the same reaction vessel. The sample (20 μL) was pipetteed, diluted with methanol (980 μL), vortexed, centrifuged at 14000 x g for 2.0 minutes, filtered through a PTFE filter (0.2 μM), and the conversion rate and ee were analyzed by HPLC. The reaction was stopped after 8 hours (conversion rate 99.7%).

[0199] The resulting reaction mixture was acidified to pH 1.3 (6N HCl, 3.6 mL). A Celite pad was prepared, and the reaction mixture was filtered through Celite. After filtration, the reaction vessel and Celite pad were rinsed with water (30 mL), and the solution was collected together with the filtrate. The reaction mixture was extracted with 2-methyltetrahydrofuran (130 mL), and the 2-methyltetrahydrofuran solution was removed. The pH of the aqueous layer was adjusted to 10.5 with 10N sodium hydroxide (4.4 mL). The aqueous layer (152 mL) was extracted with n-butanol (150 mL), and the layers were separated (organic layer volume: 190 mL, aqueous layer volume: 105 mL). The aqueous layer (105 mL) was extracted again with n-butanol (100 mL), and the aqueous layer and organic layer were separated (aqueous layer volume: 75 mL, organic layer volume: 125 mL).

[0200] The organic layer was collected and the solvent was concentrated to a 40 g viscous liquid. The resulting residue solidified at 4°C for 1 hour. The residue was suspended in MTBE (240 mL) and vigorously stirred. The precipitate was filtered, and the filtrate was removed. The precipitate (6.6 g) was stirred with water (50 mL) and the pH was adjusted to 8.5. The desired compound precipitated, which was filtered and washed with MTBE. The volume of the filtrate was reduced (15 mL), the pH was adjusted to 9.0, the precipitated compound was filtered, and washed with MTBE. The compounds obtained in two separate batches were combined and dried overnight in a vacuum oven at 35°C. The desired compound 13 was isolated as a grayish-white solid (3.94 g, yield 78.8%, AP 99.3, ee>99.9%, effective amount 97%).

[0201] 1 H NMR (400MHz, DMSO-d6)δ 9.33 (s, 1H), 8.76-8.62 (m, 1H), 7.94 (t, J H-F =57.8Hz, 1H), 7.84 (s, 1H), 7.42-7.33 (m, 1H), 7.33-7.24 (m, 1H), 4.02-3.86 (m, 1H), 2.61-2.52 (m, 1H), 2.15 (br s, 2H), 1.86-1.66 (m, 2H), 1.52-1.33 (m, 2H), 1.15-0.95 (m, 1H), 0.89-0.73 (m, 3H), 0.27-0.06 (m, 1H)

[0202] LRMS [M+H] + C 16 H 20 F2N5O + : 336.24 Example 11 Alternative synthesis method for compound 13 [ka]

[0203] To a reaction vessel (500 mL) containing water (139 mL), hydrochloric acid (12 N, 22.6 mL, 3.35 equivalents) was added over 90 minutes at 25 °C. Isopropylamine (4.05 equivalents, 25.88 mL) was then added until the pH reached 10.5. Compound 12 (25 g) and pyridoxal-5'-phosphate (0.01 g / g, 0.25 g), followed by aminotransferase: CDX-50 (0.02 g / g, 0.50 g) were added. The reaction mixture was heated at 50 °C and stirred for 24 hours. Hydrochloric acid (12 N, 0.6 equivalents, 4 ml) and 1 g of Celite (4% by mass) were added. The reaction mixture was heated at 80 °C for 2 hours, then cooled to 20 °C, filtered, and washed. The solid residue was removed, and the mixture was heated at 50 °C. Potassium hydroxide solution (10% by weight, 65 mL, 1.55 equivalents) was then added until the pH reached 9.5. The mixture was then cooled to 20°C over 3 hours. Compound 13 was isolated by filtration, rinsed with water, and dried. Example 12 Synthesis of compound (I) [ka]

[0204] DBU (15 μL, 0.100 mmol) was added to a scintillation vial containing compound 14 (0.019 g, 0.062 mmol) and HATU (33.0 mg, 0.087 mmol) / anhydrous ACN (0.5 mL). After 30 minutes, a solution of compound 13 (0.021 g, 0.062 mmol) / CH3CN (0.5 mL) and DMF (0.1 mL) was added. The resulting solution was stirred at room temperature for 2 hours and then purified by reverse-phase chromatography to obtain compound (I) as trifluoroacetate.

[0205] 1H NMR(500MHz, CD3OD) 8.91-8.83 (m, 1H), 8.78-8.71 (m, 1H), 8.33 (s, 1H), 7.88 (d, J=2.5Hz, 1H), 7.74 (s, 2H), 7.69-7.67 (m, 1H), 7.65 (s, 1H), 7.63 (t, J=58Hz, 1H), 7.52-7.50 (m, 1H), 6.36 (d, J=0.8Hz, 1H), 6.06-5.95 (m, 1H), 2.76-2.65 (m, 1H),2.36-2.21 (m, 1H), 2.08-1.93 (m, 2H), 1.63-1.53 ​​(m, 1H), 1.53-1.42 (m, 1H), 0.99(d, J=6.9Hz, 3H)

[0206] LRMS [M+H] + C 28 H 23 Cl2F2N9O2 + : 626.09 Example 13 Manufacturing of Compound 21

[0207] As shown in Scheme 3, compound 7 can be prepared by the following reaction steps. a) Synthesis of compound 16 [ka]

[0208] Magnesium (8.73 g, 359 mmol, 1.35 equivalents) and I2 crystals were added to a three-necked flask (1 L). Anhydrous THF (100 mL) was added to the reaction flask under N2 conditions. The reaction temperature was monitored with a thermometer (J-CEM). 3-Bromo-1,1-dimethoxypropane (65.8 g, 356 mmol, 1.35 equivalents) was diluted with THF (150 mL) and added to a dropping funnel. 3-Bromo-1,1-dimethoxypropane solution (20 mL) was added to the flask at 20°C, and the resulting light brown suspension was vigorously stirred using a stirring bar and rotating magnesium pieces to allow the reaction to proceed. After 30 minutes, the light brown color disappeared, and the solution temperature rose to 45-50°C. The resulting reaction mixture was then maintained at a temperature of 55-62°C, and 3-Bromo-1,1-dimethoxypropane solution was slowly added from the dropping funnel. After 1.5 hours, the dropwise addition was complete, and the entire solution was held at 60°C for a further 2 hours. The solution was placed in a water bath and cooled to 25°C. 4-Chloro-N-methoxy-N-methylpyridine-2-carboxamide; compound 15 (53.3 g, 264 mmol, 1.0 equivalent) / THF (150 mL) was added to the dropping funnel. The substrate in the solution was added to the Grignard solution within 20 minutes to obtain a reddish-yellow solution. The internal temperature was kept below a maximum of 35°C. After 15 minutes, both HPLC and TLC indicated completion of the reaction. Water (20 mL) was slowly added to the crude mixture, and a brownish gel-like solid precipitated. The entire crude product was filtered through Celite and washed twice with THF (total 100 mL). The obtained crude solution was dried over Na2SO4. The obtained crude product was concentrated under vacuum at 30-35°C to obtain compound 16 as a yellow oily substance.

[0209] Addendum: The obtained crude product could be used in the next reaction without purification. Spectral analysis: The obtained crude product was then purified using the ISCO purification system (hexane / EA 1:0~10:1) to obtain the desired product.

[0210] 1H NMR(500MHz, CDCl3)δ 8.60 (d, J=5.0Hz, 1H), 8.04 (d, J=2.0Hz, 1H), 7.49 (dd, J=5.2, 2.0Hz, 1H), 4.51 (t, J=5.6Hz, 1H), 3.35 (s, 6H), 2.10-2.05 (m, 2H), 1.66-1.60 (m, 2H)

[0211] LRMS [C 10 H 11 ClNO2] + 212.05, 212.10 b) Synthesis of compound 18-Et

change

[0212] Compound 16 (7.61 g, 38.5 mmol, 1 equivalent) was diluted with water (20 mL) and THF (80 mL) at 20°C in a round-bottom flask (250 mL). Trifluoroacetic acid (8.5 mL, 110 mmol, 2.7 equivalents) was added to this solution at room temperature. The solution was immediately heated to 50°C. After 4 hours, the solution turned dark brown, indicating completion of the reaction by HPLC and TLC. Water (60 mL) was then added to the flask. Slowly, sodium bicarbonate (9.6 g, 114 mmol, 2.8 equivalents) was added to the resulting crude product at 25°C to neutralize the solvent to pH 7. The crude product was extracted three times with SiO2 (100 mL), and the combined organic crude product was washed once with saline solution (50 mL) and dried over Na2SO4. The crude product was filtered and concentrated to a dark oily substance, which was used directly in the next step. To the obtained crude product, CH2Cl2 (75 mL) was added at 20°C. Ethyl 2-(triphenylphosphoranylidene)propionate (14.2 g, 38.2 mmol, 0.93 equivalents) was added all at once to the solution containing compound 17. This reaction mixture was kept at 20°C for 8 hours. The obtained crude product was concentrated and dried, diluted with hexane:siRNA (1:1), the precipitated solid was filtered, and washed twice with MTBE (20 mL). The combined crude product was concentrated until it became a black oil, and purified using an ISCO purification system (200 g silica gel) (hexane / EA 1:0~5:1) to obtain the desired compound 18-Et (8.21 g, 70.3%) as a yellow oil.

[0213] 1 H NMR(500MHz, CDCl3)δ 8.59 (s, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 6.80(s, 1H), 4.24-4.15 (m, 2H), 3.39-3.37 (m, 2H), 2.65-2.57 (m, 2H), 1.90 (s, 3H), 1.35-1.25 (m, 3H)

[0214] LRMS [C 14 H 17 ClNO3] + : 282.09, 282.21 c) Synthesis of compound 19-Et [ka]

[0215] Compound 18-Et (9.55 g, 33.9 mmol, 1.0 equivalent) was mixed with p-toluenesulfonic acid (2.35 g, 13.5 mmol, 0.40 equivalents), trimethyl orthoformate (24 mL, 220 mmol, 6.4 equivalents), and methanol (95 mL) at 20°C. This solution was refluxed for 60 hours. The resulting crude product was cooled to 0°C, and sodium hydroxide (1.7 mL, 17 mmol, 0.5 equivalents) was added to neutralize the solvent to pH 7. The crude product was concentrated until it became a viscous oily substance and diluted with MTBE (200 mL). This crude product was washed once with water and saline solution. The crude product was dried over Na2SO4 and filtered. This was filtered and purified with ISCO (80g silica) (hexane / EA 1:0~4:1) to obtain compound 19-Et (8.1g, 73% yield) and ethyl(E)-6-(4-chloro-2-pyridyl)-2-methyl-6-oxo-hexa-2-enoate (1.2g, 13%).

[0216] 1 H NMR(500MHz, CDCl3)δ 8.50 (d, J=4.0Hz, 1H), 7.63 (d, J=0.8Hz, 1H), 7.17 (dd, J=0.8 and 4.0Hz 1H), 6.45 (dt, J =8.0 and 0.4Hz, 1H), 4.06 (q, J=7.8Hz, 2H), 3.12 (s, 6H), 2.22-2.11 (m, 2H), 1.85-1.73 (m, 2H), 1.61 (s, 3H), 1.19 (t, J=7.8Hz, 3H)

[0217] LRMS [C 16 H 22 ClNO4-OCH3] + : 297.11, 297.10 d) Synthesis of compound 20 [ka]

[0218] A pale yellow oily compound 19-Et (1.14 g, 3.48 mmol, 1.0 equivalent) was diluted in ethanol (10 mL) at 20°C. Sodium hydroxide (2 mol / L) / water (2 mL, 4 mmol, 1.1 equivalents) was added to this solution at room temperature. The solution was heated at 60°C for 12 hours. HCl (1 mol / L, 4 mL) was added to the resulting crude product, and it was concentrated until the entire product became a white paste. Next, saturated NH4Cl aqueous solution (20 mL) was added to this crude product, and it was extracted twice with 2-methyl THF (10 mL). This crude product was dried over Na2SO4, filtered, and concentrated to obtain a pink crude product. The obtained crude product was filtered and purified with ISCO (8 g silica) (hexane / EA 1:0-2:1) to obtain compound 20 as white crystals (1.05 g, 100%).

[0219] 1 H NMR(500MHz, CDCl3)δ 8.61 (s, 1H), 7.73 (s, 1H), 7.28 (s, 1H), 6.80-6.65 (m, 1H), 3.21(s, 6H), 2.29-2.20 (m, 2H), 1.95-1.85 (m, 2H), 1.70 (s, 3H)

[0220] LRMS [C 14 H 17 ClNO4-OCH3] + : 268.08, 268.18 e) Synthesis of compound 21 [ka]

[0221] Compound 20 (632 mg, 2.11 mmol, 1.0 equivalent) and the pressure-resistant reaction vessel were both placed in a glove box. In the glove box, the catalyst: diacetato[(R)-(+)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl]ruthenium(II) (95 mg, 0.109 mmol, 5.2 mol%), and methanol (5 mL) were subsequently added, and the vial was placed in the reaction vessel and sealed. The reaction vessel was placed in a hydrogenation apparatus and purged with hydrogen several times. The reaction mixture was set to H2 at 150 psi at room temperature. After 12 hours, the reaction mixture was removed from the reaction vessel and the solution had turned dark red. Completion of the reaction was indicated by TLC and LCMS. The obtained crude product was concentrated, and the crude product was purified with ISCO (silica, 8 g) (hexane / EA 1:0~1:1) to obtain the desired product, compound 21, as a brown solid (0.63 g, 99%). The desired product was confirmed by chiral HPLC. %ee It was confirmed that this was the case.

[0222] 1 H NMR(500MHz, CDCl3)δ 8.59 (d, J=5.2Hz, 1H), 7.69 (d, J=1.8Hz, 1H), 7.25 (dd, J=5.2 and 1.8Hz, 1H), 3.17 (s, 6H), 2.39-2.31 (m, 1H), 2.14-2.03 (m, 2H), 1.65-1.57 (m, 1H), 1.35-1.20 (m, 1H),1.07 (d, J=7.0Hz, 3H), 0.98-0.90 (m, 1H)

[0223] LRMS [C 14 H 20 ClNO4-OCH3] + : 270.18, 270.19 Example 14 [ka]

[0224] Compound 37a (2.8 g) and methyl 2-(triphenylphosphanylidene)propanoate (11 g) were dissolved in DCM (100 mL) and stirred at room temperature for 4 hours. After complete conversion, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the desired compound 38a (6.9 g).

[0225] 1H NMR (CDCl3, 400 MHz): δ 6.69 ppm, (1H, m); 3.72ppm (3H, s), 2.45-2.41 (2H, m), 2.36-2.32 (2H, m), 1.84 (3H, s), 1.43 (9H, s)

[0226] Compound 38a (3g) and compound 2a (3.4g) were dissolved in THF (30mL), and the reaction mixture was cooled to -10°C. Then LiHMDS (29mL, 2.207eq) was added dropwise. After complete conversion, the resulting reaction mixture was quenched with saturated NH4Cl (150mL) and further extracted with HCl (250mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting crude compound 39a (11g) was dissolved in ACN (220mL), water (110mL), and methanesulfonic acid (100.5g, 34.967 equivalents). This reaction mixture was heated at 65°C until completely converted. After cooling to room temperature, the pH was adjusted to 5-7 with concentrated NaOH solution. The organic layer was extracted with HCl (500mL x 2), dried over Na2SO4, filtered, and compound 18a (10.8g) was obtained.

[0227] Compound 18a was dissolved in TMSCl (24.4 g, 4.928 equivalents), trimethyl orthoformate (3 g, 8.064 eq), and MeOH (200 mL). The reaction mixture was heated at 45-50°C and stirred overnight. After cooling to room temperature, the resulting reaction mixture was neutralized with saturated NaHCO3 solution (200 mL). The aqueous layer was extracted with DCM (3 x 400 mL), dried over Na2SO4, filtered, and removed under reduced pressure. The resulting residue was purified by column silica gel chromatography (petroleum ether / toluene 50:1-3:1) to obtain compound 19a (10.4 g). 1H NMR (CDCl3, 400 MHz): δ 8.56ppm (1H, d, J=8Hz), 7.70ppm (1H, s), 7.24ppm (1H, dd, J=4Hz, 8Hz), 6.52ppm (1H, t, J=4Hz), 3.68ppm (3H, s), 3.18ppm (6H, s), 3.24-3.20 (2H, m), 1.86-1.83 (2H, m) Example 15 [ka]

[0228] Paraformaldehyde (1.44 g, 1.5 equivalents) was charged into the reaction vessel under nitrogen, followed by the addition of MeOH (25 mL, 5 vol), ethyl 2-oxocyclopentane-1-carboxylate (5 g, 1 equivalent), and finally diethylamine (7.02 mL, 2.1 equivalents). The reaction mixture was stirred at 20-25°C for at least 3.5 hours. After complete conversion, sodium hydroxide (6 M, 26.6 mL, 5 equivalents) was added, and the mixture was stirred at 20-25°C for at least 2 hours until complete conversion was achieved. MeOH was vacuum distilled. Then MTBE (25 mL, 5 vol) was added to the reaction mixture and stirred for 10 minutes. The layers were allowed to stand, and the upper organic layer was removed. HCl aqueous solution (6 M) was added to the lower aqueous layer until the pH became 2. HCl (25 mL, 5 vol) was added, and the reaction mixture was stirred for at least 10 minutes. After phase separation, the mixture was washed with water. The organic layer was concentrated to dryness to obtain compound 41a. This was dissolved directly in iPrOH (50 mL, 10 vol) and H2SO4 (1 equivalent) at room temperature and stirred for 72 hours. The pH of the resulting reaction mixture was adjusted to 7.3 with 20% K2HPO4 aqueous solution. After phase separation, the iPrOH layer was diluted with 20% K2HPO4 aqueous solution (10 vol) and washed with toluene. Finally, the pH of the aqueous layer was adjusted to 4.7 with H2SO4 (2 M). The desired compound 42a was extracted with toluene, and after removing the solvent under reduced pressure, it was isolated.

[0229] 1H NMR (400MHz, CDCl3): δ 6.33ppm (1H, s); 6.69 (1H, s); 5.05-4.98 (1H, m); 2.37-2.29 (4H, m), 1.87-1.80 (2H, m), 1.24 (6H, d=4Hz)

[0230] Methyl 4-chloropicolinate (0.86 g, 1 equivalent) was charged into a nitrogen-purged three-necked flask at 20-25°C, followed by the addition of compound 42a (1 g, 1 equivalent) and THF (10 mL, 10 vol) at 20-25°C. After cooling to -30°C, LiHMDS (1 M THF solution, 12.49 mL, 2.5 equivalents) was added dropwise over 30 minutes, maintaining the temperature below -25°C, and the mixture was stirred at -20°C for at least 1 hour. After complete conversion, acetic acid (0.9 mL, 3 equivalents) was added dropwise, maintaining the temperature below -10°C, and the resulting reaction mixture was warmed to room temperature. Depositphotos (50 mL, 50 vol) was added, and the organic layer was washed with water and brine. After concentration under reduced pressure, a solution of water (15 mL, 15 vol) and sulfuric acid (6.7 mL, 25 equivalents) was slowly added. The reaction mixture was then heated at 65°C for at least 17 hours and cooled to 20-25°C. After complete conversion, the reaction mixture was diluted with water (10 mL, 10 vol) and neutralized with 33% ammonium hydroxide until the pH reached 4. Compound 18b was recovered as a solid and dried.

[0231] 1 H NMR (500MHz, DMSO): δ 8.7ppm (1H), 7.9ppm (1H), 7.8ppm (1H), 6.0ppm (1H), 5.6ppm (1H), 3.1ppm (2H), 2.3ppm (2H), 1.8ppm (2H)

[0232] Compound 18b (5 g) was dissolved in TMOF (4 equivalents), H2SO4 (1.1 equivalents), and MeOH (4 vol) and stirred overnight at 50°C. After complete conversion, NaOH (6.4 M, 8 equivalents) was added and stirred for 2 hours. After vacuum distillation of MeOH, DCM was added to the reaction mixture and the pH was adjusted to 5 with a 30% citric acid aqueous solution. After extraction with DCM, the mixture was washed with water and the organic layer was concentrated to dryness. The resulting residue was dissolved in MeCN (2.5 vol) and heated at 45°C. This reaction mixture was slowly cooled to 0°C and stirred for 1 hour. Finally, water (10 vol) was added in 2.5 vol increments. After filtration and cake washing, compound 19b was obtained as a solid in 88% yield.

[0233] 1 H NMR (500MHz, CDCl3): δ 8.6ppm (1H), 7.8ppm (1H), 7.6ppm (1H), 7.2ppm (1H), 5.5ppm (1H), 3.2ppm (6H), 2.2ppm (2H), 2.1ppm (2H), 1.1ppm (2H)

[0234] [RuCl(p-cymen)((R)-H8-binap)]Cl (0.0003 mmol) from a DCM stock solution (100 μL) was added to a 5 mL vial containing a stirring bar. Next, compound 19b (0.075 mmol) was added as a MeOH / DCM = 3 / 1 stock solution (1 mL), followed by TEA (0.375 mmol). The vial was capped and transferred to a B48 parallel reaction vessel. This reaction was carried out overnight (approximately 16 hours) at 25°C under an H2 atmosphere (40 bar). The resulting reaction solution was analyzed by HPLC to obtain the desired compound 21. Example 16 Crystallization of compound 21 [ka]

[0235] Crude compound 21 (1.0 g) was suspended in heptane (25-30 mL) and stirred at 40°C until a clear solution was obtained. After cooling to 35°C, seed crystals of this reaction mixture were added, and the mixture was stirred for 2-4 hours, then cooled to -5°C over 8-10 hours. After 6-10 hours at -5°C, the cake was filtered, washed, and dried in an oven at 30°C. mp: 64°C Example 17 Synthesis of compound 27 using enzymes a) Synthesis of compounds 24a and 25a [ka]

[0236] To a slurry of 2-methylcyclopentanone, compound 22 (93.30 g, 931.7 mmol, 98% by mass), and compound 2a (158.02 g, 902.55 mmol, 98% by mass) / THF (1500 mL, 18400 mmol, 100% by mass), potassium tert-butoxide (1 mol / L) / THF (1200 g, 1330 mmol, 1 mol / L) was added at -30°C. The resulting yellow slurry was stirred for 1 hour between -24 and -30°C. In a separate reaction vessel (4 L), sulfuric acid (13.14 mol / L) / water (92 g, 660.2 mmol, 13.14 mol / L) and water (800 g, 44407.9 mmol, 100% by mass) was added and pre-cooled to 0°C. A yellow slurry containing compound 23a-Cl was poured into a cooled acidic solution to obtain a slurry. The ambient temperature was set to 45°C, and under vacuum, THF was distilled at 115 mbar at 15°C. 500 mL of water was added to the slurry (~1 liter). The precipitated solid was collected, and the aqueous solution was removed. The collected solid was returned to the reaction vessel with MSA (320 mL) and water (1 L). The slurry was heated to 65°C, and after 60 minutes, all the solids had dissolved. The dark solution was held at 65°C for 3 hours and then cooled from room temperature to 0°C. A slurry was formed and filtered. Compound 24a was collected and dried at room temperature to obtain a total of 139.8 g of beige solid. The filtrate was returned to the reaction vessel, and the pH was adjusted to 5.1 with 28 mass% NH4OH. A solid formed during pH adjustment and was filtered at room temperature. A further 41 g of compound 24a was obtained as a grayish-white solid.

[0237] 1 H NMR (400MHz, DMSO-d6): δ 12.07 (1H, s), 8.70 (d, J=5.31Hz, 1H), 7.94 (dd, J=7.94, 1.77Hz, 1H), 7.82 (dd, J=5.18, 2.15Hz, 1H), 3.15 (m, 2H), 2.35 (m, 1H), 1.60 (m, 3H), 1.42 (m, 1H), 1.05 (d, J=6.82Hz, 3H)

[0238] LRMS [C 12 H 14 ClNO3+H] + : 258.24, 256.25

[0239] Next, 178.27 g of compound 24a was added to a 2 L reaction vessel, followed by MeOH (3.4 L), TMOF (380 mL), and TMSCl (210 mL). The external temperature was set to 57 °C, and the mixture was heated to 49 °C. After 4 hours at 50 °C, the dark solution was cooled to 10 °C and then added to saturated NaHCO3 (2.6 L) in a 20 L reaction vessel. The total volume was 6.5 L.

[0240] Most of the MeOH solvent was distilled under vacuum at an external temperature of 35°C and concentrated to a volume of 3.3 L. Then 2 L of MTBE was added. The organic layer was separated from the aqueous layer and concentrated to obtain compound 25a (207 g) as a colored liquid.

[0241] 1 H NMR (400MHz, DMSO-d6): δ 8.60 (d, J=5.05Hz, 1H), 7.60 (d, J=1.77Hz, 1H), 7.52 (dd, J=5.31, 2.02Hz, 1H), 3.50 (s, 3H), 3.02 (br s, 6H), 2.30 (m, 1H), 2.00 (m, 2H), 1.40 (m, 1H), 1.22 (m, 1H), 0.93 (d, J=7.07Hz, 3H), 0.79 (m, 2H)

[0242] LRMS [C 15 H 22 ClNO4-OCH3] + : 284.76

[0243] Kilogram scale A mixture of 2-methylcyclopentanone, compound 22 (235 kg, 0.66 X, 1.16 equivalents), and compound 2a (354 kg, 1.0 X) in 2-Me-THF (2103 L, 5.1 X, 5.9 V) was gradually added with potassium tert-butoxide (258 kg, 0.73 X, 1.1 equivalents) over 5 hours under N2 at 0°C. After 2 hours, the resulting reaction mixture was quenched with water (2839 kg, 8 X, 8 V; pre-cooled to 3-8°C) over 4 hours at 0°C. The aqueous layer was separated and washed with toluene (3003 L, 2613 kg, 7.4 X, 8.5 V) at 0°C. The pH was adjusted to 7.0-9.0 (8.68) by adding a 5% H2SO4 aqueous solution (1970 kg, 5.6X, 0.49 equivalents) over 5.5 hours at 0°C, and then adjusted to 4.0-6.0 (4.92) by adding a 0.5% H2SO4 solution (611 kg, 1.7X, 0.02 equivalents) over 2 hours at 0°C. The mixture was stirred at 0°C for 30 minutes, then filtered by centrifugation, rinsed with water (1495 kg, 4.2X, 4.2V), and a wet solid of compound 23 (565 kg) was obtained.

[0244] Compound 23 (7.60 kg, correct assay = 7.50 g, 32.37 mmol) was added to a reaction mixture containing MSA (7.60 kg, 79.08 mol), H2O (90.00 g, 90 mL), and ACN (29.25 kg, 37 L). The resulting reaction mixture was heated to 68 °C and stirred for 5 hours. The reaction mixture was cooled to 20 °C, and then 25% ammonia solution (5.50 kg) was added little by little, while stirring for 1 hour. 2.5% ammonia solution (1.50 g) was added to the reaction mixture little by little over 30 minutes to adjust the pH to 4.8. The resulting reaction mixture was heated at 43 °C for 8 hours, filtered, and compound 24a (40 kg) was obtained.

[0245] Compound 24a (37.0 kg) was mixed with 3.0 equivalents of CH(OMe)3 and 2.0 equivalents of TMSCl in MeOH (370 L). The mixture was stirred at 30-35°C for 24 hours, and the resulting reaction mixture was cooled to 20-25°C and quenched with 2.2 equivalents of TEA at 20-30°C. The reaction mixture was then concentrated to 100 L under vacuum at 40°C or below. MTBE (370 L) and H2O (300 L) were added to the residue. After phase separation, the organic layer was recovered and washed with H2O (200 L). The organic layer was then concentrated to 70 L under vacuum at 40°C or below. DMSO (1 V) was then added to the residue, and the mixture was concentrated to 70 L under vacuum at 40°C or below to obtain a concentrated DMSO solution of compound 25a (86.4 kg). b) Enzymatic resolution of dimethoxymethyl ester: [ka]

[0246] A reaction vessel (250 mL) equipped with a water circulator was used to maintain the reaction temperature at 35°C throughout the series of reactions. The pH was maintained at 7.0 using a calibrated pH meter. Compound 25a (5.0 g), DMSO (4.0 mL, 2%), and sodium phosphate buffer (180 mL, 0.1 M, pH 7.0) were added to the 250 mL reaction vessel. The reaction solution was maintained at pH 7.0 by continuously adding 5N sodium hydroxide. Lipase MH Amano 10 SD (1.0 g) was dissolved in the above buffer (10 mL) and added to the reaction vessel. The container that had held the enzyme was then rinsed with buffer (6.0 mL) and added to the same reaction vessel. A sample (80 μL) was pipetteed, diluted with methanol (1.920 mL), vortexed, centrifuged for 2 minutes, filtered, and analyzed by achiral HPLC and chiral HPLC. The reaction was stopped after 23 hours, and the pH was adjusted to 8.2 using 10N sodium hydroxide. The resulting reaction mixture was extracted with ethyl acetate (200 mL). All dimethoxymethyl esters were extracted into the organic layer. The organic layer was back-extracted with sodium potassium buffer (2 x 50 mL) at pH 8.5 to remove the acid. The organic layer was washed with saline solution (50 mL) and water (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered, the solvent was removed under reduced pressure, and the resulting residue was dried overnight in a vacuum oven. Compound 26a (1.88 g) was isolated as a brownish liquid (yield 37.6%, ee 98.7%).

[0247] 1 H NMR(400MHz, DMSO-d6)δ 8.61 (d, J=5.1Hz, 1H), 7.60 (d, J=1.5Hz, 1H), 7.52 (dd, J=5.2, 2.1Hz, 1H), 3.50 (s, 3H), 3.03 (s, 3H), 3.03 (s, 3H), 2.31 (sxt, J=7.0Hz, 1H), 2.05-1.95 (m, 2H), 1.47-1.35 (m, 1H), 1.28-1.17 (m, 1H), 0.94 (d, J=7.1Hz, 3H), 0.85-0.74 (m, 2H)

[0248] LRMS [C15 H 22 ClNO4-OCH3] + : 284.2 / 286.1 c) Hydrolysis of compound 26a to obtain compound 27a:

[0249] Compound 26a (1.0 g), methanol (20 mL), water (5.0 mL), and 10N sodium hydroxide (500 μL, 0.2 g) were added to a reaction vial. The reaction mixture was stirred at room temperature for 5 hours. A sample (30 μL) was taken out, diluted with methanol (970 μL), stirred by vortexing, filtered, and analyzed by HPLC. Most of the reaction (conversion rate ~98%) was completed within 2 hours, and no racemization was observed during hydrolysis. This reaction mixture was concentrated to an oily consistency and diluted with water (20 mL, pH 12.7). The resulting reaction mixture was extracted with MTBE (2 x 50 mL) and the MTBE was removed. The aqueous layer was cooled and acidified to pH 3.8 with 6N HCl (850 μL). The aqueous layer was extracted with MTBE (2 x 50 mL), and the MTBE solution was washed with saline (25 mL) and water (2 x 25 mL). The MTBE solution was dried over anhydrous sodium sulfate, filtered to remove the solvent, and the resulting residue was dried overnight in a vacuum oven. Compound 27a was isolated as a viscous yellow liquid (940 mg, yield 98.3%, AP 97 and ee 98%).

[0250] 1 H NMR(400MHz, DMSO-d6)δ 11.96 (s, 1H), 8.60 (d, J=5.3Hz, 1H), 7.60 (d, J=2.0Hz, 1H), 7.51 (dd, J=5.2, 2.1Hz, 1H), 3.04 (s, 3H), 3.01 (s, 3H), 2.18 (sxt, J=6.9Hz, 1H), 2.00 (dd, J=10.6, 5.8Hz, 2H), 1.47-1.33 (m, 1H), 1.26-1.13 (m, 1H), 0.91 (d, J=6.8Hz, 3H), 0.87-0.75 (m, 2H)

[0251] LRMS [C 14 H20 ClNO4] - : 300.1 An alternative method of enzyme decomposition [ka]

[0252] 13.5 L of 0.1 M Tris buffer, to which Ca(OAc)2 (50 mM) was added, was mixed with 2.5 w% enzyme (Almac Hydrolase L90 enzyme, also known as AL-L90, available from ALMAC Group Ltd., Craigavon, Northern Ireland, UK) at 20–25°C. The pH of the mixture was adjusted to 7.2–7.8. The mixture was heated at 38–42°C and maintained at pH 7.2–7.8. A solution of compound 25a (1.5 kg) / DMSO (1.5 L) was added to the mixture all at once at 38–42°C. After 22 hours, the conversion rate was 49%. The reaction mixture was cooled to 5°C and held at 0–10°C for 16 hours. As a work-up, ACN (9 L) was added to the reaction mixture at 0–10°C. Next, the pH was adjusted to 10.0 with 20% K₂CO₃, and 0.25X Celite was added to the mixture. After stirring for 20-30 minutes, the resulting reaction mixture was filtered, and the cake was rinsed with MTBE (3 L) and water (3 L). The filtrate was collected, and MTBE (15 L) was added to the mixture to separate the phases. The organic layers were washed twice with water (15 L). The aqueous layers were combined and adjusted to pH 5.5 with 20% citric acid. MTBE (15 L) was added to the mixture to separate the phases. Next, the aqueous layers were adjusted to pH 5.5 with 20% citric acid, and phase separation was performed again using MTBE (15 L). The organic layers were combined and washed with process water (15 L). The organic layers were collected, filtered, and the aqueous layer was removed. The organic layers were then concentrated to 4.5 L. Azeotropic distillation was performed twice using 15 L of MTBE to obtain 4.5 L. 7.5 L of MTBE and 3 L of ACN were added to the resulting residue to form a salt. During salt formation, the mixture was heated to 50–55°C, and DCHA (0.75 equivalents) was added to the mixture at 50–55°C. After stirring at 50–55°C for 1 hour, the resulting reaction mixture was cooled at 10°C / hour. 1.8% seed crystals were added to the mixture at 38.2°C. A white solid slowly precipitated. After holding at 38°C for 3 hours, the mixture was continued to cool at 10°C / hour. After holding at 0–5°C for 10 hours, the mixture was filtered. The cake was rinsed with pre-cooled ACN (1.5 L). After drying for 38 hours, 1.245 kg of compound 27a-DCHA was obtained as a white solid (purity 99.3%, 99.4% ee, and isolation yield 43.61%). Example 18 Synthesis of compound 10 [ka] a) Synthesis of compound 29a

[0253] To a solution of (triisopropylsilyl)acetylene (10.5 g, 57.6 mmol, 100% by mass) / THF (60 mL), n-butyllithium (2.5 mL / L) / hexane (22 mL, 55.0 mmol, 2.50 mL / L) was slowly added at -10°C. After the addition, the mixture was heated at 21°C. A solution of compound 28a (10.0 g, 49.8 mmol, 100% by mass) / THF (35 mL) was then added at 21°C. After 1 hour, HPLC analysis showed that 8% of the amide starting material remained. Bis(trimethylsilyl)amide lithium (1 M, THF solution, 8 mL) was then added. After 1 hour, HPLC analysis showed that the reaction was complete. The mixture was cooled to 0-5°C and added to a mixture of 15% citric acid aqueous solution (500 g) and heptane (0.6 L) at 5-15°C. The organic layer was washed with 3% citric acid aqueous solution (200 mL) and water (0.2 L), dried over MgSO4, and compound 29a (15.8 g) was concentrated until it became an orange oily substance (98.5% yield).

[0254] 1 H NMR (500MHz, CDCl3): δ 8.68 (1H, d, J=4.5Hz), 8.15 (1H, s), 7.50 (1H, d, J=4.5Hz), 1.25-1.05 (21 H, m)

[0255] LRMS [C 17 H 24 ClNOSi+H] + : 322.23 / 324.11 b) Synthesis of compound 30a

[0256] To a solution of compound 29a (3.00 g, 9.32 mmol) / MeOH (20 mL), trimethyl orthoformate (2.0 mL, 18 mmol), followed by chlorotrimethylsilane (3.0 mL, 24 mmol), was added at 21 °C. The mixture was then heated to 60 °C. After 1 hour, HPLC analysis showed that the starting material had been consumed. The mixture was cooled to 21 °C and added to a mixture of hexane (200 mL) and a mixture of NaHCO3 (15 g) and Na2CO3 (5 g) / water (200 mL). The separated organic layer was then dried over MgSO4 and concentrated to obtain [3-(4-chloro-2-pyridyl)-3,3-dimethoxypropa-1-inyl]-triisopropyl-silane (3.45 g, 9.38 mmol, 100% yield) as an orange oil. The resulting crude intermediate was used for the subsequent deprotection of TIPS without further purification.

[0257] [3-(4-chloro-2-pyridyl)-3,3-dimethoxypropa-1-inyl]-triisopropyl-silane (3.20 g, 8.70 mmol, 100% by mass) / 2-MeTHF (10 mL) and TBME (10 mL) were mixed with 1 M tetrabutylammonium fluoride (THF solution, 12 mL, 12.0 mmol, 1.00 mL / L) at 21 °C. After 10 minutes, HPLC analysis showed that the starting material had been consumed. The dark mixture was added to a mixed solution of TBME (0.2 L) and an aqueous solution of K2HPO4 / K3PO4 (20 g / 5 g / 130 mL water). The isolated organic layer was dried over MgSO4 and concentrated. The obtained residue was purified by column chromatography (Rf 0.39 in 20-60% alkyl / heptane; 50% alkyl / heptane) to obtain compound 30a (1.65 g) as a pale solid in 90% yield.

[0258] 1 H NMR (500MHz, CDCl3): δ 8.61 (1H, d, J=5.0Hz), 7.75 (1H, s), 7.32 (1H, d, J=5.0Hz), 3.37 (6H, s), 2.74 (1H, s)

[0259] LRMS [C 10H 10 ClNO2-OCH3] + :180.25 / 182.06 c) Synthesis of compound 31a

[0260] To a solution of bis(cyclopentadienyl)zirconium dichloride (20.7 g, 70.9 mmol, 99% by mass) / THF (200 mL), lithium tri-tert-butoxyaluminum hydride (1 mol / L) / THF (71 mL, 71 mmol, 1 mol / L) was added at 7-15°C and the mixture was stirred at 0-5°C for 1 hour. Compound 30a (12.5 g, 59.1 mmol, 100% by mass) was then added at 0-5°C. After mixing at 5-10°C for 10 minutes, the mixture was heated to 21°C and stirred at the same temperature for 0.5 hours. The dark brown solution of the mixture was then cooled to 0-5°C, and NBS (11 g, 61.8 mmol, 100% by mass) was added in solid form in two portions (6 g first, 5 g second).

[0261] After stirring at 5-10°C for 2 hours, the reaction mixture was added to a mixed solution of HCl / heptane (180 mL / 60 mL) and 15% NH4Cl aqueous solution (250 mL). The resulting slurry was filtered by Celite filtration, and the filtration line was rinsed with HCl (30 mL x 2). The aqueous layer was removed from the combined filtrate. The resulting organic layer was washed with 5% K2HPO4 aqueous solution, dried over MgSO4, and concentrated. This residue was purified by column chromatography (0-30% HCl / heptane; product Rf 0.4 in 30% HCl / heptane) to obtain compound 31a (13.2 g, 45.1 mmol, 76.4% yield) as a gray solid.

[0262] 1 H NMR (500MHz, CDCl3): δ 8.57 (1H, d, J=5.2Hz), 7.67 (1H, s), 7.26 (1H, d, J=5.2Hz), 6.78 (1H, d, J=13.5Hz), 6.11 (1H, d, J=13.5Hz), 3.24 (6H, s)

[0263] LRMS [C 10 H 11BrClNO2-OCH3-Br] + : 182.09 / 184.22 d) Synthesis of compound 32a

[0264] To a solution of compound 31a (12.0 g, 41.0 mmol, 100% by mass) / THF (50 mL), (S)-(-)-3-methoxy-2-methyl-3-oxopropyl zinc bromide (0.5 mol / L) / THF (94 mL, 47 mmol, 0.50 M) was added at 5-10°C. The mixture was degassed by bubbling with N2 for 3 minutes, and then 1,1'-bis(ditert-butylphosphino)ferrocene dichloropalladium (0.68 g, 1.03 mmol, 100% by mass) was added at 5-10°C. The resulting mixture was degassed by bubbling with N2 for 5 minutes. After holding at 5°C for 15 minutes, the dark solution was heated to 21°C. After 16 hours, TBME (150 mL) was added to the reaction mixture, followed by aqueous NH4Cl solution (25%, 200 g). The dark organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by column chromatography (5-60% toluene / heptane; Rf 0.28 in 1:1 toluene / heptane) to obtain compound 32a (11.7 g, 37.3 mmol, 100% by mass, 90.9% yield) as an orange oil.

[0265] 1 H NMR (500MHz, CDCl3): δ 8.54 (1H, d, J=5.2Hz), 7.65 (1H, s), 7.22 (1H, d, J=5.2Hz), 5.98 (1H, dt, J=15.6, 7.3Hz), 5.45 (1H, d, J=15.6Hz), 3.62 (3H, s), 3.21 (6H, s), 2.63-2.52 (1H, m), 2.32-2.45 (1H, m), 2.16-2.20 (1H, m), 1.13 (3H, d, J=7.0Hz)

[0266] LRMS [C 15 H 20 ClNO4-OCH3] + : 282.19 / 284.23 e) Synthesis of compound 33a

[0267] In the preparation of the catalyst, diacetoxypalladium (440 mg, 1.960 mmol) and bis(1-adamantyl)-butyl-phosphane (708 mg, 1.975 mmol) were added to dioxane (12 mL). The mixture was degassed by bubbling with N2 for 0.5 hours. Compound 32a (6.2 g, 20 mmol, 100% by mass), compound 8 (4.0 g, 25 mmol), pivalic acid (1.1 g, 11 mmol, 100% by mass), and potassium carbonate (8.1 g, 59 mmol) were mixed with dioxane (60 mL), and the resulting mixture was degassed by bubbling with N2 for 0.5 hours. The above pre-mixed and degassed catalyst was then transferred to a mixture containing the substrate. The resulting mixture was degassed by bubbling with N2 for 0.5 hours, then heated to 90°C, held at the same temperature for 3 hours, and then cooled to 21°C. The resulting mixture was filtered, and the filtration line was rinsed with TBME (25 mL). The combined filtrate was concentrated. The resulting residue was purified by column chromatography (Rf 0.36 in 60% siRNA / heptane; 10-80% siRNA / heptane) to obtain compound 33a (7.6 g, 16 mmol, 98% by mass, 86% yield) as a brown oil.

[0268] 1 H NMR (500MHz, CDCl3): δ 8.86 (1H, d, J=4.7Hz), 8.33 (1H, s), 7.73 (1H, s), 7.22 (1H, d, J=4.7Hz), 7.13 (1H, t, J=57.6Hz), 5.97 (1H, dt, J=15.7, 7.6Hz), 5.53 (1H, d, J=15.7Hz), 3.59 (3H, s), 3.23 (6H, s), 2.65-2.52 (1H, m), 2.35-2.48 (1H, m), 2.19-2.25 (1H, m), 1.12 (3H, d, J=7.0Hz)

[0269] LRMS [C 19 H 22 F2N4O6-OCH3] + : 409.18 f) Synthesis of compound 10a

[0270] A solution of compound 33 (6.3 g, 14 mmol) / MeOH (50 mL) and a stirring bar were added to a 100 mL pressure flask. The container was degassed under vacuum and filled with N2 six times. Then 1.35 g (0.634 mmol, 5 mass%) of Pd / carbon (10 mass%, 50% wet) was added. The container was degassed with N2, then H2. The hydrogen gas pressure was set to 80 psi and the reaction temperature to 55 °C. After maintaining the pressure and temperature for 12 hours, the mixture was filtered and the filtration line was rinsed with MeOH (35 mL). The combined filtrate was concentrated. The resulting residue was dissolved in THF (60 mL) and an aqueous NaOH solution (1 mol / L) was added. The mixture was heated to 40 °C and held at the same temperature for 6 hours. The mixture was then cooled to 21 °C. 2-MeTHF (100 mL) was added. The pH of the mixture was adjusted to approximately 6 by adding 85% H3PO4. The aqueous layer was removed, and the organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by column chromatography (0-10% MeOH / DCM; Rf 0.4 in 10% MeOH / DCM) to obtain compound 10a (4.85 g, 12.2 mmol, 89.7% yield) as a foamed solid.

[0271] 1 H NMR (500MHz, CDCl3): δ 8.77 (1H, s, br), 7.75 (1H, s. br), 7.39 (1H, s. br), 7.33 (1H, s. br), 7.11 (1H, t, J=59.1Hz), 5.75 (3H, s, br), 3.17 (6H, s), 2.35-2.25 (1H, m), 2.20-1.98 (2H, m), 1.55-1.43 (1H, m), 1.30-1.13 (1H, m), 0.80-1.09 (5H, m)

[0272] LRMS [C 18 H 24 F2N4O4+H] + : 399.18 Example 19 Synthesis of compound 14 [ka] Suzuki Coupling

[0273] In a 2 L reaction vessel, acetonitrile (500 mL, 5 L / kg), compound 43 (100 g, 1.0 equivalent), compound 44 (60 g, 1.05 equivalent), 1,1,3,3-tetramethylguanidine (93.2 g, 2.05 equivalent), and water (70.8 g, 10 equivalents) were added. The headspace of the reaction vessel was purged using a nitrogen stream. Pd(dppf)Cl2·DCM (3.2 g, 1 mol%) was added to the resulting reaction mixture, and the reaction vessel was heated at 65°C for 1 to 7 hours, followed by stirring at 1 to 17 hours. After the reaction was complete, 1,3,5-triazine-2,4,6(1H,3H,5H)-trithion sodium salt (TriNaTMT, 10 g, 10 w / w%) was dissolved in water (50 mL, 0.5 L / kg) and added to the resulting reaction mixture. To this reaction mixture, warm water (280 mL, 2.8 L / kg) was slowly added over 0.5 to 4 hours, while maintaining the internal temperature at 60 to 65°C. After standing for 1 to 4 hours, warm water (350 mL, 3.5 L / kg) was slowly added to the reaction mixture over 2 to 6 hours, while maintaining the internal temperature at 60 to 65°C. The resulting reaction mixture was then cooled to 10 to 15°C over 4 to 6 hours, and then left to stand at 10 to 15°C for 1 to 3 hours. The slurry was then filtered, and the cake was washed with cold MeCN aqueous solution (2:1 v / v%, 5 L / kg). The cake of compound 45 was vacuum-dried overnight at 45 to 50°C.

[0274] Typical results: Yield 90-95%, purity 98a%, assay >95% PD removal

[0275] In a 5 L reaction vessel, solid crude compound 45 (100 g, 1.0 equivalent), 2-methyltetrahydrofuran (MeTHF, 1.5 L, 15 L / kg), and aqueous solution of N-acetyl L-cysteine ​​(32 g / 1.5 L water) were added. The resulting mixture was stirred at 20-30°C for 1-2 hours and filtered through Celite (30 g, 0.3 kg / kg). The two-phase mixture was allowed to stand for 0.5-2 hours to separate the two layers. The upper layer was left in the reaction vessel, and aqueous solution of N-acetyl L-cysteine ​​(32 g / 1.5 L water) was added. The resulting mixture was stirred at 20-30°C for 1-2 hours, and the two-phase mixture was allowed to stand for 0.5-2 hours to separate the two layers. The upper layer was left in the reaction vessel, and aqueous solution of sodium bicarbonate (70 g / 1 L water) was added. The resulting mixture was stirred at 20-30°C for 1-2 hours, and the two-phase mixture was allowed to stand for 0.5-2 hours to separate the two layers. The upper layer was left in the reaction vessel, and aqueous sodium sulfate solution (100g / 1L water) was added. The resulting mixture was stirred at 20-30°C for 1-2 hours, and the two-phase mixture was allowed to stand for 0.5-2 hours to separate the two layers. The upper layer was left in the reaction vessel, diluted with MeTHF (1L, 10L / kg), and the resulting solution was vacuum concentrated to 500-600mL (5-6L / kg). Next, the solution was diluted with MeTHF (1L, 10L / kg), and the resulting solution was vacuum concentrated to 500-600mL (5-6L / kg). This solution was then diluted with MeTHF (1L, 10L / kg), and the water content was measured (KF: ≤0.1%).

[0276] Typical results: Yield 90-95%, purity 98% Azidization / Click response

[0277] A MeTHF solution of compound 45 (100 g / MeTHF 1.5 L), MeTHF (1.5 L, 15 L / kg), and MeCN (1 L, 10 L / kg) were added to the reaction vessel, and the mixture was cooled to 5-10°C. TMSN3 (59.0 g, 1.2 equivalents) was slowly added to the reaction vessel. tBuONO (53.0 g, 1.2 equivalents) was slowly added to the reaction vessel, and the mixture was stirred at 5-15°C for 4-8 hours. An aqueous NaOH solution (100 g / water 1 L) was slowly added to the above mixture. This was then heated to 20-30°C and stirred for 20-30 minutes, and then left to stand at 20-30°C for 30-60 minutes. After phase separation, the upper layer was left in the reaction vessel, and an aqueous NaOH solution (100 g / water 1 L) was slowly added to the above mixture. This mixture was then stirred for 20-30 minutes and left to stand at 20-30°C for 30-60 minutes. After phase separation, the upper layer was left in the reaction vessel, and NaOH aqueous solution (100g / 1L water) was slowly added to the above mixture. This mixture was then stirred for 20-30 minutes and left to stand at 20-30°C for 30-60 minutes. After phase separation, the upper layer was left in the reaction vessel, and NaOH aqueous solution (100g / 1L water) was slowly added to the above mixture. This mixture was then stirred for 20-30 minutes and left to stand at 20-30°C for 30-60 minutes. After phase separation, the upper layer was left in the reaction vessel, and the remaining azide was measured (residual N3 < 3 ppm). Sodium sulfate aqueous solution (100g / 1L water) was then added to the above mixture. This mixture was then stirred for 20-30 minutes and left to stand at 20-30°C for 30-60 minutes. After phase separation, an aqueous sodium sulfate solution (100g / 1L water) was added to the above mixture. This was then stirred for 20-30 minutes and left to stand at 20-30°C for 30-60 minutes. After phase separation, an aqueous sodium sulfate solution (100g / 1L water) was added to the above mixture. This was then stirred for 20-30 minutes and left to stand at 20-30°C for 30-60 minutes. After phase separation, an aqueous sodium sulfate solution (100g / 1L water) was added to the above mixture. This was then stirred for 20-30 minutes and left to stand at 20-30°C for 30-60 minutes. After phase separation, the pH was measured (pH<9) and the organic azide solution was cooled to 5-15°C. After bubbling with nitrogen for 20-40 minutes, the temperature was maintained at 5-15°C while triethylamine (95.0g, 2.2 equivalents) was slowly added to the reaction mixture.While slowly adding trimethylsilylacetylene (50.0 g, 1.2 equivalents) to the reaction mixture, the temperature was maintained at 5–15°C, and the reaction vessel was purged with nitrogen until the oxygen level was 0.1% or less. Copper iodide (8.0 g, 10 mol%) was charged into the reaction vessel, and this was then purged with nitrogen again until the oxygen level was 0.1% or less. The resulting reaction mixture was stirred at 5–15°C for 8–16 hours. After the reaction was complete, the reaction mixture was heated to 20–30°C, and 1,3,5-triazine-2,4,6(1H,3H,5H)-trithion sodium salt (TriNaTMT, 10 g, 10 w / w%) was added. After stirring at 20–30°C for 0.5–1.5 hours, the mixture was filtered through Celite (30 g, 0.3 kg / kg), and the cake was rinsed with MeTHF (250 mL, 2.5 L / kg). Aqueous ammonia solution (100g / 1L water) was added to the reaction vessel, and the mixture was then stirred at 20-30°C for 20-30 minutes, followed by standing at 20-30°C for 30-60 minutes. After phase separation, aqueous sodium sulfate solution (100g / 1L water) was added to the reaction vessel, and the mixture was then stirred at 20-30°C for 20-30 minutes, followed by standing at 20-30°C for 30-60 minutes. After phase separation, the upper layer was filtered through Celite (30g, 0.3kg / kg). The Celite cake was washed with MeTHF (0.5L, 5L / kg), and the mixture was concentrated under reduced pressure to 500-700mL (5-7L / kg) at 45°C. n-heptane (1L, 10L / kg) was added dropwise to the reaction vessel, and the resulting mixture was concentrated under reduced pressure to 500-700mL (5-7L / kg) at 45°C. n-heptane (1 L, 10 L / kg) was added dropwise to the reaction vessel, and the resulting mixture was concentrated under reduced pressure to 500-700 mL (5-7 L / kg) at 45°C. The reaction mixture was then heated to 55-60°C and stirred at the same temperature for 2-4 hours. After cooling the reaction vessel to 5-15°C over 3-8 hours, the slurry was aged at 5-15°C and filtered. The cake of compound 46 was washed with n-heptane (1 L, 10 L / kg) and dried under reduced pressure at 40-45°C for 6-12 hours.

[0278] Typical results: Yield 85-90%, purity 98%; assay >95% Chlorination

[0279] Compound 46 (100 g, 1.0 equivalent) and DMF (500 mL, 5 L / kg) were added to the reaction vessel, cooled to -15°C to -5°C, and purified with water (5 g, 1.0 equivalent). The internal temperature was kept below 5°C while gradually adding 1,3-dichloro-5,5-dimethylhydantoin (DCDMH, 13.7 g, 0.75 equivalents). The internal temperature was then adjusted to 0 to 10°C, and the mixture was stirred at this temperature for 5 to 12 hours. After the reaction was complete, water (70 mL, 0.7 L / kg) was added to the resulting reaction mixture over 0.5 to 1.5 hours. During this time, the internal temperature was kept below 15°C. Seed crystals of compound 47 (0.1 g, 0.001 kg / kg) were added to the resulting reaction mixture, and this was then aged at 0 to 10°C for 1 to 2 hours. Water (530 mL, L / kg) was added over 3-8 hours at 0-10°C, and the slurry was aged at 0-10°C for 4-6 hours. The mixture was filtered, and the cake was washed with cold water (0.5 L, 0-10°C). The resulting crude compound 47 was dried under reduced pressure at 40-50°C for 8-15 hours.

[0280] Typical results: Yield 90-95%, purity 98a%, assay >95% Recrystallization of compound 47

[0281] Crude compound 47 (100g, 1.0 equivalent) and DCM (0.5L, 5L / kg) were added to the reaction vessel, and the resulting solution was stirred at 20-30°C for 0.5-2 hours. The resulting mixture was filtered through a carbon-filled filter cartridge, circulated for 3-8 hours, and then concentrated under reduced pressure to 300-360 mL (3.0-3.6 L / kg). The mixture was then heated to 35-45°C, refluxed for 20-40 minutes, cooled to 0-10°C over 1-4 hours, and then aged at 0-10°C for 0.5-2 hours. n-heptane (1.6L, 16L / kg) was then charged into the reaction vessel at 0-10°C over 1-3 hours, and the slurry was aged at 0-10°C for 1-3 hours. After filtering the slurry, the cake of pure compound 47 was washed with n-heptane (500 mL, 5 L / kg) and dried under reduced pressure at 40-50°C for 6-12 hours.

[0282] Typical results: Yield 90-95%, purity >99.5a%, assay >95% Demethylation

[0283] Pure compound 47 (100 g, 1.0 equivalent) and aqueous HCl solution (35 w / w%, 320 g, 10 equivalents) were added to the reaction vessel. The reaction vessel was heated to 40-50°C for 1-3 hours and stirred at the same temperature for 10-18 hours. After the reaction was complete, aqueous ammonia solution (50 g / 500 mL) was added dropwise to the reaction vessel over 2-6 hours at 40-50°C until the pH was 5-7. The reaction mixture was then cooled to 0-10°C for 1-3 hours and aged at the same temperature for 1-3 hours. After filtering the slurry, the resulting crude compound 14 cake was washed with cold water (1 L, 0-10°C, 10 L / kg) and dried under reduced pressure at 40-50°C for 12-24 hours.

[0284] Typical results: Yield 90-95%, purity >99.5a%, assay >95% Recrystallization of compound 14

[0285] Crude compound 14 (100g, 1.0 equivalent) and acetone (1.4L, 14L / kg) were added to a reaction vessel. The reaction vessel was heated to 50-60°C and stirred at the same temperature for 1-3 hours. Crystals of compound 14 (0.5g, 0.005kg / kg) were seeded, and n-heptane (1.7L, 17L / kg) was added over 4-8 hours at 50-60°C. The mixture was stirred at the same temperature for 1-2 hours and then cooled to 5-15°C over 2-4 hours. After filtration, the cake of pure compound 14 was washed with cold n-heptane (0.5L, 5L / kg) and dried under reduced pressure at 80-90°C for 8-16 hours.

[0286] Typical results: Yield 90-95%, purity >99.9a%, assay >95%

Claims

1. Formula (II): 【Chemistry 1】 [In the formula, The dashed line (----) represents any combination; R 1 C 1-6 It is alkyl; R 2 C 1-3 It is alkyl; R 3 OH, OC 1-4 Alkyl, 【Chemistry 2】 Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3 Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I. A compound or salt thereof.

2. Compound 21: 【Transformation 3】 A compound or salt thereof according to claim 1, having the structure described in claim 1.

3. Equation (VI): 【Chemistry 4】 [In the formula, R 2 C 1-3 It is alkyl; R 3 OH, OC 1-4 Alkyl, 【Transformation 5】 Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3 Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I. Compounds or salts thereof.

4. During the ceremony, R 2 C 1-3 It is alkyl; R 3 OH, OC 1-4 Alkyl, and 【Transformation 6】 Selected from; and X is selected from F, Cl, Br, and I. The compound or a salt thereof according to claim 3.

5. Compound 34: 【Transformation 7】 A compound or salt thereof according to claim 3, having the structure described in claim 3.

6. The structural formula is compound 21: 【Transformation 8】 A method for producing a compound of formula (II) shown by, the following: a) Compound 15: 【Chemistry 9】 (CH 3 O) 2 CH(CH 2 ) 2 React with Br to form compound 16: 【Chemistry 10】 To obtain; b) Convert compound 16 in the presence of an acid to obtain compound 17: 【Chemistry 11】 To obtain; c) Compound 17 is reacted with a triphenylphosphonium ylide or a phosphonate derivative selected from methyl 2-(diethoxyphosphoryl)propanoate or ethyl 2-(diethoxyphosphoryl)propanoate. In the formula, R 3 ' is C 1-6 Compound 18 is alkyl: 【Chemistry 12】 To obtain; d) Compound 18 is reacted with trimethyl orthoformate in the presence of an acid to obtain compound 19: 【Chemistry 13】 To obtain; e) Convert compound 19 to compound 20: 【Chemistry 14】 To obtain; f) Hydrogenate compound 20 in the presence of a ruthenium catalyst to obtain the following structure: 【Chemistry 15】 A compound of formula (II) having the following characteristics is obtained; A method characterized by steps.

7. The method according to claim 6, wherein in step b, the acid is TFA.

8. The method according to claim 6, wherein in step d, the acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid.

9. The method according to claim 6, wherein in step f, the ruthenium catalyst is selected from dichloro[(R)-(+)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II), dichloro[(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl][(1R,2R-)-(+)-1,2-diphenylethylenediamine]ruthenium(II), dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II), and diacetato[(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II).

10. During the ceremony, The dashed line (----) represents any combination; R 1 That is Me; R 2 That is Me; R 3 OH, OC 1-4 Alkyl, 【Chemistry 16】 Selected from; R 6 C 1-3 Selected from alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 C 1-3 Selected from alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br, and I. The compound or a salt thereof according to claim 1.

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