Novel synthetic method towards manufacture 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-(metheno)pyrazolo[4,3-b][1,7] diazacyclotetradecin-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 generally relates to several improved processes for the manufacture of the factor XIa inhibitor (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]diazacyclotetradecin-5(6H)-one, which is useful for the treatment of thrombotic disorders (e.g., venous thrombosis and deep vein thrombosis).

Background Art

[0002] Factor XIa is a plasma serine protease involved in the regulation of blood coagulation. In vivo, tissue factor (TF) initiates the binding to factor VII (FVII), producing factor VIIa (FVIIa). The resulting TF:FVIIa complex contributes to the activation of factor IX (FIX) and the activation of factor X (FX) leading to the generation of factor Xa (FXa). The produced FXa functions as a catalyst to convert prothrombin to a small amount of thrombin, after which this pathway is inhibited by tissue factor pathway inhibitor (TFPI). The catalytic amount of thrombin causes feedback activation to factors V, VIII, and XI, further propagating the coagulation process (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007)). The increase in thrombin causes fibrinogen to polymerize into fibrin, forming the bulk of the thrombus and activating platelets, which are important cellular coagulation components (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIa plays an important 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 the above compounds has the following structure.

Chemical formula

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

[0005] When applying the multi-step synthesis disclosed in U.S. Patent No. 9,453,018 to larger-scale synthesis (e.g., production at pilot plant or manufacturing scale), there are various difficulties. One of them is that the Grubbs (II) reagent is expensive, making it difficult to apply to industrial-scale synthesis. Furthermore, in order to reduce manufacturing costs and / or reduce unreacted substances, it is necessary to continue searching for methods that can be obtained in higher yields. Preferably, inexpensive starting materials are selected in the new process.

[0006] Generally, a method suitable for producing a larger amount of compound (I) than the amount produced by laboratory-scale methods is desired. Also, a method for obtaining compound (I) in a higher yield than the previously disclosed method is desired.

[0007] The present invention relates to one or both of these aspects, as well as other important aspects.

Summary of the Invention

[0008] In one aspect, the present invention provides a method for producing compound (I), characterized by the following steps.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] In yet another aspect, the present invention provides a compound of formula (II):

Chemical formula

Chemical formula

[0010] In some embodiments of the compound of formula (II), R 1 is C 1-6 alkyl; R 2 is C 1-3 alkyl; R 3 is OH, OC 1-6 alkyl,

Chemical formula

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

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

[0013] In yet another aspect, the present invention relates to formula (IIa):

Chemical formula

Chemical formula

[0014] In some embodiments, formula (II) having the following structure:

Chemical formula

Chemical formula

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

[0016] In some embodiments, the structure of compound 21

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0017] In some embodiments of the method for producing a compound of formula (II) or (IIa) having the structure of compound 19, the following steps are characteristic.

[0018] The formula [Chemical formula] [wherein, R 1 is C 1-6 alkyl; R 10 is C 1-6 alkyl] In some embodiments of the method for producing a compound of formula (II) or (IIa) having compound 19, it is characterized by the following steps. 1) The formula: [Chemical formula] React compound 37 with pyruvate phosphonium ylide to obtain a compound of the formula: [Chemical formula] wherein R 3 ' is independently C 1-6Compound 38, which is alkyl, is obtained. 2) React compound 38 with compound 2a having the following structure

Chemical formula

Chemical formula

Chemical formula

[0019] In yet another aspect, the present invention provides a compound of formula (III):

Chemical formula

[0020] In some embodiments of the compound of formula (III), R 1 is methyl; R 2 is methyl; R​4 is NO 2 and NH 2 selected from; and R 5 is CHF 2 is.

[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 CHF 2 is.

[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), R2 is methyl, and R 5 is CHF 2 .

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

Chemical formula

Chemical formula

[0026] In some embodiments of the compound of formula (VI), R 2 is C 1-3 alkyl; R 3 is OH, OC 1-4 alkyl,

Chemical formula

[0027] In some embodiments, the compound of formula (VI) is compound 34

Chemical formula

[0028] In another aspect, the present invention provides a method for treating thrombotic and embolic disorders, which comprises administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of compound (I), which is produced using the novel synthesis method of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

[0029] Definition As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic group containing 1 to 10 carbon atoms, and unless otherwise specified, for example, alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl and the like. 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 as above is connected to the parent molecule through an oxygen atom. The alkyl part of the alkoxy group can have 1 to 10 carbon atoms (i.e., C 1 -C 10 alkoxy), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), t-butoxy (-O-C(CH 3 ) 3 or -OtBu), and the like.

[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 additional substituents selected from halogen (preferably fluoro, chloro, or bromo), hydroxy, amino, mercapto, etc. Preferred substituents in groups such as the substituted lower alkyl or substituted alkyl described herein are halogen, particularly the fluoro group.

[0033] The term "reducing agent" refers to any reagent that reduces the oxidation state of a carbon atom in a starting material by adding a hydrogen atom or by adding an electron. These reagents are apparent to those skilled in the art. Examples of "reducing agents" include, but are not limited to, borane-dimethyl sulfide complex, 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 acidic reagents enhance the activity of the reducing agent. Examples of acidic reagents as described above include acetic acid, methanesulfonic acid, hydrochloric acid, etc. Examples of Lewis acidic reagents as described above include trimethoxyborane, triethoxyborane, aluminum chloride, lithium chloride, vanadium(III) chloride, bis(cyclopentadienyl)titanium dichloride, cesium fluoride, potassium fluoride, zinc(II) chloride, zinc(II) bromide, zinc(II) iodide, etc.

[0034] The term "removable protecting group" or "protecting group" refers to any group that binds to a functional moiety (e.g., the oxygen atom of a hydroxyl or carboxyl group, or the nitrogen atom of an amino group), prevents reactions from occurring with these functional groups, and can have the protecting group removed by conventional chemical steps or enzymatic steps to reconstruct the original functional group. The type of removable protecting group used is not important.

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

[0036] As used herein, the term "silylation" refers to the process of introducing a silyl or silicon-containing group. Silyl groups include, but are not limited to, tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyloxy-methyl (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] The general aspects of these example methods are shown in the schemes and examples. Each product used in the following processes is appropriately separated, isolated, and / or purified before use.

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

[0041] Generally, oxidation and reduction reactions are carried out at a temperature around room temperature (about 20 °C), although in metal hydride reductions the temperature often drops to 0 °C to -100 °C. Generally, the solvent is aprotic for reduction reactions and may be either protic or aprotic for oxidation reactions. The reaction time is adjusted to reach the desired conversion.

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

Chemical formula

Chemical formula

[0043] The details of each step of the production 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 methods described in the literature, the starting materials are preferably purified before the reaction. Compound 1 and 2 are reacted under basic conditions in a suitable solvent to form compound 3. Suitable bases include, for example, alkoxide bases having Li + , Na + , and K + as counter cations (e.g., methoxide, ethoxide, tert-butoxide, amylate, tert-amylate).

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

[0047] This reaction can be carried out at about -78 °C to about 0 °C. Preferably, the reaction is carried out at about -50 °C to about -20 °C.

[0048] Step 2

[0049] Compound 3 is then 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 (H 2 SO 4 ) and phosphoric acid (H 3 PO 4 ). Preferably, the acid is MSA.

[0050] This reaction can be carried out over a relatively wide range of temperatures. The reaction is generally carried out at a temperature of 0 °C to 80 °C. Preferably, the reaction is carried out at about 20 °C to about 65 °C.

[0051] Step 3

[0052] Compound 4 is then converted to the corresponding ester and ketal of Compound 4 using an alcoholic solvent, an acid catalyst, and optionally a desiccant in the presence of trialkyl orthoformate. In some embodiments, the alcoholic solvent is C 1-6 an alcoholic solvent (such as methanol, ethanol, propanol, butanol, pentanol, and hexanol). The acid catalyst can be selected from HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA), and when a desiccant is required, Na 2 SO 4 and MgSO 4 can be selected from, and the trialkyl orthoformate can be selected from, but 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 (such as toluene, NMP) that is stable under basic conditions. Suitable bases are hydroxides having Li + , Na + , K + , Cs + or NH 4 + as the counter cation. Examples of counter cation associated hydroxides include, but are not limited to, KOH, NaOH, and LiOH.

[0055] Step 5

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

[0057] Asymmetric auxiliaries include, but are not limited to, oxazolidinone, 8-phenylmenthol, trans-phenylcyclohexanone, camphorsultam, pseudoephedrine (R,R) or (S,S), or pseudoephenamide (R,R) or (S,S), alkylthiazolidine-2-thione derivatives or N-(-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)-N-phenylbenzenesulfonamide. In certain embodiments, the asymmetric auxiliary is

Chemical formula

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

[0059] Step 6

[0060] Compound 6a is alkylated using an alkylating agent and a strong base to obtain compound 6b. Examples of the activating agent include, but are not limited to, alkyl halides, dialkyl sulfates, trialkyloxonium tetrafluoroborates. Preferably, the alkylating agent is a methyl halide (such as MeI). Suitable bases are NaHMDS, LiHMDS, KHMDS, 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. Then, the asymmetric auxiliary is removed under basic conditions using a hydroxide base (such as LiOH, NaOH, and KOH) to obtain compound 7.

[0061] Step 7

[0062] In the desired solvent, compound 7 is isolated 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, LiOH. Suitable solvents are ether solvents (THF, 2-Me-THF, MTBE, CPME), aromatic solvents (toluene), ketone solvents (acetone, MIBK, MEK) or ester solvents (EtOAc, PrOAc), acetonitrile, and alcohol solvents (MeOH, EtOH, IPA). Alternatively, compound 7 may be isolated as the 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. A ligand (e.g., phosphine, i.e., CX-A, XPhos, SPhos, Xantphos, DCEPhos) or an N-heterocyclic carbene (i.e., IMes, Ipr) can assist this reaction. Suitable bases include organic bases (i.e., Et 3 N, DIPEA), inorganic bases (i.e., KOPiv, KOAc, K 2 CO 3 ), or bases derived from inorganic bases and carboxylic acids (i.e., K 2 CO 3 / PivOH, Cs 2 CO 3 / PivOH, K 2 CO 3 / PhCO 2 H). 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 or 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. Also, compound 9 can react with HSiCl 3 / DIPEA, SnCl 2 or Na 2 S 2 O 4 as well to give compound 10.

[0067] Step 10

[0068] Compound 10 is then macrocyclic lactamized 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 usually include ether solvents (THF, 2-Me-THF, MTBE, CPME) and aromatic solvents (toluene).

[0069] Step 11

[0070] In Step 11, the ketone group of compound 11 is deprotected under acidic aqueous solution conditions to obtain 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 obtain compound 13. This transformation is carried out using a reducing agent (e.g., BH 3 , NaBH 3It can be carried out in the presence of an amine donor (e.g., an ammonium salt such as ammonia or ammonium chloride), a hydrogen-substituted salt (e.g., ammonium formate, or hydrogen gas when Pd / C or Pt / C is used), using a catalyst (e.g., CN, Pd / C, Pt / C).

[0073] Furthermore, reductive amination can also be obtained in the presence of an amine donor (e.g., isopropylamine, alanine, 3-aminobutyric acid, and methylbenzylamine) and a cofactor (e.g., PLP) using an aminotransferase. In the latter case, the preferred solvent is an aqueous DMSO solution. Different recycling 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 aminotransferase used in the process of the present disclosure generally comprises an amino acid sequence that is 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 any 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 that differs by one or more amino acid residues as compared to a reference sequence (e.g., ATA-113, ATA-200, ATA-237, ATA-251, ATA-254, ATA-256, and ATA-260). In some embodiments, a polynucleotide capable of hybridizing under very stringent conditions encodes an aminotransferase polypeptide that is identical at the ratios described above as compared to a reference sequence (e.g., ATA-113, ATA-200, ATA-237, ATA-251, ATA-254, ATA-256, and ATA-260) and differs by one or more residues.

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

[0076] Also, suitable reaction conditions for this process generally include a cofactor in the reaction mixture. Aminotransferases generally use members of the vitamin B 6 family, so the reaction conditions include a cofactor selected from pyridoxal-5'-phosphate (also known as pyridoxal phosphate, PLP, P5P), pyridoxine (PN), pyridoxal (PL), pyridoxamine (PM), and their phosphates; pyridoxine phosphate (PNP), and pyridoxamine phosphate (PMP). In some embodiments, the suitable 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 finally couples with compound 14 to obtain compound (I) shown in WO 2015 / 116886.

[0079] In the above process, another step may be performed between steps 1 and 13. Further, in Schemes 1 and 2, different synthetic routes may also be used to produce important intermediates. Scheme 3 shows another method for producing a specific example of compound 7 (Scheme 1) as compound 21.

Chemical formula

[0080] In a suitable solvent (e.g., THF), compound 15 is reacted with a metal (e.g., Mg) and an initiator (e.g., I 2 ) in the presence of 3-chloro-1,1-dimethoxypropane, 3-bromo-1,1-dimethoxypropane or 3-iodo-1,1-dimethoxypropane to form compound 16. Subsequently, in the presence of water and a suitable solvent, an organic acid (e.g., TFA, MSA, BSA, PTSA, PPTS) or an inorganic acid (e.g., HCl, HBr) is used to obtain compound 17 by ketal hydrolysis. Then, the aldehyde of compound 17 is reacted with 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. Next, the ketone of compound 18 is protected using an alcoholic solvent (e.g., C 1-6 alcohol), and an acid as a catalyst (e.g., HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and optionally a drying agent (e.g., Na 2 SO 4 , MgSO 4 , trimethyl orthoformate (TMOF) or triethyl orthoformate (TEOF)) to convert it to the corresponding ketal compound 19. Then the ester is hydrolyzed under basic conditions in the presence of water to obtain compound 20. Suitable bases include hydroxides having Li + , Na + , K + , Cs + , NH 4 + as the counter cation. Finally, H 2Reduce the olefin of compound 20 in the presence of a metal catalyst 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 ene reductase enzyme and ester hydrolysis under basic conditions.

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

Chemical formula

[0082] Couple aldehyde 37 with triphenylphosphonium ylide (e.g., methyl 2-(triphenylphosphoranylidene)propanoate, or ethyl 2-(triphenylphosphoranylidene)propanoate) to form compound 38, or react with a phosphonate derivative (e.g., methyl 2-(diethoxyphosphoryl)propanoate or ethyl 2-(diethoxyphosphoryl)propanoate) in the presence of a base (e.g., NaH or KOtBu) in a suitable solvent to obtain compound 38. React the resulting bis-ester 38 with compound 2 having the structure of compound 2a in the presence of a base (e.g., LiHMDS, LDA, tBuOK) in a suitable solvent to obtain compound 39. Further decarboxylate this compound in the presence of an acid (e.g., HCl, MSA, H 3 PO 4 ) 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).

Chemical formula

[0084] A cyclopentane ester derivative is coupled with formaldehyde and a dialkylamine to form Compound 40. Further treatment under basic conditions gives Compound 41, a diacid derivative. After esterification to form Compound 42, it is coupled with Compound 2a and then acid-treated to give Compound 18b, an acrylic acid derivative. Next, the ketone of Compound 18b is protected using an alcoholic solvent (e.g., C 1-6 alcohol), an acid catalyst (e.g., HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and optionally a drying agent (e.g., Na 2 SO 4 MgSO 4 , trimethyl orthoformate (TMOF) or triethyl orthoformate (TEOF)) to obtain the corresponding ketal. Then the ester is hydrolyzed under basic conditions in the presence of water to give Compound 20b. Suitable bases include hydroxides or free carboxylic acids having Li + Na + K + Cs + NH 4 + as the counter cation. Finally, the olefin of Compound 20b is reduced using a metal catalyst in the presence of H 2 to give 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, the desired enantiomer may be obtained by treatment 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 in a suitable solvent under basic conditions to give Compound 23. Li + Na+ , K + Bases such as alkoxides (methoxide, ethoxide, tert-butoxide, amylate, tert-amylate) with K as the counter cation are suitable for solvents (e.g., ether solvents (THF, 2-MeTHF, MTBE, CPME), aromatic solvents (toluene) or dipolar aprotic solvents). Compound 24 is obtained by the retro-Claisen reaction of compound 23 under acidic conditions or in an acidic aqueous solution. Suitable acids include, but are not limited to, the following: H 2 SO 4 , MSA, BSA, nitric acid, TFA or perchloric acid.

[0087] Next, compound 24 is converted to the corresponding ester and ketal compound 25 using an alcohol solvent (C 1-6 alcohol), an acid catalyst (e.g., but not limited to, HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and optionally a drying agent (e.g., Na 2 SO 4 , MgSO 4 , and trialkyl orthoformate (e.g., trimethyl orthoformate (TMOF) or triethyl orthoformate (TEOF)).

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

Chemical formula

[0089] The racemic compound 25 is resolved using an enzyme. The unwanted enantiomer in the racemic mixture of compound 25 is hydrolyzed while leaving the desired enantiomeric compound 26 unreacted. Compound 26 is then hydrolyzed using 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 (enantiomeric excess > 90%).

[0090] In Method B, the racemic compound 25 is resolved using an enzyme. The desired enantiomer in the racemic mixture compound 25 is hydrolyzed while leaving the unwanted enantiomer in a somewhat unreacted state to obtain compound 27.

[0091] In Method C, the unreacted 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 the above Method A or Method B.

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

Chemical formula

[0093] Step 1

[0094] Compound 28 is coupled with a silyl-protected acetylene in a strong base and an appropriate solvent to obtain compound 29. The base may be a strong lithium base (such as an alkyl lithium base or an aryl lithium base). Examples of alkyl lithium bases and aryl lithium bases include, but are not limited to, methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, and phenyl lithium. The solvent may be an ether-based solvent (such as THF).

[0095] Step 2 Next, the ketone moiety is treated in an alcohol-based solvent (C 1-6 alcohol), and an acid catalyst (such as HCl, chlorotrimethylsilane (TMSCl), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (PTSA)), and optionally a drying agent (such as Na 2 SO 4 、MgSO 4) and protected as the corresponding ketal using trialkyl orthoformate (e.g., trimethyl orthoformate (TMOF) or triethyl orthoformate (TEOF)). The protected silyl group is then deprotected using a fluorine source (e.g., TBAF, HF·TEA, HF) in a suitable solvent (e.g., THF, 2-MeTHF) to obtain compound 30.

[0096] Step 3

[0097] The triple bond of compound 30 is then converted to the corresponding vinyl halide compound 31 in two steps using LiAl(OtBu) 3 H / Cp 2 ZrCl 2 followed by a halide donor (e.g., N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide).

[0098] Step 4

[0099] Compound 31 is then 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., PdCl 2 , Pd(OAc) 2 ), or coordinated metals (e.g., 1,1'-bis(di-tert-butylphosphino)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. A ligand (e.g., phosphine, i.e., CX-A, XPhos, SPhos, Xantphos, DCEPhos) or N-heterocyclic carbene (i.e., IMes, Ipr) can assist in this reaction. Suitable bases include organic bases (i.e., Et 3N, DIPEA), inorganic bases (i.e., KOPiv, KOAc, K 2 CO 3 ), or bases derived from inorganic bases and carboxylic acids (i.e., K 2 CO 3 / PivOH, Cs 2 CO 3 / PivOH, K 2 CO 3 / PhCO 2 H). 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).

[0102] Step 6

[0103] Compound 33 is then reduced under reducing conditions to reduce the double bond and nitro group, and then the methyl ester is hydrolyzed to obtain compound 10. The reduction is effective 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.

Chemical Structure

[0104] Step 1

[0105] Compound 45 can be synthesized from compound 43 and compound 44 under suitable Suzuki coupling conditions, e.g., in a suitable solvent (e.g., methanol, DMF, or acetonitrile) in the presence of an appropriate level of palladium catalyst (e.g., Pd(PPh 3 ) 4 , Pd(OAc) 2 or Pd(dppf)Cl 2 -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., TMSN 3 / tBuONO) to obtain the 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 the triazole compound 46.

[0108] Step 4

[0109] Compound 47 is obtained by reacting the 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 relates to formula (II):

Chemical formula

Chemical formula

[0113] In another embodiment, the present invention is

Chemical formula

[0114] In another embodiment, the present invention is

Chemical formula

[0115] In another embodiment, the present invention is

Chemical formula

[0116] In another embodiment, the present invention is of formula (III):

Chemical formula

[0117] In another embodiment, the present invention

Chemical formula

[0118] In another embodiment, the present invention is of formula (IV):

Chemical formula

[0119] In another embodiment, the present invention

Chemical formula

[0120] In another embodiment, the present invention is of formula (V):

Chemical formula

[0121] In another embodiment, the present invention is [Chemical formula] to provide a compound of.

[0122] In another embodiment, the present invention is a compound of formula (VI): [Chemical formula] [wherein, R 2 is C 1-3 alkyl; R 3 is OH, OC 1-6 alkyl, [Chemical formula] selected from; R 6 is C 1-3 alkyl, phenyl, and benzyl; R 7 is selected from H and phenyl; R 8 is C 1-3 alkyl, phenyl, and benzyl; and X is selected from F, Cl, Br and I] to provide a compound of.

[0123] In another embodiment, the present invention provides a compound having the following structure [Chemical formula] to provide a compound having. [Examples]

[0124] To make the present invention clearer, examples will be described below. All reactions were carried out under anhydrous conditions in a nitrogen atmosphere unless otherwise specified. The reagents were used as received from the selling company unless otherwise specified. The yields described are those of the isolated substances and no correction has been made for the water content. The reactions were carried out using CH as the mobile phase3 CN / H 2 O / MeOH (containing either 0.05% TFA or 0.1% NH 4 OAc) was monitored by a normal or reverse phase HPLC system (Shimadzu).

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

[0162] The abbreviations used in this specification are defined as follows. "1x" means once, "2x" means twice, "3x" means three times, "°C" 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 millimole, "min" means minute, "h" means hour, "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 enantiomeric 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 chromatograph mass spectrometer, "HPLC" means high performance liquid chromatography, "RP HPLC" means reverse phase HPLC, "TLC" or "tlc" means thin layer chromatography, "NMR" means nuclear magnetic resonance spectroscopy, "nOe" means nuclear Overhauser effect spectroscopy, " 1 "H" means proton, "δ" means delta, "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "br" means broad, "Hz" means Hertz, and "α", "β", "R", "S", "E", and "Z" are symbols used in stereochemistry well known to those skilled in the art. [Table 25] [Table 26] [Table 27]

[0163] The production of intermediate compounds 3a-Cl, 4a, 5a, 6a, 7a, 35, and 36 is described in Scheme 10 (an embodiment of the general Scheme 1 described above) and Examples 1-4. The embodiment of general Scheme 2 for forming compound (I) is described in Examples 5-12 below. [Chemical formula] Example 1 Synthesis of Compound 3a-Cl

Chem.

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

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

[0166] The reaction solution was maintained at -35 to -30 °C for 1 hour until the reaction was complete. To another 20 L reaction vessel, water (3635 mL) was added, followed by concentrated sulfuric acid (193.3 g, 0.69 equiv). The vessel temperature of the reaction vessel was set to 10 °C, and the reaction solution was cooled to 12 °C. The cooling solution in the aforementioned cold vessel (-35 to -30 °C) was added to a 20 L reaction vessel containing a cold H 2 SO 4 aqueous solution using a transfer tube while maintaining the temperature below 10 °C. After the transfer was complete, THF was distilled under vacuum at 20 - 25 °C until the volume reached ~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] 1 1H NMR (500 MHz, DMSO-d 6)δ 14.97 (broad singlet, 0.5H), 8.73 (triplet, J = 5.1Hz, 1H), 8.02 - 7.98 (doublet, J = 24.1Hz, 1H), 7.85 - 7.75 (doublet of doublets, J = 32, 5.1Hz, 1H), 4.70 (triplet, J = 9.5Hz, 0.5H), 2.93 (triplet, J = 7.2Hz, 1H), 2.61 - 2.53 (multiplet, 1H), 2.44 - 2.21 (multiplet, 2H), 2.08 (doublet of doublet of doublets, J = 12.3, 8.2, 4.0Hz, 1H), 2.01 - 1.81 (multiplet, 1H)

[0168] C 11 H 11 ClNO 2 + Calculated value of LRMS: [M + H] + 224.05, Observed value: 224.28

[0169] Example 2 Synthesis of Compound 4a To a 20 L cold vessel, 70 wt% MSA solution (1074 g, 7823 mmol, 2.83 eq) was added, followed by water (4900 mL). The reaction mixture was heated at 65 °C. Then, the wet cake of Compound 3a - Cl was added to the vessel and heated at 65 °C for 3 hours until the reaction was complete. The reaction solution was then cooled to 20 - 25 °C, and 28 wt% NH 4 OH aqueous solution (489 g, 3907 mmol, 1.41 eq) was added. It was adjusted to pH 5.06 using a pH probe. The resulting slurry was heated at 44 °C and held at 44 °C overnight. This reaction solution was cooled to 20 - 25 °C, the slurry was filtered, and the obtained cake was washed with water (3000 mL, 6V). The wet 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] 1 H NMR (500 MHz, DMSO - d 6): 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 ClNO 3 + Calculated value of LRMS: [M + H] + 242.06, Observed value: 242.24

[0172] Example 3 Synthesis of Compound 5a and 6 - Cl To a reaction vessel of TIFF2025084766000108.tif4316420L, MeOH (4L) and Compound 4a (367.3 g, 1500 mmol, 98.9 mass%) were added. Subsequently, 3L of MeOH was added. Then, trimethyl orthoformate (734 mL, 6700 mmol, 100 mass%, 4.5 eq) was added and rinsed with MeOH (400 mL). Chlorotrimethylsilane (367 mL, 2880 mmol, 100 mass%, 1.92 eq) was added, followed by MeOH (200 mL). The resulting reaction solution was heated at an internal temperature of 49 °C for 12 hours.

[0173] To another 20L reaction vessel, NaOH (10N, 1220 mL) was added, followed by H 2O (1620 mL) was added, and the resulting reaction solution was cooled to 0 °C. The reaction solution containing the above compound 5a was transferred to a reaction solution containing an aqueous NaOH solution. The internal temperature rose to 5 °C - 22 °C. The reaction vessel was rinsed with MeOH (700 mL), and the solution was transferred to a quenching vessel. The reaction solution was stirred for 4 hours. The vessel temperature of the reaction vessel was heated to 20 °C and stirred. MTBE (2570 mL) was then added. Stirring was stopped, and the aqueous layer with a large amount of product was collected and used next. 20 wt% 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 (400 MHz, DMSO-d 6 ) δ 11.98 (br s, 1H), (8.61 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 5.2, 2.1 Hz, 1H), 3.03 (s, 6H), 2.08 (t, J = 7.5 Hz, 2H), 2.02 (br d, J = 16.9 Hz, 2H), 1.42 - 1.30 (m, 2H), 0.90 - 0.78 (m, 2H)

[0175] C 12 H 15 ClNO 3 + Calculated value of LRMS: [M - CH 3 O] + 256.07, Observed value: 256.24 Example 4 Synthesis of compound 7a - DCHA

Chemical formula

[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, THF (880 mL) was added along with triethylamine (CAS: 121-44-8, 106.4 mL, 2.5 equivalents). This solution was cooled to 0 °C, and pivaloyl chloride (CAS: 3282-30-2, 44.13 g, 1.2 equivalents) was added dropwise from a dropping funnel at a rate such that the temperature 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 auxiliary (CAS: 102049-44-7, 64.86 g, 1.2 equivalents) was added all at once as a solid. The slurry was warmed to 20 °C over 3 hours and left overnight. The THF was then distilled under reduced pressure until the final volume reached 800 mL. Toluene (530 mL) was added, followed by saturated NH 4 Cl 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% NaHCO 3 (270 mL) and water (270 mL). After phase separation, the lower aqueous layer was removed. The organic layer was distilled until it reached 220 mL. Then anhydrous THF (1860 mL) was added. This solution was passed through a 0.45 micron polish and filtered.

[0177] The solution containing compound 35 was then cooled to -45 °C, methyl iodide (95.4 g, 2.2 equivalents) was added, and then 1N NaHMDS / THF (458 mL, 1.5 equivalents) was added 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 all at once with a solution of acetic acid (29.30 g, 1.6 equivalents) / anhydrous THF (88 mL). The organic reaction solution was washed with 14 wt% NaCl solution (530 mL), and then with 7.0 wt% NaHCO 3 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. 30 wt% H 2 O 2The solution (64.18 g, 1.82 equivalents) was then added, followed by the addition of lithium hydroxide solution (12.42 g / 110 mL of water) over 10 minutes. After reacting for 6 hours, 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. THF was then distilled off until ~700 mL remained and was recovered.

[0179] The pH was then adjusted to approximately 9.5 using NaOH (10 N). 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 NaHCO 3 (360 mL). The combined aqueous layers were returned to the reaction vessel and extracted with MTBE (720 mL). The organic layer was removed.

[0180] The product-rich aqueous layer containing 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 volumes) based on the amount of compound 7a added (corrected effective amount). The resulting solution was polished filtered. Dicyclohexylamine (up to 1.5 equivalents relative to compound 7a) was then added all at once. The slurry was heated at 55 °C and reacted for 30 minutes. The reaction solution was then cooled to 0 °C. The slurry was filtered using a Buchner funnel under N 2 protection, washed with cold MeCN (2.0 volumes) at 0 °C, dried in vacuo, and then dried in a vacuum oven at 50 °C for 24 hours. Compound 7a-DCHA was obtained as a white solid, 61 g (yield 88.2% in the salt formation step, 61.6% yield over 4 steps from compound 6a). Compound 7 is a 1:1.5 complex of compound 7:dicyclohexylamine.

[0182] 1 H NMR (400 MHz, MeOH-d 4): 8.52 (d, J = 5.3 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 5.3, 2.0 Hz, 1H), 3.16 (d, J = 3.0 Hz, 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 = 6.8 Hz, 3H), 0.97 - 0.87 (m, 2H)

[0183] C 13 H 17 ClNO 3 + Calculated value of LRMS: [M - CH 3 O] + 270.09, Observed value: 270.24 Example 5 Synthesis of Compound 9a

Chemical Structure

[0184] To a clean 2 L reaction vessel equipped with an overhead stirrer, a temperature probe, and a nitrogen inlet, 2-MeTHF (500 mL), catalyst [Pd(allyl)Cl] 2 (1.57 g, 0.05 equivalent) and Xphos (4.48 g, 0.055 equivalent) were added in sequence at 20 °C to obtain an almost homogeneous pale yellow solution. The salt of Compound 7a-DCHA (98.2 g, 1.0 equivalent) and the pyrrole compound 8 (32.3 g, 1.15 equivalents) were added little by little 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 bubbled with N 2 for 30 minutes. This solution was refluxed under N 2 for 10 hours to obtain a black suspension. The resulting crude product was cooled to 20 °C, and K 3 PO 4Quench between pH 10.0 - 10.5 using (550 mL, 20% aqueous solution), separate the aqueous layer, and wash the organic layer with K 3 PO 4 -K 2 HPO 4 buffer solution (800 mL, pH 10.2 aqueous solution). Combine the aqueous layers and filter to obtain a dark solution. To the aqueous solution, add 2-MeTHF (1300 mL) and activated carbon (13.9 g, Darco G-60), add citric acid (254 g, 3.4 equivalents) to the solution little by little over 30 minutes, and acidify to pH 5 - 6. Stir this suspension at 20 °C for 30 minutes. Filter the suspension, concentrate the organic layer under reduced pressure to 300 mL as it is, and exchange the solvent to nBuOH (1000 mL) under reduced pressure at 80 °C (150 mbar). Adjust the concentration of the resulting solution to 170 - 180 mg / mL (in a 500 mL solution, 2-MeTHF at 5 mass% or less). Cool this solution gradually to 0 °C over 10 hours and keep it at 0 °C for another 10 hours to obtain a white slurry. Filter the slurry with a Buchner funnel, wash the reaction vessel with nBuOH (100 mL), and obtain a cake from the resulting suspension. Wash the cake with heptane (100 mL) and dry it in an oven (vacuum, 50 °C for 24 hours). Isolated compound 9a (73.2 g, 95 mass%) was obtained in 83% yield.

[0185] 1 H NMR (400 MHz, DMSO-d 6 ): 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, 1.8 Hz, 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 (101 MHz, DMSO-d 6) 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 F 2 N 4 O 5 + : 397.36, 397.13 Example 6 Synthesis of Compound 10a

Chem.

[0187] To a pressure-resistant reaction vessel equipped with an overhead stirrer, a temperature probe, and a nitrogen inlet, THF (900 mL), Pd / C (4.6 g, 10 mass%, 0.1 eq), and Compound 9a (46.0 g, 1.0 eq) were sequentially added at 20 °C to obtain a suspension. The reaction vessel was purged with N 2 and H 2 three times each. Under H 2 (40 psi), the solution was vigorously stirred for 18 h. The resulting crude product was taken out of the reaction vessel and filtered through a Buchner funnel. The THF solution was concentrated until a clear oil was obtained, and Compound 10a (101 g, 40 mass%) was obtained in 95% yield. A small sample was taken, concentrated thoroughly, and used for spectral analysis.

[0188] 1 H NMR (500 MHz, CDCl 3): 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 F 2 N 4 O 4 + : 399.18 Example 7 Synthesis of Compound 11a-FUM

Chemical Structure

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

[0191] The solvent of the resulting reaction solution (~50 mL per 1 g of Compound 11a added) was exchanged from THF to MIBK (~20 mL). The organic layer was washed with K 2 HPO 4Washed with aqueous solution (15%, 15 mL), and then 1.2 equivalents of solid fumaric acid was added (relative to the amount (mol) of compound 11a added). Subsequently, the mixture was concentrated under reduced pressure to ~8 mL. A yellowish-brown slurry-like product was formed, which was filtered, and the cake was washed with MIBK (2 mL), then with heptane (2 mL), and dried in vacuo. Yield = 1.01 g (75.3% of the corrected effective amount of compound 11a added); effective amount = 74.2 wt%; ee = 97.3%

[0192] 1 H NMR (400 MHz, DMSO-d6) δ 13.31 - 13.02 (m, 1H), 9.30 (s, 1H), 8.76 (d, J = 5.1 Hz, 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 = 7.1 Hz, 4H), 0.46 (br s, 1H)

[0193] C 17 H 19 F 2 N 4 O 2 + Calculated value of LRMS: 349.15 [M - CH 3 O] + Observed value: 349.08 Example 8 Synthesis of Compound 12

Chemical Structure

[0194] To a slurry of Compound 11a-FUM (0.50 g, 67 mass%, 96% ee) in water (5 mL), cyclopentyl methyl ether (2.5 mL) was added, followed by trifluoroacetic acid (0.23 mL, 3.5 eq). The resulting mixture was heated at 45 °C for 5 h. The mixture was then cooled to ambient temperature and filtered. The reaction vessel was rinsed with water (2.5 mL), which was 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 solution. The pH of the combined aqueous solution was adjusted to 9 - 10 by adding solid K 3 PO 4 (~2 g). The resulting mixture was stirred for 2 h and filtered. The filtered cake was washed with water (5 mL x 2) and MTBE (5 mL x 2) and dried under reduced pressure to obtain Compound 12 (0.25 g, 78%, 97.2% ee).

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

[0196] LRMS [M + H] + C 16 H 17 F 2 N 4 O 2 + : 335.18 Example 9 Alternative Synthesis Method of Compound 12

Chemical Structure

[0197] To a pressure-resistant container (1 L), compound 9a (75.0 g, 169 mmol), THF (525 mL), and Pt / V / C (~50% wet, 10 wt%, 7.5 g) were added. The reaction vessel was purged with N 2 and H 2 three times each. Under H 2 (1.5 bar), the solution was vigorously stirred at 20 °C for 1 hour and heated at 40 °C for 16 hours. The mixture was removed from the reaction vessel, filtered, and the resulting solution was concentrated. After distilling THF, water was then distilled off azeotropically. To another reaction vessel, THF (1.2 L) was added, followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH, 70 g, 1.52 equiv) and N,N-diisopropylamine (103 mL, 3.5 equiv). 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 / h). The mixture was then concentrated, the solvent was exchanged to acetonitrile to obtain a solution of compound 11a / acetonitrile at about 4 L / kg. Then, aqueous hydrochloric acid (3 N, 23 mL) was added, and the resulting reaction mixture was heated at 55 °C for 15 hours to obtain crude compound 12. The reaction solution was cooled to 10 °C, dichloromethane (270 mL), water (540 mL), and hydrochloric acid (10.8 N, 71 mL) were added. After stirring for 1 hour, the layers were separated and the lower organic layer was removed. To the aqueous layer, potassium hydroxide (22.5 mass%, ~169 mL) was added at 10 °C to adjust the pH to 3.0. After stirring at pH 3 for 1 hour, further potassium hydroxide (22.5 mass%, ~17 mL) was added to adjust the reaction solution to pH 9.5. Compound 12 was isolated by filtration, washed with water (169 mL) and EtOH (114 mL), and then dried. Example 10 Synthesis of Compound 13

Chemical Structure

[0198] During a series of reactions, a reaction vessel (125 mL) equipped with a water circulator was used to keep the reaction temperature at 35 °C. When adding 4 M aqueous isopropylamine 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. 1 M aqueous isopropylamine hydrochloride 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 aqueous isopropylamine hydrochloride solution (4.0 mL) and added to the reaction vessel. Further, the vessel containing the enzyme was rinsed with 1 M aqueous isopropylamine hydrochloride solution (3.0 mL) and added to the same reaction vessel. A sample (20 μL) was taken out with a pipette, diluted with methanol (980 μL), stirred by vortexing, centrifuged at 14000 xg 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 (6 N HCl, 3.6 mL). A celite pad was created and the reaction mixture was filtered through celite. After filtration, the reaction vessel and the 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 10 N 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 and organic layers were separated (aqueous layer volume: 75 mL, organic layer volume: 125 mL).

[0200] The organic layers were collected and concentrated until the solvent became a viscous liquid of 40 g. The resulting residue solidified at 4 °C for 1 hour. The residue was suspended in MTBE (240 mL) and stirred vigorously. The precipitate was filtered off 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 out, 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 portions were combined and dried overnight in a vacuum oven at 35 °C. The desired compound 13 was isolated as an off-white solid (3.94 g, yield 78.8%, AP 99.3, ee>99.9%, active amount 97%).

[0201] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.76 - 8.62 (m, 1H), 7.94 (t, J H-F =57.8 Hz, 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 F 2 N 5 O + : 336.24 Example 11 Alternative synthesis method of compound 13

Chemical formula

[0203] To a reaction vessel (500 mL) containing water (139 mL), hydrochloric acid (12 N, 22.6 mL, 3.35 equivalents) was added at 25 °C over 90 minutes. Subsequently, isopropylamine (4.05 equivalents, 25.88 mL) was added until the pH reached 10.5. Compound 12 (25 g), pyridoxal-5'-phosphate (0.01 g / g, 0.25 g), and then 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 wt%, 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) [Chemical formula]

[0204] To a scintillation vial containing Compound 14 (0.019 g, 0.062 mmol), HATU (33.0 mg, 0.087 mmol) / anhydrous ACN (0.5 mL), DBU (15 μL, 0.100 mmol) was added. After 30 minutes, a solution of Compound 13 (0.021 g, 0.062 mmol) / CH 3 CN (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 the trifluoroacetate salt.

[0205] 1 H NMR (500 MHz, CD 3OD) 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 Cl 2 F 2 N 9 O 2 + : 626.09 Example 13 Production of Compound 21

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

Chemical Structure

[0208] Magnesium (8.73 g, 359 mmol, 1.35 equiv) and crystals of I 2 were added to a three - necked flask (1 L). Anhydrous THF (100 mL) was added under N 2It was added to the reaction flask below. The reaction temperature was monitored with a thermometer (J-CEM). 3-Bromo-1,1-dimethoxy-propane (65.8 g, 356 mmol, 1.35 equiv) was diluted with THF (150 mL) and added to a dropping funnel. A 3-bromo-1,1-dimethoxy-propane solution (20 mL) was added to the flask at 20 °C, and the whole pale brown suspension was vigorously stirred using a stir bar and rotation of magnesium pieces to proceed the reaction. After 30 minutes, the pale brown color disappeared and the solution temperature rose to 45 - 50 °C. The resulting reaction solution was then maintained at a temperature of 55 - 62 °C, and the 3-bromo-1,1-dimethoxy-propane solution was slowly added from the dropping funnel. After 1.5 hours, the addition was complete, and the whole solution was further held at 60 °C for 2 hours. The solution was placed in a water bath and cooled to 25 °C. 4-Chloro-N-methoxy-N-methyl-pyridine-2-carboxamide; Compound 15 (53.3 g, 264 mmol, 1.0 equiv) / THF (150 mL) was added to a dropping funnel. The substrate of the solution was added to the Grignard solution within 20 minutes to obtain a red-yellow solution. The internal temperature was kept at 35 °C or below at most. After 15 minutes, the completion of the reaction was indicated by both HPLC and TLC. Water (20 mL) was slowly added to the crude mixture, and a brown gel-like solid precipitated. All of the crude product was filtered through celite and washed twice with THF (total 100 mL). The resulting crude solution was dried over Na 2 SO 4 . The resulting crude product was concentrated in vacuo at 30 - 35 °C to obtain Compound 16 as a yellow oil.

[0209] Note: The resulting crude product could be used in the next reaction without purification. Spectral analysis: The resulting crude product was then purified with an ISCO purification system (hexane / EA 1:0 - 10:1) to obtain the desired product.

[0210] 1 H NMR (500 MHz, CDCl 3)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 ClNO 2 + : 212.05, 212.10 b) Synthesis of Compound 18-Et

Chemical Structure

[0212] In a round-bottom flask (250 mL), Compound 16 (7.61 g, 38.5 mmol, 1 equiv) was diluted with water (20 mL) and THF (80 mL) at 20 °C. To this solution, trifluoroacetic acid (8.5 mL, 110 mmol, 2.7 equiv) was added at room temperature. The solution was immediately heated to 50 °C. After 4 hours, the solution turned dark brown, and the completion of the reaction was indicated by HPLC and TLC. Further water (60 mL) was added to the flask. To the resulting crude product, sodium bicarbonate (9.6 g, 114 mmol, 2.8 equiv) was slowly added at 25 °C to neutralize the solvent to pH 7. The crude material was extracted three times with EtOAc (100 mL), and the combined organic crude extracts were washed once with brine (50 mL) and dried over Na 2 SO 4 and concentrated to a dark oil, which was used directly in the next step. To the resulting crude product, CH 2 Cl 2 ​(75 mL) was added. Ethyl 2-(triphenylphosphoranylidene)propionate (14.2 g, 38.2 mmol, 0.93 eq) was added all at once to the solution containing Compound 17. The reaction mixture was maintained at 20 °C for 8 h. The resulting crude product was concentrated to dryness, diluted with hexane:EtOAc (1:1), the precipitated solid was filtered, and washed twice with MTBE (20 mL). The combined crude products were concentrated until they became a black oil, and purified by an ISCO purification system (200 g silica gel) (hexane / EA 1:0 to 5:1) to obtain the desired Compound 18-Et (8.21 g, 70.3%) as a yellow oil.

[0213] 1 H NMR (500 MHz, 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 ClNO 3 + : 282.09, 282.21 c) Synthesis of Compound 19-Et

Chemical Structure

[0215] To Compound 18-Et (9.55 g, 33.9 mmol, 1.0 eq) were added p-toluenesulfonic acid (2.35 g, 13.5 mmol, 0.40 eq), trimethyl orthoformate (24 mL, 220 mmol, 6.4 eq) and methanol (95 mL) at 20 °C. The solution was refluxed for 60 h. The resulting crude product was cooled to 0 °C, sodium hydroxide (1.7 mL, 17 mmol, 0.5 eq) was added, and the solvent was neutralized to pH 7. The crude product was concentrated until it became a viscous oil and diluted with MTBE (200 mL). The crude product was washed once with water and brine. The crude product was Na 2 SO​4 It was dried and filtered with . This was filtered and purified with ISCO (80 g silica gel) (hexane / EA 1:0 to 4:1) to obtain Compound 19-Et (8.1 g, 73% yield) and ethyl (E)-6-(4-chloro-2-pyridyl)-2-methyl-6-oxo-hex-2-enoate (1.2 g, 13%).

[0216] 1 H NMR (500 MHz, CDCl 3 ) δ 8.50 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 0.8 Hz, 1H), 7.17 (dd, J = 0.8 and 4.0 Hz 1H), 6.45 (dt, J = 8.0 and 0.4 Hz, 1H), 4.06 (q, J = 7.8 Hz, 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 = 7.8 Hz, 3H)

[0217] LRMS [C 16 H 22 ClNO 4 -OCH 3 + : 297.11, 297.10 d) Synthesis of Compound 20

Chemical formula

[0218] The pale yellow oily Compound 19-Et (1.14 g, 3.48 mmol, 1.0 equivalent) was diluted with ethanol (10 mL) at 20 °C. To this solution, sodium hydroxide (2 moL / L) / water (2 mL, 4 mmol, 1.1 equivalent) was added at room temperature. The solution was heated at 60 °C for 12 hours. HCl (1 moL / L, 4 mL) was added to the obtained crude product, and it was concentrated until the whole crude product became a white paste. Then, saturated NH 4 Cl 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 Na 2 SO 4It was dried, filtered, concentrated to obtain a pink crude product. The obtained crude product was filtered and purified with ISCO (8 g silica) (hexane / EA 1:0 to 2:1) to obtain Compound 20 as white crystals (1.05 g, 100%).

[0219] 1 H NMR (500 MHz, CDCl 3 ) 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 ClNO 4 -OCH 3 + : 268.08, 268.18 e) Synthesis of Compound 21

Chemical Structure

[0221] Both Compound 20 (632 mg, 2.11 mmol, 1.0 equivalent) and the pressure - resistant reaction vessel were placed in the glove box. In the glove box, the catalyst: diacetato[(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) (95 mg, 0.109 mmol, 5.2 mmol%) and methanol (5 mL) were subsequently added. The vial was placed in the reaction vessel and sealed. The reaction vessel was set on the hydrogenation apparatus and purged with hydrogen several times. The reaction solution was set at 150 psi of H 2 at room temperature. After 12 hours, when the reaction solution was taken out of the reaction vessel, the solution had turned dark red. TLC and LCMS indicated the completion of the reaction. After concentrating the obtained crude product, the crude product was purified with ISCO (silica, 8 g) (hexane / EA 1:0 to 1:1) to obtain the desired product, Compound 21, as a brown solid (0.63 g, 99%). It was confirmed by chiral HPLC that the desired product had 92 ee.​

[0222] 1 H NMR (500 MHz, CDCl 3 ) δ 8.59 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 5.2 and 1.8 Hz, 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 = 7.0 Hz, 3H), 0.98 - 0.90 (m, 1H)

[0223] LRMS [C 14 H 20 ClNO 4 -OCH 3 + : 270.18, 270.19 Example 14

Chem.

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

[0225] 1 H NMR (CDCl 3 , 400 MHz): δ 6.69 ppm, (1H, m); 3.72 ppm (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 (3 g) and compound 2a (3.4 g) were dissolved in THF (30 mL), and the reaction mixture was cooled to -10 °C. Then LiHMDS (29 mL, 2.207 eq) was added dropwise. After complete conversion, the resulting reaction mixture was quenched with saturated NH 4 Cl (150 mL) and further extracted with EtOAc (250 mL × 2). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The resulting crude compound 39a (11 g) was dissolved in ACN (220 mL), water (110 mL), and methanesulfonic acid (100.5 g, 34.967 eq). The reaction solution was heated at 65 °C until complete conversion. After cooling to room temperature, the pH was adjusted to 5 - 7 with concentrated NaOH solution. The organic layer was extracted with EtOAc (500 mL × 2), dried over Na 2 SO 4 , filtered, and compound 18a (10.8 g) was obtained.

[0227] The obtained compound 18a was dissolved in TMSCl (24.4 g, 4.928 eq), trimethyl orthoformate (339 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 NaHCO 3 solution (200 mL). The aqueous layer was extracted with DCM (3 × 400 mL), dried over Na 2 SO 4 , filtered, and removed under reduced pressure. The resulting residue was purified by column silica gel chromatography (petroleum ether / EtOAc 50:1 - 3:1) to obtain compound 19a (10.4 g). 1 1H NMR (CDCl 3 , 400 MHz): δ 8.56 ppm (1H, d, J = 8 Hz), 7.70 ppm (1H, s), 7.24 ppm (1H, dd, J = 4 Hz, 8 Hz), 6.52 ppm (1H, t, J = 4 Hz), 3.68 ppm (3H, s), 3.18 ppm (6H, s), 3.24 - 3.20 (2H, m), 1.86 - 1.83 (2H, m) Example 15 [Chemistry]

[0228] Paraformaldehyde (1.44 g, 1.5 eq) was charged into the reaction vessel under nitrogen, followed by MeOH (25 mL, 5 vol), ethyl 2-oxocyclopentane-1-carboxylate (5 g, 1 eq) and finally diethylamine (7.02 mL, 2.1 eq). The reaction mixture was stirred at 20 - 25 °C for at least 3.5 h. After complete conversion, sodium hydroxide (6 M, 26.6 mL, 5 eq) was added and stirred at 20 - 25 °C for at least 2 h until complete conversion. MeOH was distilled off under vacuum. Then MTBE (25 mL, 5 vol) was added to the reaction mixture and stirred for 10 min. The layers were allowed to stand, and the upper organic layer was taken out and removed. Aqueous HCl solution (6 M) was added to the lower aqueous layer until pH 2 was reached. EtOAc (25 mL, 5 vol) was added and this reaction mixture was stirred for at least 10 min. After phase separation, it was washed with water. The organic layer was concentrated to dryness to obtain Compound 41a. This was directly dissolved in iPrOH (50 mL, 10 vol) and H 2 SO 4 (1 eq) at room temperature and stirred for 72 h. The pH of the resulting reaction mixture was adjusted to 7.3 with 20% K 2 HPO 4 aqueous solution. After phase separation, the iPrOH layer was diluted with 20% K 2 HPO 4 aqueous solution (10 vol) and washed with toluene. Finally, the pH of the aqueous layer was adjusted to 4.7 with H 2 SO 4 (2 M). The desired Compound 42a was extracted with toluene and isolated after removing the solvent under reduced pressure.

[0229] 1 H NMR (400 MHz, CDCl 3 ): δ 6.33 ppm (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 = 4 Hz)

[0230] Methyl 4-chloropicolinate (0.86 g, 1 equivalent) was charged into a three-necked flask purged with nitrogen 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 while 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 while maintaining the temperature below -10 °C, and the resulting reaction mixture was warmed to room temperature. EtOAc (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 to pH 4. Compound 18b was recovered as a solid and dried.

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

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

[0233] 1 1H NMR (500 MHz, CDCl 3 ): δ 8.6 ppm (1H), 7.8 ppm (1H), 7.6 ppm (1H), 7.2 ppm (1H), 5.5 ppm (1H), 3.2 ppm (6H), 2.2 ppm (2H), 2.1 ppm (2H), 1.1 ppm (2H)

[0234] To a 5 mL vial containing a stir bar, [RuCl(p-cymene)((R)-H8-binap)]Cl (0.0003 mmol) in DCM stock solution (100 μL) was added. Next, compound 19b (0.075 mmol) was added as a stock solution (1 mL) of MeOH / DCM = 3 / 1, followed by TEA (0.375 mmol). The vial was capped and transferred to a B48 parallel reaction vessel. This reaction was carried out at 25 °C overnight (about 16 hours) under a H 2 atmosphere (40 bar). The resulting reaction solution was analyzed by HPLC to obtain the desired compound 21. Example 16 Crystallization of Compound 21

Chemical Structure

[0235] The 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, a seed crystal of this reaction mixture was added, and the mixture was stirred for 2 - 4 hours and 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 Enzyme a) Synthesis of Compounds 24a and 25a

Chemical Structure

[0236] A mixture 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) / a slurry of THF (1500 mL, 18400 mmol, 100% by mass) was added dropwise with potassium tert-butoxide (1 mol / L) / THF (1200 g, 1330 mmol, 1 mol / L) at -30 °C. The resulting yellow slurry was stirred for 1 hour between -24 and 30 °C. In another 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) were added and pre-cooled to 0 °C. The yellow slurry containing Compound 23a-Cl was poured into the cooled acidic solution to obtain a slurry. The external temperature was set to 45 °C, and THF was distilled at 15 °C under vacuum at 115 mbar. 500 mL of water was added to the slurry (~1 liter). The precipitated solid was recovered and the aqueous solution was removed. The recovered solid was returned to the reaction vessel together with MSA (320 mL) and water (1 L). The slurry was heated at 65 °C, and after 60 minutes, all the solid dissolved. The dark solution was kept at 65 °C for 3 hours and cooled from room temperature to 0 °C. A slurry was formed and filtered. Compound 24a was recovered and dried at room temperature to obtain a total of 139.8 g of a beige solid. The filtrate was returned to the reaction vessel and the pH was adjusted to 5.1 with 28% by mass NH 4 OH. Solid formed during pH adjustment and was filtered at room temperature. An additional 41 g of Compound 24a was obtained as an off-white solid.

[0237] 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.07 (1H, s), 8.70 (d, J = 5.31 Hz, 1H), 7.94 (dd, J = 7.94, 1.77 Hz, 1H), 7.82 (dd, J = 5.18, 2.15 Hz, 1H), 3.15 (m, 2H), 2.35 (m, 1H), 1.60 (m, 3H), 1.42 (m, 1H), 1.05 (d, J = 6.82 Hz, 3H)

[0238] LRMS [C 12 H14 ClNO 3 +H] + : 258.24, 256.25

[0239] Subsequently, 178.27 g of Compound 24a was added to a 2 L reaction vessel, followed by the addition of MeOH (3.4 L), TMOF (380 mL), and TMSCl (210 mL). The external temperature was set to 57 °C, and the mixture was heated at 49 °C. After 4 hours at 50 °C, the dark-colored solution was cooled to 10 °C and then added to saturated NaHCO 3 (2.6 L) in a 20 L reaction vessel. The total volume was 6.5 L.

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

[0241] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.60 (d, J = 5.05 Hz, 1H), 7.60 (d, J = 1.77 Hz, 1H), 7.52 (dd, J = 5.31, 2.02 Hz, 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 = 7.07 Hz, 3H), 0.79 (m, 2H)

[0242] LRMS [C 15 H 22 ClNO 4 -OCH 3 + : 284.76

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

[0244] To a reaction mixture containing MSA (7.60 kg, 79.08 mol), H 2 O (90.00 g, 90 mL) and ACN (29.25 kg, 37 L), Compound 23 (7.60 kg, collect assay = 7.50 g, 32.37 mmol) was added. The resulting reaction mixture was heated to 68 °C and stirred for 5 hours. The reaction mixture was cooled to 20 °C, then 25% ammonia solution (5.50 kg) was added little by little and stirred for 1 hour. 2.5% ammonia solution (1.50 g) was added little by little to the reaction mixture 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] In MeOH (370 L), Compound 24a (37.0 kg) was mixed with 3.0 eq of CH(OMe) 3 and 2.0 eq of TMSCl. After the mixture was stirred at 30 - 35 °C for 24 hours, the resulting reaction mixture was cooled to 20 - 25 °C and quenched with 2.2 eq of TEA at 20 - 30 °C. Then, the reaction mixture was concentrated to 100 L under vacuum at 40 °C or lower. MTBE (370 L) and H 2O(300L) was added to the residue. After phase separation, the organic layer was recovered and washed with H 2 O(200L). The organic layer was concentrated to 70L under vacuum at 40 °C or lower. Then DMSO (1V) was added to the residue, and the mixture was concentrated to 70L under vacuum at 40 °C or lower to obtain a concentrated DMSO solution (86.4 kg) of compound 25a. b) Enzymatic resolution of dimethoxymethyl ester:

Chemical formula

[0246] During a series of reactions, a reaction vessel (250 mL) equipped with a water circulator was used to keep the reaction temperature at 35 °C. The pH was maintained at 7.0 using a calibrated pH meter. To a 250 mL reaction vessel were added compound 25a (5.0 g), DMSO (4.0 mL, 2%) and sodium phosphate buffer (180 mL, 0.1 M, pH 7.0). The reaction solution was kept at pH 7.0 using 5N sodium hydroxide continuously. Lipase MH Amano 10 SD (1.0 g) was dissolved in the above buffer (10 mL) and added to the reaction vessel. The vessel containing the enzyme was rinsed with buffer (6.0 mL) and added to the same reaction vessel. A sample (80 μL) was pipetted out, diluted with methanol (1.920 mL), stirred by vortexing, 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 solution 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 brine (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 in a vacuum oven overnight. Compound 26a (1.88 g) was isolated as a light brown liquid (yield 37.6%, ee 98.7%).

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

[0248] LRMS [C 15 H 22 ClNO 4 -OCH 3 + : 284.2 / 286.1 c) Hydrolysis of Compound 26a to Obtain Compound 27a:

[0249] To a reaction vial were added Compound 26a (1.0 g), methanol (20 mL), water (5.0 mL), and 10 N sodium hydroxide (500 μL, 0.2 g). The reaction solution 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. The reaction mixture was concentrated until it became an oily substance 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 6 N HCl (850 μL). The aqueous layer was extracted with MTBE (2 x 50 mL), and the MTBE solution was washed with brine (25 mL) and water (2 x 25 mL). The MTBE solution was dried over anhydrous sodium sulfate, filtered, the solvent was removed, and the resulting residue was dried in a vacuum oven overnight. Compound 27a was isolated as a viscous yellow liquid (940 mg, yield 98.3%, AP 97 and ee 98%).

[0250] 1 ​1H NMR (400 MHz, DMSO-d 6 ) δ 11.96 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 5.2, 2.1 Hz, 1H), 3.04 (s, 3H), 3.01 (s, 3H), 2.18 (sxt, J = 6.9 Hz, 1H), 2.00 (dd, J = 10.6, 5.8 Hz, 2H), 1.47 - 1.33 (m, 1H), 1.26 - 1.13 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.87 - 0.75 (m, 2H)

[0251] LRMS [C 14 H 20 ClNO 4 - : 300.1 Alternative method of enzymatic resolution

Chemical formula

[0252] Ca(OAc) 2 (50 mM) was added to 0.1 M Tris buffer (13.5 L), and the mixture 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 above mixture at 38 - 42 °C all at once. 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 post-treatment, ACN (9 L) was added to the reaction mixture at 0 - 10 °C. Then the pH was adjusted with 20% K 2 CO 3 ​It was adjusted to 10.0, 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 washed with MTBE (3 L) and water (3 L). The filtrate was collected, MTBE (15 L) was added to the mixture, and the phases were separated. The organic layer was 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, and the phases were separated. Then the aqueous layer was adjusted to pH 5.5 with 20% citric acid, and phase separation was carried out again using MTBE (15 L). The organic layers were combined and washed with process water (15 L). The organic layer was recovered, filtered, and the aqueous layer was removed. Then the organic layer was concentrated to 4.5 L. It was subjected to azeotropic distillation twice using 15 L of MTBE to make it 4.5 L. 7.5 L of MTBE and 3 L of ACN were added to the obtained residue to form a salt. In salt formation, the mixture was heated at 50 - 55 °C, and DCHA (0.75 equivalent) 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% of 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 continuously cooled at 10 °C / hour. After holding at 0 - 5 °C for 10 hours, the mixture was filtered. The cake was washed 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 isolated yield 43.61%). Example 18 Synthesis of Compound 10

Chemical Structure

[0253] A solution of (triisopropylsilyl)acetylene (10.5 g, 57.6 mmol, 100% by mass) in THF (60 mL) was slowly added with n-butyllithium (2.5 mol / L) / hexane (22 mL, 55.0 mmol, 2.50 mol / L) 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) in THF (35 mL) was then added at 21 °C. After 1 hour, HPLC analysis showed that 8% of the amide starting material remained. Lithium bis(trimethylsilyl)amide (1 M, THF solution, 8 mL) was then added. After 1 hour, HPLC analysis indicated the completion of the reaction. The mixture was cooled to 0 - 5 °C and added to a mixture of 15% aqueous citric acid (500 g) and heptane (0.6 L) at 5 - 15 °C. The organic layer was washed with 3% aqueous citric acid (200 mL) and water (0.2 L), and dried over MgSO 4 and concentrated to give compound 29a (15.8 g) as an orange oil (98.5% yield).

[0254] 1 H NMR (500 MHz, CDCl 3 ): δ 8.68 (1H, d, J = 4.5 Hz), 8.15 (1H, s), 7.50 (1H, d, J = 4.5 Hz), 1.25 - 1.05 (21H, 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) in MeOH (20 mL) were added trimethyl orthoformate (2.0 mL, 18 mmol) and then chlorotrimethylsilane (3.0 mL, 24 mmol) at 21 °C. The mixture was then heated at 60 °C. After 1 hour, HPLC analysis showed that the starting material had been consumed. The mixture was cooled to 21 °C, and hexane (200 mL), NaHCO 3 (15 g), and Na 2CO 3 It was added to a mixed solution of (5 g) / water (200 mL). The separated organic layer was then dried over MgSO 4 and concentrated to obtain [3-(4-chloro-2-pyridyl)-3,3-dimethoxy-prop-1-ynyl]-triisopropyl-silane (3.45 g, 9.38 mmol, 100% yield) as an orange oil. The obtained crude intermediate was used for the subsequent deprotection of TIPS without further purification.

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

[0258] 1 H NMR (500 MHz, CDCl 3 ): δ 8.61 (1H, d, J = 5.0 Hz), 7.75 (1H, s), 7.32 (1H, d, J = 5.0 Hz), 3.37 (6H, s), 2.74 (1H, s)

[0259] LRMS [C 10 H 10 ClNO 2 -OCH 3 + : 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) in 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 hour. The mixture of dark brown solution was then cooled to 0 - 5 °C, and NBS (11 g, 61.8 mmol, 100% by mass) was added in two portions as a solid (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 EtOAc / heptane (180 mL / 60 mL) and 15% NH 4 Cl aqueous solution (250 mL). The resulting slurry was filtered through celite, and the filtration line was rinsed with EtOAc (30 mL x 2). The aqueous layer was removed from the combined filtrate. The obtained organic layer was washed with 5% K 2 HPO 4 aqueous solution, dried over MgSO 4 and concentrated. This residue was purified by column chromatography (0 - 30% EtOAc / heptane; product Rf 0.4 in 30% EtOAc / heptane) to obtain Compound 31a (13.2 g, 45.1 mmol, 76.4% yield) as a gray solid.

[0262] 1 H NMR (500 MHz, CDCl 3 ): δ 8.57 (1H, d, J = 5.2 Hz), 7.67 (1H, s), 7.26 (1H, d, J = 5.2 Hz), 6.78 (1H, d, J = 13.5 Hz), 6.11 (1H, d, J = 13.5 Hz), 3.24 (6H, s)

[0263] LRMS [C 10 H 11 BrClNO2 -OCH 3 -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) in THF (50 mL) was added (S)-(-)-3-methoxy-2-methyl-3-oxopropylzinc bromide (0.5 moL / L) / THF (94 mL, 47 mmol, 0.50 M) at 5 - 10 °C. The mixture was degassed by N 2 bubbling for 3 minutes, and then 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (0.68 g, 1.03 mmol, 100% by mass) was added at 5 - 10 °C. The resulting mixture was degassed by N 2 bubbling for 5 minutes. After holding at 5 °C for 15 minutes, the dark solution was warmed to 21 °C. After 16 hours, TBME (150 mL) was added to the reaction mixture, followed by addition of an aqueous NH 4 Cl solution (25%, 200 g). The dark organic layer was dried over MgSO 4 and concentrated. The resulting residue was purified by column chromatography (5 - 60% EtOAc / heptane; Rf 0.28 in 1:1 EtOAc / 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 (500 MHz, CDCl 3 ): δ 8.54 (1H, d, J = 5.2 Hz), 7.65 (1H, s), 7.22 (1H, d, J = 5.2 Hz), 5.98 (1H, dt, J = 15.6, 7.3 Hz), 5.45 (1H, d, J = 15.6 Hz), 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 = 7.0 Hz)

[0266] LRMS [C 15 H20 ClNO 4 -OCH 3 + : 282.19 / 284.23 e) Synthesis of Compound 33a

[0267] In the preparation of the catalyst, palladium diacetate (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 N 2 bubbling for 0.5 h. 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 in dioxane (60 mL), and the resulting mixture was degassed by N 2 bubbling for 0.5 h. The above-prepared and degassed catalyst was then transferred to the mixture containing the substrate. The resulting mixture was degassed by N 2 bubbling for 0.5 h, then heated at 90 °C, held at the same temperature for 3 h, and then cooled to 21 °C. The resulting mixture was filtered, and the filtration line was rinsed with TBME (25 mL). The combined filtrates were concentrated. The resulting residue was purified by column chromatography (Rf = 0.36 in 60% EtOAc / heptane; 10 - 80% EtOAc / heptane) to obtain Compound 33a (7.6 g, 16 mmol, 98% by mass, 86% yield) as a brown oil.

[0268] 1 H NMR (500 MHz, CDCl 3 ​): 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 F 2 N 4 O 6 -OCH 3 + : 409.18 f) Synthesis of Compound 10a

[0270] A solution of Compound 33 (6.3 g, 14 mmol) in MeOH (50 mL) and a stir bar were added to a 100 mL pressure flask. The vessel was degassed under vacuum and filled with N 2 six times. Then, 1.35 g (0.634 mmol, 5 wt%) of Pd / C (10 wt%, 50% wet) was added. The vessel was degassed with N 2 , then with H 2 . The hydrogen gas pressure was set to 80 psi and the reaction temperature to 55 °C. After maintaining the pressure and temperature for 12 h, the mixture was filtered and the filter 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 at 40 °C and held at the same temperature for 6 h. The mixture was then cooled to 21 °C. 2-MeTHF (100 mL) was added. The pH of the mixture was adjusted to pH ~ 6 by adding 85% H 3 PO 4 . The aqueous layer was removed and the organic layer was dried over MgSO 4 ​It was dried 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 foamy solid.

[0271] 1 H NMR (500 MHz, CDCl 3 ): 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 = 59.1 Hz), 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 F 2 N 4 O 4 +H] + : 399.18 Example 19 Synthesis of Compound 14

Chemical Structure

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

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

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

[0276] General results: Yield 90 - 95%, purity 98a% Azidation / click reaction

[0277] A MeTHF solution of Compound 45 (100 g in 1.5 L of MeTHF), MeTHF (1.5 L, 15 L / kg), and MeCN (1 L, 10 L / kg) were added to a 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 in 1 L of water) was slowly added to the above mixture. This was then warmed to 20 - 30 °C, stirred for 20 - 30 minutes, and left standing 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 in 1 L of water) was slowly added to the above mixture. This was then stirred for 20 - 30 minutes and left standing 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 in 1 L of water) was slowly added to the above mixture. This was then stirred for 20 - 30 minutes and left standing 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 in 1 L of water) was slowly added to the above mixture. This was then stirred for 20 - 30 minutes and left standing 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 (remaining N 3(<3 ppm). An aqueous sodium sulfate solution (100 g / 1 L of water) was then 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 (100 g / 1 L of water) was added to the above mixture. Then this was 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 (100 g / 1 L of 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 (100 g / 1 L of 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, triethylamine (95.0 g, 2.2 equivalents) was slowly added to the reaction mixture while maintaining the temperature at 5 - 15 °C. Trimethylsilylacetylene (50.0 g, 1.2 equivalents) was slowly added to the reaction mixture while maintaining the temperature at 5 - 15 °C, and the reaction vessel was purged with nitrogen until the oxygen level in the reaction vessel was 0.1% or less. Copper iodide (8.0 g, 10 mol%) was charged into the reaction vessel, and then this was 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 completion of the reaction, the reaction mixture was warmed to 20 - 30 °C, and sodium 1,3,5-triazine-2,4,6(1H,3H,5H)-trithionate (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 washed with MeTHF (250 mL, 2.5 L / kg). An aqueous ammonia solution (100 g / 1 L of water) was added to the reaction vessel, which was then stirred at 20 - 30 °C for 20 - 30 minutes and left to stand at 20 - 30 °C for 30 - 60 minutes. After phase separation, an aqueous sodium sulfate solution (100 g / 1 L of water) was added to the reaction vessel, which was then stirred at 20 - 30 °C for 20 - 30 minutes and left to stand at 20 - 30 °C for 30 - 60 minutes. After phase separation, the upper layer was filtered through celite (30 g, 0.3 kg / kg). After washing the celite cake with MeTHF (0.5 L, 5 L / kg), the mixture was concentrated under reduced pressure at 45 °C to 500 - 700 mL (5 - 7 L / kg).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. 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. This reaction mixture was then heated to 55 - 60 °C and stirring was continued 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] General results: Yield 85 - 90%, Purity 98a%, 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). While adding 1,3 - dichloro - 5,5 - dimethylhydantoin (DCDMH, 13.7 g, 0.75 equivalent) little by little, the internal temperature was maintained below 5 °C. The internal temperature was then adjusted to 0 - 10 °C and the mixture was stirred at the same temperature for 5 - 12 hours. After completion of the reaction, water (70 mL, 0.7 L / kg) was added to the resulting reaction mixture over 0.5 - 1.5 hours. During this time, the internal temperature was maintained below 15 °C. A seed crystal of Compound 47 (0.1 g, 0.001 kg / kg) was added to the resulting reaction mixture, which was then aged at 0 - 10 °C for 1 - 2 hours. Water (530 mL, L / kg) was added at 0 - 10 °C over 3 - 8 hours, and the slurry was aged at 0 - 10 °C for 4 - 6 hours. This mixture was filtered and the cake was washed with cold water (0.5 L, 0 - 10 °C). The obtained crude Compound 47 was dried under reduced pressure at 40 - 50 °C for 8 - 15 hours.

[0280] General results: Yield 90 - 95%, Purity 98a%, Assay > 95% Recrystallization of Compound 47

[0281] To the reaction vessel, crude compound 47 (100 g, 1.0 equivalent) and DCM (0.5 L, 5 L / kg) were added, and the resulting solution was stirred at 20 - 30 °C for 0.5 - 2 hours. The obtained mixture was filtered through a filter cartridge filled with carbon, 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 further aged at 0 - 10 °C for 0.5 - 2 hours. n - Heptane (1.6 L, 16 L / kg) was then charged into the reaction vessel over 1 - 3 hours at 0 - 10 °C, 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] General results: Yield 90 - 95%, purity > 99.5a%, assay > 95% Demethylation

[0283] To the reaction vessel, pure compound 47 (100 g, 1.0 equivalent) and aqueous HCl solution (35 w / w%, 320 g, 10 equivalents) were added. The reaction vessel was heated to 40 - 50 °C for 1 - 3 hours and stirred at the same temperature for 10 - 18 hours. After completion of the reaction, aqueous ammonia solution (50 g / 500 mL) was added dropwise to the reaction vessel at 40 - 50 °C over 2 - 6 hours until pH = 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 cake of crude compound 14 obtained 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] General results: Yield 90 - 95%, purity > 99.5a%, assay > 95% Recrystallization of Compound 14

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

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

Claims

1. Compound (I): 【Chemistry 1】 A method for producing a compound comprising the steps of: 1) Formula 【Chemistry 2】 Compound 1 having the structure of the formula 【Chemistry 3】 [In the formula, X is selected from Cl, Br, and I; Y is OR 9 , N.H.O.C. 1-3 alkyl, Cl, Br, and I; and R 9 is C 1-3 Alkyl, C 1-3 hydroxyalkyl, substituted phenyl and substituted benzyl] in a suitable solvent, 【Chemistry 4】 to obtain compound 3a or 3b; 2) reacting compound 3a or 3b with a compound of the formula 【Chemistry 5】 to compound 4; 3) Next, compound 4 is reacted with trialkyl orthoformate in an alcohol solvent to obtain the compound of the formula: 【Chemistry 6】 [In the formula, R 1 is C 1-6 is alkyl; and R 3 ' is C 1-6 alkyl, optionally substituted phenyl and benzyl] to obtain compound 5; 4) The ester of compound 5 is hydrolyzed under basic conditions, or R 3 When ' is a substituted benzyl, hydrogenolysis is carried out, 【Chemistry 7】 In the formula, R 1 and X is defined as above to obtain compound 6; 5) The carboxyl moiety of compound 6 is then activated and reacted with a chiral auxiliary to give the compound of formula 【Chemistry 8】 [In the formula, Xa is a chiral auxiliary, and R 1 and X is defined as above, to obtain compound 6a; 6) Compound 6a is then reacted with a base in the presence of a methyl donor (e.g., an alkyl halide) and a chiral auxiliary; 【Chemistry 9】 In the formula, R 1 , X, and Xa are defined as above to obtain compound 6b; 7) Remove Xa, 【Chemistry 10】 In the formula, R 1 and X is defined as above to obtain compound 7; 8) Next, compound 7 is reacted with the compound having the following structure in the presence of a metal catalyst: 【Chemistry 11】 React with compound 8 to give compound 9 【Chemistry 12】 get; 9) The nitro group of compound 9 is reduced to give the compound of the formula 【Chemistry 13】 to obtain compound 10; 10) Compound 10 is cyclized with a suitable coupling agent to give the compound of formula 【Chemistry 14】 to obtain compound 11; 11) Deprotecting the ketone group in the presence of an acid to give a compound of the formula 【Chemistry 15】 to obtain compound 12; 12a) reducing compound 12 with an equivalent amount of ammonia in the presence of a reducing agent; or 12b) Compound 12 is reduced by aminotransferase in the presence of an amine donor, a different recyclization system, and a cofactor to give 【Chemistry 16】 to obtain the amine stereocenter shown in compound 13; 13) Compound 13 is then reacted with the compound having the following structure: 【Chemistry 17】 Coupling with compound 14 to give the compound of formula 【Chemistry 18】 to obtain compound (I); A method comprising the steps of:

2. 2. The method of claim 1, wherein in step 2, the acid is selected from sulfuric acid, methylsulfonic acid (MSA), benzenesulfonic acid, nitric acid, hydrochloric acid, trichloroacetic acid, and perchloric acid.

3. In step 5 of claim 1, the chiral auxiliary is 【Chemistry 19】 is selected from the group consisting of R 6 is C 1-3 selected from alkyl, phenyl, benzyl; R 7 is selected from H and phenyl; and R 8 is C 1-3 alkyl, phenyl, and benzyl.

4. The chiral auxiliary is 【Chemistry 20】 4. The method of claim 3, wherein the

5. The method of claim 1, wherein in step 6, the methyl donor is an alkyl halide.

6. 2. The method of claim 1, wherein in step 8, the metal catalyst comprises palladium and a phosphine ligand.

7. 7. The method of claim 6, wherein the phosphine ligand is XPhos or SPhos.

8. The method of claim 1, wherein in step 10, the coupling agent is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH).

9. 2. The method of claim 1, wherein in step 12b, the aminotransferase is selected from ATA-113, ATA-200, ATA-237, ATA-251, ATA-254, ATA-256, and ATA-260.

10. The method of claim 1, wherein in step 12b, the transamination is carried out in the presence of (4-formyl-5-hydroxy-6-methylpyridin-3-yl)methyl phosphate (PLP).

11. The method of claim 1, wherein in step 12b, the amine donor is selected from isopropylamine, alanine, 3-aminobutyric acid, and methylbenzylamine.

12. 12. The method of claim 11, wherein the amine donor is isopropylamine.

13. The structural formula is compound 21 【Chemistry 21】 A method for preparing a compound of formula (II) comprising the steps of: a) Formula 【Chemical 22】 Compound 15 (CH 3 O) 2 CH(CH 2 ) 2 Br to give the formula 【Chemistry 23】 to obtain compound 16; b) converting compound 16 in the presence of an acid to give a compound of formula 【Chemistry 24】 to obtain compound 17; c) reacting compound 17 with a triphenylphosphonium ylide or phosphonate derivative in the presence of a suitable solvent; 【Chemistry 25】 In the formula, R 3 ' is C 1-6 alkyl, to obtain compound 18; d) reacting compound 18 with trimethyl orthoformate in the presence of an acid to give a compound of the formula 【Chemistry 26】 to obtain compound 19; e) converting compound 19 to the following structure: 【Chemical 27】 to obtain compound 20; f) hydrogenating compound 20 in the presence of a ruthenium catalyst to give the following structure: 【Chemistry 28】 to obtain a compound of formula (II) having the formula: A method comprising the steps of:

14. The method of claim 13, wherein in step b, the acid is TFA.

15. 14. The method of claim 13, wherein in step f, the acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid.

16. In step f of claim 13, the ruthenium catalyst is selected from the group consisting of 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'-bipyridine], phthalocyanine]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).

17. Formula (III): 【Chemical 29】 [In the formula, R 1 is methyl; R 2 is methyl; R 4 No 2 and R 5 CHF 2 is] A method for producing a compound of the present invention comprising the steps of: 1) Formula 【Chemistry 30】 Compound 28 of the formula, wherein X is selected from F, Cl, Br, and I, is reacted with (triisopropylsilyl)acetylene to give 【Chemistry 31】 to obtain compound 29; 2) Converting compound 29 to the compound of formula 【Chemistry 32】 to obtain compound 30; 3) Compound 30 is then reacted with bis(cyclopentadienyl)zirconium dichloride to give a compound of the formula 【Chemical 33】 to obtain compound 31; 4) Compound 31 is then reacted with (S)-(-)-3-methoxy-2-methyl-3-oxopropylzinc bromide; 【Chemical Formula 34】 In the formula, R 1 and X is defined as above to obtain compound 32; 5) Next, compound 32 is reacted with the compound of the formula 【Chemistry 35】 and reacting with compound 8 of the formula 【Chemical 36】 to obtain compound 33; A method comprising the steps of:

18. Furthermore, the formula: 【Chemical 37】 2. The method of claim 1 comprising preparing compound 14 of the formula: 1) Formula: 【Chemical 38】 Compound 43 is treated with the following structure: 【Chemical Formula 39】 in a suitable solvent under suitable Suzuki coupling conditions to give the compound of the following structure: 【Chemistry 40】 to obtain compound 45; 2) Compound 45 is converted to an azide, which is reacted with trimethylsilylacetylene and a metal catalyst in a suitable solvent to give the following structure: 【Chemistry 41】 to obtain compound 46; 3) Reacting compound 46 with 1,3-dichloro-5,5-dimethylhydantoin in a suitable solvent to give the following structure: 【Chemistry 42】 to obtain compound 47; and 4) Compound 47 is demethylated in hydrochloric acid to give compound 14; A method comprising the steps of:

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