Preparation method of tetrahydropyrazine fused ring derivative

Abstract

The present disclosure provides a method for preparing a tetrahydropyrazine fused ring derivative. Specifically, the method for preparing a tetrahydropyrazine fused ring derivative provided by the present disclosure significantly inhibits the generation of impurities and improves the purity and yield of the product by adding an alkaline substance in the catalytic hydrogenation reaction, and is suitable for industrial production.

Description

Technical Field

[0001] The present disclosure relates to the field of pharmaceutical chemistry, and in particular to a method for preparing a class of tetrahydropyrazine fused ring derivatives. Background Art

[0002] Tetrahydropyrazine fused ring derivatives are key fragments and synthetic intermediates of many drug molecules. For example, Sitagliptin Phosphate (III-b), a dipeptidyl peptidase-IV (DPP-IV) inhibitor developed by Merck, was approved for marketing by the US FDA in October 2006 for the treatment of type 2 diabetes. Retagliptin Phosphate (III-a), which also has a tetrahydropyrazine fused ring derivative fragment, has been applied for marketing, and the results show that it has excellent DPP-IV inhibitory effect.

[0003]

[0004] There are many reports on the preparation of tetrahydropyrazine fused ring derivatives in the prior art. For example, WO2009082881A discloses the following preparation method:

[0005]

[0006] Using 2-cyanopyrazine as the starting material, 3-trifluoromethyl-imidazo[1,5-a]pyrazine is obtained through reduction, acylation and intramolecular dehydration cyclization, and then the tetrahydropyrazine fused ring intermediate is obtained through hydrogen / palladium carbon catalytic hydrogenation, which is subsequently used in the synthesis of repagliptin.

[0007] CN103724352A and CN106892926A disclose similar intermediate preparation methods:

[0008]

[0009] 2-Amino-2-pyrazine-acetic acid methyl ester is acylated with TFFA and then dehydrated and cyclized to obtain an imidazopyrazine intermediate, which is then catalytically hydrogenated with hydrogen / palladium on carbon to obtain a tetrahydropyrazine fused ring derivative.

[0010] It can be seen that in the prior art, tetrahydropyrazine fused ring derivatives are usually prepared by catalytic hydrogenation, but the inventors found in the actual production process that a large molecular impurity will appear when the pyrazine fused ring substrate is catalytically hydrogenated. This impurity is difficult to remove by means of recrystallization or beating, which seriously affects the yield and purity of the final product. It is speculated that this is caused by Michael addition between the hydrogenation product and the hydrogenation intermediate containing a single double bond.

[0011] At the same time, the current dehydration and cyclization steps generally use phosphorus-containing reagents, which will produce a large amount of phosphorus-containing wastewater during the industrial production process, which is not conducive to environmental protection and also increases the post-processing cost. Summary of the invention

[0012] In order to overcome the deficiencies of the prior art, the present disclosure provides a method for preparing a tetrahydropyrazine fused ring derivative.

[0013] In a first aspect, the present disclosure provides a method for preparing a compound as shown in Formula I, characterized in that it comprises the steps of preparing a compound as shown in Formula II by catalytic hydrogenation in the presence of an alkaline substance to obtain a compound as shown in Formula I:

[0014]

[0015] Wherein, X is N or C-R3;

[0016] R1 is selected from hydrogen, deuterium, halogen, cyano or the following groups which are optionally substituted: C 1-6 Alkyl, C 3-8 Cycloalkyl;

[0017] R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino or the following groups which are optionally substituted: C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0018] R3 is selected from hydrogen, deuterium, halogen, cyano, nitro, -O-R4, -OC(=O)-R4, -NH-R4, -NHC(=O)-R4, NHC(=O)NH-R4, -NHS(=O)2-R4, -C(=O)O-R4, -C(=O)NH-R4, -S(=O)2NH-R4 or the following groups optionally substituted: C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0019] R4 is selected from hydrogen, deuterium, C optionally substituted by halogen or deuterium 1-6 alkyl, optionally substituted by halogen or deuterium 3-8 Cycloalkyl.

[0020] In some embodiments, X is N; in other embodiments, X is C-R3.

[0021] In some embodiments, R1 is selected from hydrogen, deuterium, halogen, cyano, C optionally substituted with halogen. 1-6 Alkyl, optionally substituted by halogen 3-8 Cycloalkyl; preferably selected from hydrogen, halogen, C 1-3 Alkyl, optionally substituted by halogen 3-6Cycloalkyl; more preferably hydrogen.

[0022] In some embodiments, R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more selected from deuterium, halogen, cyano, hydroxyl, amino, carboxyl, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

[0023] Wherein, R2 can be further selected from hydrogen, deuterium, C optionally substituted by halogen 1-6 Alkyl, optionally halogen-substituted C 3-8 Cycloalkyl; preferably selected from C optionally substituted by halogen 1-3 Alkyl; more preferably trifluoromethyl.

[0024] When X is C-R3, R3 is selected from hydrogen, deuterium, halogen, cyano, nitro, -O-R4, -OC(=O)-R4, -NH-R4, -NHC(=O)-R4, NHC(=O)NH-R4, -NHS(=O)2-R4, -C(=O)O-R4, -C(=O)NH-R4, -S(=O)2NH-R4, C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more selected from deuterium, halogen, cyano, hydroxyl, amino, carboxyl, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

[0025] Wherein, R3 can be further selected from hydrogen, deuterium, halogen, cyano, -O-R4, -OC(=O)-R4, -NH-R4, -NHC(=O)-R4, -C(=O)OR4, -C(=O)NHR4, C(=O)-R4 optionally substituted by halogen, 1-6 Alkyl, halogen substituted C 3-8 Cycloalkyl; preferably selected from hydrogen, deuterium, halogen, cyano, -C(=O)O-R4, -C(=O)NH-R4, C optionally substituted by halogen 1-3 Alkyl, optionally halogen-substituted C 3-6 Cycloalkyl; more preferably -C(=O)O-R4.

[0026] In some embodiments, R4 is selected from hydrogen, deuterium, C optionally substituted with halogen or deuterium. 1-3 alkyl, optionally substituted by halogen or deuterium 3-6 Cycloalkyl; preferably selected from hydrogen, methyl, ethyl, propyl, isopropyl; more preferably methyl.

[0027] In a specific embodiment, in the compounds represented by Formula I and Formula II, X is C-R3, R1 is hydrogen, R2 is trifluoromethyl, R3 is -C(=O)O-R4, and R4 is methyl;

[0028] That is, the present disclosure provides a method for preparing a compound as shown in Formula Ia, comprising the step of preparing a compound as shown in Formula II-a by catalytic hydrogenation in the presence of an alkaline substance to obtain a compound as shown in Formula Ia:

[0029]

[0030] In another specific embodiment, in the compounds represented by Formula I and Formula II, X is N, R1 is hydrogen, and R2 is trifluoromethyl;

[0031] That is, the present disclosure also provides a method for preparing a compound as shown in Formula Ib, comprising the step of preparing a compound as shown in Formula II-b by catalytic hydrogenation in the presence of an alkaline substance to obtain a compound as shown in Formula Ib:

[0032]

[0033] The alkaline substance disclosed in the present invention can be selected from an inorganic base, an organic base or an alkaline salt, and can be specifically selected from one or more of Li2CO3, Na2CO3, K3PO4, Cs2CO3, K2CO3, NaHCO3, KHCO3, KF, CsF, Bu4NF, LiOH, NaOH, KOH, Ba(OH)2, Pd(OH)2, triethylamine, pyridine, DIPEA, DABCO, NaOR', KOR', wherein R' is independently selected from C 1-6 alkyl;

[0034] The alkaline substance is preferably one or more of Na2CO3, K2CO3, NaHCO3, KHCO3, NaOH, KOH, and Pd(OH)2; more preferably one or more of Pd(OH)2, Na2CO3, K2CO3, NaHCO3, and KHCO3; even more preferably one or two of Pd(OH)2 and NaHCO3.

[0035] In a specific embodiment, the alkaline substance selected is NaHCO3.

[0036] In the present disclosure, the molar ratio of the alkaline substance to the catalytic hydrogenation substrate (e.g., compounds of Formula II, Formula II-a, Formula II-b) is 0.1 to 10:1, preferably 1 to 5:1, more preferably 2 to 4:1, and even more preferably 2:1.

[0037] There is no particular limitation on the catalyst used for catalytic hydrogenation, and the optional catalysts include but are not limited to palladium on carbon (Pd / C), Pd(OH)2, Pd(OAc)2, PdCl2, Raney nickel (Raney Ni), platinum (Pt), platinum oxide (PtO2), triphenylphosphine rhodium chloride ((Ph3P)3RhCl), etc.;

[0038] In some embodiments, palladium on carbon is used as a catalyst, wherein the content of palladium is 5%-10%.

[0039] The catalytic hydrogenation reaction disclosed herein can be carried out in water or an organic solvent, wherein the organic solvent is selected from a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, an amide solvent, a nitrile solvent or an alcohol solvent, wherein the halogenated hydrocarbon solvent can be selected from dichloromethane or chloroform, the ether solvent can be selected from tetrahydrofuran or diethyl ether, the ester solvent can be selected from ethyl acetate, methyl acetate or butyl acetate, the amide solvent can be selected from N,N-dimethylformamide, the nitrile solvent can be selected from acetonitrile, and the alcohol solvent can be selected from methanol, ethanol, isopropanol or n-butanol;

[0040] In some embodiments, the solvent is preferably water, tetrahydrofuran, ethyl acetate, methanol or ethanol, more preferably water, ethyl acetate or methanol, and even more preferably ethyl acetate.

[0041] In a second aspect, the present disclosure further provides a method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula I by catalytic hydrogenation of a compound of formula II in the presence of an alkaline substance:

[0042]

[0043]

[0044] Wherein, the definitions of X, R1, R2, R3, and R4 and the reaction conditions are as described in the first aspect;

[0045] Ar is an aryl group selected from phenyl or naphthyl, which is optionally substituted by one or more selected from halogen, trifluoromethyl, amino, cyano, nitro, phenyl, C 1-6 Alkyl or C 1-6 or Ar is a heteroaryl group selected from pyridine, pyrazine, pyrimidine, furan, pyrrole, thiophene, indole or quinoline groups, which are optionally substituted with one or more selected from halogen, trifluoromethyl, amino, cyano, nitro, phenyl, C 1-6Alkyl or C 1-6 The substituents of the alkoxy group are substituted.

[0046] In some embodiments, Ar is phenyl, which is optionally substituted with one or more halogens. When it is substituted with multiple halogens, the multiple halogens may be the same or different.

[0047] In one embodiment, Ar is preferably phenyl, which is optionally substituted with one or more fluorine atoms; Ar is more preferably

[0048] In some embodiments, the preparation method may further include the following steps:

[0049]

[0050] The amino-protected compound of formula V is condensed with the compound of formula I to obtain the compound of formula III', and the compound of formula III' is deprotected under appropriate conditions to obtain the compound of formula III;

[0051] The "PG" shown is an amino protecting group, which refers to a group that can protect the amino group to avoid reaction. The amino protecting group can be selected from alkoxycarbonyl amino protecting groups, acyl amino protecting groups, sulfonyl amino protecting groups or alkyl amino protecting groups; the amino protecting group is preferably selected from alkoxycarbonyl protecting groups, more preferably tert-butyloxycarbonyl (Boc).

[0052] The preparation method may further include the step of preparing a pharmaceutically acceptable salt thereof from the compound of formula III.

[0053] The present disclosure also provides a method for preparing a compound of formula III-a or a pharmaceutically acceptable salt thereof, which comprises the steps of preparing a compound of formula Ia by catalytic hydrogenation of the compound of formula II-a in the presence of an alkaline substance:

[0054]

[0055] The specific reaction conditions for the optional catalytic hydrogenation are as described in the first aspect.

[0056] In some embodiments, the alkaline substance is selected from NaHCO3 or Pd(OH)2, and the solvent is selected from ethyl acetate.

[0057] In one embodiment, the compound of formula II-a is subjected to catalytic hydrogenation reaction with 10% wet palladium carbon and hydrogen in the presence of 2 equivalents of NaHCO3 using ethyl acetate as solvent to obtain the compound of formula Ia.

[0058] The preparation method of the compound represented by formula III-a may further include the step of obtaining the compound represented by formula II-a by reacting the compound represented by formula IV-a:

[0059]

[0060] In some embodiments, the compound of formula IV-a undergoes intramolecular cyclization under the action of POCl3, and then is dehydrated under the action of P2O5 to obtain the compound of formula II-a.

[0061] In some embodiments, the compound of formula IV-a reacts with trifluoroacetic anhydride (TFFA) to obtain the compound of formula II-a; the molar ratio of the added amount of trifluoroacetic anhydride to the compound of formula IV-a is 0.5 to 3:1, preferably 1 to 2:1.

[0062] The reaction to generate II-a can be carried out in an organic solvent, and the organic solvent is selected from a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, an amide solvent, a nitrile solvent or an alcohol solvent, preferably an ether solvent, an ester solvent or an amide solvent, and more preferably an ether solvent;

[0063] In some embodiments, the ether solvent is selected from diethyl ether, isopropyl ether, n-butyl ether, methyl tert-butyl ether, anisole, tetrahydrofuran, and dioxane, preferably isopropyl ether, n-butyl ether, tetrahydrofuran, and dioxane, and more preferably tetrahydrofuran.

[0064] In a specific embodiment, the compound of formula IV-a is added to tetrahydrofuran, trifluoroacetic anhydride is added dropwise in an ice bath, and then stirred at room temperature. After the reaction is completed, methanol is added to quench, and an oil is obtained by vacuum distillation. A saturated NaHCO3 solution is added thereto, stirred, filtered, and washed with water to obtain a compound of formula II-a.

[0065] The compound of formula IV-a can be synthesized by the method disclosed in, but not limited to, patent documents CN103724352A and CN106892926A.

[0066] The preparation method of the compound represented by formula III-a may further include the steps of reacting the compound represented by formula Ia with the compound represented by formula Va to generate the compound represented by formula VI-a, and then removing the protecting group to obtain the compound represented by formula III-a:

[0067]

[0068] In some embodiments, N,N′-carbonyldiimidazole and imidazole hydrochloride are present in the reaction system of the compound of Formula Ia and the compound of Formula Va.

[0069] In some embodiments, the molar ratio of the amount of N,N'-carbonyldiimidazole added to the compound of formula Va is 0.5 to 1.5:1, preferably 0.8 to 1.2:1, more preferably 0.9 to 1.1:1;

[0070] The molar ratio of the amount of imidazole hydrochloride added to the compound of formula Va is 0.5 to 5:1, preferably 1 to 3:1, and more preferably 1 to 2:1.

[0071] The reaction for producing the compound of formula VI-a can be carried out in an organic solvent, and the organic solvent is selected from a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, an amide solvent, a nitrile solvent or an alcohol solvent, preferably an ether solvent, an ester solvent or an amide solvent, and more preferably an ether solvent;

[0072] In some embodiments, the ether solvent is selected from diethyl ether, isopropyl ether, n-butyl ether, methyl tert-butyl ether, anisole, tetrahydrofuran, and dioxane, preferably isopropyl ether, n-butyl ether, tetrahydrofuran, and dioxane, and more preferably tetrahydrofuran.

[0073] In a specific embodiment, the compound of formula Va, N,N'-carbonyldiimidazole and imidazole hydrochloride are added to tetrahydrofuran, the temperature is raised to 50-55°C under nitrogen protection and stirred, and then the compound of formula Ia is added, and the temperature is kept and stirred. After the reaction is completed, most of the solvent is removed by concentration under reduced pressure, and the remaining reaction liquid is subjected to water separation, filtration, water washing, and drying to obtain a crude product, which is further purified to obtain a compound of formula VI-a.

[0074] The compound of formula VI-a is then dissolved in ethyl acetate, and HCl dioxane solution is added and stirred at room temperature. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove the solvent to obtain an oily substance, which is then extracted with saturated NaHCO3 solution after adding dichloromethane, and the organic phase is dried, filtered, and concentrated to obtain the compound of formula III-a.

[0075] The synthesis of the compound of formula Va can adopt but is not limited to the methods disclosed in patent documents WO2003004498A1, WO2009082881A1, and CN101633625A.

[0076] In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula III-a is a phosphate, and the preparation method thereof further comprises the step of preparing the compound of formula III-A from the compound of formula III-a:

[0077]

[0078] Wherein, the compound of formula III-a reacts under organic solvent / H3PO4 conditions to obtain the compound of formula III-A.

[0079] The organic solvent is selected from halogenated hydrocarbon solvents, ether solvents, ester solvents, amide solvents, nitrile solvents or alcohol solvents, halogenated hydrocarbon solvents can be selected from dichloromethane or chloroform, ether solvents can be selected from ether, tetrahydrofuran or dioxane, ester solvents can be selected from ethyl acetate, methyl acetate or butyl acetate, amide solvents can be selected from N, N-dimethylformamide, nitrile solvents can be selected from acetonitrile, and alcohol solvents can be selected from methanol, ethanol, isopropanol or n-butanol. In some embodiments, the organic solvent for the first step reaction is selected from ethyl acetate and dioxane, and the organic solvent for the second step reaction is selected from isopropanol.

[0080] In a specific embodiment, the compound of formula III-a is added to isopropanol, phosphoric acid is added, and stirred at room temperature. After the reaction is completed, the filter is filtered and the filter cake is washed with isopropanol to obtain a wet product. The wet product is further purified to obtain a compound of formula III-A.

[0081] At the same time, the present disclosure further provides a method for preparing a compound as shown in formula III-b, which comprises the steps of preparing a compound as shown in formula Ib by catalytic hydrogenation of the compound as shown in formula II-b in the presence of an alkaline substance:

[0082]

[0083] The specific reaction conditions for the optional catalytic hydrogenation are as described in the first aspect.

[0084] The synthesis of the compound of formula II-b may adopt but is not limited to the methods disclosed in patent documents WO2003004498A1 and WO2005003135A1.

[0085] The preparation method may further include the step of reacting the compound of formula Ib with the compound of formula Va to generate the compound of formula VI-b, and then removing the protecting group to obtain the compound of formula III-b:

[0086]

[0087] In some embodiments, N,N'-carbonyldiimidazole and imidazole hydrochloride may be present in the reaction system of the compound of formula Ib and the compound of formula Va; the added amounts of N,N'-carbonyldiimidazole and imidazole hydrochloride are as described above.

[0088] In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula III-b is a phosphate salt, and the preparation method thereof further comprises the step of preparing the compound represented by formula III-B from the compound represented by formula III-b:

[0089]

[0090] In a third aspect, the present disclosure provides a method for preparing a pharmaceutical composition comprising the compound represented by the aforementioned formula III-a or a pharmaceutically acceptable salt thereof, comprising the step of mixing the compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, wherein the compound represented by formula III-a or a pharmaceutically acceptable salt thereof is prepared according to the method provided by the present disclosure.

[0091] The present disclosure also provides a method for preparing a pharmaceutical composition comprising the compound represented by the aforementioned formula III-b or a pharmaceutically acceptable salt thereof, comprising the step of mixing the compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, wherein the compound represented by formula III-b or a pharmaceutically acceptable salt thereof is prepared according to the method provided by the present disclosure.

[0092] The disclosed method is used to prepare tetrahydropyrazine fused-ring organisms, and the impurity content in the obtained product is significantly reduced compared with the general method, and the product purity is significantly improved, which is particularly suitable for the industrial production of drug molecules such as repagliptin and sitagliptin.

[0093] In the specification and claims of the present disclosure, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present disclosure, the definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided in the present disclosure are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in the present disclosure shall prevail.

[0094] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both and Two configurations.

[0095] Any isotope-labeled derivatives of the compounds or pharmaceutically acceptable salts thereof or isomers thereof described in the present disclosure are covered by the present disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be labeled with isotopes. 2 H(D), 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (ie, at least 45% deuterium incorporation).

[0096] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0097] "Alkyl" refers to a linear or branched alkane substituent containing 1 to 20 carbon atoms, and unless otherwise specified, the alkyl group may be substituted or unsubstituted.

[0098] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring contains 3 to 20 carbon atoms, non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused and bridged cycloalkyl. Unless otherwise specified, the cycloalkyl may be substituted or unsubstituted.

[0099] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl includes spirocyclic, condensed ring and bridged heterocycloalkyl. The heterocyclic ring can be fused on aryl, heteroaryl or cycloalkyl ring, and the ring connected with the parent structure is a heterocyclic radical. If not particularly limited, the heterocycloalkyl can be substituted or unsubstituted.

[0100] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system. The aryl group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl group. Unless otherwise specified, the aryl group may be substituted or unsubstituted.

[0101] "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6 to 12 members, more preferably 5 or 6 members. For example. Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazine, The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. If not specifically limited, the heteroaryl may be substituted or unsubstituted.

[0102] "Alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein the alkyl group is as defined above. Unless otherwise specified, the alkoxy group may be substituted or unsubstituted.

[0103] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1-6 "Alkyl" means that halogen or deuterium may but need not be present, and this description includes C 1-6 Alkyl groups substituted by halogen or deuterium 1-6 The alkyl group is not substituted by halogen or deuterium.

[0104] "Substituted by one or more substituents selected from A, B, ... " means that the compound may be substituted by a single or multiple substituents. When substituted by multiple substituents, the substituents may be the same or a combination of one or more different substituents. DETAILED DESCRIPTION

[0105] The present invention will be explained in detail below in conjunction with specific examples so that those skilled in the art can more fully understand the present invention. The specific examples are only used to illustrate the technical solutions of the present invention and do not limit the present invention in any way.

[0106] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0107] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard. The spatial configuration of the optical isomers (isomers) of the compound can be further confirmed by measuring the single crystal parameters.

[0108] HPLC determination uses Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).

[0109] MS was determined using a Waters SQD2 mass spectrometer in positive / negative ion mode with a mass scan range of 100-1200.

[0110] Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mmI.D., 3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5um, Chiralcel OJ-3 150×4.6mm ID, 3um columns;

[0111] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0112] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0113] Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-filled ultra-pure normal phase silica gel column (40-63μm, 60, 12g, 25g, 40g, 80g or other specifications).

[0114] Reverse phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45μm, 40g, 80g, 120g, 220g or other specifications).

[0115] The high-pressure column purification system uses Waters AutoP in combination with Waters XBridge BEH C18 OBDPrep Column. 5μm, 19mm X 150mm or Atlantis T3 OBD Prep Column, 5μm, 19mm X 150mm.

[0116] The chiral preparative column used was DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um) or Phenomenex-Amylose-1 (250 mm*30 mm, 5 um).

[0117] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (AccelaChemBioInc), Darui Chemicals and other companies.

[0118] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0119] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0120] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0121] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0122] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0123] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0124] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0125] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0126] The progress of the reactions in the examples was monitored by thin layer chromatography (TLC).

[0127] Example 1

[0128]

[0129] Benzophenone (50.0 g, 274 mmol, 1.0 eq) was added to anhydrous dichloromethane and stirred to dissolve, placed in an ice-water bath, and TiCl4 (72.9 g, 383.6 mmol, 1.4 eq) was added and ammonia was passed until the raw material reacted completely. Water was added and stirred, and the liquid was separated. The dichloromethane phase was collected, washed with water, dried, filtered, and concentrated under reduced pressure to a residual of about 500 mL. The obtained benzophenone imine solution was directly used for the next step reaction;

[0130] Add glycine methyl ester hydrochloride (36.0 g, 287 mmol, 1.05 eq), react at room temperature for 24 hours, filter, wash the filter cake with dichloromethane, and concentrate the filtrate under reduced pressure. Add petroleum ether to the residue and stir, filter and dry to obtain 47 g of compound VIII-a; the mother liquor is cooled to -20°C and filtered, and dried to obtain 11 g of compound VIII-a, a total of 58 g, with a yield of 83%.

[0131] Example 2

[0132]

[0133] The compound of formula VIII-a (50.0 g, 197.4 mmol, 1.0 eq), TBAB (63.6 g, 197.2 mmol, 1.0 eq), K2CO3 (81.8 g, 592.2 mmol, 3.0 eq), and 2-chloropyrazine (45.2 g, 394.8 mmol, 2 eq) were added to DMF and heated to 85°C with stirring. After the reaction was completed, the system was cooled to room temperature, ethyl acetate was added to the reaction solution, filtered, water was added to the filtrate, and the layers were stirred; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered, and the filtrate was concentrated under reduced pressure and pulped to obtain 53.8 g of the compound of formula IX-a, with a yield of 82.3%.

[0134] Example 3

[0135]

[0136] Add the compound of formula IX-a (53.8 g, 162.7 mmol, 1.0 eq) to acetone, add a mixed solution of concentrated hydrochloric acid (17.6 mL) and acetone in an ice-water bath, and after the addition, warm to room temperature to react until the raw material disappears. Filter the solid, wash the filter cake with acetone and dry it to obtain 32.6 g of the compound of formula Xa, with a yield of 98.6%.

[0137] Example 4

[0138]

[0139] The compound of formula Xa (32.6 g, 160.1 mmol, 1.0 eq.) was added to trifluoroacetic anhydride (74.5 g, 354.2 mmol, 2.2 eq.) in batches and stirred at room temperature. After the reaction was completed, the oil was distilled under reduced pressure, and then water was added and stirred, and the crude product was filtered. Isopropanol / petroleum ether mixed solution was added to the crude product and heated and stirred for 1 h. After the temperature naturally dropped to room temperature, it was filtered, washed, and dried to obtain 31.66 g of compound of formula IV-a, with a yield of 77.3%.

[0140] Example 5

[0141]

[0142] The compound of formula IV-a (31.65 g, 120.26 mmol, 1.0 eq.) was added to tetrahydrofuran, and TFAA (37.9 g, 180.2 mmol, 1.5 eq.) was slowly added dropwise under an ice bath, and then stirred at room temperature for 15 h. After the reaction was completed, methanol was added dropwise to the reaction solution to quench, and the oil was distilled under reduced pressure to obtain an oily substance, to which a saturated NaHCO3 aqueous solution was added and stirred, and the mixture was filtered, the filter cake was washed with water, and dried to obtain 27.11 g of the compound of formula II-a, with a yield of 92.0%.

[0143] Example 6

[0144]

[0145] Formula II-a compound (26.15g, 106.7mmol, 1.0eq.) and ethyl acetate were added to a hydrogenation bottle, and NaHCO3 solid (17.92g, 213.3mmol, 2.0eq.) and 10% wet palladium carbon (1.31g) were added. Argon and hydrogen were used for replacement three times in sequence, and the hydrogenation reaction was carried out at 40°C for 18h. After the reaction was completed, the reaction mixture was cooled to room temperature, and palladium carbon and NaHCO3 in the reaction solution were filtered out. The filter cake was washed with dichloromethane, and the crude product was obtained by vacuum distillation. A mixture of ethyl acetate / petroleum ether was added to the crude product, stirred at room temperature, filtered, washed, and the filter cake was collected and dried to obtain 24.79g of formula Ia compound, with a yield of 93.3%.

[0146] Example 7

[0147]

[0148] Add the compound of formula Va (31.4 g, 94.21 mmol, 1.0 eq.), N,N'-carbonyldiimidazole (16.03 g, 98.92 mmol, 1.05 eq.), and imidazole hydrochloride (14.77 g, 141.31 mmol, 1.5 eq.) to tetrahydrofuran, and heat the reaction solution to 50-55°C and stir for 30 min under nitrogen protection. Add the compound of formula Ia (24.64 g, 98.92 mmol, 1.05 eq.) to the system, and stir and react at 50-55°C for 7-20 h. After the reaction is completed, most of the solvent is removed by concentration under reduced pressure, and the remaining reaction liquid is added dropwise to water to precipitate a large amount of solid, which is filtered, washed with water, and dried to obtain a crude product; the crude product is added to isopropanol, heated to 80-85°C and stirred for 30 minutes, then slowly cooled to room temperature and stirred for 18 hours, filtered, washed, and dried to obtain 49.64 g of compound VI-a, with a yield of 93.3%.

[0149] Example 8

[0150]

[0151] The compound of formula VI-a (49.52 g, 87.73 mmol, 1.0 eq.) was added to ethyl acetate, and a 4.0 M solution of hydrogen chloride in dioxane (219 mL) was added. After the addition, the mixture was stirred at room temperature for 5 to 7 hours. The reaction solution was concentrated under reduced pressure to remove the solvent to obtain an oily substance, which was dissolved in dichloromethane, extracted and layered with a saturated NaHCO3 solution, and the organic phase was dried, filtered, and concentrated under reduced pressure to obtain a compound of formula III-a. The compound of formula III-a was added to isopropanol, and then an isopropanol solution of phosphoric acid (10.31 g, 105.2 mmol) was added dropwise, and stirred at room temperature for 2 hours. After the reaction was completed, the filter cake was filtered and washed with isopropanol, and the filter cake was collected to obtain a wet product. The wet product was added to purified water, heated to 50 to 55 ° C, stirred for 30 minutes, filtered, and the filtrate was concentrated to dryness with a diaphragm pump. The solid was dried to obtain 46.06 g of the compound of formula III-a, with a yield of 93.4%.

[0152] Comparative Example

[0153] The effects of different conditions on the catalytic hydrogenation of the compound of formula II-a were investigated. The specific reaction conditions are shown in Table 1. HPLC was used to detect the amount of dimer impurities generated and the product purity was calculated. Other operations were the same as in Example 6.

[0154] Table 1 Screening of catalytic hydrogenation reaction conditions

[0155]

[0156] As can be seen from Table 1, when catalytic hydrogenation is carried out under neutral or acidic conditions, the impurity content is >1%, while when alkaline substances such as NaHCO3 and Pd(OH)2 exist in the reaction system, the formation of impurities is significantly inhibited and the purity of the product is also improved.

Claims

1. A method for preparing a compound as shown in formula I, characterized in that: The method comprises the steps of preparing a compound represented by formula I by catalytic hydrogenation of a compound represented by formula II in the presence of an alkaline substance: Wherein, X is N or C-R3; R1 is selected from hydrogen, halogen, C 1-3 Alkyl, optionally halogen-substituted C 3-6 Cycloalkyl; R2 is selected from C optionally substituted by halogen 1-3 alkyl; R3 is selected from hydrogen, deuterium, halogen, cyano, -C(=O)OR4, -C(=O)NHR4, C(=O) 1-3 Alkyl, optionally halogen-substituted C 3-6 Cycloalkyl; R4 is selected from hydrogen, methyl, ethyl, propyl, isopropyl; The catalyst used in the catalytic hydrogenation is selected from one or more of palladium on carbon (Pd / C), Pd(OH)2, Pd(OAc)2, and PdCl2; The alkaline substance is selected from one or more of Na2CO3, K2CO3, NaHCO3, KHCO3, NaOH, KOH, and Pd(OH)2.

2. The preparation method according to claim 1, characterized in that: In the compounds represented by formula I and formula II, X is C-R3, R1 is hydrogen, R2 is trifluoromethyl, R3 is -C(=O)O-R4, and R4 is methyl: Alternatively, in the compounds represented by Formula I and Formula II, X is N, R1 is hydrogen, and R2 is trifluoromethyl:

3. The preparation method according to claim 1, wherein The alkaline substance is selected from NaHCO3.

4. The preparation method according to any one of claims 1 to 3, wherein The molar ratio of the alkaline substance to the compound of formula II is 1:1 to 5:

1.

5. The preparation method according to claim 4, wherein: The molar ratio of the basic substance to the compound of formula II is 2:

1.

6. A method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof, characterized in that: The method comprises the steps of condensing a compound of formula V having an amino group protected with a compound of formula I to obtain a compound of formula III', removing the protection of the compound of formula III' under appropriate conditions to obtain a compound of formula III, and preparing the compound of formula I by the method according to any one of claims 1 to 5, Wherein, Ar is a phenyl group which is optionally substituted by one or more halogens, and PG is an amino protecting group.

7. The preparation method according to claim 6, wherein: Ar 8. A method for preparing a compound of formula III-a or a pharmaceutically acceptable salt thereof, characterized in that: The method comprises the steps of reacting a compound of formula Ia with a compound of formula Va to generate a compound of formula VI-a, removing the protecting group to obtain a compound of formula III-a, and preparing the compound of formula Ia by the method according to claim 2.

9. The preparation method according to claim 2, characterized in that: The method further comprises the step of reacting the compound of formula IV-a with trifluoroacetic anhydride (TFFA) to obtain the compound of formula II-a:

10. The preparation method according to claim 9, characterized in that: The molar ratio of the amount of trifluoroacetic anhydride added to the compound of formula IV-a is 0.5:1 to 3:

1.

11. The preparation method according to claim 10, characterized in that: The molar ratio of the added amount of trifluoroacetic anhydride to the compound of formula IV-a is 1:1 to 2:

1.

12. The preparation method according to claim 8, wherein: In the reaction system of the compound of formula Ia and the compound of formula Va, N,N'-carbonyldiimidazole and imidazole hydrochloride exist.

13. The preparation method according to claim 12, wherein: The molar ratio of the added amount of N,N'-carbonyldiimidazole to the compound of formula Va is 0.5:1 to 1.5:

1.

14. The preparation method according to claim 13, wherein: The molar ratio of the added amount of N,N'-carbonyldiimidazole to the compound of formula Va is 0.9:1 to 1.1:

1.

15. The preparation method according to claim 12, wherein: The molar ratio of the added amount of imidazole hydrochloride to the compound of formula Va is 0.5:1 to 5:

1.

16. The preparation method according to claim 15, wherein: The molar ratio of the added amount of imidazole hydrochloride to the compound of formula Va is 1:1 to 2:

1.

17. A method for preparing a compound of formula III-b or a pharmaceutically acceptable salt thereof, characterized in that: The method comprises the steps of reacting a compound of formula Ib with a compound of formula Va to generate a compound of formula VI-b, and then removing the protecting group to obtain a compound of formula III-b, and preparing the compound of formula Ib by the method according to claim 2:

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