Synthesis method of upatinib, intermediate of upatinib and preparation method of intermediate of upatinib

Abstract

The invention discloses a synthesis method of upatinib, an intermediate of the upatinib and a preparation method of the intermediate of the upatinib, and the synthesis method of the upatinib comprises the following steps: in a solvent, carrying out Alloc removal reaction as shown in the specification on a compound shown in a formula II in the presence of a deprotection reagent to obtain a compound shown in a formula I; the synthesis method of upatinib is higher in production efficiency, and further has one or more advantages of avoiding generation of genotoxic impurities, being higher in safety, lower in production cost and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a synthesis method of upadacitinib, an intermediate thereof and a preparation method of the intermediate thereof. Background Art

[0002] In the synthesis of upadacitinib, since the molecular structure of upadacitinib contains more N atoms, protection and deprotection on N are usually involved. In the existing synthesis route of upadacitinib, more sulfonyl N-amino protecting groups are involved, such as the amino protecting group Ts (toluenesulfonyl). Ts is a group with a potential genotoxic warning structure, and TsOH (toluenesulfonic acid) produced by deprotection of the intermediate is easy to react with alcohol solvents to produce sulfonate genotoxic impurities.

[0003] Patent CN108368121B discloses a synthetic route of upadacitinib:

[0004]

[0005] In this process route, the Ts amino protecting group introduced into the intermediate is obtained by reacting compound a with TsCl (toluenesulfonyl chloride), and TsCl is very likely to produce genotoxic impurities methyl toluenesulfonate or ethyl toluenesulfonate when it encounters alcohol solvents, and the intermediate containing Ts in the synthesis process may produce impurities methyl toluenesulfonate or ethyl toluenesulfonate in the deprotection reaction. However, clinical studies have found that sulfonates can directly undergo alkylation reactions with biomacromolecules (DNAs, RNAs and proteins), which may cause DNA mutations. Methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate have been proven to be genotoxic, and other substances with sulfonic acid groups may have potential genotoxicity, posing a threat to human health. The standards for genotoxic impurities are nearly 100 times or even 1,000 times stricter than those for ordinary impurities. Therefore, how to avoid the generation of genotoxic impurities in the synthesis of upadacitinib is a technical problem that needs to be solved in this field.

[0006] In addition, in this process route, compound e uses flammable and explosive hydrogen and precious metal catalyst Pd(OH) in the step of removing the Cbz amino protecting group. 2 / C, hydrogen has great safety risks in the industrial large-scale production process, the precious metal palladium is expensive, and the production cost is high. In addition, the total yield of the final product upadacitinib prepared from compound c in this process route is about 43.8%, and the production efficiency is low. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method for synthesizing upadacitinib in order to overcome the defects of low production efficiency of the existing method for synthesizing upadacitinib, further, the existence of one or more defects such as potential genotoxic impurities, low safety and high production cost. The method for synthesizing upadacitinib of the present invention has higher production efficiency, further has one or more advantages such as avoiding the generation of genotoxic impurities, higher safety and lower production cost.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a method for preparing a compound of formula I, comprising the following steps: in a solvent, a compound of formula II is reacted with a deprotecting agent (C 1-6 alkyl) 4 Carry out the de-Alloc (allyloxycarbonyl) reaction as shown below in the presence of amine halide to obtain the compound of formula I;

[0010]

[0011] In one embodiment of the present invention, in the de-Alloc reaction, the solvent is preferably one or more of an ether solvent, a nitrile solvent and an aromatic hydrocarbon solvent, the ether solvent is preferably one or both of tetrahydrofuran and 2-methyltetrahydrofuran, the nitrile solvent is preferably acetonitrile, and the aromatic hydrocarbon solvent is preferably toluene; the solvent is more preferably tetrahydrofuran.

[0012] In one embodiment of the present invention, in the de-Alloc reaction, the molar volume ratio of the compound of formula II to the solvent is preferably 0.1 to 0.2 mol / L, more preferably 0.13 mol / L.

[0013] In one embodiment of the present invention, in the de-Alloc reaction, the deprotection agent is preferably tetrabutylammonium halide, more preferably tetrabutylammonium fluoride.

[0014] In one embodiment of the present invention, in the deAlloc reaction, the molar ratio of the deprotection reagent to the compound of formula II is preferably 2:1 to 3:1, more preferably 2.4:1.

[0015] In one embodiment of the present invention, the reaction temperature of the de-Alloc reaction may be a reaction temperature at which the reaction solution is refluxed, preferably 60-80°C, for example 70°C.

[0016] In one embodiment of the present invention, the progress of the de-Alloc protection reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound of formula II disappears or no longer reacts or the product no longer increases. The reaction time of the de-Alloc protection reaction is preferably 0.3 to 0.7 hours, for example 0.5 hours.

[0017] In one embodiment of the present invention, the preparation method of the compound of formula I may further include a preparation method of the compound of formula II, wherein the preparation method of the compound of formula II comprises the following steps: in a solvent, in the presence of a condensing agent, a compound of formula III or a pharmaceutically acceptable salt thereof and trifluoroethylamine or a pharmaceutically acceptable salt thereof are subjected to a condensation reaction as shown below to obtain the compound of formula II;

[0018]

[0019] In one embodiment of the present invention, in the condensation reaction, the solvent is preferably one or more of an ether solvent, a nitrile solvent, an aromatic hydrocarbon solvent and a mixed solvent of an organic solvent and water, and the organic solvent is one or more of the ether solvent, nitrile solvent and aromatic hydrocarbon solvent; the ether solvent is preferably one or both of tetrahydrofuran and 2-methyltetrahydrofuran, the nitrile solvent is preferably acetonitrile, and the aromatic hydrocarbon solvent is preferably toluene; the solvent is more preferably a mixed solvent of tetrahydrofuran and water.

[0020] In one embodiment of the present invention, in the condensation reaction, the molar volume ratio of the compound of formula III to the solvent is preferably 0.2 to 0.4 mol / L, more preferably 0.32 mol / L.

[0021] In one embodiment of the present invention, when the solvent is a mixed solvent of tetrahydrofuran and water, the volume ratio of tetrahydrofuran to water is preferably 4:1 to 5:1, more preferably 4.3:1.

[0022] In one embodiment of the present invention, in the condensation reaction, the condensation reagent is preferably N,N'-carbonyldiimidazole.

[0023] In one embodiment of the present invention, in the condensation reaction, the molar ratio of the condensation reagent to the compound of formula III is preferably 1:1 to 2:1, more preferably 1.4:1.

[0024] In one embodiment of the present invention, in the condensation reaction, the molar ratio of the trifluoroethylamine to the compound of formula III is preferably 1:1 to 3:1, more preferably 2.1:1.

[0025] In one embodiment of the present invention, the reaction temperature of the condensation reaction may be room temperature, preferably 20°C to 30°C, for example 25°C.

[0026] In one embodiment of the present invention, the progress of the condensation reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound of formula III disappears or no longer reacts or the product no longer increases. The reaction time of the condensation reaction is preferably 5 to 7 hours, for example 6 hours.

[0027] In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula III may be hydrochloride or trifluoroacetate, preferably trifluoroacetate.

[0028] In one embodiment of the present invention, the condensation reaction can be carried out under alkaline conditions, and the alkaline conditions are preferably pH=8-10, more preferably pH=9.

[0029] In one embodiment of the present invention, the method for preparing the compound of formula II preferably comprises the following steps: in the solvent, in the presence of the condensing agent and the base, the pharmaceutically acceptable salt of the compound of formula III and trifluoroethylamine or a pharmaceutically acceptable salt thereof are subjected to the condensation reaction to obtain the compound of formula II. The base may be a base used to adjust the condensation reaction to the alkaline conditions, preferably, the base is K 2 HPO 4 and KOH buffer solution.

[0030] In a certain embodiment of the present invention, the operation steps of the preparation method of the compound of formula II can be conventional operation steps of such reactions in the art. Preferably, the preparation method of the compound of formula II comprises the following operation steps: the trifluoroethylamine and N,N'-carbonyldiimidazole are dissolved in the solvent to obtain reaction solution 1, the compound of formula III or its pharmaceutically acceptable salt is dissolved in the solvent to obtain reaction solution 2, the reaction solution 1 is mixed with the reaction solution 2 to obtain the compound of formula II. The condensation reaction preferably comprises the following operation steps: the trifluoroethylamine or its pharmaceutically acceptable salt and N,N'-carbonyldiimidazole are dissolved in the solvent to obtain reaction solution 1, the pharmaceutically acceptable salt of the compound of formula III and the alkali are dissolved in the solvent to obtain reaction solution 2, the reaction solution 1 is mixed with the reaction solution 2 to obtain the compound of formula II.

[0031] In a certain embodiment of the present invention, the preparation method of the compound of formula II preferably comprises the following steps: in the solvent, in the presence of the condensing agent, the trifluoroacetate salt of the compound of formula III and trifluoroethylamine or a pharmaceutically acceptable salt thereof undergo a condensation reaction as shown below to obtain the compound of formula II; the reaction conditions of the condensation reaction are as described in any one of the present invention.

[0032] In one embodiment of the present invention, the preparation method of the compound of formula I may further include a preparation method of a compound of formula III, wherein the preparation method of the compound of formula III comprises the following steps: in a solvent, the compound of formula IV is subjected to a deprotection reaction as shown below in the presence of a deprotection agent to obtain the compound of formula III or a pharmaceutically acceptable salt thereof;

[0033]

[0034] Wherein, PG is an amino protecting group.

[0035] In one embodiment of the present invention, in the deprotection reaction, the solvent is preferably one or more of a halogenated hydrocarbon solvent, an ether solvent, a nitrile solvent and an aromatic hydrocarbon solvent, for example, one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and toluene.

[0036] In one embodiment of the present invention, in the deprotection reaction, PG is preferably Cbz (benzyloxycarbonyl).

[0037] In one embodiment of the present invention, in the deprotection reaction, the deprotection agent is preferably trifluoroacetic acid.

[0038] In one embodiment of the present invention, in the deprotection reaction, when the deprotection reagent is H 2 +Pd / C or trifluoroacetic acid, preferably trifluoroacetic acid, the solvent is preferably trifluoroacetic acid.

[0039] In one embodiment of the present invention, in the deprotection reaction, the molar ratio of the deprotection reagent to the compound of formula IV is preferably 10:1 to 20:1, more preferably 17:1.

[0040] In one embodiment of the present invention, in the deprotection reaction, when the deprotection agent is trifluoroacetic acid, the pharmaceutically acceptable salt of the compound of formula III is the trifluoroacetate of the compound of formula III.

[0041] In one embodiment of the present invention, the reaction temperature of the deprotection reaction may be room temperature to 80°C, preferably 70°C to 80°C, and more preferably 75°C.

[0042] In one embodiment of the present invention, the progress of the deprotection reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound of formula IV disappears or no longer reacts or the product no longer increases. The reaction time of the deprotection reaction is preferably 2 to 4 hours, for example 3 hours.

[0043] In one embodiment of the present invention, the method for preparing the trifluoroacetate salt of the compound of formula III comprises the following steps: in the solvent, the compound of formula IV-1 is subjected to a deprotection reaction as shown below in the presence of trifluoroacetic acid to obtain the trifluoroacetate salt of the compound of formula III;

[0044]

[0045] The reaction conditions of the deprotection reaction are as described in any one of the present invention.

[0046] In one embodiment of the present invention, the preparation method of the compound of formula I may further include a preparation method of a compound of formula IV, wherein the preparation method of the compound of formula IV comprises the following steps: in a solvent, in the presence of an organic base and perfluoroanhydride, subjecting the compound of formula V to a cyclization reaction as shown below to obtain a compound of formula IV;

[0047]

[0048] Where R is C 1-4 Alkyl and PG are as defined in any one of the present invention.

[0049] In one embodiment of the present invention, in the cyclization reaction, the solvent is preferably a nitrile solvent, more preferably acetonitrile.

[0050] In one embodiment of the present invention, in the cyclization reaction, the molar volume ratio of the compound of formula IV to the solvent is preferably 0.2 to 0.5 mol / L, more preferably 0.3 mol / L.

[0051] In one embodiment of the present invention, in the cyclization reaction, the organic base is preferably one or two of aliphatic amines and aromatic nitrogen heterocycles, and the aliphatic amine is preferably C 1-4 The aliphatic amine is preferably triethylamine, and the aromatic nitrogen heterocycle is preferably C 3-5 The aromatic nitrogen heterocycle is more preferably pyridine; and the organic base is more preferably triethylamine.

[0052] In one embodiment of the present invention, in the cyclization reaction, the molar ratio of the organic base to the compound of formula IV is preferably 1.5:1 to 2.5:1, more preferably 1.9:1.

[0053] In one embodiment of the present invention, in the cyclization reaction, the perfluoroanhydride is preferably trifluoroacetic anhydride.

[0054] In one embodiment of the present invention, in the cyclization reaction, the molar ratio of the perfluoroanhydride to the compound of formula IV is preferably 3:1 to 5:1, more preferably 4.1:1.

[0055] In one embodiment of the present invention, the reaction temperature of the cyclization reaction may be a reaction temperature at which the reaction solution is refluxed, preferably 70°C to 80°C, for example 75°C.

[0056] In one embodiment of the present invention, the progress of the cyclization reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound of formula V disappears or no longer reacts or the product no longer increases. The reaction time of the cyclization reaction is preferably 1.5 to 3 hours, for example 2 hours.

[0057] In one embodiment of the present invention, R is preferably a methyl group, an ethyl group or a tert-butyl group, more preferably a tert-butyl group.

[0058] In a certain embodiment of the present invention, the preparation method of the compound of formula IV is preferably a preparation method of formula IV-1, which comprises the following steps: in the solvent, in the presence of the organic base and the perfluoroanhydride, the compound of formula V-1 undergoes a cyclization reaction as shown below to obtain the compound of formula IV-1;

[0059]

[0060] The reaction conditions of the cyclization reaction are as described in any one of the present invention.

[0061] In one embodiment of the present invention, the method for preparing the compound of formula V preferably comprises the following steps: in a solvent, in the presence of an alkaline agent, a compound of formula VII and a compound of formula VI undergo a substitution reaction as shown below to obtain the compound of formula V;

[0062]

[0063] Wherein, X is Br or Cl, and R and PG are defined as described in any one of the present invention.

[0064] In one embodiment of the present invention, in the substitution reaction, the solvent is preferably an amide solvent, more preferably one or both of N,N-dimethylformamide and N,N-dimethylacetamide.

[0065] In one embodiment of the present invention, in the substitution reaction, the molar volume ratio of the compound of formula II to the solvent is preferably 0.05 to 0.2 mol / L, more preferably 0.07 mol / L.

[0066] In one embodiment of the present invention, in the substitution reaction, the alkaline reagent may be a conventional deprotection reagent for such reactions in the art, and the alkaline reagent is preferably lithium tert-butoxide.

[0067] In one embodiment of the present invention, in the substitution reaction, the molar ratio of the alkaline reagent to the compound of formula VI is preferably 1:1 to 1.5:1, more preferably 1.2:1.

[0068] In one embodiment of the present invention, in the substitution reaction, the molar ratio of the compound of formula VII to the compound of formula VI is preferably 1:1 to 1.5:1, more preferably 1.2:1.

[0069] In one embodiment of the present invention, the reaction temperature of the substitution reaction is -10°C to 10°C, preferably 0°C.

[0070] In one embodiment of the present invention, the progress of the substitution reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound of formula VI disappears or no longer reacts or the product no longer increases. The reaction time of the substitution reaction is preferably 8 to 10 hours, for example 9 hours.

[0071] In one embodiment of the present invention, X is preferably Br.

[0072] In one embodiment of the present invention, R is methyl, ethyl or tert-butyl, preferably tert-butyl.

[0073] In a certain embodiment of the present invention, the preparation method of the compound of formula V is preferably a preparation method of the compound of formula V-1, which comprises the following steps: in the solvent, in the presence of the alkaline reagent, the compound of formula VII-1 and the compound of formula VI-1 undergo a substitution reaction as shown below to obtain the compound of formula V-1;

[0074]

[0075] The reaction conditions of the substitution reaction are as described in any one of the present invention.

[0076] In one embodiment of the present invention, the compound of formula VI-1 is preferably prepared by the synthesis route shown in the following formula:

[0077]

[0078] In one embodiment of the present invention, the reaction conditions for preparing the compound of formula VI-1 can be conventional reaction conditions for such reactions in the art.

[0079] The present invention also provides a method for preparing a compound of formula I, wherein the compound of formula I is prepared by the following synthetic route:

[0080]

[0081] Wherein, the definitions of X, PG and R, and the parameters and conditions in the preparation method of the compound of formula I are as described in any one of the present invention.

[0082] In one embodiment of the present invention, in the method for preparing the compound of formula I, the compound of formula I is preferably prepared by the following synthetic route:

[0083]

[0084] Wherein, the parameters and conditions in the preparation method of the compound of formula I are as described in any one of the present invention.

[0085] The present invention also provides a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V or a compound of formula VI as shown below:

[0086]

[0087] Wherein, PG and R are defined as described in any one of the present invention.

[0088] In one embodiment of the present invention, the compound of formula III is preferably the trifluoroacetate salt of the compound of formula III, the compound of formula IV is preferably the compound of formula IV-1, the compound of formula V is preferably the compound of formula V-1, and the compound of formula VI is preferably the compound of formula VI-1;

[0089]

[0090] The present invention also provides the use of the aforementioned compound of formula II, compound of formula III, compound of formula IV, compound of formula IV-1, compound of formula V, compound of formula V-1, compound of formula VI or compound of formula VI-1 in the preparation of the aforementioned compound of formula I.

[0091] The present invention also provides a method for preparing a compound of formula II, characterized in that it comprises the following steps: in a solvent, in the presence of a condensation agent N,N'-carbonyldiimidazole, subjecting a compound of formula III or a salt thereof to a condensation reaction as shown below with trifluoroethylamine or a pharmaceutically acceptable salt thereof to obtain the compound of formula II;

[0092]

[0093] Preferably, the parameters and conditions in the preparation method of the compound of formula II are as described in any one of the present invention.

[0094] The present invention also provides a method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps: in a solvent, a compound of formula IV is subjected to a deprotection reaction as shown below in the presence of a deprotection agent to obtain the compound of formula III or a pharmaceutically acceptable salt thereof;

[0095]

[0096] Wherein, PG is an amino protecting group, preferably Cbz;

[0097] Preferably, the parameters and conditions in the method for preparing the compound of formula III or a pharmaceutically acceptable salt thereof are as described in any one of the present invention.

[0098] The present invention also provides a method for preparing a compound of formula IV, characterized in that the method for preparing the compound of formula IV comprises the following steps: in a solvent, in the presence of an organic base and perfluoroanhydride, subjecting the compound of formula V to a cyclization reaction as shown below to obtain the compound of formula IV;

[0099]

[0100] Where R is C 1-4 Alkyl, preferably tert-butyl;

[0101] Preferably, the parameters and conditions in the preparation method of the compound of formula IV are as described in any one of the present invention.

[0102] The present invention also provides a method for preparing a compound of formula V, characterized in that it comprises the following steps: in a solvent, in the presence of an alkaline agent, a compound of formula VII and a compound of formula VI undergo a substitution reaction as shown below to obtain the compound of formula V;

[0103]

[0104] Wherein, X is Br or Cl;

[0105] PG is an amino protecting group, preferably Cbz;

[0106] R is C 1-4 The alkyl group is preferably tert-butyl.

[0107] Preferably, the parameters and conditions in the method for preparing the compound of formula V are as described in any one of the present invention.

[0108] Definition of terms

[0109] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid. The pharmaceutically acceptable acid includes inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0110] The term "amino protecting group" includes, but is not limited to, formyl; acyl, for example, alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0111] The term "C 1-4 "Alkyl" refers to an independent methyl, ethyl, C 3 Alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 Alkyl (ie, butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

[0112] The term "C 1-6 "Alkyl" except for the above "C 1-4 In addition to the definition of "alkyl", it also refers to independently C 5 Alkyl (i.e., pentyl, including n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl), C 6 Alkyl (i.e. hexyl, including 17 isomers).

[0113] The term "C 1-4 The term "fatty amine" refers to methylamine, ethylamine, C3 alkylamine (i.e. propylamine, including n-propylamine and isopropylamine), C4 alkylamine (i.e. butylamine, including n-butylamine, isobutylamine, sec-butylamine and tert-butylamine).

[0114] The term "C 3-5 The term "aromatic nitrogen heterocycle" refers to an aromatic nitrogen heterocycle having 3 to 5 carbon atoms, such as pyrazole, pyrrole, pyrimidine, pyridine, pyrazine, etc.

[0115] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0116] The abbreviations of the present invention are defined as follows:

[0117] Alloc represents: allyloxycarbonyl; Cbz represents: benzylcarbonyloxy.

[0118] The reagents and raw materials used in the present invention are commercially available.

[0119] The positive and progressive effects of the present invention are: the present invention provides a method for synthesizing upadacitinib that is completely different from the prior art, the method for synthesizing upadacitinib of the present invention uses Alloc to protect the intermediate, the total yield is 67.7%, the production efficiency is higher, and further has one or more advantages such as avoiding the generation of genotoxic impurities, higher safety and lower production cost. DETAILED DESCRIPTION

[0120] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0121] Example 1: Synthesis of Upadacitinib

[0122]

[0123] Step 1:

[0124] Using conventional reaction conditions in the art, 2-bromo-5H-pyrrolo[2,3-b]pyrazine was added to tert-butyl carbamate to obtain tert-butyl 5H-pyrrolo[2,3-b]pyrazine-2-ylcarbamate. MS (M+H) + :235.12.

[0125] Using conventional reaction conditions in the art, 5H-pyrrolo[2,3-b]pyrazine-2-ylcarbamic acid tert-butyl ester was added with AllocCl to obtain 5-allyloxycarbonyl-5H-pyrrolo[2,3-b]pyrazine-2-carbamic acid tert-butyl ester (Formula VI-1 compound). MS (M+H) + :319.13.

[0126] Step 2:

[0127]

[0128] Add tert-butyl 5-allyloxycarbonyl-5H-pyrrolo[2,3-b]pyrazine-2-carbamate (40g, 125.7mmol) and N,N-dimethylformamide (1000mL) to the reaction flask. Cool the mixture to 0°C and add a solution of lithium tert-butoxide (12g, 150mmol) in N,N-dimethylformamide (400mL) dropwise. Then add a solution of (3R,4S)-3-(2-bromoacetyl)-4-ethyl-1-pyrrolidinecarboxylic acid benzyl ester (54g, 152.5mmol) in N,N-dimethylformamide (400mL) dropwise. Stir the reaction under ice bath for 9h, add acetic acid (12mL,) to quench the reaction. The reaction solution is concentrated to dryness under reduced pressure, ethyl acetate (0.75L) and water (0.5L) are added, stirred until dissolved and separated, and the upper organic phase is collected. The organic phase was washed with saturated sodium chloride (0.25 L) and then dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness to obtain 80.1 g of 2-((2-((3R, 4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidin-3-yl)-2-oxoethyl)(tert-butoxycarbonyl)amino)-5H-pyrrolo[2,3-b]pyrazine-5-carboxylic acid allyl ester, yield: 89.2%, purity: 82.8% (LCMS detection purity, Agilent, chromatographic column: ACQUITY UPLC CSH C18 Column; NMR confirmed the structure, Bruker AV-400NMR, solvent: DMSO-d6, internal standard TMS, 400 MHz).

[0129] LCMS (M+H): 592.20, 1 H NMR (400 MHz, DMSO-d 6 )δ8.75(s,1H),8.12(dd,J=14.9,4.1Hz,1H),7.28(ddd,J=12.7,7.7,3.8Hz,5H),6.63(dd,J=45.4,4.1Hz,1H ),6.05(ddd,J=22.3,10.5,5.2Hz,1H),5.54(dd,J=17.2,1.5Hz,1H),5.31(dd,J=10.6,1.3Hz,1H),5.06–5.0 0(m,2H),4.93(d,J=5.2Hz,2H),4.81–4.72(m,2H),3.59(dd,J=18.6,9.4Hz,1H),3.54–3.41(m,3H),3.23–3. 13(m,1H),2.44–2.34(m,1H),1.44(dd,J=16.8,6.6Hz,9H),1.33–1.18(m,2H),0.88(dt,J=12.9,5.1Hz,3H).

[0130] Step 3:

[0131]

[0132] To a 500 mL single-necked bottle, 2-((2-((3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidin-3-yl)-2-oxoethyl)(tert-butoxycarbonyl)amino)-5H-pyrrolo[2,3-b]pyrazine-5-carboxylic acid allyl ester (35 g, 59.2 mmol), acetonitrile (195 mL), triethylamine (16 mL, 115 mmol), and trifluoroacetic anhydride (33.5 mL, 241 mmol) were added, and the reaction solution was refluxed in an oil bath at 75 °C for 2 h. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain 26.3 g of 8-((3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboxylic acid allyl ester, with a yield of 94.0%.

[0133] LCMS (M+H): 474.33, 1 H NMR (400 MHz, DMSO-d 6 )δ8.78(s,1H),7.90(d,J=4.0Hz,1H),7.68(d,J=3.8Hz,1H),7.43–7.32(m,5H),7.30(d,J=4.4Hz,1H),6.0 7(ddt,J=17.2,10.6,5.3Hz,1H),5.55(ddd,J=17.2,3.2,1.6Hz,1H),5.32(dt,J=11.9,1.3Hz,1H),5.15–5 .04(m,2H),4.99–4.91(m,2H),4.40–4.30(m,1H),3.77(ddd,J=18.2,12.1,6.6Hz,2H),3.31–3.23(m,1H), 1.19 (s, 2H), 0.98 (dd, J = 7.9, 4.6Hz, 1H), 0.82 (ddd, J = 13.2, 8.2, 4.6Hz, 1H), 0.57 (dt, J = 11.7, 5.8Hz, 3H).

[0134] Step 4:

[0135]

[0136] 8-((3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboxylic acid allyl ester (2 g, 4.2 mmol) and TFA (10 mL, 71.9 mmol) were added to a 100 mL single-mouth bottle, and stirred in an oil bath at 75°C for 3 h. The reaction solution was concentrated to dryness under reduced pressure to obtain 2.4 g (yield: 100%) of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboxylic acid allyl ester trifluoroacetate, which was used directly in the next step.

[0137] Step 5:

[0138]

[0139] CDI (0.96 g, 5.9 mmol) and THF (7 mL) were added to the reaction bottle, stirred at room temperature, and trifluoroethylamine (0.5 mL, 8.76 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for more than 1 h to obtain reaction solution 1. 8-((3R, 4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboxylic acid allyl ester trifluoroacetate (2.4 g, 4.2 mmol), THF (6 mL), water (3 mL), K 2 HPO 4 (0.81g, 4.65mmol), 10% KOH solution (about 8.5mL) was added dropwise to pH = 9, and the reaction solution 2 was stirred. The reaction solution 1 was added to the reaction solution 2, and the mixture was stirred for 6h. A 20% citric acid aqueous solution (10mL) was added to the reaction solution and stirred; EA (25mL) was added and extracted 3 times; the organic phase was washed once with saturated sodium chloride (10mL), and the organic phase was dried over anhydrous sodium sulfate; the organic phase was concentrated to dryness and separated by column chromatography to obtain 8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboxylic acid allyl ester 1.8g (yield 92.3%).

[0140] LCMS (M+H): 465.80, 1 H NMR (400 MHz, DMSO-d 6)δ8.80(s,1H),7.92(d,J=4.1Hz,1H),7.59(s,1H),7.38(d,J=4.2Hz,1H),6.95(t,J=6.3Hz,1H),6. 08(ddt,J=17.2,10.6,5.3Hz,1H),5.56(ddd,J=17.2,3.3,1.6Hz,1H),5.35–5.31(m,1H),4.97(dt,J =5.3,1.4Hz,2H),4.35(d,J=6.1Hz,1H),3.89–3.81(m,2H),3.77(dt,J=10.4,4.8Hz,2H),3.66(dd, J=10.2,6.9Hz,1H),3.25–3.21(m,1H),1.08–0.98(m,1H),0.86–0.72(m,2H),0.60(t,J=7.3Hz,3H).

[0141] Step 6:

[0142]

[0143] 8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboxylic acid allyl ester (1.2 g, 2.59 mmol), tetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.6 g, 6.1 mmol) were added to a 100 mL single-mouth bottle, and the mixture was refluxed for 0.5 h in an oil bath at 70°C. The reaction solution was concentrated to dryness under reduced pressure. The product (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was purified by chromatography to obtain 0.86 g (yield 87.5%).

[0144] LCMS (M+H): 381.72. 1 H NMR (400 MHz, DMSO-d 6 )δ12.27(s,1H),8.54(s,1H),7.42(dd,J=6.8,3.7Hz,2H),7.00–6.92(m,2H),4.32(dd,J=12.2,6.0Hz,1H),3.88–3.70(m,4H),3.66( dd,J=10.2,6.9Hz,1H),3.24(dd,J=10.2,6.2Hz,1H),2.59–2.50(m,1H),1.12–1.02(m,1H),0.84–0.75(m,1H),0.61(t,J=7.3Hz,3H).

[0145] Comparative Example 1

[0146] The following synthetic route of upadacitinib was designed by selecting an Ac-protected intermediate. In step 1, except for the different reaction raw materials, the other reaction conditions were the same as those in step 1 of Example 1. The reaction results showed that the Ac protecting group was removed during the reaction, and the following compound 2 was not successfully prepared. Therefore, the Ac-protected intermediate could not be used to prepare upadacitinib by the following synthetic route.

[0147]

Claims

1. A method for preparing a compound of formula I, characterized in that: The method comprises the following steps: in a solvent, a compound of formula II is reacted with a deprotection reagent (C 1-6 The de-Alloc reaction is carried out in the presence of an alkyl)4-halogenated amine as shown below to obtain the compound of formula I; 2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: 1) In the de-Alloc reaction, the solvent is one or more of an ether solvent, a nitrile solvent and an aromatic hydrocarbon solvent, the ether solvent is preferably one or both of tetrahydrofuran and 2-methyltetrahydrofuran, the nitrile solvent is preferably acetonitrile, and the aromatic hydrocarbon solvent is preferably toluene; The solvent is more preferably tetrahydrofuran; 2) In the de-Alloc reaction, the molar volume ratio of the compound of formula II to the solvent is 0.1 to 0.2 mol / L, preferably 0.13 mol / L; 3) In the de-Alloc reaction, the deprotection reagent is tetrabutylammonium halide, preferably tetrabutylammonium fluoride; 4) In the de-Alloc reaction, the molar ratio of the deprotection reagent to the compound of formula II is 2:1 to 3:1, preferably 2.4:1; 5) In the de-Alloc reaction, the reaction temperature of the de-Alloc reaction is 60-80° C., for example, 70° C.; 6) In the de-Alloc reaction, the reaction time of the de-Alloc protection reaction is 0.3 to 0.7 hours, For example, 0.5 hours.

3. The preparation method according to claim 1, characterized in that: The preparation method of the compound of formula I also includes the preparation method of the compound of formula II, and the preparation method of the compound of formula II comprises the following steps: in a solvent, in the presence of a condensing agent, a compound of formula III or a pharmaceutically acceptable salt thereof and trifluoroethylamine or a pharmaceutically acceptable salt thereof are subjected to a condensation reaction as shown below to obtain the compound of formula II; Preferably, the preparation method of the compound of formula II satisfies one or more of the following conditions: 1) In the condensation reaction, the solvent is one or more of an ether solvent, a nitrile solvent, an aromatic hydrocarbon solvent and a mixed solvent of an organic solvent and water; the organic solvent is one or more of the ether solvent, nitrile solvent and aromatic hydrocarbon solvent; the ether solvent is preferably one or both of tetrahydrofuran and 2-methyltetrahydrofuran, the nitrile solvent is preferably acetonitrile, and the aromatic hydrocarbon solvent is preferably toluene; the solvent is more preferably a mixed solvent of tetrahydrofuran and water; preferably, when the solvent is a mixed solvent of tetrahydrofuran and water, the volume ratio of tetrahydrofuran to water is 4:1 to 5:1, preferably 4.3:1; 2) In the condensation reaction, the molar volume ratio of the compound of formula III to the solvent is 0.2 to 0.4 mol / L, preferably 0.32 mol / L; 3) In the condensation reaction, the condensation reagent is preferably N,N'-carbonyldiimidazole; 4) In the condensation reaction, the molar ratio of the condensation reagent to the compound of formula III is 1:1 to 2:1, preferably 1.4:1; 5) In the condensation reaction, the molar ratio of the trifluoroethylamine to the compound of formula III is 1:1 to 3:1, preferably 2.1:1; 6) In the condensation reaction, the reaction temperature of the condensation reaction is room temperature, preferably 20°C to 30°C, for example 25°C; 7) In the condensation reaction, the reaction time of the condensation reaction is 5 to 7 hours, for example, 6 hours; 8) In the condensation reaction, the pharmaceutically acceptable salt of the compound of formula III is hydrochloride or trifluoroacetate, preferably trifluoroacetate; 9) The condensation reaction is carried out under alkaline conditions, wherein the alkaline conditions are preferably pH=8-10, more preferably pH=9; 10) The preparation method of the compound of formula II comprises the following steps: in the solvent, in the presence of the condensing agent and the base, the pharmaceutically acceptable salt of the compound of formula III and trifluoroethylamine or its pharmaceutically acceptable salt undergo the condensation reaction to obtain the compound of formula II; wherein the base is preferably a buffer solution of K2HPO4 and KOH; 11) The preparation method of the compound of formula II comprises the following steps: the trifluoroethylamine or a pharmaceutically acceptable salt thereof and N,N'-carbonyldiimidazole are dissolved in the solvent to obtain a reaction solution 1, the compound of formula III or a pharmaceutically acceptable salt thereof is dissolved in the solvent to obtain a reaction solution 2, and the reaction solution 1 is mixed with the reaction solution 2 to obtain the compound of formula II; 12) The preparation method of the compound of formula II comprises the following steps: in the solvent, in the presence of the condensing agent, the trifluoroacetate salt of the compound of formula III and trifluoroethylamine or a pharmaceutically acceptable salt thereof undergo a condensation reaction as shown below to obtain the compound of formula II.

4. The preparation method according to claim 3, characterized in that: The preparation method of the compound of formula I also includes the preparation method of the compound of formula III, and the preparation method of the compound of formula III comprises the following steps: in a solvent, the compound of formula IV is subjected to a deprotection reaction as shown below in the presence of a deprotection agent to obtain the compound of formula III or a pharmaceutically acceptable salt thereof; Wherein, PG is an amino protecting group; Preferably, the preparation method of the compound of formula III satisfies one or more of the following conditions: 1) In the deprotection reaction, the solvent is a halogenated hydrocarbon solvent, an ether solvent, or a nitrile solvent. and one or more of aromatic hydrocarbon solvents, such as one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and toluene; 2) In the deprotection reaction, PG is Cbz; 3) In the deprotection reaction, the deprotection reagent is H2+Pd / C or trifluoroacetic acid, preferably trifluoroacetic acid; when the deprotection agent is trifluoroacetic acid, the solvent is preferably trifluoroacetic acid. acid; 4) In the deprotection reaction, the molar ratio of the deprotection reagent to the compound of formula IV is 10:1 to 20:1, preferably 17:1; 5) In the deprotection reaction, the pharmaceutically acceptable salt of the compound of formula III is trifluoroacetate salt of the compound; 6) The reaction temperature of the deprotection reaction is room temperature to 80°C, preferably 70°C to 80°C, more preferably 75°C; 7) The reaction time of the deprotection reaction is the reaction time required for the compound of formula IV to react completely, preferably 2 to 4 hours, for example 3 hours; 8) The preparation method of the trifluoroacetate of the compound of formula III comprises the following steps: in the solvent, the compound of formula IV-1 is subjected to a deprotection reaction as shown below in the presence of trifluoroacetic acid to obtain the trifluoroacetate of the compound of formula III; 5. The preparation method according to claim 4, characterized in that: The preparation method of the compound of formula I also includes the preparation method of the compound of formula IV, and the preparation method of the compound of formula IV comprises the following steps: in a solvent, in the presence of an organic base and perfluoroanhydride, the compound of formula V is subjected to a cyclization reaction as shown below to obtain a compound of formula IV; Where R is C 1-4 alkyl; Preferably, the preparation method of the compound of formula IV satisfies one or more of the following conditions: 1) In the cyclization reaction, the solvent is preferably a nitrile solvent, more preferably acetonitrile; 2) In the cyclization reaction, the molar volume ratio of the compound of formula IV to the solvent is 0.2 to 0.5 mol / L, preferably 0.3 mol / L; 3) In the cyclization reaction, the organic base is one or both of aliphatic amine and aromatic nitrogen heterocycle, and the aliphatic amine is preferably C 1-4 The aliphatic amine is preferably triethylamine, and the aromatic nitrogen heterocycle is preferably C 3-5 Aromatic nitrogen heterocycle, more preferably pyridine; the organic base is preferably triethylamine; 4) In the cyclization reaction, the molar ratio of the organic base to the compound of formula IV is 1.5:1 to 2.5:1, Preferably 1.9:1; 5) In the cyclization reaction, the perfluoroanhydride is trifluoroacetic anhydride; 6) In the cyclization reaction, the molar ratio of the perfluoroanhydride to the compound of formula IV is 3:1 to 5:1, Preferably 4.1:1; 7) The reaction temperature of the cyclization reaction is 70°C to 80°C, for example, 75°C; 8) The reaction time of the cyclization reaction is 1.5 to 3 hours, for example, 2 hours; 9) R is methyl, ethyl or tert-butyl, preferably tert-butyl; 10) The preparation method of the compound of formula IV is a preparation method of the compound of formula IV-1, which comprises the following steps: in the solvent, in the presence of the organic base and the perfluoroanhydride, the compound of formula V-1 undergoes a cyclization reaction as shown below to obtain the compound of formula IV-1; 6. The preparation method according to claim 5, characterized in that: The preparation method of the compound of formula I also includes the preparation method of the compound of formula V, and the preparation method of the compound of formula V comprises the following steps: in a solvent, in the presence of an alkaline agent, a compound of formula VII and a compound of formula VI undergo a substitution reaction as shown below to obtain the compound of formula V; Wherein, X is Br or Cl; R is C 1-4 alkyl; Preferably, the method for preparing the compound of formula V satisfies one or more of the following conditions: 1) In the substitution reaction, the solvent is an amide solvent, more preferably one or two of N,N-dimethylformamide and N,N-dimethylacetamide; 2) In the substitution reaction, the molar volume ratio of the compound of formula II to the solvent is 0.05 to 0.2 mol / L, preferably 0.07 mol / L; 3) In the substitution reaction, the alkaline reagent is lithium tert-butoxide; 4) In the substitution reaction, the molar ratio of the alkaline reagent to the compound of formula VI is 1:1 to 1.5:1, Preferably 1.2:1; 5) In the substitution reaction, the molar ratio of the compound of formula VII to the compound of formula VI is 1:1 to 1.5:1, preferably 1.2:1; 6) The reaction temperature of the substitution reaction is -10°C to 10°C, preferably 0°C; 7) The reaction time of the substitution reaction is 8 to 10 hours, for example, 9 hours; 8) X is Br; 9) R is methyl, ethyl or tert-butyl, preferably tert-butyl; 10) The preparation method of the compound of formula V also includes the preparation method of the compound of formula V-1, which comprises The following steps: In the solvent, in the presence of the alkaline reagent, the compound of formula VII-1 and the compound of formula VI-1 undergo a substitution reaction as shown below to obtain the compound of formula V-1; 7. A method for preparing a compound of formula I, characterized in that: The compound of formula I is prepared by the following synthetic route: Wherein, the definitions of X, PG and R, and the parameters and conditions in the preparation method of the compound of formula I are as described in any one of claims 1-6.

8. The preparation method according to claim 7, characterized in that: The compound of formula I is prepared by the following synthetic route:

9. A compound of formula II, formula III, formula IV, formula V or formula VI: in, PG and R are as defined in claim 7; The compound of formula III is preferably the trifluoroacetate salt of the compound of formula III, the compound of formula IV is preferably the compound of formula IV-1, the compound of formula V is preferably the compound of formula V-1, and the compound of formula VI is preferably the compound of formula VI-1; 10. Use of the compound according to claim 9 in the preparation method according to any one of claims 1 to 8.

11. A method for preparing a compound of formula II, characterized in that: It includes the following steps: In a solvent, in the presence of a condensation agent N,N'-carbonyldiimidazole, the compound of formula III or its salt is subjected to a condensation reaction as shown below with trifluoroethylamine or its pharmaceutically acceptable salt to obtain the compound of formula II; Preferably, the parameters and conditions in the preparation method of the compound of formula II are as described in any one of claims 3-6.

12. A method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof, characterized in that: It includes the following steps: In a solvent, the compound of formula IV is subjected to a deprotection reaction as shown below in the presence of a deprotection agent to obtain the compound of formula III or a pharmaceutically acceptable salt thereof; Wherein, PG is an amino protecting group, preferably Cbz; Preferably, the parameters and conditions in the method for preparing the compound of formula III or a pharmaceutically acceptable salt thereof are as described in any one of claims 4-6.

13. A method for preparing a compound of formula IV, characterized in that: The preparation method of the compound of formula IV comprises the following steps: in a solvent, in the presence of an organic base and perfluoroanhydride, the compound of formula V undergoes a cyclization reaction as shown below to obtain the compound of formula IV; Where R is C 1-4 Alkyl, preferably tert-butyl; Preferably, the parameters and conditions in the preparation method of the compound of formula IV are as described in claim 5 or 6.

14. A method for preparing a compound of formula V, characterized in that: It includes the following steps: In a solvent, in the presence of an alkaline agent, the compound of formula VII and the compound of formula VI undergo a substitution reaction as shown below to obtain the compound of formula V; Wherein, X is Br or Cl, preferably Br; PG is an amino protecting group, preferably Cbz; R is C 1-4 Alkyl, preferably tert-butyl; Preferably, the parameters and conditions in the preparation method of the compound of formula V are as described in claim 6.

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