Preparation method for JAK inhibitor, and intermediate thereof

Abstract

The present invention provides a preparation method for a JAK inhibitor, and an intermediate thereof. Specifically, the present invention provides a method for preparing (R)-2-{3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(N-cyclopropyliminoethylsulfonyl)azetidin-3-yl}acetonitrile, and a corresponding intermediate thereof.

Description

Process for the preparation of a JAK inhibitor and intermediates thereof TECHNICAL FIELD

[0001] The present invention belongs to the field of pharmaceutical synthesis, in particular, the present invention relates to a process for the preparation of a JAK enzyme inhibitor, intermediates used therein and a process for the preparation of related intermediates. BACKGROUND

[0002] Janus-activated kinase Singal transducers and activators of transcriprion (JAK-STAT) is a newly discovered intracellular signal transduction pathway closely related to cytokines, which is involved in cell proliferation, differentiation, apoptosis and immune regulation and many other important biological processes. Blocking signal transduction at the JAK kinase level is expected to treat diseases such as inflammatory diseases, autoimmune diseases, and bone marrow biopsy diseases.

[0003] WO2018 / 133875A1 provides a JAK inhibitor having a sulfur atom as a chiral center, which makes the JAK inhibitor have high selectivity for JAK1, thereby reducing the toxic side effects of the JAK inhibitor.

[0004] However, there is still a lack of a method suitable for industrial production of such JAK inhibitors in the art. SUMMARY

[0005] The purpose of the present invention is to provide a process for preparing (R)-2-{3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(N-cyclopropyliminoethylsulfonyl)azetidin-3-yl}acetonitrile.

[0006] In a first aspect of the present invention, an intermediate for synthesizing a JAK enzyme inhibitor is provided, wherein the structure of the intermediate is shown in formula III:

[0007] wherein R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl;

[0008] R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2.

[0009] In another preferred embodiment, the intermediate has the structure of formula (R)-III or (S)-III:

[0010] wherein R 1 and R 3 are as defined in the first aspect of the present application.

[0011] In a second aspect, the present application provides a process for preparing a compound of formula III as defined in the first aspect of the present application, comprising the steps of:

[0012] reacting a compound of formula XVI with a compound of formula XI in an inert solvent to obtain a compound of formula III;

[0013] wherein R 1 and R 3 are as defined in the first aspect of the present application.

[0014] In another preferred embodiment, the reaction is carried out in the presence of N,N- diisopropylethylamine.

[0015] In another preferred embodiment, the inert solvent is dichloromethane.

[0016] In another preferred embodiment, the reaction temperature is between -65 and -55 °C.

[0017] In another preferred embodiment, the reaction time is between 0.5 and 8 hours.

[0018] In another preferred embodiment, the process further comprises separating the compound of formula III obtained by a chiral column to obtain a compound of formula (R)-III:

[0019] wherein R 1 and R 3 are as defined in the first aspect of the present application.

[0020] In another preferred embodiment, the process further comprises:

[0021] reacting a compound of formula XV with t-BuClO in an inert solvent to obtain a compound of formula XVI.

[0022] In another preferred embodiment, the reaction is carried out in dichloromethane.

[0023] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0024] In another preferred embodiment, the inert atmosphere is argon.

[0025] In another preferred embodiment, the reaction temperature is -65 to -55°C.

[0026] In another preferred embodiment, the reaction time is 0.1 to 0.5 h.

[0027] In another preferred embodiment, R 1 is ethyl, R 3 is cyclopropyl, and the method further comprises:

[0028] reacting a compound of formula 13 with a compound of formula 14 in an inert solvent to give a compound of formula 15.

[0029] In another preferred embodiment, the reaction is carried out in methyl tert-butyl ether.

[0030] In another preferred embodiment, the reaction is carried out in the presence of triethylamine.

[0031] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0032] In another preferred embodiment, the inert atmosphere is nitrogen.

[0033] In another preferred embodiment, the reaction temperature is -10 to -5°C.

[0034] In another preferred embodiment, the reaction time is 0.5 to 2 h.

[0035] In another preferred embodiment, the method further comprises:

[0036] reacting a compound of formula 12 with SO2Cl2in an inert solvent to give a compound of formula 13.

[0037] In another preferred embodiment, the reaction is carried out in glacial acetic acid.

[0038] In another preferred embodiment, the reaction is carried out in the presence of triethylamine.

[0039] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0040] In another preferred embodiment, the inert atmosphere is argon.

[0041] In another preferred embodiment, the reaction temperature is -30 to 25°C.

[0042] In another preferred embodiment, the reaction time is 0.5 to 18 h.

[0043] In another preferred embodiment, the method further comprises:

[0044] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0045] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0046] In another preferred embodiment, the inert atmosphere is argon.

[0047] In another preferred embodiment, the inert solvent is dichloromethane.

[0048] In another preferred embodiment, the HCl is HCl isopropanol solution.

[0049] In another preferred embodiment, the reaction temperature is 5-10°C.

[0050] In another preferred embodiment, the reaction time is 0.5-8h.

[0051] In another preferred embodiment, the compound of formula III is prepared by the following method:

[0052] wherein R 1 and R 3 are as defined in the first aspect of the present application.

[0053] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0054] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0055] In another preferred embodiment, the inert atmosphere is nitrogen.

[0056] In another preferred embodiment, the reaction is carried out in the presence of triphenylphosphine and hexachloroethane. In another preferred embodiment, the reaction is carried out in the presence of triethylamine.

[0057] In another preferred embodiment, the inert solvent is chloroform. In another preferred embodiment, the reaction temperature is -5-5°C.

[0058] In another preferred embodiment, the reaction time is 0.1-0.5h. In another preferred embodiment, R 3 is (t-Bu)Si(Ph)2.

[0059] In another preferred embodiment, the method further comprises:

[0060] In another preferred embodiment, the reaction is carried out in an inert atmosphere. with TBDPSCl in the presence of a strong base (preferably NaH) in an inert solvent to obtain a compound of formula 17.

[0061] In another preferred embodiment, the inert solvent is DMAc.

[0062] In another preferred embodiment, the reaction temperature is 25-30 °C.

[0063] In another preferred embodiment, the reaction time is 0.5-8 h.

[0064] In another preferred embodiment, the method further comprises:

[0065] In an inert solvent, the compound of formula (III) is reacted with to form the compound of formula (R)-III;

[0066] wherein R 1 and R 3 are as defined in the first aspect of the application, and R 3’ is selected from H, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C8 cycloalkyl.

[0067] In another preferred embodiment, the method further comprises forming a negatively charged salt of the compound of formula (III).

[0068] In another preferred embodiment, the negatively charged salt of the compound of formula (III) is a D-DTA salt of the compound of formula (III).

[0069] In another preferred embodiment, R 1 is ethyl, and the method further comprises:

[0070] In an inert solvent, compound 23 is converted to compound 24.

[0071] In another preferred embodiment, the inert solvent is MTBE.

[0072] In another preferred embodiment, the reaction is performed in the presence of an acid.

[0073] In another preferred embodiment, the acid is trifluoroacetic acid.

[0074] In another preferred embodiment, the reaction temperature is 0-10 °C.

[0075] In another preferred embodiment, the reaction time is 1-8 h.

[0076] In another preferred embodiment, R 1 is ethyl, R 3 is (t-Bu)SiMe2, and the method further comprises:

[0077] Compound 21 is converted to compound 22 and then reacted with compound 11 in an inert solvent to obtain compound 23.

[0078] In another preferred embodiment, the inert solvent is dichloromethane.

[0079] In another preferred embodiment, compound 21 is converted to compound 22 after being reacted with dichlorotriphenylphosphor in the reaction.

[0080] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0081] In another preferred embodiment, the inert atmosphere is nitrogen.

[0082] In another preferred embodiment, the reaction is carried out in the presence of triethylamine.

[0083] In another preferred embodiment, the reaction temperature is -25 to -15°C.

[0084] In another preferred embodiment, the reaction time is 1-5h.

[0085] In another preferred embodiment, the molar ratio of compound 21 to compound 11 in the reaction is (1.0-1.5):1.

[0086] In another preferred embodiment, R 1 is ethyl, R 3 is (t-Bu)SiMe2, and the method further comprises:

[0087] Compound 21 is obtained by reacting ethylsulfonamide with tert-butyldimethylchlorosilane in an inert solvent.

[0088] In another preferred embodiment, the reaction is carried out in the presence of triethylamine.

[0089] In another preferred embodiment, the inert solvent is dichloromethane.

[0090] In another preferred embodiment, the reaction is carried out in an inert atmosphere.

[0091] In another preferred embodiment, the inert atmosphere is nitrogen.

[0092] In another preferred embodiment, the reaction temperature is 5-50°C.

[0093] In another preferred embodiment, the reaction time is 5-30h.

[0094] In another preferred embodiment, the molar ratio of ethylsulfonamide to tert-butyldimethylchlorosilane in the reaction is (0.8-1.2):1.

[0095] In another preferred embodiment, the method further comprises isolating the compound of Formula 21 from the reaction mixture comprising the compound of Formula 21.

[0096] In another preferred embodiment, the isolating comprises: extraction and recrystallization.

[0097] In a third aspect of the present application, there is provided a method for preparing a compound of Formula I:

[0098] wherein:

[0099] R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl;

[0100] R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2.

[0101] characterized in that it is prepared using the compound III as defined in the first aspect of the present application as starting material.

[0102] In another preferred embodiment, the compound is characterized in that R 1 is ethyl and R 3 is cyclopropyl.

[0103] In another preferred embodiment, the method for preparing a compound of Formula I comprises the steps of:

[0104] (a) reacting a compound of Formula III with hydrazine in acetonitrile to obtain a compound of Formula IV;

[0105] In another preferred embodiment, the step (a) is carried out in the dark.

[0106] In another preferred embodiment, the step (a) is carried out under inert gas protection.

[0107] In another preferred embodiment, the inert gas in the step (a) is nitrogen.

[0108] In another preferred embodiment, the reaction temperature in the step (a) is 10-20 °C.

[0109] In another preferred embodiment, the reaction time in the step (a) is 1-2 h.

[0110] (b) reacting a compound of Formula IV with a compound of Formula II in methanol to obtain a compound of Formula I;

[0111] wherein X is N + (R 4 )R 5 or O; Y is NR 4 R 5 or hydroxyl; wherein, R 4 and R 5 are each independently selected from the group consisting of C1-C4 alkyl, or R 4 and R 5 together with the N atom to which they are attached form a 4-7 membered saturated heterocyclic ring, and said saturated heterocyclic ring can include 1, 2, or 3 heteroatoms selected from N or O; R 1 and R 3 are as defined in the first aspect of the present application.

[0112] In another preferred embodiment, the reaction time of step (b) is 1.5-36h;

[0113] In another preferred embodiment, the reaction temperature of step (b) is 25-45°C.

[0114] In another preferred embodiment, the compound II is compound 2f, and the compound 2f is prepared by the following method:

[0115] reacting 2e with Et2NH in an inert solvent to obtain compound 2f.

[0116] In another preferred embodiment, the inert solvent in the reaction is anhydrous ethanol.

[0117] In another preferred embodiment, the reaction time is 2-5h;

[0118] In another preferred embodiment, the reaction temperature is 60-80°C.

[0119] In another preferred embodiment, the compound II is compound 2e, and the compound 2e is prepared by the following method:

[0120] reacting a compound of formula II-A with a base in an inert solvent to obtain compound 2e;

[0121] In another preferred embodiment, the inert solvent in the reaction is water.

[0122] In another preferred embodiment, the base in the reaction is NaOH.

[0123] In another preferred embodiment, the reaction is carried out under protection of an inert gas.

[0124] In another preferred embodiment, the inert gas in the reaction is nitrogen.

[0125] In another preferred embodiment, the reaction temperature is 25-40 °C.

[0126] In another preferred embodiment, the reaction time is 10-30 h.

[0127] wherein R is selected from the group consisting of Me, Et, Bu; or two R on the same N atom together form -(CH2)5- or -(CH2)20(CH2)2-; and two R are optionally the same or different substituents, preferably the same substituents.

[0128] In another preferred embodiment, the preparation method comprises the step of:

[0129] (c) reacting the compound of formula III with a compound of formula VII in the presence of a base, preferably DBU, in an inert solvent, preferably THF, to obtain a compound of formula VIII;

[0130] In another preferred embodiment, the step (c) is carried out in the presence of pinacol.

[0131] In another preferred embodiment, the step (c) is carried out under inert gas protection.

[0132] In another preferred embodiment, the inert gas in the step (c) is nitrogen.

[0133] In another preferred embodiment, the reaction temperature in the step (c) is 10-40 °C.

[0134] In another preferred embodiment, the reaction time in the step (c) is 8-36 h.

[0135] (d) reacting the compound of formula VIII with a compound of formula 6 in the presence of PdCl2-XantPhos in an inert solvent, preferably THF / H2O mixture, to obtain a compound of formula IX;

[0136] In another preferred embodiment, the step (d) is carried out in the presence of K3PO4.

[0137] In another preferred embodiment, the step (d) is carried out under inert gas protection.

[0138] In another preferred embodiment, the reaction temperature in the step (d) is 50-60 °C.

[0139] In another preferred embodiment, the reaction time in the step (d) is 1-9 h.

[0140] (e) deprotecting the compound of formula IX in an inert solvent to obtain a compound of formula I;

[0141] wherein R 1 and R 3 are as defined in the first aspect of the present application.

[0142] In another preferred embodiment, the inert solvent of step (e) comprises a mixture of n-butanol and water.

[0143] In another preferred embodiment, the reaction temperature of step (e) is 80-100°C.

[0144] In another preferred embodiment, the reaction time of step (e) is 3-5h.

[0145] In another preferred embodiment, the compound 6 is prepared by the following method:

[0146] reacting the compound of formula 5 with Boc2O in an inert solvent to obtain the compound of formula 6.

[0147] In another preferred embodiment, the inert solvent of the reaction is a mixture of THF and DMAP.

[0148] In another preferred embodiment, the reaction temperature is 10-30°C.

[0149] In another preferred embodiment, the reaction time is 3-5h

[0150] In a fourth aspect of the present application, there is provided an intermediate selected from the group consisting of:

[0151] wherein R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl;

[0152] R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2;

[0153] X is N + (R 4 )R 5 or O; Y is NR 4 R 5 or hydroxyl; wherein R 4 and R 5 are each independently selected from the group consisting of C1-C4 alkyl, or R 4 and R 5together with the N atom to which it is attached, form a 4-7 membered saturated heterocyclic ring, and said saturated heterocyclic ring can include 1, 2, or 3 heteroatoms selected from N or O.

[0154] In another preferred embodiment, the method for preparing the compound of formula IV in the intermediate comprises:

[0155] reacting the compound of formula III with hydrazine in an inert solvent to obtain the compound of formula IV; wherein each group is defined as described in the fourth aspect of the present application.

[0156] In another preferred embodiment, the inert solvent comprises acetonitrile.

[0157] In another preferred embodiment, the reaction is carried out in the dark.

[0158] In another preferred embodiment, the reaction is carried out under inert gas protection.

[0159] In another preferred embodiment, the reaction temperature is 10-20 °C.

[0160] In another preferred embodiment, the reaction time is 1-8 h.

[0161] In another preferred embodiment, the molar ratio of the compound of formula III to hydrazine in the reaction is 1:(1-4).

[0162] In another preferred embodiment, the reaction further comprises obtaining a salt solution of the compound of formula III.

[0163] In another preferred embodiment, the salt solution of the compound of formula III comprises a tartaric acid salt solution of the compound of formula III.

[0164] In another preferred embodiment, the method for preparing the compound of formula II in the intermediate comprises:

[0165] reacting the compound of formula I with compound 1, POCl3 in an inert solvent to obtain the compound of formula II; wherein each group is defined as described above.

[0166] In another preferred embodiment, the inert solvent is acetonitrile.

[0167] In another preferred embodiment, the reaction is carried out under inert gas protection.

[0168] In another preferred embodiment, the inert gas is nitrogen.

[0169] In another preferred embodiment, POCl3, the compound of formula I, and compound 1 are added in batches in the reaction.

[0170] In another preferred embodiment, the reaction comprises:

[0171] In another preferred embodiment, the reaction comprises:

[0172] a) adding POCl3 in an inert solvent at a temperature of 0-20°C;

[0173] b) adding the compound of formula I to the reaction mixture while maintaining the temperature at 0-20°C during the addition;

[0174] c) increasing the temperature of the reaction mixture to 20-30°C, adding compound 1 in portions, and controlling the reaction temperature not to exceed 25-35°C.

[0175] In another preferred embodiment, the reaction temperature is 40-90°C.

[0176] In another preferred embodiment, the reaction time is 2-10h.

[0177] In another preferred embodiment, the reaction comprises a molar ratio of the compound of formula I to compound 1 of 2.0-2.5:1.

[0178] In a fifth aspect, the present application provides a method for preparing a compound of formula Ia, which comprises the steps of:

[0179] (1) reacting a compound of formula R-3 with hydrazine in acetonitrile to obtain a compound of formula R-4;

[0180] (2) reacting a compound of formula R-4 with any one of compounds of formula 2a-2g in methanol to obtain a compound of formula Ia; wherein, R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C8 cycloalkyl;

[0181] R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C8 cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2.

[0182] In another preferred embodiment, the method further comprises:

[0183] (1) reacting compound 1 with POCl3 in an inert solvent to obtain a compound of formula 2p; preferably, the inert solvent is acetonitrile;

[0184] (2) reacting compound 2p with a base in an inert solvent to obtain compound 2e; preferably, the base is NaOH;

[0185] (3) reacting 2e with Et2NH in an inert solvent to obtain compound 2f; in another preferred embodiment, the inert solvent in the reaction is anhydrous ethanol;

[0186] wherein each R is independently selected from the group consisting of Me, Et, Bu; or two R on the same N atom together form -(CH2)5- or -(CH2)2O(CH2)2-; and two R on one nitrogen atom are the same substituent.

[0187] In another preferred embodiment, the method further comprises:

[0188] (1) reacting a compound of formula (S)-3 with hydrazine in acetonitrile to obtain a compound of formula (S)-4;

[0189] (2) reacting a compound of formula (S)-4 with a compound of formula 2a in methanol to obtain a compound of formula Ib.

[0190] In another preferred embodiment, the method further comprises:

[0191] (1) reacting a compound of formula (S)-3 with hydrazine in acetonitrile to obtain a compound of formula (S)-4;

[0192] (2) reacting a compound of formula (S)-4 with a compound of formula 2g in acetonitrile to obtain a compound of formula 20;

[0193] (3) reacting a compound of formula 20 with BF3·Et2O in acetonitrile to obtain a compound of formula Ic.

[0194] In a fifth aspect, the present application provides a method for preparing a compound of formula Ia, which comprises the steps of:

[0195] (1) reacting a compound of formula 5 with Boc2O in DMAP to obtain a compound of formula 6;

[0196] (2) reacting a compound of formula 3 with a compound of formula 7 in the presence of a base and pinacol in THF to obtain a compound of formula 8;

[0197] (3) reacting a compound of formula 8 with 6 in acetonitrile to obtain a compound of formula 9.

[0198] (4) reacting a compound of formula 9 with n-BuOH in water to obtain a compound of formula Ia.

[0199] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0200] Figure 1 is a schematic diagram of the asymmetric unit of the single crystal structure model of compound 2a. DETAILED DESCRIPTION

[0201] The present application provides a method for preparing (R)-2-{3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(N-cyclopropyliminoethylsulfonyl)azetidin-3-yl}acetonitrile, which successfully prepares a compound with a chiral center by introducing a chiral center and then performing subsequent reactions. Based on the above findings, the inventors completed the present application.

[0202] Preparation of the compound of formula I

[0203] The present application provides a method for synthesizing compound I and its intermediates. The chemical structure of compound I is shown in formula I:

[0204] Chinese patent CN108341820 discloses a method for synthesizing compound I. Compound I is a class of highly effective JAK1 selective inhibitors.

[0205] In WO2018 / 133875A1, the method for preparing (R)-2-{3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(N-cyclopropyliminoethylsulfonyl)azetidin-3-yl}acetonitrile is:

[0206] The disadvantage of this route is that the separation is carried out in the last stage, which is costly. Moreover, step 7 cannot be scaled up to hundreds of grams due to the instability of the intermediate in the reaction process; the product of step 7 is an oil, and the by-product triphenylphosphine oxide cannot be removed by recrystallization or slurry method, but only by column chromatography, which requires a long time for separation and purification, and is costly. The last step for removing the SEM protecting group is harsh in conditions, and purification is difficult. This route is not suitable for scale-up production.

[0207] To solve the above technical problems, the present application provides a synthetic route of (R)-2-{3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(N-cyclopropyliminoethylsulfonyl)azetidin-3-yl}acetonitrile, specifically, the synthetic route uses compound R-3 as raw material, and obtains compound of formula Ia through two-step reaction, and the specific process is as follows:

[0208] comprising the following steps:

[0209] 1. Compound R-3 reacts with hydrazine to generate compound R-4.

[0210] 2. Compound R-4 and any one of 2a-2g generate compound Ia.

[0211] In another embodiment, the compound 3 can also be prepared by coupling with borate to generate compound of formula Ia,

[0212] Preparation of compound of formula III

[0213] The present application also provides a preparation method of compound of formula III, and the compound of formula III can be prepared by following method A, B or C:

[0214] Method A

[0215] In inert solvent, compound of formula XVI reacts with compound of formula XI to generate compound of formula III.

[0216] In another preferred embodiment, the reaction is carried out in the presence of N,N-diisopropyl ethylamine.

[0217] In another preferred embodiment, the inert solvent is dichloromethane.

[0218] In another preferred embodiment, the reaction temperature is -65 to -55℃.

[0219] In another preferred embodiment, the reaction time is 0.5-8h.

[0220] Method B

[0221] In inert solvent, compound of formula XVII reacts with compound of formula XI to generate compound of formula III.

[0222] In another preferred embodiment, the reaction is carried out in the presence of triphenyl phosphine and hexachloroethane.

[0223] In another preferred embodiment, the reaction is carried out in the presence of triethylamine.

[0224] In another preferred embodiment, the inert solvent is chloroform.

[0225] In another preferred embodiment, the reaction temperature is -5 to 5°C.

[0226] In another preferred embodiment, the reaction time is 0.1 to 0.5 h.

[0227] In another preferred embodiment, the R 3 is (t-Bu)Si(Ph)2.

[0228] After the preparation process, the chiral compound can be obtained by chiral column separation.

[0229] Method C

[0230] In an inert solvent, the compound of formula (III) is reacted with to obtain the (R)-III compound.

[0231] In another preferred embodiment, the R 1 is ethyl, and the method further comprises:

[0232] In another preferred embodiment, the R 1 is ethyl, and the R 3 is (t-Bu)SiMe2, and the method further comprises:

[0233] In another preferred embodiment, the R 1 is ethyl, and the R 3 is (t-Bu)SiMe2, and the method further comprises:

[0234] The main advantage of the present application compared to the prior art is that:

[0235] The preparation route of the present application is simple in operation, the intermediates in each step are easy to purify, the quality is controllable, the final product is easy to purify, the overall cost is low. The product prepared by the process has stable quality, and only needs to be treated by recrystallization or beating and washing, the product purity can reach more than 99.5%, meeting the quality control requirements, and having good process reproducibility.

[0236] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The experimental methods in the following examples without specific conditions are usually carried out according to conventional conditions, or according to the conditions suggested by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0237] Example 1: Synthesis of (R)-{1-(N-cyclopropyliminoethylsulfonyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile

[0238] Synthesis Route 1:

[0239] Step 1-1a: Synthesis of [(2E)-3-(diethylammonio)-2-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)prop-2-enylidene]diethylammonium dichloride

[0240] Under N2protection, POCI3(170 mL) was added to acetonitrile (1.00 L), and the temperature was lowered to 5-10 °C in an ice bath. N,N-diethylformamide (500 mL) was added dropwise, and the temperature was controlled to be within 5-15 °C. The addition was completed in 40 minutes. After the addition was completed, the temperature was raised to 20 °C, and 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (100 g) was added in batches, and the temperature was not allowed to exceed 30 °C. After stirring for about 10 minutes, the temperature was raised to 70 °C, and the reaction was performed for 5 h. The solid was completely dissolved, and a sample was taken for HPLC detection (1.66% of the raw material remained). The temperature was lowered to 50 °C, THF (800 mL) was added, and the solid was precipitated. The mixture was stirred at room temperature overnight, and then acetonitrile / methyl tert-butyl ether (500 mL, 1:1) was added. The mixture was filtered, the filter cake was rinsed with acetonitrile / methyl tert-butyl ether (500 mL, 1:1), and the filter cake was dried under vacuum to obtain a light yellow solid 285.6 g (containing 6.9% acetonitrile), with a yield of 95.1% and a purity of 99.67%. 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.99 (s, 1H), 8.33 (s, 2H), 7.87 (t, J = 2.5 Hz, 1H), 6.68 (dd, J = 3.6, 1.7 Hz, 1H), 3.56 (q, J = 7.1 Hz, 4H), 2.76 (s, 4H), 2.09 (s, 2H), 1.28 (t, J = 7.1 Hz, 6H), 0.64 (t, J = 7.1 Hz, 6H).

[0241] The single crystal X-ray diffraction results of compound 2a are shown in FIG. 1, and the single crystal diffraction data are as follows:

[0242] 1. Single crystal diffraction data collection

[0243] A single crystal of suitable size and diffraction quality was selected from a crystal sample of compound 2a, wrapped in Santovac Cryo Oil crystal protective oil and stuck on a Cryoloop. The single crystal sample was then mounted on a goniometer head in a random orientation, with the crystal immersed in a stream of cold (T = 120 K) nitrogen gas. The diffraction pre-experiment and data collection were performed using a Rigaku XtaLAB Synergy R single crystal diffractometer (Cu target, = 1.5418 A) at 120 K. ) at 120 K.

[0244] The lowest and highest theta angles for data collection were 4.385° and 77.175°, respectively. Based on 20655 reflections collected in the range 4.3470° < θ < 76.9030°, the unit cell parameters and orientation matrix were determined by indexing (T-vector algorithm) using the CrysAlisPro (version: 1.171.42.89a) program. The data were truncated to a maximum resolution of The data completeness was 99.92% and the average signal-to-noise ratio (I / σ) was 60.0.

[0245] 2. Reduction of single crystal diffraction data

[0246] Each frame of diffraction image collected by the detector was reduced and integrated simultaneously using the CrysAlisPro (version: 1.171.42.89a) program with Lorentz and polarization corrections. A total of 24693 reflections were collected in the range 4.385° < θ < 77.175°, of which 4849 were unique. The diffraction data were empirically absorption-corrected (Spherical Harmonics method) using the SCALE3 ABSPACK algorithm in the CrysAlisPro (version: 1.171.42.89a) program. The linear absorption coefficient of the crystal sample for X-rays of wavelength was 2.666 mm -1 , the minimum transmission coefficient (T min ) was 0.72924, and the maximum transmission coefficient (T max ) was 1.00000. The average value of the intensity agreement factors (R int ) for all equivalent reflections was 2.72%, indicating that the intensities of equivalent reflections were essentially equal within experimental error.

[0247] 3. Method of single crystal structure solution and refinement

[0248] Single crystal structure analysis was performed using Olex2 (version: 1.5) software. The structure was solved (using Intrinsic Phasing method) and the space group was determined to be P212121 using ShelXT (version: 2018 / 2) as the initial program. Subsequently, ShelXL (Version: 2018 / 3) refinement program was used for full-matrix least-squares structure refinement based on F 2 values. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined using the riding model.

[0249] 4. Software for calculating the theoretical XRPD of single crystal structure

[0250] The calculated XRPD pattern (Cu target X-ray) of single crystal structure data was calculated by Mercury (version: 4.3.1) software based on the atomic coordinates, space group and unit cell parameters of the crystal structure.

[0251] 5. Software for drawing a schematic diagram of single crystal structure

[0252] The crystal structure schematic diagram was drawn using Olex2 (version: 1.5) software and Diamond (version: 3.2k) software. The thermal ellipsoid plot was drawn using ORTEP-III (version: 2014.1) software.

[0253] 6. Instrument information

[0254] The single crystal X-ray diffraction data of compound 2a was collected at a temperature of 120 K using a Rigaku XtaLAB Synergy R single crystal diffractometer. The instrument parameter information of the single crystal diffractometer is listed in Table 1 below, respectively.

[0255] 7. Single crystal structure model data table

[0256] Table 2: Coordinates of non-hydrogen atoms (x 10 4 ) and equivalent isotropic displacement parameters in the single crystal structure model of compound 2a

[0257] Table 3: Anisotropic displacement parameters of non-hydrogen atoms in the single crystal structure model of compound 2a

[0258] Table 4: Bond length table in the single crystal structure model of compound 2a

[0259] Table 5: Table of bond angles in the single crystal structure model of compound 2a

[0260] Table 6: Table of torsion angles in the single crystal structure model of compound 2a

[0261] Table 7: Table of hydrogen atom coordinates in the single crystal structure model of compound 2a and isotropic displacement parameters

[0262] Step 1-1b: Synthesis of [(2E)-3-(dibutylammoniumyl)-2-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)prop-2-enylidene]dibutylammonium dichloride

[0263] POCl3(8 mL) was added to acetonitrile (50 mL) under N2protection, cooled to 0 °C, N,N-dibutylformamide (25 mL) was added dropwise, temperature controlled within 10 °C. After dropwise addition, the temperature was raised to room temperature, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine, compound 1 (5 g) was added, stirred for about 10 minutes, then the temperature was raised to 70 °C, stirred for 3 h, the reaction solution was clear. TLC monitoring compound 1 disappeared, the solvent was concentrated under reduced pressure, water (100 mL) was added, extracted with ethyl acetate (150 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated to nearly dry under reduced pressure, the oil product was solidified after standing overnight, added ethyl acetate (100 mL) and stirred at room temperature, filtered to give 13.5 g of yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.90 (s, 1H), 8.07 (s, 2H), 7.77 (t, J = 2.9 Hz, 1H), 6.50 (dd, J = 3.6, 1.7 Hz, 1H), 3.45 (t, J = 7.4 Hz, 4H), 2.62 - 2.55 (m, 4H), 1.62 (m, 4H), 1.31 (m, 4H), 1.22 (m, 1H), 0.93 (t, J = 7.3 Hz, 6H), 0.89 (br, 2H), 0.37 (br, 6H), 0.21 (br, 2H).

[0264] Step 1-1c: Synthesis of 1-[(2E)-3-(hexahydropyridin-1-yl)-2-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)prop-2-enylidene]hexahydropyridine dichloride

[0265] POCI3(8 mL) was added to acetonitrile (50 mL) under N2protection, cooled to 0 °C, N- formylpiperidine (25 mL) was added dropwise, temperature controlled within 10 °C. After dropwise addition, the reaction was allowed to warm to room temperature, 4-methyl-7H-pyrrolo[2,3- d]pyrimidine, compound 1 (5 g) was added, stirred for about 10 minutes, the reaction was clear, warmed to 70 °C, solid appeared, the reaction was clear again, stirred for 3 h. TLC monitored compound 1 disappeared. Cooled to room temperature, no solid appeared. THF (40 mL) was added dropwise, oily sticky substance appeared. After standing, the supernatant was poured out, the remaining sticky substance was slurried with ethyl acetate / n-heptane (100 mL, 1:1), filtered, the solid was slurried with THF (50 mL) again, filtered, the filter cake was dried under vacuum to give yellow solid 10.7 g.

[0266] Step 1-1d: Synthesis of 1-[(2E)-3-(morpholine-1-yl)-2-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)prop-2-enylidene]morpholine-1,4-dione

[0267] POCI3(8 mL) was added to acetonitrile (50 mL) under N2protection, cooled to 0 °C, N- formylpiperidine (25 mL) was added dropwise, temperature controlled within 10 °C. After dropwise addition, the reaction was allowed to warm to room temperature, 4-methyl-7H-pyrrolo[2,3- d]pyrimidine, compound 1 (5 g) was added, stirred for about 10 minutes, the reaction was clear, warmed to 70 °C, solid appeared, the reaction was clear again, stirred for 3 h. TLC monitored compound 1 disappeared. Cooled to room temperature, no solid appeared. THF (40 mL) was added dropwise, oily sticky substance appeared. After standing, the supernatant was poured out, the remaining sticky substance was slurried with ethyl acetate / n-heptane (100 mL, 1:1), filtered, the solid was slurried with THF (50 mL) again, filtered, the filter cake was dried under vacuum to give yellow solid 10.7 g. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.44 (s, 1H), 8.95 (s, 1H), 8.32 (s, 2H), 8.03 (s, 1H), 7.94 - 7.84 (m, 1H), 6.76 (s, 1H), 3.80 (s, 8H), 3.63 - 3.36 (m, 8H).

[0268] Step 1-2: Synthesis of 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2-enal

[0269] [(2E)-3-(Diethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2-enylidene] diethylammonium dichloride (10.00 g) was added to an aqueous sodium hydroxide solution (4.30 g of sodium hydroxide in 100 mL of water) under N2protection, stirred at room temperature overnight, after TLC tracking showed the disappearance of the starting material, the reaction system was cooled with an ice water bath, 6N hydrochloric acid was added dropwise until the pH was 4-5, a solid was precipitated, filtered, the solid was washed with water, and dried under vacuum to obtain a white solid 4.46 g, with a yield of 87.8%. 1 H NMR (400 MHz, DMSO-d6) δ 15.72 (s, 1H), 12.80 (s, 1H), 9.52 (s, 2H), 8.75 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 7.53 (s, 1H).

[0270] Step 1-3: Synthesis of (2E)-3-(diethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2- enal

[0271] 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2-enal (2.00 g) and diethylamine (7.75 g) were added to anhydrous ethanol (100 mL), heated to reflux for 4 h, the solid was completely dissolved, TLC showed that the starting material was substantially disappeared, the solvent was concentrated to dryness under reduced pressure, acetonitrile (25 mL) was added to the residue, heated to reflux until a large amount of solid precipitated, then cooled to room temperature, filtered, the filter cake was washed with acetonitrile and methyl tert-butyl ether in turn, and dried under vacuum to obtain a solid 1.89 g, with a yield of 73.0%. 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.09 (s, 1H), 8.68 (s, 1H), 7.43 (d, J = 2.9 Hz, 1H), 7.40 (s, 1H), 6.24 (s, 1H), 3.38 (br, 2H), 2.96 (br, 2H), 1.22 (br, 3H), 0.53 (br, 3H).

[0272] Step 1-1g: Synthesis of [(2E)-3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2- enylidene]dimethylammonium perchlorate

[0273] POCI3(80 mL, 2.3 eq) was added to acetonitrile (500 mL, 10 V) under N2protection, cooled to 0-10 °C, dropwise added DMF (250 mL, 5 V), after dropwise addition, the system was allowed to warm to room temperature (20-25 °C) and stirred for 40 min, then 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (50 g, 1.0 eq) was added in batches. The system first dissolved and then precipitated solid. After stirring at room temperature for 10 min, it was warmed to 70 °C and incubated for 3.0 h. HPLC showed that the remaining 0.04% of the starting compound 1. It was cooled to about 35 °C, THF (400 mL, 8 V) was added, and it was stirred at room temperature overnight. Acetonitrile / MTBE = 1:1 (250 mL, 5 V) was added, and it was stirred at 0-10 °C for 3-4 h. It was filtered, eluted with MTBE, dried, and the solid was dissolved in water (300 mL, 6 V). NaOH solution (25 g NaOH dissolved in 50 mL water) was added to adjust the pH to 7. 10 g of activated carbon was added and stirred at room temperature for 1.0 h. It was filtered, the solid was washed with water (50 mL), the filtrate and the washing liquid were combined, NaClO4(80 g, 1.5 eq) was added, and it was cooled to 0-10 °C and stirred for 1.0 h. It was filtered, the solid was washed with n-heptane, and it was dried at 40 °C under vacuum to give 119.55 g of light yellow solid with a yield of 92.6% and a purity of 99.13%.

[0274] Step 2a: Synthesis of (R)-[l-(N-cyclopropylimine ethylsulfonyl)-3-hydrazino-azetidin-3- yl]acetonitrile

[0275] (R)-2-[l-(N-cyclopropylimine ethylsulfonyl)azetidin-3-ylidene]acetonitrile (10 g, 1.0 eq) was dissolved in acetonitrile (20 mL, 2 V) under N2protection and light protection, and cooled to 10 °C. The temperature was controlled at 10-20 °C, and hydrazine hydrate (4.3 g, 1.55 eq) was added dropwise. After dropwise addition, it was reacted at 10-20 °C for 1.5 h. HPLC showed that the starting compound (R)-3 was substantially completely reacted. Water (10 mL) was added to the system, and it was extracted with DCM (100 mL x 2). The organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 18 °C water bath to give an oil. The purity was 93.09%.

[0276] Step 2b: Synthesis of (R)-[l-(N-cyclopropylimine ethylsulfonyl)-3-hydrazino-azetidin-3- yl]acetonitrile di(D-tartaric acid) salt

[0277] Under N2protection, (R)-2-[1-(N-cyclopropylimineethanesulfonyl)azetidin-3- yl]acetonitrile di(D-tartaric acid) salt (1.65 g, 1.1 eq) and [(2E)-3-(diethylammoniumyl)- 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2-enylidene] diethylammonium dichloride (1 g, 1.0 eq) were added into methanol (10 mL, 10 V), heated to 45 °C for 20 h, sampled HPLC, the starting material compound 2a was left 0.5%, cooled to room temperature, added water (10 mL), then adjusted pH value to 7-8 with 5N NaOH solution, added seed crystal, stirred at room temperature for 40 min, added water (10 mL) dropwise, after dropping, stirred at room temperature overnight, filtered, the solid was rinsed with water, and dried at 45 °C with air blowing to obtain 0.774 g of light-colored solid, with a yield of 64.85%.

[0278] 1 H NMR (400 MHz, DMSO-d6) δ 4.27 (s, 4H), 3.91 (dd, J = 12.2, 8.4 Hz, 2H), 3.51 (d, J = 8.3 Hz, 2H), 3.08 (q, J = 7.5 Hz, 2H), 2.98 (s, 2H), 2.47 (m, 1H), 1.20 (t, J = 7.4 Hz, 3H), 0.46 - 0.35 (m, 2H), 0.33 - 0.18 (m, 2H).

[0279] Step 3a: Synthesis of (R)-{1-(N-cyclopropylimineethanesulfonyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile

[0280] N2protection, (R)-2-[1-(N-cyclopropylimineethanesulfonyl)azetidin-3- yl]acetonitrile di(D-tartaric acid) salt (1.65 g, 1.1 eq) and [(2E)-3-(diethylammoniumyl)- 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2-enylidene] diethylammonium dichloride (1 g, 1.0 eq) were added into methanol (10 mL, 10 V), heated to 45 °C for 20 h, sampled HPLC, the starting material compound 2a was left 0.5%, cooled to room temperature, added water (10 mL), then adjusted pH value to 7-8 with 5N NaOH solution, added seed crystal, stirred at room temperature for 40 min, added water (10 mL) dropwise, after dropping, stirred at room temperature overnight, filtered, the solid was rinsed with water, and dried at 45 °C with air blowing to obtain 0.774 g of light-colored solid, with a yield of 64.85%.

[0281] Step 3b: Synthesis of (R)-{1-(N-cyclopropylimine ethylsulfonyl)-3-[4-(7H- pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl} acetonitrile

[0282] (R)-[1-(N-cyclopropylimine ethylsulfonyl)-3-hydrazino-azetidin-3-yl] acetonitrile di(D-tartaric acid) salt (2.2 g, 1.5 eq) and 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) acrolein (0.5 g, 1.0 eq) were added to methanol (7.5 mL, 15V) and stirred at 25-30 °C for 4.5 h. HPLC sample was taken, purity: 97.68%, residual starting material: 0.13%. Water (15 mL) was added dropwise at room temperature. After the addition was completed, the mixture was stirred in an ice-water bath for 2.0 h. The solid was filtered, washed with methanol:H2O (5:1) solution and n-heptane, and dried under vacuum at 40 °C to give a solid 0.92 g in 85% yield.

[0283] Step 3c: Synthesis of (R)-{1-(N-cyclopropylimine ethylsulfonyl)-3-[4-(7H- pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl} acetonitrile

[0284] (R)-[1-(N-cyclopropylimine ethylsulfonyl)-3-hydrazino-azetidin-3-yl] acetonitrile di(D-tartaric acid) salt (2.2 g, 1.5 eq) and 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) acrolein (0.5 g, 1.0 eq) were added to methanol (7.5 mL, 15V) and stirred at 25-30 °C for 4.5 h. HPLC sample was taken, purity: 97.68%, residual starting material: 0.13%. Water (15 mL) was added dropwise at room temperature. After the addition was completed, the mixture was stirred in an ice-water bath for 2.0 h. The solid was filtered, washed with methanol:H2O (5:1) solution and n-heptane, and dried under vacuum at 40 °C to give a solid 0.92 g in 85% yield.

[0285] Step 3d: Synthesis of (R)-{1-(N-cyclopropylimine ethylsulfonyl)-3-[4-(7H- pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl} acetonitrile

[0286] (R)-[1-(N-cyclopropylimineethyisulfanyl)-3-hydrazino-azetidin-3-yl]acetonitrile di(D-tartaric acid) salt (1.78 g, 1.1 eq) and [(2E)-3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2-enylidene]dimethylammonium perchlorate (1.00 g, 1.0 eq) were added to methanol (10 mL, 10V) under N2protection, heated to 45 °C for 3 h, sampled HPLC, starting material remaining 0.55%, 40 °C water bath evaporated methanol under reduced pressure, added water (20 mL), then adjusted pH to 7-8 with 5N NaOH solution, stirred at room temperature overnight, filtered, solid washed with water, 45 °C air-dried to get 0.69 g solid, yield: 57.8%, purity: 97.03%.

[0287] Step 3e: Synthesis of (R)-{1-(N-cyclopropylimineethyisulfanyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3-yl}acetonitrile

[0288] N2protection, (R)-[l-(N-cyclopropylimineethyisulfanyl)-3-hydrazino-azetidin-3- yl]acetonitrile di(D-tartaric acid) salt (1.78 g, 1.1 eq) and [(2E)-3-(dimethylamino)-2- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2-enylidene]dimethylammonium perchlorate (1.00 g, 1.0 eq) were added to methanol (10 mL, 10V), heated to 45 °C for 3 h, sampled HPLC, starting material remaining 0.55%, 40 °C water bath evaporated methanol under reduced pressure, added water (20 mL), then adjusted pH to 7-8 with 5N NaOH solution, stirred at room temperature overnight, filtered, solid washed with water, 45 °C air-dried to get 0.69 g solid, yield: 57.8%, purity: 97.03%.

[0289] Example 2: Synthesis of (S)-{l-(N-cyclopropylimineethyisulfanyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3-yl}acetonitrile

[0290] Step 1: Synthesis of (S)-[l-(N-cyclopropylimineethyisulfanyl)-3-hydrazino- azetidin-3-yl]acetonitrile

[0291] Under N2protection, (S)-2-[l-(N-cyclopropylimineethyle sulfuryl)-azetidin-3- yl]acetonitrile (60 g, 1.0 eq) was dissolved in acetonitrile (120 mL, 2V) and cooled to 10 °C, and 80% hydrazine hydrate (25 g, 1.5 eq) was added dropwise at a temperature of 10-20 °C. After the dropwise addition was completed, the reaction was allowed to proceed at 10-20 °C for 1.5 h. A sample was taken for HPLC analysis, which showed that the starting compound (S)-3 was substantially completely reacted. Water (60 mL) was added to the system, and extraction was performed with DCM (600 mL x 2). The combined organic phase was washed once with saturated brine (60 mL), and the organic phase was dried over anhydrous sodium sulfate. The oil obtained after concentration under reduced pressure at a water bath temperature of 18 °C was 68 g.

[0292] Step 2:

[0293] Under N2protection, (S)-2-[l-(N-cyclopropylimineethyle sulfuryl)-azetidin-3- yl]acetonitrile (60 g, 1.0 eq) was dissolved in acetonitrile (120 mL, 2V) and cooled to 10 °C, and 80% hydrazine hydrate (25 g, 1.5 eq) was added dropwise at a temperature of 10-20 °C. After the dropwise addition was completed, the reaction was allowed to proceed at 10-20 °C for 1.5 h. A sample was taken for HPLC analysis, which showed that the starting compound (S)-3 was substantially completely reacted. Water (60 mL) was added to the system, and extraction was performed with DCM (600 mL x 2). The combined organic phase was washed once with saturated brine (60 mL), and the organic phase was dried over anhydrous sodium sulfate. The oil obtained after concentration under reduced pressure at a water bath temperature of 18 °C was 68 g.

[0294] Example 3: Synthesis of (R)-{l-(N-cyclopropylimineethyle sulfuryl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3-yl}acetonitrile

[0295] Synthesis Route 2:

[0296] Step 1: Synthesis of 4-chloropyrrolo[2,3-d]pyrimidine-7-carboxylic acid-2- methylprop-2-yl ester

[0297] To a three-necked flask, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (96 g, 625 mmol, 1.00 eq), DMAP (153 mg, 1.25 mmol, 0.002 eq) and THF (960 mL, 10 V) were added successively at 20-30 °C. The solids were stirred to dissolve completely. A solution of (Boc)2O (157 g, 719 mmol, 1.15 eq) in THF (580 mL, 6 V) was added dropwise through a dropping funnel. The system was controlled to prevent the solution from rushing out due to the gas evolution. After the addition was completed, the system became a suspension, which turned into a red-brown solution after stirring for about 4 h. HPLC showed that compound 5 was consumed completely. The solvent was concentrated under reduced pressure to give a solid. n-Heptane (400 mL) was added to disperse the solid at 20-25 °C. The system was slowly cooled to 0-5 °C. After stirring for 2 h, the solid was filtered and dried under vacuum to give a solid 135 g in 85.1% yield, 1 H NMR (400 MHz, CDC13) δ 8.85 (s, 1H), 7.72 (d, J = 4.1 Hz, 1H), 6.66 (d, J = 4.1 Hz, 1H), 1.70 (s, 9H).

[0298] Step 2a: Synthesis of (R)-{l-(N-cyclopropyliminoethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]azetidin-3-yl}acetonitrile

[0299] Into a three-necked flask, was added THF (890 mL, 2.7 V / W), pinacol (52.1 g, 0.44 mol, 0.3 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (341.7 g, 1.76 mol, 1.2 eq) and (R)-2-[1-(N- cyclopropylimineethylsulfonyl)azetidin-3-ylidene]acetonitrile (330.0 g, 1.46 mol, 1.0 eq) under N2protection. The solid was dissolved by heating, and the solution was clear at 25 °C. DBU (44.7 g, 0.29 mol, 0.2 eq) was added dropwise, and the temperature was raised to 30 °C and stirred overnight. The solvent was evaporated under reduced pressure (300 mL). Methyl tert-butyl ether (900 mL) was added, and the solvent was evaporated under reduced pressure (800 mL). Methyl tert-butyl ether (500 mL) was added, and the solvent was evaporated under reduced pressure (200 mL, oil bath 40 °C, internal temperature < 30 °C). Isopropanol (2 L) was added. The solvent was evaporated under reduced pressure (600 mL, oil bath 40-45 °C, internal temperature 30-40 °C). Methyl tert-butyl ether (330 mL) was added, and the sample was analyzed by GC to determine that the THF content in the solvent was < 1%. The distillation was stopped, and the temperature was lowered to 20 °C with stirring. The solid was filtered, rinsed with isopropanol:methyl tert-butyl ether = 4:1 (800 mL), and n-heptane (1 L), and the filter cake was collected and dried to give a white solid (493.4 g, 1.18 mol, 80.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.77 (s, 1H), 4.43 (dd, J = 9.0, 6.5 Hz, 2H), 4.09 (dd, J = 8.9, 3.9 Hz, 2H), 3.57 (s, 2H), 3.11 (q, J = 7.3 Hz, 2H), 1.27 (s, 12H), 1.18 (t, J = 7.3 Hz, 3H), 0.54 - 0.08 (m, 4H).

[0300] LCMS: 420 [M+H] +

[0301] Step 2b: Synthesis of (R)-{1-(N-cyclopropylimineethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile:

[0302] 32 °C oil bath, 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (353 g, 1.82 mol, 1.2 eq), (R)-2-[l-(N-cyclopropylimineethylsulfonyl)azetidin-3-ylidene]acetonitrile (342 g, 1.52 mol, 1.0 eq) and pinacol (54 g, 0.45 mol, 0.3 eq) were added into THF (1026 mL, 3V, KF <0.1%) and stirred, the solution was clear at 18 °C, DBU (36 g, 0.30 mol, 0.2 eq) was added dropwise, the reaction system was exothermic, and the temperature rose to 25 °C. The oil bath was raised to 38 °C, and the internal temperature rose to 28 °C. Stirring was continued for 16 h. HPLC detection showed that the conversion rate of compound 3 was 90%, 0.1 eq of compound 7 was added, and stirring was continued at 29 °C for 3 h. 0.05 eq of DBU was added, and stirring was continued at 29 °C for 2 h. The conversion rate was 94%. The solvent was concentrated under reduced pressure, isopropyl alcohol (1.00 L) was added, and the solvent was concentrated under reduced pressure again. A brown oil-solid mixture weighing 954.9 g was obtained. Isopropyl alcohol (1.36 L) and methyl tert-butyl ether (342 mL) were added, and stirring was continued at 38 °C for 3 hrs. The temperature was cooled to 10-15 °C, and filtration was performed. Isopropyl alcohol:methyl tert-butyl ether = 4:1 and n-heptane were used for washing in sequence. The filter cake was collected and dried to obtain a white solid powder weighing 518.7 g, with a yield of 81%. HPLC purity was 99.76%, and the pinacol content detected by gas chromatography was 1.43%.

[0303] Steps 2a and 2b can optionally be prepared using suitable methods, and the resulting products can be used in step 3.

[0304] Step 3a: Synthesis of (R)-4-{l-[l-(N-cyclopropylimineethylsulfonyl)-3-(cyanomethyl)- azetidin-3-yl]pyrazol-4-yl}pyrrolo[2,3-d]pyrimidine-7-carboxylic acid-2-methylprop-2-yl ester

[0305] Into a 3-necked flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-chloropyrrolo[2,3-d]pyrimidine-7-carboxylic acid-2-methylprop-2-yl ester (44 g, 173.4 mmol, 1.05 eq), (R)-{1-(N-cyclopropyliminoethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile (70 g, 166.9 mmol, 1.0 eq), K3PO4 (70 g, 329.8 mmol, 2.0 eq), PdCl2-XantPhos (2 g, 2.50 mmol, 0.015 eq). The flask was replaced with argon three times. THF (700 mL, 10V) and pure water (210 mL, 3V) were added, and the flask was replaced with argon three times again. The mixture was heated to 54 °C and stirred for 3 h. HPLC detection showed that the compound 6 was less than 0.3%, which was considered as complete reaction. Mercaptosilica gel (7.0 g) was added, and the heating was stopped. The mixture was cooled to room temperature. Filtration was performed, and the organic phase was stirred at 70 °C. n-Heptane (910 mL, 13V) was added in batches. The internal temperature was maintained at 50-55 °C, and solids gradually precipitated. The temperature was slowly decreased to 15-25 °C, and the mixture was continuously stirred at this temperature for 3 h. Filtration was performed, and the filter cake was collected and dried under vacuum to obtain the product as a pink to white solid 82.5 g in yield of 97.0%. HPLC purity 99.5%. 1 H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 7.70 (d, J = 4.1 Hz, 1H), 6.78 (d, J = 4.1 Hz, 1H), 4.61 (d, J = 8.9 Hz, 2H), 4.24 (t, J = 8.2 Hz, 2H), 3.41 (s, 2H), 3.10 (ddq, J = 28.7, 14.4, 7.2 Hz, 2H), 2.63 (tt, J = 6.8, 3.9 Hz, 1H), 1.68 (s, 9H), 1.38 (t, J = 7.4 Hz, 3H), 0.56 (m, 3H), 0.39 (tt, J = 8.1, 5.0 Hz, 1H).

[0306] LCMS: 511 [M+H] +

[0307] Step 3b: Synthesis of (R)-4-{1-[1-(N-cyclopropyliminoethylsulfonyl)-3-(cyanomethyl)-azetidin-3-yl]pyrazol-4-yl}pyrrolo[2,3-d]pyrimidine-7-carboxylic acid-2-methylprop-2-yl ester

[0308] To a three-necked flask, was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9.6 g, 62.6 mmol, 1.05 eq), DMAP (15.2 mg, 0.14 mmol, 0.002 eq) and THF (96 mL, 10 V) at 20-30 °C, dropwise added a solution of (Boc)20 (15.7 g, 72.0 mmol, 1.15 eq) in THF (58 mL, 6 V). The system was bubbled with gas, and the dropwise addition speed was appropriate to avoid overflow. After the dropwise addition was completed, the system became gray turbid. After about 2 h, it slowly dissolved again, and became a red-brown solution at 4 h. HPLC showed that 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was consumed completely, and a THF solution of 4-chloropyrrolo[2,3-d]pyrimidine-7-carboxylic acid-2-methylprop-2-yl ester was obtained. To the above solution was added (R)-{1-(N-cyclopropylimine ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile (25 g, 59.6 mmol, 1.0 eq), K3PO4 (25.3 g, 119.2 mmol, 2.0 eq), PdCl2-XantPhos (676 mg, 0.89 mmol, 0.015 eq) and pure water (75 mL, 3 V), and the system was replaced with argon three times, then the temperature was raised to 60 °C and stirred for 3 h. HPLC detection showed that the reaction was complete, the system was cooled to room temperature, separated, and the organic phase was collected. The aqueous phase was extracted with THF (25 mL) once. The combined organic phases were filtered. The filtrate was added to a three-necked flask, heated to 60 °C with stirring, added with n-heptane (100 mL) and methyl tert-butyl ether (60 mL), slowly reduced to room temperature, stirred overnight, filtered, and the filter cake was collected and dried under vacuum to obtain a solid (25.5 g, 49.9 mmol, yield 83.8%).

[0309] Steps 3a and 3b can optionally be prepared using suitable methods, and the resulting products can be used in step 4.

[0310] Step 4: Synthesis of (R)-{1-(N-cyclopropylimine ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile

[0311] (R)-4-{1-[1-(N-cyclopropylimineethylethylsulfonyl)-3-(cyanomethyl)-azetidin-3- yl]pyrazol-4-yl}pyrrolo[2,3-d]pyrimidine-7-carboxylic acid-2-methylprop-2-yl ester (610 g, 27.4 mmol, 1.0 eq) was added into n-butanol (4 L, 6.5 V) and purified water (1.22 L, 2 V), the system was heated to 90 °C, and the reaction was carried out for 4 h. HPLC detection showed that the residual raw material was less than 0.3%. Activated carbon (30 g, 0.5% wt%) was added for decolorization. The heating was stopped, and the system was cooled to 20-30 °C. Filtration was carried out, and the filtrate was concentrated under reduced pressure. Purified water (2.0 L) was added, and the solvent was further concentrated under reduced pressure. A large amount of solid was precipitated in the system, which was cooled to 20-25 °C and stirred overnight. Filtration was carried out, and the filter cake was washed with purified water. The filter cake was collected and dried under vacuum at 40 °C to obtain 426 g of solid, with a yield of 86.9% and a purity of 99.6%. 1 H NMR (600 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.93 (d, J = 0.7 Hz, 1H), 8.71 (s, 1H), 8.48 (d, J = 0.7 Hz, 1H), 7.62 (dd, J = 3.6, 2.4 Hz, 1H), 7.09 (dd, J = 3.6, 1.8 Hz, 1H), 4.59 (dd, J = 9.2, 5.0 Hz, 2H), 4.19 (dd, J = 9.2, 5.0 Hz, 2H), 3.67 (s, 2H), 3.15 (qd, J = 7.3, 1.3 Hz, 2H), 2.53 (tt, J = 7.2, 3.9 Hz, 1H), 1.20 (t, J = 7.3 Hz, 3H), 0.47-0.36 (m, 2H), 0.34-0.30 (m, 1H), 0.25-0.22 (m, 1H).

[0312] Example 4: Synthesis of (R)-2-[1-(N-cyclopropylimineethylethylsulfonyl)azetidin-3- ylidene]acetonitrile

[0313] Synthetic Route 3:

[0314] Step 1: Synthesis of azetidin-3-ylidenemethylcyanide hydrochloride

[0315] tert-Butyl 3-(cyanomethylidene)azetidine-1-carboxylate (1000 g) was dissolved in DCM (2 L, 2 V) under argon protection, and the temperature was lowered to 0-10 °C. HCl isopropanol solution (7.7 M, 4 L, 4 V) was added dropwise, and the dropping speed was controlled so that the temperature did not exceed 10 °C. After the dropwise addition was completed, the system was kept at 5-10 °C for 2 h. The reaction was sampled and sent for HPLC detection. The residual raw material was 0.8%, and the system was cooled to -10-0 °C. Methyl tert-butyl ether (6 L) was added dropwise, and the mixture was stirred at -10-0 °C for 1-2 h. The solid was filtered, washed with methyl tert-butyl ether, and the filter cake was collected and dried at 40 °C under vacuum to obtain 605 g of white solid, with a yield of 90% and a purity of 87%. The main impurity was 2-(3-chloroazetidin-3-yl)acetonitrile hydrochloride, which could be converted to the product in the next step.

[0316] Step 2: Synthesis of ethylsulfinyl chloride

[0317] Diethyl disulfide (3.0 kg, 24.54 mol, 1 eq) was added to glacial acetic acid (2.95 kg, 49.08 mol, 2 eq) under argon protection, and the mixture was stirred while the temperature was lowered to -20--10 °C. Sulfuryl chloride (10.27 kg, 76.08 mol, 3.1 eq) was added dropwise, and the temperature was controlled to be no higher than -5 °C during the dropwise addition. After the dropwise addition was completed, the mixture was stirred at -10--5 °C for 1 h, and then the temperature was naturally increased to 17-25 °C. During this period, a large amount of hydrogen chloride gas was released, and the mixture was stirred at 17-25 °C overnight until almost no hydrogen chloride gas was released. The sample was subjected to GC detection, and the residual diethyl disulfide was no more than 2%. The vacuum was controlled to be less than -0.09 MPa, and the external bath temperature was controlled to be 30-40 °C. Acetyl chloride was removed by distillation under reduced pressure to obtain ethylsulfinyl chloride as a light yellow liquid (5.52 kg), with a yield of 99%. The sample was subjected to GC detection, and the purity was 91%.

[0318] Step 3: Synthesis of N-cyclopropyl-ethylsulfmide

[0319] Cyclopropylamine (507 g, 8.88 mol, 1.0 eq) was dissolved in methyl-tert-butyl ether (8 L, 8 mL / g) under nitrogen protection, then triethylamine (944 g, 9.33 mol, 1.05 eq) was added, the temperature was lowered to -10 to -5 °C, and ethyl sulfinyl chloride (1000 g, 8.88 mol, 1.0 eq) in methyl-tert-butyl ether (2 L, 2 mL / g) was added dropwise through a dropping funnel, and the temperature was kept below -5 °C by controlling the dropping speed. After the dropwise addition was completed, the system was slowly warmed to 10 to 15 °C and stirred for 1 h. The reaction solution was filtered, the filter cake was washed with methyl-tert-butyl ether (2 L), and the filtrate was concentrated to obtain a light yellow oil. Fast column chromatography (ethyl acetate / n-hexane = 1:1) was performed to obtain 1057 g of light yellow to brown solid, with a yield of 89.3% and a purity of 85.8% (GC).

[0320] Step 4: Synthesis of (±)-2-[1-(N-cyclopropyliminoethylsulfonyl)azetidin-3- yliden]acetonitrile

[0321] N-cyclopropyl-ethylsulfonamide (860 g, 6.46 mol, 1.25 eq, calculated by 1H NMR external standard) was dissolved in dichloromethane (12.9 L, 15 mL / g) and cooled to <-70 °C under argon. Tert-butyl hypochlorite (700 g, 6.46 mol, 1.25 eq) was added dropwise while maintaining the temperature below -60 °C. After the addition was complete, the mixture was stirred for 10 minutes and then ground azetidin-3-ylidenacetonitrile hydrochloride (675 g, 5.17 mol, 1.0 eq) was added in one portion. The temperature was maintained below -60 °C while N,N-diisopropylethylamine (1595 g, 12.30 mol, 2.38 eq) was added dropwise. After the addition was complete, the mixture was stirred for 2 hours at -65 to -55 °C. The reaction was quenched by the addition of 9.1% sulfuric acid solution while maintaining the temperature at 0 °C. The pH of the aqueous phase was adjusted to 4-5. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined and concentrated under vacuum at a temperature of 30-40 °C and a pressure of less than -0.085 MPa. The residue was diluted with toluene (4 L) and added to 4 kg of 9.1% sulfuric acid. The mixture was stirred and separated. The aqueous phase was extracted with toluene (2 L) and the organic phases were combined. The combined organic phases were washed with 2 kg of 9.1% sulfuric acid. The aqueous phases were combined and stirred with activated carbon (100 g) for 30 minutes. The mixture was filtered and the filtrate was added to 13% ammonia water at 5-15 °C. When the pH reached 5-6, the total amount of 13% ammonia water added was about 1.4 kg. The mixture was stirred for 30 minutes at 5-15 °C and then filtered. The solid was collected to give crude (±)-2-[1-(N-cyclopropyliminoethylsulfanyl)azetidin-3-ylidene]acetonitrile. The crude (±)-2-[1-(N-cyclopropyliminoethylsulfanyl)azetidin-3-ylidene]acetonitrile was dissolved in dichloromethane (7 mL / g of crude product) and filtered through celite. The filtrate was concentrated under vacuum at a temperature of 30-40 °C and a pressure of less than -0.085 MPa. The residue was weighed and dissolved in dichloromethane (2 mL / g of concentrated residue). N-heptane (8 mL / g) was added dropwise while maintaining the temperature at 30-35 °C. When 2-2.6 mL / g of the concentrated residue was added, (±)-2-[1-(N-cyclopropyliminoethylsulfanyl)azetidin-3-ylidene]acetonitrile seed crystals were added in portions until the seed crystals were not dissolved. Additional seed crystals (about 3 g) were added and the remaining n-heptane was added. After the addition was complete, the mixture was cooled to 25-28 °C and stirred for 16 hours.Filter, the filter cake was washed with a mixed solvent of n-heptane / methyl tert-butyl ether = 4, and then dried at a temperature of 30-40 °C and a vacuum degree of <-0.09 MPa to obtain 531 g of a solid, a yield of 45.6% (calculated based on azetidin-3-ylideneacetonitrile hydrochloride), and a purity of 99.0%. 1 H NMR (400 MHz, CDC13) δ 5.44 (p, J = 2.5 Hz, 1H), 4.75 (t, J = 3.1 Hz, 2H), 4.72-4.66 (m, 2H), 3.20-3.08 (m, 1H), 3.02 (dq, J = 14.4, 7.3 Hz, 1H), 2.61 (tt, J = 7.0, 4.0 Hz, 1H), 1.37 (t, J = 7.4 Hz, 3H), 0.70-0.49 (m, 3H), 0.41 (tq, J = 8.0, 4.6, 4.1 Hz, 1H). LCMS: 226 [M+H] +

[0322] Step 5: Chiral resolution of (±)-2-[1-(N-cyclopropylimineethylsulfonyl)azetidin-3- ylidene]acetonitrile

[0323] (±)-2-[1-(N-cyclopropylimineethylsulfonyl)azetidin-3-ylidene]acetonitrile (80 g) was dissolved in n-heptane / isopropanol (4:1, 500 mL) and separated by preparative HPLC, with a Chiralpak AY-H column, a column temperature of 25-35 °C, and a mobile phase of n-heptane / isopropanol (4:1). The first fraction was collected as the mobile phase for (R)-2-[1-(N-cyclopropylimineethylsulfonyl)azetidin-3-ylidene]acetonitrile, and concentrated under reduced pressure to obtain 35 g of a solid, a yield of 43.8%, 99.52 ee%, and the second fraction was collected as the mobile phase for (S)-2-[1-(N-cyclopropylimineethylsulfonyl)azetidin-3-ylidene]acetonitrile, and concentrated under reduced pressure to obtain 38 g of a solid, a yield of 47.5%, 99.48 ee%.

[0324] Example 5:

[0325] Synthetic Route 4:

[0326] Step 1: Synthesis of N-diphenyl tert-butylsilyl ethyl sulfonamide

[0327] NaH (3.67 g, 2.0 eq) was added to DMAc (50 mL, 10 V) under nitrogen protection and cooled to 0 °C. Ethyl sulfonamide (5 g, 1.0 eq) and TBDPSCl (15.11 g, 1.2 eq) were dissolved in DMAc (50 mL, 10 V) and added dropwise to the above suspension at a temperature <20 °C. After the dropwise addition, the temperature was increased to 25-30 °C and the reaction was allowed to proceed for 2 h. The reaction solution was poured into 0.5 N aqueous hydrochloric acid (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to dryness. The residue was added to n-heptane (50 mL) and stirred for 2 h. The solid was filtered and dried under vacuum to obtain 13.31 g of white solid with a yield of 83.7%.

[0328] Step 2: Synthesis of 2-[1-(N-diphenyl-tert-butylsilyliminoethylsulfonyl)azetidin-3- ylidene]acetonitrile

[0329] Under nitrogen protection, triphenylphosphine (15.03 g, 1.7 eq) and hexachloroethane (13.56 g, 1.7 eq) were added to chloroform (120 mL, 10 V) and refluxed for 2-3 h. The temperature was decreased to 0 °C and triethylamine (15.35 g, 4.5 eq) was added and stirred for 5 min. A solution of N-diphenyl-tert-butylsilyl ethyl sulfonamide (11.7 g, 1.0 eq) in chloroform (150 mL, 12 V) was added dropwise and stirred for 10-15 min after the dropwise addition. Azetidin-3-ylidene acetonitrile hydrochloride (8.77 g, 2.0 eq) was added and stirred for 0.5-1.0 h. Water (100 mL) was added and the aqueous phase was extracted with chloroform. The combined organic phase was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was concentrated. Column chromatography was used to separate 13.2 g of yellow oil with a yield of 92.4%.

[0330] Step 3: Synthesis of [1-(N-diphenyl-tert-butylsilyliminoethylsulfonyl)-3-hydrazino- azetidin-3-yl]acetonitrile D-tartaric acid salt

[0331] Under nitrogen protection, 2-[1-(N-tert-butyldiphenylsilyliminoethylsulfonyl)azetidin-3- yliden]acetonitrile (13.08 g, 1.0 eq) was dissolved in acetonitrile (26 mL, 2V) at 20-30 °C, and hydrazine hydrate (3.8 g, 2.0 eq) was added dropwise. After the dropwise addition was completed, the mixture was stirred at 10-20 °C for 2-3 h. TLC sampling showed that the reaction was substantially complete. D-tartaric acid (7.0 g, 2.0 eq) was dissolved in water (26 mL, 2V), and the solution was added dropwise to the reaction mixture. After the dropwise addition was completed, acetonitrile (156 mL, 12V) was added dropwise, and the mixture was stirred at room temperature overnight. A solid precipitated, which was filtered, and the filter cake was washed with a small amount of acetonitrile. The solid was discarded, and the filtrate and the washing liquid were combined to obtain a solution of [1-(N-tert-butyldiphenylsilyliminoethylsulfonyl)-3-hydrazinyl-azetidin-3-yl]acetonitrile D-tartrate, which was directly used in the next step.

[0332] Step 4: Synthesis of {1-(N-tert-butyldiphenylsilyliminoethylsulfonyl)-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile

[0333] Under argon protection, [(2E)-3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)prop-2- enylidene]dimethylammonium perchlorate (8.2 g) was added to a solution of [1-(N-tert- butyldiphenylsilyliminoethylsulfonyl)-3-hydrazinyl-azetidin-3-yl]acetonitrile D-tartrate (crude product solution obtained in the previous step, calculated based on a theoretical yield of 100%) at 45 °C, and the mixture was stirred overnight. LCMS sampling showed that the reaction was substantially complete. Water (200 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (300 mL x 2). The organic phase was washed once with water and once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography, eluted with 4%-5% methanol / dichloromethane, and concentrated to obtain 12.77 g of a light yellow foamy solid with a purity of 97.5%.

[0334] Step 5: Synthesis of {1-(N-tert-butyldiphenylsilyliminoethylsulfonyl)-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile

[0335] {1-(N-tert-butyldiphenylsilyliminoethylsulfonyl)-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl}acetonitrile (13.85 g, 1.0 eq) was dissolved in acetonitrile (83 mL, 6 V), and trifluoroboron-ether (19.37 g, 6.0 eq) was added dropwise at room temperature. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. Ice water (100 mL) was added, and the pH was adjusted to 7-8 with ammonia water. The mixture was extracted with ethyl acetate (100 mL x 6), and the combined organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to dryness, and the residue was column chromatographed to obtain 6.83 g of a light yellow solid. The HPLC purity was 99.56%, and the yield was 81.05%. 1 HNMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.93 (s, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7.63 (dd, J = 3.6, 2.4 Hz, 1H), 7.09 (dd, J = 3.6, 1.8 Hz, 1H), 4.45 (d, J = 8.9 Hz, 2H), 4.19 (s, 1H), 4.07 (dd, J = 8.9, 4.1 Hz, 2H), 3.64 (s, 2H), 3.05 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H).

[0336] Example 6:

[0337] Synthesis Route 5:

[0338] Step 1: Synthesis of N-tert-butyldimethylsilyl ethyl sulfonamide

[0339] Ethyl sulfonamide (109.1 g, 1.0 eq, moisture K-F <0.5%) and tert-butyldimethylsilyl chloride (165.8 g, 1.1 eq) were added to dichloromethane (500 mL) under nitrogen protection. After stirring for 10 min, the system temperature was cooled with cold water to not exceed 20°C. Triethylamine (116.4 g, 1.15 eq) was added at one time, and the system temperature was not allowed to exceed 30°C. After the addition was completed, the system was heated (oil bath temperature 48°C, internal temperature 45°C) to micro-reflux for 18 h. During the reaction, ethyl sulfonamide was completely dissolved after about 30 min, and then a large amount of white solid, triethylamine hydrochloride, was generated. The reaction liquid was taken for GC detection, and ethyl sulfonamide / (ethyl sulfonamide + 21) <1.0% was considered as the completion of the reaction.

[0340] The reaction was terminated by adding ice water (500 mL) and the mixture was allowed to stand to separate into two phases. The aqueous phase was extracted with dichloromethane (200 mL), and the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was washed with dichloromethane (100 mL). The combined filtrate and washings were concentrated under reduced pressure with heating (oil bath 50°C, -0.075 MPa) until the internal temperature reached 15°C. When the internal temperature reached 40°C, n-heptane (650 mL) was added, and the mixture was further concentrated under reduced pressure (-0.090 to -0.095 MPa) until 300 mL of solvent was distilled off. The vacuum was released, and the temperature was raised to 50 to 55°C (if solid was precipitated, the solid was dissolved). Then, the mixture was cooled to 40 to 45°C, and seed crystals (0.8 g) were added. The mixture was slowly cooled to 0 to 5°C at a rate of 5°C / h, and stirred at 0 to 5°C overnight. The solid was filtered, and washed with cold n-heptane (80 mL). The solid was dried under vacuum at 40°C to give a white solid (182.4 g, 81.6% yield, 99.8% GC purity).

[0341] Step 2: Synthesis of 2-[1-(N-tert-butyldimethylsilyliminoethylsulfonyl)azetidin-3- ylidene]acetonitrile

[0342] Dichlorotriphenylphosphorane (38.32 g, 1.15 eq) was added to dichloromethane (200 mL, 15 V) under nitrogen protection, and the mixture was cooled to -25 to -15°C. Triethylamine (35.42 g, 3.50 eq) was added, and the mixture was stirred for 10 min. Compound 21 (26.81 g, 1.20 eq) in dichloromethane (50 mL, 3.8 V) was added dropwise through a dropping funnel. After the addition was completed, the mixture was stirred at -25 to -15°C for 20 min. Finely ground compound 11 (13.06 g, 1.00 eq) was added, and the mixture was stirred at -25 to -15°C for 1 h.

[0343] The reaction was terminated by adding acetic acid (2.1 eq), and water (100 mL) was added. The solid was dissolved by stirring, and the mixture was allowed to stand to separate into two phases. The aqueous phase was extracted with dichloromethane (100 mL), and the combined dichloromethane solution was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with heating (water bath 40°C) until no liquid was distilled off. n-Heptane (300 mL) was added, and the mixture was further concentrated under reduced pressure with heating (water bath 50°C) until 200 mL of solvent was distilled off. The vacuum was released, and the temperature was raised to normal pressure. The mixture was stirred at 40 to 45°C for 3 h, filtered, and the solid was washed with n-heptane. The combined filtrate and washings were concentrated under reduced pressure with heating (water bath 50°C) until 60 mL of solvent was distilled off. The vacuum was released, and the temperature was raised to normal pressure. The mixture was slowly cooled to 0 to 5°C, and stirred at 0 to 5°C for 3 h. The solid was filtered, and dried under vacuum at room temperature to give a white solid (24.00 g, 80% yield).

[0344] Step 3: Synthesis of 2-[l-(iminoethylsulfonyl)azetidin-3-ylidene]acetonitrile

[0345] The 2-[l-(N-tert-butyldimethylsilyliminoethylsulfonyl)azetidin-3-ylidene]acetonitrile (30.00 g, 0.10 mol) was dissolved in MTBE (300 mL, 10V) and cooled to 0-5 °C, then trifluoroacetic acid (22.84 g, 0.20 mol) was added, controlling the internal temperature not higher than 5 °C for 4 h. Ice water (60 mL, 2V) was added and stirred for 15 min, then separated, the organic phase was extracted with ice water (30 mL, 1V) once, the water phase was combined and cooled to 0-5 °C, then adjusted to pH 6-8 with sodium carbonate solid for standby.

[0346] Step 4: Synthesis of (R)-2-[l-(iminoethylsulfonyl)azetidin-3-ylidene]acetonitrile D-DTA salt

[0347] D-DTA (19.32 g, 0.05 mol, 0.5 eq) was added to isopropanol (90 mL) and cooled to 0-5 °C, then the aqueous solution of compound 24 in step 3 was added dropwise to the isopropanol solution of D-DTA through a dropping funnel, and crystal seeds were added during the dropwise addition, a large amount of solid precipitated, and the dropwise addition of water (90 mL) was continued, then stirred at 0-5 °C for 12 h after dropwise addition, filtered, and vacuum dried, the product had an ee value of 83% and a purity of 97.32%. The obtained solid was further recrystallized with isopropanol and water system twice to obtain a solid with an ee value of more than 98%, 22.12 g, a yield of 38.7%, 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.8 Hz, 4H), 7.41 (d, J = 7.9 Hz, 4H), 5.88 (t, J = 2.6 Hz, 1H), 5.83 (s, 2H), 4.60 (m, 2H), 4.52 (m, 2H), 3.03 (dq, J = 7.34, 2.04, 2H), 2.41 (s, 6H), 1.21 (t, J = 7.4 Hz, 3H).

[0348] Step 5: Synthesis of (R)-2-[l-(N-cyclopropyliminoethylsulfonyl)azetidin-3-ylidene]acetonitrile

[0349] (R)-2-[1-(iminoethylsulfonyl)azetidin-3-ylidene]acetonitrile D-DTA salt (5.8 kg, 1.0 eq.) and K3PO4(5.4 kg, 2.5 eq.) were added to a mixture of H2O (23.2 L, 4 V) and dichloromethane (35 L, 6 V, 87 L total 15 V) and stirred until the solid was completely dissolved. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted with dichloromethane (12 L x 4) and the organic phases were combined. To the dichloromethane solution was added DIEA (3.9 kg, 3.0 eq.), cyclopropylboronic acid (1.74 kg, 2.0 eq.), Cu(OAc)2(370.0 g, 0.2 eq.) and 2,2'-bipyridine (285.0 g, 0.18 eq.), and the mixture was stirred at 25-30 °C for 72 h while air was bubbled through. After the reaction was complete as determined by HPLC, the pH was adjusted to 5-7 by the addition of 2N hydrochloric acid. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted with dichloromethane (20 L) and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate and concentrated to give (R)-3 as a crude product. The crude product was recrystallized from a mixture of methyl tert-butyl ether and n-heptane to give 1.6 kg of the product. 1 H NMR (400 MHz, CDC13) δ 5.44 (p, J = 2.5 Hz, 1H), 4.75 (t, J = 3.1 Hz, 2H), 4.72-4.66 (m, 2H), 3.20-3.08 (m, 1H), 3.02 (dq, J = 14.4, 7.3 Hz, 1H), 2.61 (tt, J = 7.0, 4.0 Hz, 1H), 1.37 (t, J = 7.4 Hz, 3H), 0.70-0.49 (m, 3H), 0.41 (tq, J = 8.0, 4.6, 4.1 Hz, 1H). LCMS: 226 [M+H] +

[0350] All documents mentioned in the present application are incorporated herein by reference as if each document were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without materials details, quantifications, and other specific items, in some instances, details have been presented in a specific form for purposes of illustration and description. However, it is to be fully understood that the scope of the application is fully encompassed by the appended claims and their equivalents.

Claims

1. An intermediate for the synthesis of a JAK inhibitor, characterized in that, The structure of the intermediate is shown in formula III: wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; 1 selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; R 3 selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2.

2. The intermediate of claim 1, wherein, The intermediate has a structure represented by the following formula (R)-III or (S)-III: wherein R 1 and R 3 are as defined in claim 1.

3. The process for the preparation of a compound of formula III according to claim 1, characterized in that, comprising the steps of: reacting a compound of formula XVI with a compound of formula XI in an inert solvent to obtain a compound of formula III; wherein R 1 and R 3 are as defined in claim 1.

4. The process for the preparation of a compound of formula III according to claim 1, characterized in that, The compound of formula III is prepared by the following method: reacting a compound of formula XVII with a compound of formula XI in an inert solvent to obtain a compound of formula III; wherein R 1 and R 3 are as defined in claim 1.

5. The process for the preparation of a compound of formula III according to claim 1, characterized in that, The method further comprises: In an inert solvent, a compound of formula (III) is reacted with to obtain a compound of formula (R)-III; wherein R 1 and R 3 are as defined in claim 1, R 3’ is selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl.

6. A process for the preparation of a compound of formula I: ###0002### I wherein: R 1 selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; R 3 selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2; characterized in that it is prepared using a compound III as defined in claim 1 as starting material.

7. The method of claim 6, wherein, said method of preparation comprising the steps of: (a) reacting a compound of formula III with hydrazine in an acetonitrile solvent to obtain a compound of formula IV; (b) reacting a compound of formula IV with a compound of formula II in a methanol solvent to obtain a compound of formula I; wherein X is N + (R 4 )R 5 or O; Y is NR 4 R 5 or hydroxy; wherein, R 4 and R 5 are each independently selected from the group consisting of C1-C4 alkyl, or R 4 and R 5 together with the N atom to which they are attached form a 4-7 membered saturated heterocyclic ring, and said saturated heterocyclic ring can include 1, 2, or 3 heteroatoms selected from N or O; R 1 and R 3 are as defined in claim 1.

8. The method of claim 6, wherein, said method of preparation comprising the steps of: (c) reacting a compound of formula III with a compound of formula VII in the presence of a base, preferably DBU, in an inert solvent, such as THF, to give a compound of formula VIII; (d) reacting a compound of formula VIII with a compound of formula 6 in the presence of PdCl2-XantPhos in an inert solvent (such as THF / H2O mixture) to give a compound of formula IX; (e) deprotection of the compound of formula IX in an inert solvent, to give the compound of formula I; wherein R 1 and R 3 are as defined in claim 6.

9. An intermediate selected from the group consisting of: wherein, R 1 selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; R 3 selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2; X is N + (R 4 )R 5 or O; Y is NR 4 R 5 or hydroxyl; wherein R 4 and R 5 are each independently selected from the group consisting of C1-C4 alkyl, or R 4 and R 5 together with the N atom to which they are attached form a 4-7 membered saturated heterocyclic ring, and said saturated heterocyclic ring can include 1, 2, or 3 heteroatoms selected from N or O.

10. The intermediate of claim 9, wherein, The process for the preparation of the compound of formula IV in said intermediates comprises: reacting a compound of formula III with hydrazine in an inert solvent to obtain a compound of formula IV; wherein the various radicals are as defined in claim 9.

11. The intermediate of claim 9, wherein, The process for preparing the intermediate compound of formula II comprises: reacting a compound of formula I with 4-methyl-7H-pyrrolo[2,3-d]pyrimidine, i.e. compound 1, POCl3 in an inert solvent to obtain a compound of formula II; wherein the various radicals are as defined in claim 9.

12. A process for the preparation of a compound of formula la, characterized by, The method of making comprises the steps of: (1) reacting a compound of formula R-3 with hydrazine in acetonitrile to obtain a compound of formula R-4; (2) reacting a compound of formula R-4 with any one of compounds 2a-2g in methanol to obtain a compound of formula la; wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; 1 selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; R 3 selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, SiMe3, SiEt3, (t-Bu)SiMe2, (t-Bu)Si(Ph)2.

13. A process for the preparation of a compound of formula la, characterized by, The method of making comprises the steps of: (1) reacting a compound of formula 5 with Boc2O in DMAP to obtain a compound of formula 6; (2) reacting a compound of formula 3 with a compound of formula 7 in the presence of a base and pinacol in THF to obtain a compound of formula 8; (3) reacting a compound of formula 8 with 6 in acetonitrile to obtain a compound of formula 9; (4) reacting a compound of formula 9 with n-BuOH in water to obtain a compound of formula la.

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