阅读说明：本技术 用于制备(3r,4r)-1-苄基-n,4-二甲基哌啶-3-胺或其盐的方法以及使用其制备托法替尼的方法 (Process for preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof and process for preparing tofacitinib using the same ) 是由 吴相昊 李斗炳 权景燦 金相沅 黃孝益 李京实 赵益秀 崔智惠 赵成希 李秀英 于 2020-04-03 设计创作，主要内容包括：本发明提供了用于制备(3R,4R)-1-苄基-N,4-二甲基哌啶-3-胺或其盐的方法,(3R,4R)-1-苄基-N,4-二甲基哌啶-3-胺或其盐为用于制备托法替尼的中间体。本发明还提供了一种该方法中使用的中间体,即((3R,4R)-1-苄基-4-甲基哌啶-3-基)氨基甲酸甲酯二苯甲酰基-L-酒石酸盐的异丙醇溶剂化物。本发明还提供了一种具有优异的稳定性,可用于制备托法替尼的中间体,即(3R,4R)-1-苄基-N,4-二甲基哌啶-3-胺乙酸盐。此外,本发明提供了使用该方法制备托法替尼或其药学上可接受的盐的方法。(The present invention provides a process for the preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or salts thereof, (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or salts thereof being intermediates for the preparation of tofacitinib. The invention also provides an intermediate used in the process, namely isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate. The invention also provides an intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine acetate which has excellent stability and can be used for preparing tofacitinib. In addition, the present invention provides a method for preparing tofacitinib or a pharmaceutically acceptable salt thereof using the method.)

1. A process for preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof, which comprises:

(a) reacting racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester with dibenzoyl-L-tartaric acid in a solvent selected from the group consisting of isopropanol, an aqueous solution of isopropanol, and a mixed solvent of isopropanol and an organic solvent by heating under reflux, followed by preparing an isopropanol solvate of dibenzoyl-L-tartrate of ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester by cooling; and

(b) reacting the isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate prepared in step (a) with a base to convert into methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate; the methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate is then reduced to produce (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine.

2. The method according to claim 1, wherein the mixed solvent of isopropyl alcohol and an organic solvent is a mixed solvent of isopropyl alcohol and an organic solvent selected from the group consisting of methanol, ethanol, n-propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.

3. The process of claim 1, wherein step (a) further comprises recrystallizing the isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate in a mixed solvent of isopropanol and methanol or a mixed solvent of isopropanol and ethanol.

4. The method of claim 1, wherein the cooling in step (a) is performed to a temperature range of 0 ℃ to 55 ℃.

5. The process of claim 1, wherein the base used in step (b) is one or more selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide.

6. The process of claim 1, wherein the reduction in step (b) is carried out by using one or more reducing agents selected from the group consisting of lithium aluminum hydride, lithium bis (2-methoxyethoxy) aluminum hydride, and sodium hydride.

7. The process of claim 1, wherein step (b) further comprises reacting the (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine with acetic acid to produce (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate.

8. The process according to claim 7, wherein the reaction of the (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine with acetic acid is carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, N-propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and a mixed solvent thereof.

An isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate.

(3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate.

11. A process for preparing tofacitinib, or a pharmaceutically acceptable salt thereof, comprising:

preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof according to the method of any one of claims 1 to 8;

(ii) reacting said (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof with 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine to produce (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine;

(iii) debenzylating said (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine to produce (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine; and

(iv) reacting said (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine with ethyl cyanoacetate to prepare tofacitinib.

12. The method of claim 11, wherein the salt of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine is (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate.

Technical Field

The present invention relates to a novel process for the preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or salts thereof, (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or salts thereof being intermediates for the preparation of tofacitinib. The invention also relates to novel intermediates used in the process and to novel salts obtained by the process. Furthermore, the present invention relates to a method for preparing tofacitinib or a pharmaceutically acceptable salt thereof using the method.

Background

Tofacitinib (Tofacitinib), whose chemical name is 3- [ (3R,4R) -4-methyl-3- [ methyl ({ 7H-pyrrolo [2,3-d ] pyrimidin-4-yl }) amino ] piperidin-1-yl ] -3-oxopropanenitrile, is used in the form of the citrate salt of the following formula 1. Tofacitinib is a Janus kinase inhibitor and can be used for the treatment of rheumatoid arthritis (rheumatoid arthritis), active psoriatic arthritis (active psoriatic arthritis) and severe ulcerative colitis (severere ulcerative colitis).

< formula 1>

Methods for preparing tofacitinib or its citrate have been disclosed in WO 2001/042246, WO2002/096909 and the like. The process involves converting the intermediate (i.e., 1-benzyl-N, 4-dimethylpiperidin-3-amine) to its stable form (i.e., its hydrochloride salt) and then subjecting it to resolution using a resolving agent such as L-tartaric acid or a derivative thereof or (+) -phncyphosphos ((S) - (+)2-hydroxy-5,5-dimethyl-4-phenyl-1,3, 2-dioxaphosphorinan-2-oxide) ((S) - (+)2-hydroxy-5,5-dimethyl-4-phenyl-1,3, 2-dioxaphosphorine-2-oxide). However, the step of converting racemic 1-benzyl-N, 4-dimethylpiperidin-3-amine to its hydrochloride salt showed a significantly lower yield (62%). Also, (+) -Phencyphos are very expensive resolving agents, so that there is a problem that their use is not suitable for industrial mass production.

WO 2014/102826 discloses an improved process for the preparation of tofacitinib. WO 2014/102826 also discloses a process for the preparation of an optically active intermediate useful in the preparation of tofacitinib, which process comprises converting racemic methyl (4-methylpiperidin-3-yl) carbamate into racemic methyl (1-trityl-4-methylpiperidin-3-yl) carbamate, converting racemic methyl (1-trityl-4-methylpiperidin-3-yl) carbamate into racemic 1-trityl-N, 4-dimethylpiperidin-3-amine hydrochloride and resolving racemic 1-trityl-N, 4-dimethylpiperidin-3-amine hydrochloride. However, the method disclosed in WO 2014/102826 has the disadvantage that the step of introducing the trityl group should be performed additionally.

EP 3078665 discloses a process for the preparation of tofacitinib, which comprises resolving the final intermediate of tofacitinib (i.e. N-methyl-N- (4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine) and then reacting it with cyanoacetic acid. However, since the resolution is performed almost at the last step of tofacitinib synthesis, there is a problem that the manufacturing cost increases.

EP 3421455 discloses a process for the preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine hydrochloride which comprises asymmetric hydrogenation (asymmetric hydrogenation) of racemic methyl (1-benzyl-4-methylpiperidin-3-yl) carbamate with a chiral catalyst such as a rhodium catalyst having a ferrocene ligand to prepare methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate, followed by reduction and conversion to its hydrochloride. However, the optical purity (optical purity) of the methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate prepared by asymmetric hydrogenation is very low (82.3% ee (enantiomeric excess%). The optical purity of the (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine hydrochloride obtained is also very low (97.3% ee). And, since the chiral catalyst used in asymmetric hydrogenation is an expensive rhodium complex, there is a disadvantage that the manufacturing cost is increased. Furthermore, there is a disadvantage that the yield (yield) of the step of preparing the hydrochloride salt is very low (60%).

Disclosure of Invention

Technical problem

The present inventors have conducted various studies to develop an improved method suitable for industrial mass production of tofacitinib. In particular, the present inventors have conducted various studies to develop an improved process for preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof, which is an intermediate for preparing tofacitinib.

The present inventors have found that (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof can be produced in high yield and high optical purity when racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester is directly dissolved in a specific solvent to produce a specific solvate, followed by a step of conversion to its free base and a reduction step. Furthermore, the present inventors have found that when (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine is isolated in the form of a certain salt (i.e., in the form of acetate), the product thereof (i.e., (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate) can be isolated with high optical purity and has excellent stability (e.g., storage stability, etc.).

Accordingly, the present invention provides a novel process for the preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or salts thereof, which is an intermediate for the preparation of tofacitinib.

Also, the present invention provides a novel intermediate used in the method.

And, the present invention provides (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate having excellent stability such as storage stability and the like.

In addition, the present invention provides a method for preparing tofacitinib or a pharmaceutically acceptable salt thereof using the method.

Means for solving the problems

According to one aspect of the present invention, there is provided a process for preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof, which comprises:

(a) reacting racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester with dibenzoyl-L-tartaric acid in a solvent selected from the group consisting of isopropanol, an aqueous solution of isopropanol, and a mixed solvent of isopropanol and an organic solvent by heating under reflux, followed by preparing an isopropanol solvate of dibenzoyl-L-tartrate of ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester by cooling; and

(b) reacting the isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate prepared in step (a) with a base to convert to methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate; (3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester is then reduced to prepare (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine.

In one embodiment, step (b) may further comprise reacting (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine with acetic acid to produce (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate [ i.e., step (c) ].

According to another aspect of the present invention, there is provided an isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate.

According to yet another aspect of the present invention, there is provided (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate.

According to yet another aspect of the present invention, there is provided a process for preparing tofacitinib, or a pharmaceutically acceptable salt thereof, comprising:

preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof according to the above method;

(ii) reacting (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof with 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine to produce (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine;

(iii) debenzylating (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine to produce (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine; and

(iv) reacting (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine with ethyl cyanoacetate to prepare tofacitinib.

The invention has the advantages of

The process according to the present invention can provide (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof in high yield and high optical purity. Also, a certain salt obtained by the present invention, that is, (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate, has excellent stability (e.g., storage stability, etc.). And thus can be effectively used as an intermediate for the preparation of tofacitinib. In particular, when (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine is isolated as an acetate salt, the optical purity of the methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate can be increased, for example from a chiral purity of 95.2% to a chiral purity of 99.8%.

Drawings

Fig. 1 shows a PXRD pattern of isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate prepared in example 2.

FIG. 2 shows a Fourier transform infrared (FT-IR) spectrum of an isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate prepared in example 2.

FIG. 3 shows a PXRD spectrum of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared in example 6.

FIG. 4 shows a Differential Scanning Calorimetry (DSC) thermogram of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared in example 6.

FIG. 5 shows the FT-IR spectrum of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared in example 6.

FIG. 6 is a photograph showing the results of stability test (appearance) of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared in example 7 under long-term storage conditions of 6 months. (initial: initial time, 6 months: after 6 months).

Fig. 7 is a photograph showing the results of stability test (appearance) of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine hydrochloride under long-term storage conditions of 6 months. (initial: initial time, 6 months: after 6 months).

FIG. 8 shows a DSC thermogram of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared in example 7, which is obtained by measurement at the initial time of stability test.

FIG. 9 shows a DSC thermogram obtained by measuring (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared in example 7 after storage for 6 months under long-term storage conditions.

Figure 10 shows the DSC thermogram of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine hydrochloride, obtained by measurement at the initial time of the stability test.

Fig. 11 shows DSC thermograms obtained by measurement after storing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine hydrochloride for 6 months under long-term storage conditions.

Detailed Description

The invention provides a novel method for preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine or salts thereof, wherein the (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine or salts thereof are intermediates for preparing tofacitinib. Specifically, the present invention provides a process for preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof, which comprises:

(a) reacting racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester with dibenzoyl-L-tartaric acid in a solvent selected from the group consisting of isopropanol, an aqueous solution of isopropanol, and a mixed solvent of isopropanol and an organic solvent by heating under reflux, followed by preparing an isopropanol solvate of dibenzoyl-L-tartrate of ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester by cooling; and

(b) reacting the isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate prepared in step (a) with a base to convert to methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate; (3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester is then reduced to prepare (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine.

In the process of the present invention, racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester is a known compound and is therefore commercially available. If necessary, an acid addition salt such as racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester hydrochloride is treated with a base such as potassium carbonate to convert it to racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester which can be used in the process.

The reaction of step (a) is carried out in a solvent selected from the group consisting of isopropanol, an aqueous solution of isopropanol, and a mixed solvent of isopropanol and an organic solvent. The mixed solvent of isopropyl alcohol and an organic solvent may be a mixed solvent of isopropyl alcohol and an organic solvent selected from the group consisting of methanol, ethanol, n-propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile. Preferably, the reaction of step (a) may be carried out in isopropanol, an aqueous solution of isopropanol, a mixed solvent of isopropanol and methanol, a mixed solvent of isopropanol and ethanol, or a mixed solvent of isopropanol and n-propanol. In the aqueous solution of isopropyl alcohol and the mixed solvent of isopropyl alcohol and an organic solvent, the volume ratio of isopropyl alcohol to water or isopropyl alcohol to the organic solvent may be 60:1 to 30: 1.

In step (a), the dibenzoyl-L-tartaric acid used as a resolving agent can be used in a ratio of 0.5 to 2.0 equivalents, preferably 0.7 to 1.1 equivalents, based on 1 equivalent of racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester. dibenzoyl-L-tartaric acid can be added directly to a solution of racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester. Alternatively, the dibenzoyl-L-tartaric acid can be added to a solution of racemic methyl (1-benzyl-4-methylpiperidin-3-yl) carbamate in the form of a solution containing dibenzoyl-L-tartaric acid. The reaction of racemic (1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester with dibenzoyl-L-tartaric acid is carried out by heating under reflux. The reflux heating may be performed at a temperature in the range of, for example, 55 to 100 c, although this varies depending on the solvent used. The cooling after the reflux heating may be carried out to a temperature range of 0 to 55 ℃. Cooling results in the precipitation of the stereospecific enantiomer (stereospeicic enantiomer). The cooling/precipitation process may be performed for, for example, 1 to 24 hours, preferably 2 to 5 hours, and more preferably about 3 hours, but is not limited thereto. The resulting precipitate can be isolated by filtration, washing, and drying. For example, the drying may be performed at 30 to 60 ℃, preferably at 40 to 50 ℃, but is not limited thereto.

The present inventors have found that the product obtained in step (a) is in the form of isopropanol solvate of ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester dibenzoyl-L-tartrate, which is represented by the following formula 3. That is, the product obtained in step (a) is in the form of a solvate in which methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate, dibenzoyl-L-tartaric acid and isopropanol are mixed in an equivalent ratio of 1:1: 1. The isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate can then be reacted with a base (e.g., carbonate or hydroxide, etc.) to convert it to the free base form, which enables the next reaction step to be efficiently carried out. Since the process of the present invention is carried out via isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate, the chiral resolution is carried out in a more advanced step than in the known processes, which makes it possible to reduce the manufacturing cost and to provide a product with high optical purity.

< formula 3>

The present inventors have found that recrystallization of an isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate salt obtained in step (a) with a specific solvent can increase the chiral purity thereof to more than 99%, more preferably to more than 99.5%, still more preferably to more than 99.8%, particularly preferably to more than 99.9%. Thus, step (a) may further comprise a recrystallization step. Specifically, step (a) may further comprise recrystallizing the obtained isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate in a mixed solvent of isopropanol and methanol or a mixed solvent of isopropanol and ethanol. For example, recrystallization can be carried out by precipitating a mixture of an isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate and a mixed solvent of isopropanol and methanol or a mixture of an isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate and a mixed solvent of isopropanol and ethanol by heating under reflux, followed by cooling to a temperature of 5 ℃ to 15 ℃. The resulting precipitate can be isolated by processes such as filtration, washing, and drying. For example, the drying may be performed at 30 to 60 ℃, preferably at 40 to 50 ℃, but is not limited thereto.

The process of the present invention comprises reacting the isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate prepared above with a base to convert into methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate; (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine is then prepared by reducing methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate [ i.e., step (b) ].

The base used for conversion to methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate (i.e. for conversion to the free base form) may be a conventional inorganic base, such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, preferably potassium carbonate. The base may be used in a ratio of 1.0 to 5.0 equivalents based on 1 equivalent of isopropyl alcohol solvate of ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester dibenzoyl-L-tartrate, but is not limited thereto. The reaction of isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate with a base may be carried out in a conventional organic solvent such as methyl tert-butyl ether.

The reducing agent used for forming (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine may be, for example, lithium aluminum hydride, lithium bis (2-methoxyethoxy) aluminum hydride, sodium hydride or the like, preferably lithium aluminum hydride. The reducing agent may be used in a ratio of 1.0 to 5.0 equivalents based on 1 equivalent of ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester, but is not limited thereto. The reduction may be carried out in a conventional organic solvent such as tetrahydrofuran.

The present inventors have found that when (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine is converted into a certain salt form (i.e., into an acetate form), the resulting (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate can be isolated with high optical purity (99% ee or more) and has excellent stability (e.g., storage stability, etc.). Thus, the process of the present invention may further comprise converting (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine into its acetate salt. Specifically, the method of the present invention may further comprise reacting (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine with acetic acid to prepare (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate [ step (c) ].

Acetic acid may be used in a ratio of 0.8 to 1.5 equivalents, preferably 0.9 to 1.1 equivalents, based on 1 equivalent of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine. The reaction of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine with acetic acid may be carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, N-propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and a mixed solvent thereof. Preferably, the reaction may be carried out in acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, or a mixed solvent thereof. Further, the reaction may be carried out at a temperature of 30 ℃ to 50 ℃, preferably 30 ℃ to 40 ℃ for 1 to 3 hours. For example, the product may be isolated by cooling, filtering the precipitate, washing and drying. For example, cooling may be carried out at-5 ℃ to 10 ℃, preferably at 0 ℃ to 5 ℃; the drying may be performed at 20 to 50 ℃, preferably at 35 to 45 ℃, but is not limited thereto.

The present invention also includes within its scope a novel solvate of formula 3, i.e. an isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate, useful as an intermediate in this process.

The present invention also includes within its scope a novel stereoisomer intermediate (steroisomer intermediate) useful in the preparation of tofacitinib, i.e., (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate of formula 4.

< formula 4>

The present invention also includes within its scope a process for the preparation of tofacitinib or a pharmaceutically acceptable salt thereof, comprising converting (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof (preferably the acetate salt) prepared according to the above process into tofacitinib. Specifically, the present invention provides a process for preparing tofacitinib, or a pharmaceutically acceptable salt thereof, comprising:

preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof according to the above method;

(ii) reacting (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or a salt thereof with 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine to produce (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine;

(iii) debenzylating (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine to produce (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine; and

(iv) reacting (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine with ethyl cyanoacetate to prepare tofacitinib.

In this process, the salt of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine may be (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate.

Steps (ii) to (iv) may be carried out according to known methods (for example, as disclosed in WO2002/096909, j.heterocyclic. chem,53,1259(2016), org.process res.dev.2014,18,1714, etc.) except for the use of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine or its acetate salt prepared according to the present invention.

The overall reaction scheme of the process of the present invention is shown as reaction scheme 1 below.

< reaction scheme 1>

The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Powder X-ray diffraction (PXRD) spectra were measured using a Bruker D8 advanced X-ray powder diffractometer (X-ray source: CuK α, tube voltage: 40kV, tube current: 40mA, divergence slit: 0.3 °, scattering slit: 0.3 °). FT-IR spectra were measured using an Agilent Cary 630FT-IR spectrometer, where the sample was brought into close contact with the ATR prism surface and then measured at 4000 to 650cm^-1The reflection spectrum is measured over a wave number range of (c). Mass measurements were carried out on a Waters e2695 QDa mass spectrometer (Waters e2695 separation module with QDa detector) (capillary voltage: 0.8kV, probe temperature: 600 ℃, cone voltage: 10V, source: electrospray, analytical mode: positive mode, scanning range: 50 to 1000 Da). Melting point (M.P) measurements were made using the Mettler Toledo MP80 melting point system (onset temperature: 120 ℃, end temperature: 200 ℃, heating rate: 1 ℃/min). Using Jasco P-2000 polarimeter (wavelength: 589nm, optical path length: 100mm, 1g/100mL CHCl at 20 deg.C)₃Middle) was performed. Differential Scanning Calorimetry (DSC) measurements were performed using a Mettler Toledo DSC 1STAR differential scanning calorimeter (sample vessel: sealed aluminum pan, 99% nitrogen conditions, onset temperature: 30 ℃, end temperature: 300 ℃, heating rate: 10 ℃/min). NMR (NMR) spectroscopic analysis was carried out with a Bruker 400MHz spectrometer and chemical shifts were analyzed in ppm.

Example 1: preparation of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate

A mixture of racemic methyl (1-benzyl-4-methylpiperidin-3-yl) carbamate hydrochloride (840g), methyl tert-butyl ether (8.4L) and potassium carbonate solution (427g in 3.4L pure water) was stirred at room temperature for about 15 minutes. The organic layer was separated and then concentrated under reduced pressure. To the concentrate was added isopropanol (1.7L), and the resulting mixture was further concentrated under reduced pressure. To the concentrate was added isopropanol (3.4L) and the resulting mixture was stirred for about 15 minutes. A solution of dibenzoyl-L-tartaric acid (1.0kg) in isopropanol (10.0L) was slowly added to the above solution of racemic methyl (1-benzyl-4-methylpiperidin-3-yl) carbamate in isopropanol. The reaction mixture was heated to reflux for 3 hours, cooled to about 50 ℃, and then stirred at 50 ± 5 ℃ for about 3 hours. The product was filtered and then washed with isopropanol (0.8L). The resulting wet cake was dried under vacuum (wet cake) at about 45 ℃ to give 897.5g of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate. (yield: 46.9%)

Chiral purity: 98.0 percent

¹H-NMR(400MHz,DMSO-d₆)δ8.0(m,4H)，7.69(m,2H)，7.55(m,4H)，7.30-7.38(m,5H)，7.09(m,1H)，5.79(d,2H)，3.74-3.89(m,4H)，3.46(s,3H)，2.81-2.91(m,2H)，2.62(m,2H)，1.73(b,1H)，1.41-1.53(m,2H),1.03(d,6H),0.73(d,3H)

Example 2: purification of isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate

A mixture of the isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate (100g, chiral purity: 98.0%), isopropanol (2.7L) and methanol (0.3L) prepared in example 1 was heated under reflux for about 3 hours, cooled to about 10 ℃, and then stirred at 10. + -. 5 ℃ for about 3 hours. The product was filtered, and then washed with a mixed solvent of isopropanol and methanol (0.2L, 27:3 (v/v)). The resulting wet cake was dried under vacuum at about 45 deg.C to give 94.2g of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate. (yield: 94.2%)

Chiral purity: 99.90 percent

The melting point is 134.5-136.5 DEG C

MS m/z 263(M⁺+H)

¹H-NMR(400MHz，DMSO-d₆)δ8.0(m,4H)，7.69(m,2H)，7.55(m，4H)，7.30-7.38(m,5H)，7.09(m,1H)，5.79(d，2H)，3.74-3.89(m,4H)，3.46(s,3H)，2.81-2.91(m,2H)，2.62(m,2H)，1.73(b,1H)，1.41-1.53(m,2H)，1.03(d,6H)，0.73(d,3H)。

Optical rotation: 8.93-10.02 degree

The PXRD pattern of the isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate obtained is shown in figure 1. As shown in FIG. 1, diffraction peaks exist at angles 2 θ of 5.18. + -. 0.2 °, 10.34. + -. 0.2 °, 15.52. + -. 0.2 °, 20.73. + -. 0.2 °, 22.53. + -. 0.2 ° and 36.66. + -. 0.2 °.

Further, the FT-IR spectrum of the obtained isopropyl alcohol solvate of ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamic acid methyl ester dibenzoyl-L-tartrate is shown in FIG. 2. As shown in FIG. 2, the infrared absorption frequencies (cm)^-1) 3287, 2970, 1732, 1713, 1697, 1557, 1498, 1450, 1373, 1354, 1307, 1265, 1247, 1221, 1172, 1107, 1070, 1050, 1015, 976, 927, 895, 847, 811, 752, 723, 705, 664, 649, 592, 563, 515 and 497.

Example 3: purification of isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate

A mixture of isopropanol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate (100g, chiral purity: 98.0%), isopropanol (2.7L) and absolute ethanol (absolute ethanol) (0.3L) prepared in example 1 was heated under reflux for about 3 hours, cooled to about 10 ℃, and then stirred at 10. + -. 5 ℃ for about 3 hours. The product was filtered, and then washed with a mixed solvent of isopropyl alcohol and absolute ethyl alcohol (0.2L, 27:3 (v/v)). The resulting wet cake was dried under vacuum at about 45 ℃ to give 95.4g of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate. (yield: 95.4%)

Chiral purity: 99.86 percent

¹H-NMR(400MHz，DMSO-d₆)δ8.0(m,4H)，7.69(m,2H)，7.55(m,4H)，7.30-7.38(m,5H)，7.09(m,1H)，5.79(d,2H)，3.74-3.89(m,4H)，3.46(s,3H)，2.81-2.91(m,2H)，2.62(m，2H)，1.73(b，1H)，1.41-1.53(m,2H)，1.03(d,6H)，0.73(d,3H)

Example 4: preparation of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate

A mixture of racemic methyl (1-benzyl-4-methylpiperidin-3-yl) carbamate hydrochloride (10g), methyl tert-butyl ether (100mL), and potassium carbonate solution (5g in 40mL pure water) was stirred at room temperature for about 15 minutes. The organic layer was separated and then concentrated under reduced pressure. To the concentrate was added isopropanol (20mL), and the resulting mixture was further concentrated under reduced pressure. To the concentrate were added isopropanol (285mL) and pure water (15mL), and the resulting mixture was stirred for about 15 minutes. To the above solution was added dibenzoyl-L-tartaric acid (12.0 g). The reaction mixture was heated to reflux for 1 hour, cooled to about 50 ℃, and then stirred at 50 ± 5 ℃ for about 3 hours. The product was filtered and then washed with isopropanol (10 mL). The resulting wet cake was dried under vacuum at about 45 deg.C to give 8.3g of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate. (yield: 36.5%)

Chiral purity: 96.54 percent

¹H-NMR(400MHz，DMSO-d₆)δ8.0(m,4H)，7.69(m,2H)，7.55(m,4H)，7.30-7.38(m,5H)，7.09(m,1H)，5.79(d,2H)，3.74-3.89(m,4H)，3.46(s,3H)，2.81-2.91(m,2H)，2.62(m,2H)，1.73(b,1H)，1.41-1.53(m,2H)，1.03(d,6H)，0.73(d,3H)

Example 5: preparation of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate

A mixture of racemic methyl (1-benzyl-4-methylpiperidin-3-yl) carbamate hydrochloride (3.0kg), methyl tert-butyl ether (30.0L) and potassium carbonate solution (1.5kg in 12L of pure water) was stirred at room temperature for about 15 minutes. The organic layer was separated and then concentrated under reduced pressure. To the concentrate was added isopropanol (6.0L), and the resulting mixture was further concentrated under reduced pressure. To the concentrate was added isopropanol (6.0L) and the resulting mixture was stirred for about 15 minutes. A solution of dibenzoyl-L-tartaric acid (2.5kg) in isopropanol (30.0L) was slowly added to the above solution of racemic methyl (1-benzyl-4-methylpiperidin-3-yl) carbamate in isopropanol. The reaction mixture was heated to reflux for 3 hours, cooled to about 50 ℃, and then stirred at 50 ± 5 ℃ for about 3 hours. The product was filtered and then washed with isopropanol (3.0L). The resulting mixture of wet cake, isopropanol (85.4L) and methanol (10.2L) was heated at reflux for 3 hours, cooled to about 10 deg.C, and then stirred at 10 + -5 deg.C for about 3 hours. The product was filtered, and then washed with a mixed solvent of isopropanol and methanol (6.8L, 27:3 (v/v)). The resulting wet cake was dried under vacuum at about 45 ℃ to give 3.0kg of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate. (yield: 43.9%)

Chiral purity: 99.93 percent

¹H-NMR(400MHz，DMSO-d₆)δ8.0(m,4H)，7.69(m,2H)，7.55(m,4H)，7.30-7.38(m,5H)，7.09(m,1H)，5.79(d,2H)，3.74-3.89(m，4H)，3.46(s，3H)，2.81-2.91(m,2H)，2.62(m,2H)，1.73(b,1H)，1.41-1.53(m,2H)，1.03(d，6H)，0.73(d，3H)

Example 6: preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate

A mixture of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate isopropanol solvate (1:1:1, chiral purity: 99.93%) (2.5kg) and methyl tert-butyl ether (25.0L) was cooled to below 10 ℃ and then 10% potassium carbonate solution (15.0L) was added thereto. The reaction mixture was stirred for about 30 minutes. The organic layer was separated, washed with pure water (2.5L), and then concentrated under reduced pressure. Tetrahydrofuran (3.5L) was added to the concentrate, and the resulting mixture was further concentrated under reduced pressure. Tetrahydrofuran (16.3L) was added to the concentrate and the resulting mixture was stirred for about 15 minutes. Lithium aluminum hydride (181.6g) was added to the solution in three portions. The reaction mixture was heated to reflux for 3 hours and cooled to-10 ℃ to-5 ℃. To this was slowly added an aqueous tetrahydrofuran solution (1.8L, THF: pure water 5:2(v/v)) while keeping the internal temperature (internal temperature) at 0 ℃ or lower. After the temperature of the reaction mixture was raised to room temperature, the reaction mixture was stirred for about 30 minutes, and then filtered. The wet cake was washed with tetrahydrofuran (5.0L). The filtrate and the washed solution were combined, and the resulting mixture was concentrated under reduced pressure. Isopropyl acetate (5.0L) was added to the concentrate, and the resulting mixture was further concentrated under reduced pressure. Methyl ethyl ketone (12.5L) was added to the concentrate, and the resulting mixture was stirred at 35. + -. 5 ℃ for about 15 minutes. To the resulting solution was added acetic acid (220.5 g). The reaction mixture was stirred for about 30 minutes, cooled to about 5 ℃, and then stirred at 0 ℃ to 5 ℃ for about 1 hour. The product was filtered and then washed with cold methyl ethyl ketone (2.5L). The resulting wet cake was dried under vacuum at about 40 deg.C to give 889.3g of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate. (yield: 87.0%)

Chemical purity: 99.99 percent

Chiral purity: 100 percent

M.P 116.5～118.5℃

MS m/z 219(M⁺+H)

¹H-NMR(400MHz，DMSO-d₆)δ8.0(m,4H)，7.31(m,4H)，7.25(m,2H)，3.61(d,1H)，3.40(d,1H)，2.76(b，3H)，2.35(s,3H)，2.21(b,2H)，1.99(s,3H)，1.83(b,1H)，1.50(b,2H)，1.04(d,3H)

Optical rotation: 26.9-28.2 degree

The PXRD spectrum of the obtained (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate is shown in FIG. 3. As shown in FIG. 3, diffraction peaks exist at 2 θ angles of 7.60. + -. 0.2 °, 10.49. + -. 0.2 °, 13.53. + -. 0.2 °, 14.44. + -. 0.2 °, 14.99. + -. 0.2 °, 15.27. + -. 0.2 °, 16.37. + -. 0.2 °, 16.89. + -. 0.2 °, 17.49. + -. 0.2 °, 18.47. + -. 0.2 °, 20.47. + -. 0.2 °, 22.08. + -. 0.2 °, 23.00. + -. 0.2 °, 24.07. + -. 0.2 °, 24.63. + -. 0.2 °, 26.67. + -. 0.2 °, 27.24. + -. 0.2 °, 27.87. + -. 0.2 °, 29.12. + -. 0.2 °, 31.84. + -. 0.2 °, 35.55. + -. 0.2 °, and 37.42. + -. 0.2 °.

And, DSC thermogram and FT-IR spectrum of the obtained (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate are shown in FIG. 4 and FIG. 5, respectively. As shown in FIG. 5, the infrared absorption frequency (cm)^-1) 2944, 2917, 1546, 1477, 1395, 1332, 1262, 1211, 1162, 1124, 1099, 1073, 1057, 1006, 961, 930, 911, 815, 784, 746, 702, 652, 616, 485, 448 and 403.

Example 7: preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate

A mixture of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate isopropanol solvate (1:1:1, chiral purity: 97.20%) (25.0g) and methyl tert-butyl ether (250mL) was cooled to below 10 ℃ and then 10% potassium carbonate solution (150mL) was added thereto. The reaction mixture was stirred for about 30 minutes. The organic layer was separated, washed with pure water (25mL), and then concentrated under reduced pressure. Tetrahydrofuran (35mL) was added to the concentrate, and the resulting mixture was further concentrated under reduced pressure. Tetrahydrofuran (163mL) was added to the concentrate, and the resulting mixture was stirred for about 15 minutes. Lithium aluminum hydride (1.99g) was added to the solution. The reaction mixture was heated to reflux for 3 hours and cooled to-10 ℃ to-5 ℃. An aqueous tetrahydrofuran solution (18mL, THF: pure water ═ 5:2(v/v)) was slowly added thereto while keeping the internal temperature at 0 ℃ or lower. After the temperature of the reaction mixture was raised to room temperature, the reaction mixture was stirred for about 30 minutes, and then filtered. The wet cake was washed with tetrahydrofuran (50 mL). The filtrate and the rinsed solution were combined, and the resulting mixture was concentrated under reduced pressure. Methyl ethyl ketone (125mL) was added to the concentrate, and the resulting mixture was stirred at 35 ℃. + -. 5 ℃ for about 15 minutes. To the resulting solution was added acetic acid (2.21 g). The reaction mixture was stirred for about 30 minutes, cooled to about 5 ℃, and then stirred at 0 ℃ to 5 ℃ for about 1 hour. The product was filtered and then washed with cold methyl ethyl ketone (25 mL). The resulting wet cake was dried under vacuum at about 40 deg.C to give 8.45g of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate. (yield: 82.7%)

Chemical purity: 100 percent

Chiral purity: 99.91 percent

¹H-NMR(400MHz，DMSO-d₆)δ8.0(m,4H)，7.31(m,4H)，7.25(m,2H)，3.61(d,1H)，3.40(d,1H)，2.76(b,3H)，2.35(s,3H)，2.21(b,2H)，1.99(s,3H)，1.83(b,1H)，1.50(b,2H)，1.04(d,3H)

Example 8: preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate

A mixture of isopropyl alcohol solvate of methyl ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) carbamate dibenzoyl-L-tartrate (1:1:1, chiral purity: 95.20%) (25.0g) and methyl tert-butyl ether (250mL) was cooled to 10 ℃ or below, and then 10% potassium carbonate solution (150mL) was added thereto. The reaction mixture was stirred for about 30 minutes. The organic layer was separated, washed with pure water (25mL), and then concentrated under reduced pressure. Tetrahydrofuran (35mL) was added to the concentrate, and the resulting mixture was further concentrated under reduced pressure. Tetrahydrofuran (163mL) was added to the concentrate, and the resulting mixture was stirred for about 15 minutes. Lithium aluminum hydride (1.99g) was added to the solution. The reaction mixture was heated to reflux for 3 hours and cooled to-10 ℃ to-5 ℃. An aqueous tetrahydrofuran solution (18mL, THF: pure water ═ 5:2(v/v)) was slowly added thereto while keeping the internal temperature at 0 ℃ or lower. After raising the temperature of the reaction mixture to room temperature, the reaction mixture was stirred for about 30 minutes and then filtered through a celite pad. The wet cake was washed with tetrahydrofuran (50 mL). The filtrate and the washed solution were combined, and the resulting mixture was concentrated under reduced pressure. Methyl ethyl ketone (125mL) was added to the concentrate, and the resulting mixture was stirred at 35 ℃. + -. 5 ℃ for about 15 minutes. To the resulting solution was added acetic acid (2.21 g). The reaction mixture was stirred for about 30 minutes, cooled to about 5 ℃, and then stirred at 0 ℃ to 5 ℃ for about 1 hour. The product was filtered and then washed with cold methyl ethyl ketone (25 mL). The resulting wet cake was dried under vacuum at about 40 deg.C to give 8.06g of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate. (yield: 78.9%)

Chemical purity: 100 percent

Chiral purity: 99.87 percent

¹H-NMR(400MHz，DMSO-d₆)δ8.0(m,4H)，7.31(m,4H)，7.25(m,2H)，3.61(d,1H)，3.40(d,1H)，2.76(b，3H)，2.35(s,3H)，2.21(b,2H)，1.99(s,3H)，1.83(b,1H)，1.50(b，2H)，1.04(d,3H)

Example 9: preparation of (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine

A mixture of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate (chiral purity: 99.98%) (50.0g) and 5% sodium hydrogencarbonate solution (1.5L) was stirred for about 30 minutes. 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine (33.8g) was added to the reaction mixture, followed by stirring at 100 ℃. + -. 5 ℃ for 12 hours. The reaction mixture was cooled to room temperature, stirred for about 1 hour, and then filtered. The resulting product was washed with pure water (500 mL). The resulting wet cake was dried under vacuum at about 50 ℃ to give 64.1g of (3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine. (yield: 97%)

Chemical purity: 98 percent of

Chiral purity: 99.98 percent

¹H-NMR(400MHz，DMSO-d₆)δ11.80(s,1H)，7.31(m,4H)，7.21-7.25(m,1H)，7.12(s,1H)，6.58(b,1H)，4.99(b,1H)，3.38-3.50(m,5H)，2.77-2.81(m,1H)，2.64(b,1H)，2.53-2.55(m，1H)，2.24(b,1H)，2.18(b,1H)，1.60-1.63(m,2H)，0.87(d,3H)

Example 10: preparation of (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine

(3R,4R) - (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine (chemical purity: 99.7%, chiral purity: 99.98%) (450.0g) and pure water (4.5L) were added to the hydrogenation reactor. To this was added 10% Palladium on carbon hydroxide catalyst (20.5g) and hydrochloric acid solution (53 mL). The hydrogenation reactor was charged with hydrogen, pressurized to 30psi, and stirred at 70 ℃. + -. 5 ℃ for 3 hours. The reaction mixture was cooled to room temperature, and hydrogen gas was removed therefrom by nitrogen substitution. The reaction mixture was filtered through a celite pad. The wet cake was washed with pure water (0.9L). To the combined filtrate and washings was added dichloromethane (4.5L) and then stirred for about 30 minutes. The pH of the reaction mixture is adjusted to about 10-12 with 50% sodium hydroxide solution. The organic layer was separated and then concentrated under reduced pressure to give 287g of (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine. (yield: 96%)

Chemical purity: 99.8 percent

Chiral purity: 99.98 percent

¹H-NMR(400MHz，DMSO-d₆)δ11.61(s,1H)，8.08(s,1H)，7.11(d,1H)，6.52(d,1H)，4.78(s,1H)，3.31(s,3H)，3.09-3.14(m,1H)，2.78-2.84(m,2H)，2.74(m，1H)，2.29-2.32(m,1H)，1.70-1.76(m,1H)，1.44-1.48(m,1H)，0.96(d，3H)

Example 11: preparation of tofacitinib

To a mixture of (3R,4R) - (4-methylpiperidin-3-yl) -N-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amine (chemical purity: 99.8%, chiral purity: 99.98%) (270.0g) and tetrahydrofuran (2.7L) were added ethyl cyanoacetate (187g) and 1,8-diazabicyclo [5,4,0] undec-7-ene (1,8-diazabicyclo [5,4,0] undec-7-ene) (168 g). The reaction mixture was stirred for 24 hours while maintaining the reaction temperature at 20 ℃ to 30 ℃. Pure water (5.4L) was added to the reaction mixture, and the pH was adjusted to 7 to 8 with a 20% hydrochloric acid solution. The reaction mixture was stirred for 12 hours and then filtered. The resulting product was washed with 33% aqueous tetrahydrofuran (0.8L). The resulting wet cake was dried at about 60 ℃ to give 267g of tofacitinib. (yield: 78%)

Chemical purity: 99.2 percent

Chiral purity: 99.98 percent

¹H-NMR(400MHz，DMSO-d₆)δ11.67(s,1H)，8.11(d,1H)，7.14(s,1H)，6.56(s,1H)，4.85(s,1H)，3.62-4.15(m,4.5H)，3.37-3.43(m,1.5H)，3.25(s,3H)，2.38-2.42(m,1H)，1.68-1.72(m,1H)，1.53-1.59(m，1H)，0.99-1.03(m,3H)

Experimental example: stability test

The stability test under long-term storage conditions of Table 1 below was carried out on (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared in example 7 and (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine hydrochloride prepared according to a known method.

TABLE 1

	Long term storage conditions
		Temperature of	25±2℃
Relative humidity	60. + -. 5% relative humidity
		Container with a lid	20mL glass vial
Sampling	Initial/after 6 months

The results of the stability test under long-term storage conditions are shown in fig. 6 to 11. Table 2 summarizes the results.

TABLE 2

As can be seen from the above stability test results, (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine acetate prepared according to the present invention did not show any significant change in appearance, chemical purity, chiral purity and DSC peak temperature between the initial time and the final time of the test.