CN111233866B - Process for the preparation of tofacitinib or a salt thereof - Google Patents

Process for the preparation of tofacitinib or a salt thereof Download PDF

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CN111233866B
CN111233866B CN201811438999.2A CN201811438999A CN111233866B CN 111233866 B CN111233866 B CN 111233866B CN 201811438999 A CN201811438999 A CN 201811438999A CN 111233866 B CN111233866 B CN 111233866B
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reaction
compound
deprotection reaction
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CN111233866A (en
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朱建荣
陈玉龙
林庆
顾晋文
唐飞宇
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Shaoxing Jingxin Pharmaceutical Co ltd
Zhejiang Jingxin Pharmaceutical Co Ltd
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Shangyu Jingxinn Pharmaceutical Co ltd
Zhejiang Jingxin Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a preparation method of tofacitinib or a salt thereof, wherein the preparation method of the tofacitinib intermediate compound shown in the formula V comprises the following steps: (1) carrying out a mitsunobu reaction on the compound II and the compound III to generate an intermediate IV; (2) carrying out methylation reaction on the intermediate IV and a methylation reagent to generate a compound shown in the formula V; wherein R is1And R2Each independently an amino protecting group. The preparation method does not need to carry out isomer resolution and purification in the process, avoids using lithium aluminum hydride, has low synthesis cost and higher yield, has simple reaction conditions and post-treatment operation, and is suitable for industrial production.

Description

Process for the preparation of tofacitinib or a salt thereof
Technical Field
The invention belongs to the field of organic and pharmaceutical synthesis, and particularly relates to a preparation method of tofacitinib or a salt thereof.
Background
Tofacitinib citrate is an oral JAK inhibitor developed by the company pfeiri, and has the chemical name: 3- [ (3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl ] -3-oxopropanenitrile citrate, approved by the FDA in the united states for risk assessment and mitigation strategies at 11 months 2012 for the treatment of moderate to severe active rheumatoid arthritis during the active period of adults and with an adverse reaction to methylamine purines, under the trade name Xeljanz, having the following structural formula:
Figure BDA0001884266920000011
at present, the synthetic routes of tofacitinib reported in the literature are as follows:
route one: the synthetic route of US6627754 is as follows:
Figure BDA0001884266920000012
the method uses 1-benzyl-4-methyl-piperidine-3-ketone as a raw material, and comprises the steps of reductive amination of upper methylamino, butt joint with a chlorinated heterocyclic ring, removal of benzyl under the catalytic hydrogenation condition, acylation and resolution to obtain tofacitinib. The raw materials of the route are expensive, the final product is subjected to isomer resolution and purification, the isomer is difficult to control, the cost is high, the yield is low, and the method is not suitable for industrial production.
And a second route: the published preparation route reported in WO2007012953 is as follows:
Figure BDA0001884266920000021
the process takes 3-amino-4-methylpyridine as a raw material, obtains an intermediate cis-1-benzyl-3-methylamino-4-methylpiperidine through amino protection, rhodium catalytic reduction of the pyridine and lithium aluminum hydride reduction, and obtains tofacitinib through resolution, coupling, debenzyl protection and amidation. The rhodium is used for catalyzing in the route, the price of the whole material is high, a large amount of lithium aluminum hydride is used in the reaction, the property is active, the post-treatment is very dangerous and complex, the heat can be rapidly released when meeting water, the safety is poor, and the industrial amplification is difficult to realize.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art and provide a novel preparation method of tofacitinib or salt thereof. The preparation method does not need to carry out isomer resolution and purification in the process, avoids using lithium aluminum hydride, has low synthesis cost and higher yield, has simple reaction conditions and post-treatment operation, and is suitable for industrial production.
The present invention solves the above-described problems by the following technical means.
The invention provides a preparation method of a compound shown in a formula V, which comprises the following steps:
(1) carrying out a mitsunobu reaction on the compound II and the compound III to generate an intermediate IV;
(2) carrying out methylation reaction on the intermediate IV and a methylation reagent to generate a compound shown in the formula V;
Figure BDA0001884266920000031
wherein R is1And R2Each independently an amino protecting group.
The amino protecting group may be an amino protecting group conventionally used in the art. In the present invention, R is1preferably-Bn (benzyl), -PMB (p-methoxybenzyl), -Boc (t-butyloxycarbonyl), -Cbz (benzyloxycarbonyl) or-Ts (p-toluenesulfonyl), more preferably-Bn; the R is2preferably-Ts, -Cbz, -Boc, -Bn, -PMB or-Teoc (trimethylsiloxyethylcarbonyl), more preferably-Ts.
In the step (1), the method and conditions of the mitsunobu reaction may be those conventional to the reaction. The phosphine ligand of the mitsunobu reaction is preferably triphenylphosphine and/or tributylphosphine. The azo compound of the mitsunobu reaction is preferably diisopropyl azodicarboxylate and/or diethyl azodicarboxylate. The solvent for the mitsunobu reaction is preferably one or more of tetrahydrofuran, acetonitrile, isopropyl acetate, ethyl acetate and dioxane, more preferably dioxane. The temperature of the calendering reaction is preferably 50 to 100 c, more preferably 90 to 100 c. The time of the mitsunobu reaction is based on the completion of the reaction, and is preferably 3 to 4 hours.
Furthermore, the inventors have found that the compound of formula V can also be prepared by first preparing compound III' from compound III by methylation and then reacting with compound II. However, when the reaction is carried out according to the route, the mono-methyl substituted product and the di-methyl substituted product can appear simultaneously in the reaction process, and the mono-substituted product is difficult to separate and purify subsequently; or, harsh reaction conditions are adopted, and the compound III is firstly formyl and then reduced to obtain a compound III'. And the compound II and the compound III are adopted for direct reaction, the reaction selectivity is good, other obvious byproducts are not generated, and the yield is also high.
Figure BDA0001884266920000032
In step (2), the method and conditions of the methylation reaction may be those conventional in the art. The methylating agent is preferably methyl iodide, dimethyl sulfate or dimethyl carbonate, more preferably methyl iodide. The methylation reaction is generally carried out in the presence of a base, preferably one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide, more preferably potassium carbonate. The solvent for the methylation reaction is preferably one or more of tetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethyl sulfoxide, and more preferably dimethylformamide. The temperature of the methylation reaction is preferably 0 to 50 deg.C, more preferably 20 to 30 deg.C. The methylation reaction time is based on the complete reaction, and is preferably 5 to 6 hours.
The invention also provides a preparation method of tofacitinib or salt thereof, which comprises the following steps:
step (1) and step (2) as described above, and then removing R1And R2Protecting groups to produce intermediate VII; then, performing an amide-amination reaction on the intermediate VII and the compound X to obtain tofacitinib (a compound shown in a formula I);
Figure BDA0001884266920000041
wherein R is1And R2The radicals are as defined above, R3Is halogen, hydroxyl, imidazole, mesyloxy, p-toluenesulfonyloxy, pivaloyl or alkoxy of C1-C6. The halogen is fluorine, chlorine, bromine or iodine.
Wherein R is removed1And R2The order of the protecting groups is not limited as long as intermediate VII is obtained. For example, R may be removed first2Protecting group, removing R1A protecting group; alternatively, R may be removed first1Protecting group, removing R2A protecting group; or when R is1And R2When they are the same amino protecting group, they may beBy one-step removal of R1And R2A protecting group.
In a preferred embodiment of the present invention, the removing R is performed1And R2The protecting groups are as follows:
(3) removing R from the compound of formula V by deprotection reaction2Group to obtain intermediate VI;
(4) removing R from the intermediate VI through deprotection reaction1Obtaining an intermediate VII;
Figure BDA0001884266920000051
in another preferred embodiment of the present invention, said removing R1And R2The protecting groups are as follows:
removing R from compound of formula V by deprotection reaction1Obtaining an intermediate VIII;
removing R from intermediate VIII through deprotection reaction2Obtaining an intermediate VII;
Figure BDA0001884266920000052
in the neutralization step (3) and in the neutralization step (R), the method and conditions for the deprotection reaction may be those conventional in the art as long as the corresponding R can be removed2The group is just needed.
For example, at R2In the case of-Ts, the deprotection reaction is carried out in the presence of a base, preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide, more preferably sodium hydroxide. The solvent for the deprotection reaction is preferably one or more of tetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide and water, more preferably water. The temperature of the deprotection reaction is preferably 60 to 100 ℃, more preferably 90 to 100 ℃.
Also for example, in R2In the case of-Bn, the deprotection reaction is carried out in a hydrogen atmosphere, and the metal used isThe catalyst is preferably Pd/C, Pd (OH)2/C, Pt/C or Pd/CaCO3More preferably Pd (OH)2and/C. The solvent for the deprotection reaction is preferably one or more of tetrahydrofuran, acetonitrile, methanol, ethanol, ethyl acetate, isopropyl acetate and water, more preferably methanol. The temperature of the deprotection reaction is preferably 0 to 50 ℃ and more preferably 10 to 30 ℃.
Also for example, R2In the case of-Boc, the deprotection reaction is carried out in the presence of an acid, preferably one or more of hydrochloric acid, sulfuric acid, formic acid, phosphoric acid and trifluoroacetic acid, more preferably hydrochloric acid; the solvent for the deprotection reaction is preferably one or more of tetrahydrofuran, toluene, methanol, ethyl acetate, isopropyl acetate and dichloromethane, and more preferably ethyl acetate; the deprotection reaction temperature is 0-30 ℃, preferably 10-25 ℃.
In step (4) and step (c), the deprotection reaction may be performed by a method and conditions conventional in the art as long as the corresponding R can be removed1The group is just needed.
For example, at R1In the case of-Bn, the deprotection reaction is carried out under a hydrogen atmosphere, and the metal catalyst used is preferably Pd/C, Pd (OH)2/C, Pt/C or Pd/CaCO3More preferably Pd (OH)2and/C. The solvent for the deprotection reaction is preferably one or more of tetrahydrofuran, acetonitrile, methanol, ethanol, ethyl acetate, isopropyl acetate and water, more preferably methanol. The temperature of the deprotection reaction is preferably 0 to 50 ℃ and more preferably 10 to 30 ℃.
Also for example, in R1In the case of-Ts, the deprotection reaction is carried out in the presence of a base, preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide, more preferably sodium hydroxide. The solvent for the deprotection reaction is preferably one or more of tetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide and water, more preferably water. The temperature of the deprotection reaction is preferably 60 to 100 ℃, more preferably 90 to 100 ℃.
Also for example, R1In the case of-Boc, the deprotection reaction is carried out in the presence of an acid, preferably one or more of hydrochloric acid, sulfuric acid, formic acid, phosphoric acid and trifluoroacetic acid, more preferably hydrochloric acid; the solvent for the deprotection reaction is preferably one or more of tetrahydrofuran, toluene, methanol, ethyl acetate, isopropyl acetate and dichloromethane, and more preferably ethyl acetate; the deprotection reaction temperature is 0-30 ℃, preferably 10-25 ℃.
In another preferred embodiment of the invention, R1And R2All are-Bn, -PMB, -Boc, -Cbz or-Ts, then removing R1And R2The protecting groups are provided by: removing R from the compound of formula V by one-step deprotection reaction1And R2And (4) directly generating an intermediate VII. The deprotection reaction may be carried out by methods and conditions conventional in the art, as long as the corresponding amino protecting group can be removed.
Following preparation of the compound of formula I, further salt formation may be carried out to obtain a salt of the compound of formula I, as is common in the art. The salt is preferably a citrate, hydrochloride, sulphate, phosphate or hydrobromide salt, more preferably a citrate salt.
In the present invention, the amounts of the respective reaction materials, reagents, solvents, etc. may be selected according to the general knowledge in the art. After completion of the reactions of the present invention, one or more of the workup operations, including but not limited to extraction, filtration, washing, and drying, can be performed according to common knowledge in the art. In a preferred embodiment of the present invention, the steps of the preparation method do not include isomer resolution purification and column chromatography separation.
In the present invention, the term "compound a" is sometimes expressed as "compound of formula a" or "compound of formula a", as can be understood by those skilled in the art. For example, both compound II and the compound of formula II refer to the same compound.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the preparation method does not need to carry out isomer resolution and purification in the process, has low synthesis cost and higher yield, and is simple in reaction condition and post-treatment operation and suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, unless otherwise specified, the reaction is carried out at room temperature, generally 10 to 30 ℃.
In the following examples, no additional purification was carried out between the individual preparation steps, unless otherwise specified.
Example 1
Figure BDA0001884266920000081
Preparation of Compound IV-1
Dissolving 20 g of compound II-1 and 25 g of compound III-1 in 150 ml of dioxane, adding 28 g of triphenylphosphine, cooling the system to 0 ℃, dropwise adding 26 g of diisopropyl azodicarboxylate, reacting at room temperature for 3h, and reacting at 100 ℃ for 3 h. After the reaction is finished, the temperature is reduced to room temperature, the system is concentrated and dried, dichloromethane and water are added for extraction, then saturated sodium bicarbonate water solution and saturated saline solution are used for washing, and 30.2 g of compound IV-1 is obtained after drying, filtering and concentrating of anhydrous sodium sulfate.
Preparation of Compound V-1
Dissolving 23 g of compound IV-1 in 60 g of dimethylformamide, adding 16.7 g of potassium carbonate, stirring at room temperature for 0.5h, dropwise adding 13.7 g of methyl iodide into the reaction solution, and reacting at room temperature overnight after the addition is finished. After the reaction was completed, 200 g of water and 150 g of ethyl acetate were added, stirred for 15 minutes, allowed to stand for separation, and the aqueous layer was extracted once with 100 g of ethyl acetate. The ethyl acetate layer was collected, washed with 200 g x 3 of water, dried over anhydrous sodium sulfate, filtered and concentrated to give 18.1 g of compound V-1.
Preparation of Compound VI-1
100 ml of water and 18 g of compound V-1 are added into a 250 ml reaction flask, 80 g of sodium hydroxide is added in three times, and after the addition is finished, the reflux reaction is carried out for 6h at 100 ℃. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with water and dried to obtain 12 g of an off-white solid (compound VI-1).
Preparation of Compound VII
Dissolving 10 g of compound VI-1 in 60 ml of anhydrous methanol, adding 1 g of 10% palladium carbon, replacing twice with nitrogen, introducing hydrogen for replacing once, reacting at room temperature under a hydrogen environment overnight, filtering off the palladium carbon after the reaction is finished, and concentrating the filtrate to obtain 6 g of off-white solid (compound VII).
Preparation of Compound I
5 g of compound VII are dissolved in 60 ml of dichloromethane, 6.5 g of triethylamine are added and stirring is carried out. 3.5 g of cyanoacetyl chloride (X-1) was slowly added dropwise thereto, and after completion of the addition, the mixture was stirred at room temperature overnight. After the reaction is finished, 30 g of water is added, stirring and layering are carried out, an organic phase is collected, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 5 g of compound I with the purity of 97.1%.
Example 2
Figure BDA0001884266920000091
Preparation of Compound IV-2
10 g of compound II-1 and 14 g of compound III-2 are dissolved in 70 ml of dioxane, 15 g of triphenylphosphine is added, the system is cooled to 0 ℃, 14 g of diisopropyl azodicarboxylate is added dropwise, after the addition is finished, the reaction is carried out at room temperature for 2h, and then the reaction is carried out for 3h at 100 ℃. After the reaction is finished, the temperature is reduced to room temperature, the system is concentrated and dried, dichloromethane and water are added for extraction, then saturated sodium bicarbonate water solution and saturated saline solution are used for washing, and the compound IV-2 of 12.2 g is obtained after drying, filtering and concentrating of anhydrous sodium sulfate.
Preparation of Compound V-2
10 g of compound IV-2 is dissolved in 35 g of dimethylformamide, 8.7 g of potassium carbonate is added, stirring is carried out at room temperature for 0.5h, 9.7 g of methyl iodide is added dropwise to the reaction solution, and after the addition is finished, the reaction is carried out at room temperature overnight. After the reaction was completed, 100 g of water and 60 g of ethyl acetate were added, stirred for 15 minutes, and allowed to stand to separate, and the aqueous layer was extracted once with 50 g of ethyl acetate. The ethyl acetate layer was collected, washed with 200 g x 3 of water, dried over anhydrous sodium sulfate, filtered and concentrated to give 7.1 g of compound V-2.
Preparation of Compound VIII-2
Dissolving 7 g of compound V-2 in 50 ml of anhydrous methanol, adding 0.7 g of 10% palladium carbon, replacing twice with nitrogen, introducing hydrogen for replacing once, reacting at room temperature under a hydrogen environment overnight, filtering off the palladium carbon after the reaction is finished, and concentrating the filtrate to obtain 4 g of off-white solid (compound VIII-2).
Preparation of Compound VII
4 g of the compound VIII-2 was dissolved in 40 ml of tetrahydrofuran, and then a hydrogen chloride gas was introduced thereinto to react at room temperature for 1 hour. The solid was precipitated, filtered, added with ethyl acetate and water, made basic with 10% aqueous sodium bicarbonate, and the organic layer was recovered, dried, filtered, and concentrated to give 2.3 g of an off-white solid (compound VII).
Preparation of Compound I
2 g of compound VII are dissolved in 60 ml of dichloromethane, 3 g of triethylamine are added and stirring is carried out. 1.6 g of cyanoacetyl chloride (X-1) was slowly added dropwise thereto, and after completion of the addition, the mixture was stirred at room temperature overnight. After the reaction is finished, 20 g of water is added, stirring and layering are carried out, an organic phase is collected, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 2 g of compound I with the purity of 96.2%.
Comparative example 1
Figure BDA0001884266920000111
Preparation of Compound III' -2
Dissolving 20 g of compound III-2 in 40 g of dimethylformamide, adding 17 g of potassium carbonate, cooling to 0 ℃, slowly dropwise adding 13.5 g of methyl iodide into the reaction solution, and reacting for 24 hours at 15-25 ℃ after the addition is finished. After the reaction was completed, 150 g of water and 80 g of ethyl acetate were added, stirred for 15 minutes, allowed to stand for separation, and the aqueous layer was extracted once with 60 g of ethyl acetate. The ethyl acetate layer was collected, washed with 200 g x 3 of water, dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, which was separated by column chromatography to give 2.6 g of monomethylation product. The detection shows that the reaction has a double methylation byproduct (the content accounts for about 20wt percent), column chromatography is required for separation, the yield is low, and the large-scale production is not easy.
Preparation of Compound V-2
Dissolving 2.5 g of compound III' -2 and 1.8 g of compound II-1 in 30 ml of dioxane, adding 2.7 g of triphenylphosphine, cooling the system to 0 ℃, dropwise adding 2.5 g of diisopropyl azodicarboxylate, reacting at room temperature for 2h, and reacting at 100 ℃ for 3 h. After the reaction is finished, the temperature is reduced to room temperature, the system is concentrated and dried, dichloromethane and water are added for extraction, then saturated sodium bicarbonate water solution and saturated saline solution are used for washing, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and 1.7 g of compound V-2 is obtained.
Preparation of Compound VIII-2
Dissolving 1.7 g of compound V-2 in 10 ml of anhydrous methanol, adding 0.17 g of 10% palladium carbon, replacing twice with nitrogen, introducing hydrogen for replacing once, reacting at room temperature under a hydrogen environment overnight, filtering off the palladium carbon after the reaction is finished, and concentrating the filtrate to obtain 0.8 g of off-white solid (compound VIII-2).
Preparation of Compound VII
0.8 g of the compound VIII-2 was dissolved in 10 ml of tetrahydrofuran, and hydrogen chloride gas was introduced thereinto to conduct a reaction at room temperature for 1 hour. The solid was precipitated, filtered, added with ethyl acetate and water, made basic with 10% aqueous sodium bicarbonate, and the organic layer was recovered, dried, filtered, and concentrated to give 0.5 g of an off-white solid (compound VII).
Preparation of Compound I
0.5 g of compound VII was dissolved in 10 ml of dichloromethane, and 0.8 g of triethylamine was added thereto and stirred. 0.4 g of cyanoacetyl chloride (X-1) was slowly added dropwise thereto, and after completion of the addition, the mixture was stirred at room temperature overnight. After the reaction is finished, 10 g of water is added, stirring and layering are carried out, an organic phase is collected, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 0.3 g of compound I with the purity of 93.4%.
Example 3
Figure BDA0001884266920000121
Preparation of Compound IV-3
Dissolving 8 g of compound II-2 and 12 g of compound III-2 in 46 ml of dioxane, adding 12 g of triphenylphosphine, cooling the system to 0 ℃, dropwise adding 11 g of diisopropyl azodicarboxylate, reacting at room temperature for 1h, and reacting at 90 ℃ for 3 h. After the reaction is finished, the temperature is reduced to room temperature, the system is concentrated and dried, dichloromethane and water are added for extraction, then saturated sodium bicarbonate water solution and saturated saline solution are used for washing, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and 9.2 g of compound IV-3 is obtained.
Preparation of Compound V-3
Dissolving 9 g of compound IV-3 in 35 g of dimethylformamide, adding 8.5 g of potassium carbonate, stirring at room temperature for 0.5h, dropwise adding 8.6 g of methyl iodide into the reaction solution after the completion of the addition, and reacting at room temperature for 24 h. After the reaction was completed, 100 g of water and 40 g of ethyl acetate were added, stirred for 15 minutes, allowed to stand for separation, and the aqueous layer was extracted once with 40 g of ethyl acetate. The ethyl acetate layer was collected, washed with 200 g x 3 of water, dried over anhydrous sodium sulfate, filtered and concentrated to give 6.1 g of compound V-3.
Preparation of Compound VII
6 g of the compound V-2a was dissolved in 60 ml of tetrahydrofuran, and then reacted at room temperature for 1 hour with hydrogen chloride gas introduced. The solid was precipitated, filtered, added with ethyl acetate and water, made basic with 10% aqueous sodium bicarbonate, and the organic layer was recovered, dried, filtered, and concentrated to give 2.1 g of an off-white solid (compound VII).
Preparation of Compound I
2.1 g of compound VII are dissolved in 25 ml of dichloromethane, 3.8 g of triethylamine are added and stirring is carried out. 1.8 g of cyanoacetyl chloride (X-1) was slowly added dropwise thereto, and after completion of the addition, the mixture was stirred at room temperature overnight. After the reaction, 30 g of water is added, and the mixture is stirred and layered, an organic phase is collected, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 1.6 g of compound I with the purity of 94.1%.

Claims (9)

1. A process for the preparation of tofacitinib or a salt thereof, characterized in that it comprises the following steps:
(1) carrying out a mitsunobu reaction on the compound II and the compound III to generate an intermediate IV;
(2) carrying out methylation reaction on the intermediate IV and a methylation reagent to generate a compound shown in the formula V;
(3) removal of R1And R2Protecting groups to produce intermediate VII;
(4) performing an amide-amination reaction on the intermediate VII and the compound X to obtain tofacitinib;
Figure FDA0003053424140000011
wherein R is1And R2Each independently is an amino protecting group, R3Is halogen, hydroxyl, imidazole, mesyloxy, p-toluenesulfonyloxy, pivaloyl or alkoxy of C1-C6.
2. The method of claim 1, wherein R is1is-Bn, -PMB, -Boc, -Cbz or-Ts;
the R is2is-Ts, -Cbz, -Boc, -Bn, -PMB or-Teoc.
3. The production method according to claim 1 or 2, wherein in the step (1), the phosphine ligand of the mitsunobu reaction is triphenylphosphine or tributylphosphine;
the azo compound of the mitsunobu reaction is diisopropyl azodicarboxylate or diethyl azodicarboxylate;
the solvent of the mitsunobu reaction is one or more of tetrahydrofuran, acetonitrile, isopropyl acetate, ethyl acetate and dioxane;
the temperature of the mitsunobu reaction is 50-100 ℃;
the time of the mitsunobu reaction is 3-4 hours.
4. The method according to claim 1 or 2, wherein in the step (2), the methylating agent is methyl iodide, dimethyl sulfate or dimethyl carbonate;
the methylation reaction is carried out in the presence of a base, wherein the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide;
the solvent of the methylation reaction is one or more of tetrahydrofuran, acetonitrile, dimethylformamide, toluene and dimethyl sulfoxide;
the temperature of the methylation reaction is 0-50 ℃;
the methylation reaction time is 5-6 hours.
5. The process of claim 1 or 2, wherein said removing R is carried out1And R2The protecting groups are as follows:
(1) removing R from the compound of formula V by deprotection reaction2Group to obtain intermediate VI;
(2) removing R from the intermediate VI through deprotection reaction1Obtaining an intermediate VII;
Figure FDA0003053424140000021
6. the process of claim 1 or 2, wherein said removing R is carried out1And R2The protecting groups are as follows:
(1) removing R from the compound of formula V by deprotection reaction1Obtaining an intermediate VIII;
(2) removing R from the intermediate VIII through deprotection reaction2Obtaining an intermediate VII;
Figure FDA0003053424140000022
7. the method of claim 1, wherein R is1And R2All are-Bn, -PMB, -Boc, -Cbz or-Ts, and the removal of R1And R2The protecting groups are provided by: removing R from the compound of formula V by one-step deprotection reaction1And R2And (4) directly generating an intermediate VII.
8. The method of claim 1, wherein R is1And R2is-Ts, the deprotection reaction is carried out in the presence of a base, and the base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide; the solvent of the deprotection reaction is one or more of tetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethyl sulfoxide and the like; the temperature of the deprotection reaction is 60-100 ℃;
or, R1And R2to-Bn, the deprotection reaction is carried out in a hydrogen atmosphere, and the metal catalyst used is Pd/C, Pd (OH)2/C, Pt/C or Pd/CaCO3(ii) a The solvent of the deprotection reaction is one or more of tetrahydrofuran, acetonitrile, methanol, ethanol, ethyl acetate, isopropyl acetate and water; the temperature of the deprotection reaction is 0-50 ℃;
or, R1And R2for-Boc, the deprotection reaction is carried out in the presence of an acid, which is one or more of hydrochloric acid, sulfuric acid, formic acid, phosphoric acid, and trifluoroacetic acid; the solvent for the deprotection reaction is one or more of tetrahydrofuran, toluene, methanol, ethyl acetate, isopropyl acetate and dichloromethane; the deprotection reaction temperature is 0-30 ℃.
9. The method of claim 1, wherein after the compound of formula I is obtained, a salt forming reaction is further performed to obtain a salt of the compound of formula I, wherein the salt is a citrate, a hydrochloride, a sulfate, a phosphate, or a hydrobromide.
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