CN108752254B - Preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile - Google Patents

Preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile Download PDF

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CN108752254B
CN108752254B CN201810492567.3A CN201810492567A CN108752254B CN 108752254 B CN108752254 B CN 108752254B CN 201810492567 A CN201810492567 A CN 201810492567A CN 108752254 B CN108752254 B CN 108752254B
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heptane
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acetonitrile
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CN108752254A (en
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王西龙
甲宗青
杜军明
董向生
宋伟国
杨振勇
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Daohe Weifang Pharmaceutical Technology Co ltd
Shandong Daohe Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention relates to the technical field of medical chemistry, in particular to a preparation method of a Baricitinib four-membered ring intermediate; the invention also provides a green oxidation reaction carried out in the microchannel reactor; the process route provided by the invention has the advantages of easily available raw materials, economy, greenness and environmental protection, and is suitable for industrial production.

Description

Preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile
Technical Field
The invention relates to the technical field of medical chemistry, in particular to a preparation method of an improved Baricitinib four-membered ring intermediate. The invention also provides a green oxidation reaction carried out in the microchannel reactor.
Background
Baricitinib is a novel and efficient small molecule drug which is developed by Rieger and Incyte which is a partner thereof, can selectively inhibit JAK1 and JAK2, can inhibit intracellular signal conduction of various inflammatory cytokines such as IL-6he IL-23 and the like, but does not inhibit JAK 3. The product was approved by the european union for the treatment of moderate to severe rheumatoid arthritis in month 3 in 2017, and was approved by japan in month 7 in 2017 for the treatment of rheumatoid arthritis patients who do not respond well to current standard therapies. The chemical structural formula is as follows:
Figure BDA0001668283320000011
the prior art discloses a preparation method of barrectin benzoate and a key intermediate thereof, and an Incyte corporation ioin a patent WO2009114512A1 reports a preparation method of a barrectin benzoate key intermediate (a quaternary heterocyclic intermediate) as follows:
Figure BDA0001668283320000021
in the prior art, the preparation yield of the compound 4 is lower and is only 43.4%, and after the catalytic hydrogenation is carried out to remove the benzhydryl protective group in the next step, the obtained by-product diphenylmethane is not easy to remove, and the product quality is influenced.
In addition, when compound 6 is prepared by oxidizing compound 5 with TEMPO, a large amount of mixed salt wastewater is generated, which brings great pressure to environmental protection and is not suitable for industrial production.
Definition of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. Some of which are defined below:
“(Boc)2o' is Boc anhydride or di-tert-butyl dicarbonate;
"Boc" is t-butyloxycarbonyl;
"TEMPO" is 2,2,6, 6-tetramethylpiperidinoxide;
"t-BuOK" is potassium tert-butoxide;
"DIPEA" is N, N-diisopropylethylamine;
"NHPI" is N-hydroxyphthalimide;
"MCBA" is 3-chlorobenzoic acid;
disclosure of Invention
In order to overcome the disadvantages of the prior art, the present invention provides a preparation method of one or more key quaternary heterocyclic intermediates (chemical structural formula is shown as formula 9) of barrectin benzoate, which overcomes the disadvantages and shortcomings of the related art. The process route provided by the invention has the advantages of easily available raw materials, economy, greenness and environmental protection, and is suitable for industrial production.
Figure BDA0001668283320000031
The invention discloses a preparation method of a Baricitinib four-membered ring intermediate, which comprises the following specific reaction equation:
Figure BDA0001668283320000032
the route of the invention comprises the following steps:
(a) benzylamine is used for replacing benzhydrylamine to construct cyclobutylamine compound 11:
firstly, the cost of raw materials of benzylamine is much lower than that of benzhydrylamine, and secondly, considering the stability that the benzhydrylamine can deteriorate after being stored for a long time and is partially converted into benzophenone;
in the step, the molar ratio of the raw material 10 to the raw material 2 is 1: (1.0-1.5) taking raw materials of each component, wherein the alkali used in the reaction can be sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, N-dimethylacetamide, pyridine, N-methylmorpholine, triethylamine and the like, and the reaction solvent is any one of methanol, ethanol, isopropanol, acetone and acetonitrile.
After the reaction is finished, purifying the product in a salifying mode, wherein the acid used in the method comprises hydrochloric acid, acetic acid, p-toluenesulfonic acid, oxalic acid and the like;
(b) and (3) carrying out catalytic hydrogenation on the intermediate 11 in a wet palladium-carbon catalyst to remove a protecting group and simultaneously carry out Boc application to obtain an intermediate 5:
in the invention, methylbenzene is taken as a byproduct from catalytic hydrogenation by using benzylamine as a raw material, and the methylbenzene can be removed in a rectification mode, so that the operation is convenient, and the yield is high; however, the boiling point of the diphenylmethane serving as a byproduct obtained by catalytic hydrogenation with the benzhydrylamine as a raw material is high, the boiling point of the diphenylmethane is 265 ℃, the diphenylmethane cannot be removed by a rectification mode, the diphenylmethane can only be removed by a crystallization mode, the product loss in the mother liquor is large, the yield is low, and a part of diphenylmethane always remains in the obtained product compound 5.
In this step, the mass ratio of the raw material 11 to the palladium on carbon catalyst is 1: (0.01-0.1), wherein the molar ratio of the raw material 11 to the Boc anhydride is 1: (1.0-1.5), the solvent used in the method can be any one of methanol, ethanol, tetrahydrofuran and acetonitrile, and the pressure of hydrogen is 20-60 psi.
After the reaction is finished, filtering the catalyst, and purifying the catalyst by a crystallization mode, wherein the crystallization solvent which can be used comprises methyl tert-butyl ether, n-heptane, a n-heptane-ethyl acetate composite solvent and the like;
(c) the intermediate 6 is obtained by oxidizing the intermediate 5 through a TEMPO reaction, and the invention researches the following two paths:
route 1. by a conventional TEMPO reaction with sodium hypochlorite as oxidant:
in the invention, the production amount of sewage is reduced and the yield is improved by screening alkali and the concentration thereof, but in the actual experimental process, the following results are found: regardless of how the reaction conditions are changed, there is always one impurity associated with the product, which is identified as compound 12, and from the structure of compound 12, this TEMPO reaction is accompanied by Baeyer-Villiger oxidative rearrangement, which occurs to compound 12 as an impurity requiring peroxide, and the peroxide generation mechanism may be as follows:
Figure BDA0001668283320000041
firstly, hydrogen peroxide is obtained through the process, and is used for Baeyer-Villiger oxidation rearrangement reaction to produce an impurity compound 12; as the residence time of the reaction solution is long, the impurity is generated all the time, and the impurity can be controlled within 5-10% by screening the reaction condition, so that a path 2 is invented.
In the step, the molar ratio of the raw material 5 to TEMPO, KBr, alkali and NaClO is 1: 0.02: 0.2 (12-24): (1.5-3.0), wherein the selected alkali is sodium bicarbonate and potassium bicarbonate, and the reaction temperature is-5-10 ℃.
After the reaction in the present invention is completed, it is purified by crystallization, and the crystallization solvent which can be used herein includes methyl t-butyl ether, n-heptane-ethyl acetate complex solvent and the like.
Route 2: intermediate 6 was obtained by oxidation of intermediate 5 in a microchannel reactor:
the invention has two schemes in the micro-channel reactor for oxidation:
the first scheme is as follows: with TEMPO and hydrogen peroxide systems:
in order to reduce the problems of mixed salt wastewater and reaction residence time, the reaction is carried out in a microchannel reactor in a continuous flow mode, and reaction liquid discharged from a discharge port of the microchannel reactor directly flows into a quenching reaction kettle, so that the residence time of a product in the reaction is greatly shortened, and the generation amount of a byproduct 12 is effectively inhibited; after the reaction is finished, the salt content in the water phase is very low, and the water phase can directly enter a sewage plant.
In this step, the raw material 5 is mixed with TEMPO and H2O2In a molar ratio of 1: 0.02: (2-10), setting the reaction temperature to be 0-30 ℃, setting the temperature of heat conduction oil of the microchannel reactor to be a specified temperature, dissolving the raw materials 5 and TEMPO into a dichloromethane (10Vol) solution, pumping the dichloromethane solution into the microchannel reactor at the speed of 6.5g/min by using a high performance liquid pump, pumping a 30% hydrogen peroxide solution into the microchannel reactor at the speed of 1.31 g-6.55 g/min by using the high performance liquid pump, keeping the reaction time for 0.5-50 s, and separating the reaction liquid in an oil-water separator after the reaction is finished.
After the reaction in the present invention is completed, it is purified by crystallization, and the crystallization solvent which can be used herein includes methyl t-butyl ether, n-heptane-ethyl acetate complex solvent and the like.
Scheme II: with a composite catalyst (catalyst and cocatalyst) and oxygen system:
the scheme adopts the composite catalyst and oxygen as the oxidant, and can fundamentally solve the problems of mixed salt wastewater and Baeyer-Villiger oxidation rearrangement byproducts 12; the reaction in a continuous microchannel reactor is utilized to ensure the safety problem of using oxygen.
In the scheme, the molar ratio of the raw material 5 to the catalyst and the cocatalyst is 1: (0.01-0.1): (0.01-0.1), the selected catalyst is cobalt acetate and manganese acetate, the cocatalyst is N-hydroxyphthalimide and 3-chlorobenzoic acid, the reaction temperature is 25-75 ℃, the heat conducting oil temperature of the microchannel reactor is set to be a specified temperature, the raw material 5 and the composite catalyst are added into a solution of acetonitrile (10Vol) and acetic acid (0.5Vol), then the mixture is pumped into the micro-mixing reactor at the speed of 1mL/min by a high-efficiency liquid phase pump (compared with the microchannel reactor, the micro-mixing reactor is more suitable for the conditions of high pressure and small amount of solid materials), oxygen is pumped into the micro-mixing reactor at the speed of 10mL/min by a precision flowmeter, the residence time is 0.5-50 s, after the reaction is finished, the solvent is concentrated and recovered, and the residue is washed by water and crystallized.
After the reaction in the present invention is completed, it is purified by crystallization, and the crystallization solvent which can be used herein includes methyl t-butyl ether, n-heptane-ethyl acetate complex solvent and the like.
(d) The intermediate 6 is subjected to Wittig reaction to obtain an intermediate 7:
in the step, the molar ratio of the intermediate 6 to the diethyl cyanomethylphosphonate and the base is 1: (1.0-1.4): (1.0-1.5), wherein the selected base is potassium tert-butoxide, N-diisopropylethylamine, triethylamine, pyridine and the like, the solvent is tetrahydrofuran, methanol, ethanol, N-propanol and the like, the reaction temperature is-15-5 ℃, and the method does not need purification and can be directly applied to the next step.
(e) And (3) deprotecting and sulfonylating the intermediate 7 to obtain 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile:
in this step, the molar ratio of the intermediate 7 to ethylsulfonyl chloride, base was 1: (1.0-2.0): (1.5-4.0), wherein the selected N-methylmorpholine, N-diisopropylethylamine, triethylamine, pyridine and the like, the solvent is tetrahydrofuran, acetonitrile, dichloromethane and the like, and the reaction temperature is-5-25 ℃.
After the reaction in the present invention is completed, it is purified by crystallization, and the crystallization solvent which can be used herein includes methyl t-butyl ether, n-heptane-ethyl acetate complex solvent, and the like.
Drawings
FIG. 1 is a hydrogen spectrum of intermediate 11 prepared in example 1;
FIG. 2 is a hydrogen spectrum of intermediate 5 prepared in example 2;
FIG. 3 is a hydrogen spectrum of intermediate 6 prepared in example 3;
FIG. 4 is a gas chromatogram of intermediate 6 prepared in example 3;
FIG. 5 is a mass spectrum of intermediate 6 prepared in example 3;
FIG. 6 is a mass spectrum of by-product 12 formed in example 3;
FIG. 7 is a hydrogen spectrum of intermediate 6 prepared in example 4;
FIG. 8 is a process flow diagram of intermediate 6 prepared in example 5;
FIG. 9 is a hydrogen spectrum of intermediate 6 prepared in example 5;
FIG. 10 is a gas chromatogram of intermediate 6 prepared in example 5
FIG. 11 is a process flow diagram of intermediate 6 prepared in example 6;
FIG. 12 is a hydrogen spectrum of intermediate 6 prepared in example 6;
figure 13 is a hydrogen spectrum of intermediate 7 prepared in example 7;
FIG. 14 is a hydrogen spectrum of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile prepared according to example 8.
Detailed Description
Before the description of the specific embodiments, the essential aspects of the sources of the raw materials employed have been described in the present specification. It is to be understood that the sources of the raw materials described in the embodiments herein are not limiting, and that one skilled in the art can select appropriate raw materials and test equipment to perform the relevant tests and obtain the corresponding results in light of the teachings and teachings of the present invention.
Example 1
Preparation of intermediate 11:
adding 30.0 g of benzylamine and 450 ml of process water into a 1000 ml four-neck flask, slowly cooling to 0-5 ℃, controlling the temperature to be below 0-5 ℃, slowly dropwise adding 30.0 g of propylene oxide through a constant-pressure dropping funnel, after dropwise adding, continuously stirring for 16 hours at 0-5 ℃, sampling, confirming the end of the reaction through TLC, filtering, washing with 60 ml of process water, placing a filter cake in a vacuum drying box, and drying at the temperature of below 50 ℃ to obtain 40 g of intermediate compound of the intermediate 11.
Under the protection of nitrogen, 40 g of the intermediate compound and 485 ml of acetonitrile obtained in the previous step are added into a 1000 ml four-neck flask, the temperature is controlled below 30 ℃, 42 g of sodium carbonate is added into a reaction bottle in batches, the temperature is raised to 80-90 ℃ after the addition, the mixture is stirred for 16 hours under a reflux state, the completion of the reaction is confirmed by sampling through TLC, and the mixture is concentrated and the solvent is removed to obtain a viscous white solid.
Dissolving the viscous white solid into 180 ml of methyl tert-butyl ether, slowly dropwise adding oxalic acid (28 g) methyl tert-butyl ether (140 ml) solution under the stirring state, adjusting the temperature to be 20-25 ℃, stirring for 2-3 hours, and filtering; the filter cake and 300 ml of ethyl acetate were added to a 1000 ml four-necked flask, 150 ml of 10% sodium carbonate solution was slowly added dropwise thereto, the layers were separated, and the organic phase was concentrated to give 39.6 g of a colorless oily product with a yield of 88.7%.
1H NMR(400MHz,CDCl3)δ2.40-2.46(s,1H),2.96-2.99(m,2H),
3.60-3.70(m,4H),4.40-4.44(m,1H),7.21-7.34(m,5H)
Example 2
Preparation of intermediate 5:
adding 35.0 g of the intermediate 11, 1.75 g of 5% wet palladium-carbon catalyst and 350 ml of tetrahydrofuran into a 1000 ml high-pressure reaction kettle, stirring for 10-20 minutes, sequentially replacing with nitrogen for three times and hydrogen for three times, adjusting the temperature to 25-30 ℃ and the pressure to 45-50 psi, stirring and reacting for 20 hours at the temperature and the pressure, sampling, confirming the end of the reaction by TLC, filtering to remove the palladium-carbon catalyst, concentrating the filtrate, and removing the solvent and the byproduct toluene to obtain a white solid.
Dissolving the white solid into 105 ml of n-heptane, slowly cooling to 0-5 ℃ under the protection of nitrogen, stirring for 1-2 ℃ at 0-5 ℃, filtering, and drying a filter cake in a vacuum drying oven at the temperature lower than 40 ℃ to obtain 33.8 g of white solid with the yield of 91%.
1H NMR(400MHz,CDCl3)δ1.40(s,1H),3.76-3.78(m,2H),
4.08-4.10(m,2H),4.51-4.55(m,1H)
Example 3
Preparation of intermediate 6 (by conventional TEMPO reaction using sodium hypochlorite as oxidant):
adding 10.0 g of intermediate 5 and 200 ml of dichloromethane into a 1000 ml four-neck flask, stirring until the intermediate 5 is completely dissolved, then adding 15.1 g of 9.1% potassium bromide aqueous solution, cooling to 0-5 ℃, adding 0.18 g of TEMPO, controlling the temperature to be 0-5 ℃, slowly dropwise adding aqueous solution of potassium bicarbonate and sodium hypochlorite (dissolving 104 g of potassium bicarbonate and 85.95 g of 12% sodium hypochlorite aqueous solution into 389.2 ml of process water), after dropwise adding, continuously stirring for 20-30 minutes at 0-5 ℃, controlling the temperature to be 0-5 ℃ after reaction, quenching with 100 ml of 15% sodium thiosulfate aqueous solution, layering, washing an organic phase with 30 ml of process water, and concentrating under reduced pressure until no solvent is evaporated.
Dissolving the residue into 5 ml of ethyl acetate, controlling the temperature to be 10-15 ℃, slowly dripping 10ml of n-heptane, adding 0.1 g of seed crystal, stirring for 10-20 minutes, adding the remaining 5 ml of n-heptane, slowly cooling to-5-0 ℃, stirring for 20-30 minutes at-5-0 ℃, filtering, placing the filter cake into a vacuum drying oven, and drying at 35 ℃ to obtain 8.1 g of product with the purity of 60%, wherein the proportion of the byproduct 12 accounts for 40%.
1H NMR(400MHz,CDCl3) δ 1.47(s,9H), 4.67(s,4H) (this set of peaks is the hydrogen spectrum of intermediate 6, with a mass spectrum of: 98(M-73)), δ 1.48(s,9H),4.00(s,2H), 5.35(s,2H) (this set of peaks is the hydrogen spectrum of byproduct 12, which is the spectrum ofThe mass spectrum is as follows: 114(M-73)
Example 4
Preparation of intermediate 6 (by conventional TEMPO reaction using sodium hypochlorite as oxidant):
adding 10.0 g of intermediate 5 and 200 ml of dichloromethane into a 1000 ml four-neck flask, stirring until the intermediate 5 is completely dissolved, then adding 15.1 g of 9.1% potassium bromide aqueous solution, cooling to-10-5 ℃, adding 0.18 g of TEMPO, controlling the temperature to be-10-5 ℃, slowly dropwise adding aqueous solution of potassium bicarbonate and sodium hypochlorite (dissolving 104 g of potassium bicarbonate and 85.95 g of 12% sodium hypochlorite aqueous solution into 389.2 ml of process water), after dropwise adding, continuously stirring for 20-30 minutes at-10-5 ℃, controlling the temperature to be-10-5 ℃ after reaction, quenching by using 100 ml of 15% sodium thiosulfate aqueous solution, layering, washing an organic phase by using 30 ml of process water, and concentrating under reduced pressure until no solvent is evaporated.
Dissolving the residue into 5 ml of ethyl acetate, controlling the temperature to be 10-15 ℃, slowly dripping 10ml of n-heptane, adding 0.1 g of seed crystal, stirring for 10-20 minutes, adding the remaining 5 ml of n-heptane, slowly cooling to-5-0 ℃, stirring for 20-30 minutes at-5-0 ℃, filtering, placing the filter cake into a vacuum drying oven, and drying at 35 ℃ to obtain 8.5 g of product with the purity of 95%, wherein the proportion of the byproduct 12 accounts for 4.3%.
1H NMR(400MHz,CDCl3) δ 1.45(s,9H), 4.65(s,4H) (the set of peaks is the hydrogen spectrum of intermediate 6), δ 1.46(s,9H),3.97(s,2H), 5.32(s,2H) (the set of peaks is the hydrogen spectrum of by-product 12)
Example 5
Preparation of intermediate 6 (intermediate 6 was prepared with a TEMPO and hydrogen peroxide system via a microchannel reactor):
adding 10.0 g of intermediate 5, 0.18 g of TEMPO and 120 ml of dichloromethane into a premixing reactor A, setting the temperature of heat conducting oil of the microchannel reactor to be 5 ℃, pumping the solution of the premixing reactor A into a precooling pipeline by a high-efficiency liquid phase pump at the speed of 6.5g/min, then entering the microchannel reactor, simultaneously pumping 30% of hydrogen peroxide solution into the precooling pipeline by the high-efficiency liquid phase pump at the speed of 4.5g/min, then entering the microchannel reactor, keeping the reaction time for 30s, after the reaction is finished, entering an oil-water separator for separation, collecting for 20 minutes, washing an organic phase by 30 ml of process water, and concentrating under reduced pressure until no solvent is evaporated.
Adding the residue into 15 ml of n-heptane, heating to 30 ℃, completely dissolving the materials, slowly cooling to 15 ℃, adding 0.1 g of seed crystal, stirring for 10-20 minutes, slowly cooling to-5-0 ℃, stirring for 20-30 minutes at-5-0 ℃, filtering, placing the filter cake in a vacuum drying oven, and drying at 35 ℃ to obtain 9.1 g of product with the purity of 99.07% and the yield of 92.1%.
1H NMR(400MHz,CDCl3) δ 1.46(s,9H), 4.66(s,4H) (no by-product 12 was observed).
Example 6
Preparation of intermediate 6 (preparation of intermediate 6 by microchannel reactor with composite catalyst and oxygen system):
adding 5.0 g of the intermediate 5, 0.94 g of N-hydroxyphthalimide and 50 mL of acetonitrile into a premixing reactor A, dissolving 0.14 g of cobalt acetate into 2.5 mL of acetic acid, then adding the acetic acid into the premixing reactor A, setting the temperature of heat conducting oil of a microchannel reactor to be 75 ℃, pumping the solution of the premixing reactor A into a micromixing reactor by using a high-efficiency liquid phase pump at the speed of 1mL/min, simultaneously pumping 30% of hydrogen peroxide solution into the microchannel reactor by using the high-efficiency liquid phase pump at the flow speed of 4.5g/min, keeping the residence time to be 90s, feeding the reaction solution into a post-treatment reactor after the reaction is finished, collecting the reaction solution for 55 minutes, concentrating the reaction solution in the post-treatment reactor, adding 50 mL of dichloromethane, then sequentially washing by using 20 mL of process water and 20 mL of saturated salt water, and concentrating an organic phase to obtain a white crude product.
Dissolving the residue into 2.5 ml of ethyl acetate, controlling the temperature to be 10-15 ℃, slowly dripping 5 ml of n-heptane, adding 0.1 g of seed crystal, stirring for 10-20 minutes, adding the rest 2.5 ml of n-heptane, slowly cooling to-5-0 ℃, stirring for 20-30 minutes at-5-0 ℃, filtering, placing the filter cake into a vacuum drying oven, and drying at 35 ℃ to obtain 4.3 g of product with the purity of 99% and the yield of 87%.
1H NMR(400MHz,CDCl3) δ 1.48(s,9H), 4.68(s,4H) (no by-product 12 was observed).
Example 7
Preparation of intermediate 7:
under the protection of nitrogen, 24.8 g of diethyl cyanomethylphosphonate and 300 ml of anhydrous tetrahydrofuran are added into a 1000 ml four-neck flask, the temperature is slowly reduced to minus 15 to minus 10 ℃, under the protection of nitrogen, 128.5 ml of 1.0N potassium tert-butoxide tetrahydrofuran solution is slowly dripped, the temperature is controlled to be below minus 5 ℃, and after the dripping is finished, the temperature is controlled to be minus 10 to minus 5 ℃, and the stirring reaction is continuously carried out for 3 hours; controlling the temperature below-5 ℃, slowly dropwise adding a tetrahydrofuran solution of the intermediate 6 (20.0 g of the intermediate 6 is dissolved in 67 ml of tetrahydrofuran), and after dropwise adding, controlling the temperature between-10 ℃ and-5 ℃ to continue stirring and reacting for 2 hours; the reaction solution was slowly warmed to 25 to-30 ℃ and stirred at this temperature for 16 hours. After the reaction was completed, 300 ml of 12.5% aqueous sodium chloride solution was slowly added, the layers were separated, the aqueous phase was extracted with 300 ml of ethyl acetate, the organic phases were combined and washed with 200 ml of saturated brine, and the organic phase was concentrated to obtain a 20.65 white solid product with a yield of 91%.
1H NMR(400MHz,CDCl3)δ1.44(s,9H),4.60(s,2H)，4.69(s,2H)， 5.37(s,1H)。
Example 8
Preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile:
adding 36.0 g of the intermediate 7, 252 ml of acetonitrile and 252 ml of 3N hydrochloric acid solution into a 1000 ml four-neck flask, stirring for 16 hours at 25-30 ℃, concentrating the reaction solution after the reaction until no liquid flows out, adding 144 ml of acetonitrile, stirring for 2 hours at 30 ℃, then slowly cooling to 5-10 ℃, stirring for 2 hours, filtering, discarding the mother solution, and keeping the filter cake for later use.
Adding the filter cake and 432 ml of acetonitrile into a 1000 ml four-neck flask, and slowly dropwise adding 97.1 ml of N, N-diisopropylethylamine under the protection of nitrogen; the temperature was controlled below 15 ℃, 26.3 ml of ethylsulfonyl chloride was slowly added dropwise, after the end of the addition, the temperature was slowly raised to 20 ℃, and stirred at this temperature for 12 hours. After the reaction is finished, concentrating the reaction liquid until no liquid flows out, sequentially adding 360 ml of dichloromethane and 180 ml of 12.5% sodium chloride aqueous solution, layering, and concentrating an organic phase to obtain a crude product of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile.
Dissolving the crude product into 36 ml of ethyl acetate, heating to 50 ℃, controlling the temperature to be 40-50 ℃, slowly dripping 48 ml of n-heptane, slowly cooling to 30 ℃, adding 0.2 g of seed crystal, stirring for 10-20 minutes, adding the rest 48 ml of n-heptane, slowly cooling to 0-5 ℃, stirring for 30-50 minutes at 0-5 ℃, filtering, placing the filter cake into a vacuum drying oven, and drying at 40 ℃ to obtain 30.5 g of product, wherein the yield is 88.4%.
1H NMR(400MHz,CDCl3)δ1.36-1.38(t,3H)，3.01-3.05(m,2H), 4.68(d,2H)，4.76(d,4.76)，5.42-5.43(d,1H)。

Claims (7)

  1. A process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile, a four-membered ring intermediate of Baricitinib, having the following reaction equation:
    Figure FDA0003159375200000011
    the method comprises the following steps:
    (a) benzylamine 10 reacts with compound 2 to construct intermediate 11;
    (b) carrying out catalytic hydrogenation on the intermediate 11 in a wet palladium-carbon catalyst to remove a protecting group, and simultaneously adding Boc to obtain an intermediate 5;
    (c) oxidizing the intermediate 5 through TEMPO reaction to obtain an intermediate 6, adopting a TEMPO and hydrogen peroxide system to carry out reaction in a microchannel reactor in a continuous flow mode, and directly flowing reaction liquid discharged from a discharge port of the microchannel reactor into a quenching reaction kettle;
    (d) carrying out a Wittig reaction on the intermediate 6 to obtain an intermediate 7;
    (e) and deprotecting and sulfonylating the intermediate 7 to obtain 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile.
  2. 2. The process for the preparation of a Baricitinib four-membered ring intermediate according to claim 1, wherein in step (a), the molar ratio of starting material 10 to starting material 2 is 1: 1.0-1.5, wherein the used alkali is any one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, pyridine, N-methylmorpholine and triethylamine, and the reaction solvent is any one of methanol, ethanol, isopropanol, acetone and acetonitrile; after the reaction in the step (a) is finished, purifying the product in a salt forming mode with acid, wherein the acid is selected from hydrochloric acid, acetic acid, p-toluenesulfonic acid and oxalic acid.
  3. 3. The process for preparing a Baricitinib four-membered ring intermediate according to claim 1, wherein in step (b), the mass ratio of the starting material 11 to the palladium on carbon catalyst is 1: 0.01-0.1, wherein the molar ratio of the raw material 11 to Boc anhydride is 1: 1.0-1.5, wherein the used solvent is any one of methanol, ethanol, tetrahydrofuran and acetonitrile, and the pressure of hydrogen is 20-60 psi; after the reaction is finished, filtering the catalyst, and purifying the catalyst in a crystallization mode, wherein a crystallization solvent is selected from methyl tert-butyl ether, n-heptane and a n-heptane-ethyl acetate composite solvent.
  4. 4. The process for preparing a Baricitinib four-membered ring intermediate of claim 1, wherein starting material 5 is reacted with TEMPO, H2O2In a molar ratio of 1: 0.02: 2-10, setting the reaction temperature to be 0-30 ℃, setting the temperature of heat conduction oil of the microchannel reactor to be a specified temperature, dissolving the raw materials 5 and TEMPO into 10Vol solution of dichloromethane, pumping the solution into the microchannel reactor at the speed of 6.5g/min by using a high performance liquid pump, pumping 30% hydrogen peroxide solution into the microchannel reactor at the speed of 1.31-6.55 g/min by using the high performance liquid pump, keeping the solution for 0.5-50 s, and separating the reaction solution in an oil-water separator after the reaction is finished; after the reaction is finished, purifying the product by a crystallization mode, wherein a crystallization solvent is selected from methyl tert-butyl ether, n-heptane and n-heptane-ethyl acetate composite solvent.
  5. 5. The process for the preparation of a Baricitinib four-membered ring intermediate according to claim 1, wherein step (c) further comprises the use of a composite catalyst consisting of a catalyst and a cocatalyst and an oxygen system.
  6. 6. The process of claim 5, wherein the molar ratio of starting material 5 to catalyst and cocatalyst is 1: 0.01-0.1: 0.01-0.1, selecting a selected catalyst from cobalt acetate and manganese acetate, selecting a cocatalyst from N-hydroxyphthalimide and 3-chlorobenzoic acid, setting the reaction temperature to be 25-75 ℃, setting the heat conduction oil temperature of a microchannel reactor to be a specified temperature, adding a raw material 5 and a composite catalyst into a solution of acetonitrile 10Vol and acetic acid 0.5Vol, pumping the solution into a micro-mixing reactor at the speed of 1mL/min by using a high-efficiency liquid phase pump, pumping oxygen into the micro-mixing reactor at the speed of 10mL/min by using a precision flowmeter, keeping the time for 0.5-50 s, concentrating and recovering the solvent after the reaction is finished, washing the residue with water, and purifying the residue in a crystallization mode, wherein the crystallization solvent is selected from methyl tert-butyl ether, N-heptane and N-heptane-ethyl acetate composite solvents.
  7. 7. The process for the preparation of a Baricitinib four-membered ring intermediate according to claim 1, wherein in step (d), the molar ratio of intermediate 6 to cyanomethyl diethyl phosphate and base is 1: 1.0-1.4: 1.0-1.5, wherein the selected base is selected from potassium tert-butoxide, N-diisopropylethylamine, triethylamine and pyridine, the solvent is selected from tetrahydrofuran, methanol, ethanol and N-propanol, the reaction temperature is-15-5 ℃, and the method does not need purification and can be directly applied to the next step; in the step (e), the molar ratio of the intermediate 7 to the ethylsulfonyl chloride to the base is 1: 1.0-2.0: 1.5-4.0, wherein the used base is selected from N-methylmorpholine, N-diisopropylethylamine, triethylamine and pyridine, the solvent is selected from tetrahydrofuran, acetonitrile and dichloromethane, and the reaction temperature is-5-25 ℃; after the reaction is finished, purifying the product by a crystallization mode, wherein a crystallization solvent is selected from methyl tert-butyl ether and an n-heptane-ethyl acetate composite solvent.
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