Method for synthesizing Upactinib chiral intermediate by using microchannel reaction technology
阅读说明：本技术 一种利用微通道反应技术合成乌帕替尼手性中间体的方法 (Method for synthesizing Upactinib chiral intermediate by using microchannel reaction technology ) 是由 郑旭春 张一平 付晨晨 吴怡华 于 2020-12-30 设计创作，主要内容包括：本发明提供一种乌帕替尼关键手性中间体(3R,4S)-苄基3-(2-溴乙酰基)-4-乙基吡咯烷基-1-甲酸酯的微通道反应合成方法,包括：1)将N-甲基-N-亚硝基对甲苯磺酰胺溶液和氢氧化钾水溶液混合后在微通道反应器中发生重氮反应得到重氮甲烷；2)将(3R,4S)-1-((苄氧基)羰基)-4-乙基吡咯烷-3-甲酰氯溶液与重氮甲烷在微通道反应器中发生重氮吸收反应；3)步骤2得到的产物与氢溴酸水溶液在微通道反应器中发生溴化反应得到目标产物。该可连续性生产的微通道反应技术可以使重氮甲烷应用于放大生产,可以极大地降低重氮甲烷及重氮中间体的危险性,使增碳溴化反应可以稳定量化进行,提高了路线效率。(The invention provides a microchannel reaction synthesis method of a key chiral intermediate (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidine-1-formate of Upactinib, which comprises the following steps: 1) mixing an N-methyl-N-nitroso-p-toluenesulfonamide solution and a potassium hydroxide aqueous solution, and carrying out diazo reaction in a microchannel reactor to obtain diazomethane; 2) carrying out diazo absorption reaction on a (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride solution and diazomethane in a microchannel reactor; 3) and (3) carrying out bromination reaction on the product obtained in the step (2) and an aqueous solution of hydrobromic acid in a microchannel reactor to obtain a target product. The microchannel reaction technology capable of realizing continuous production can enable diazomethane to be applied to amplification production, greatly reduce the danger of diazomethane and diazo intermediates, enable the recarburization bromination reaction to be carried out stably and quantitatively, and improve the route efficiency.)
a microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate, which is characterized by comprising the following steps:
1) mixing an N-methyl-N-nitroso-p-toluenesulfonamide solution and a potassium hydroxide aqueous solution, and carrying out diazo reaction in a microchannel reactor to obtain diazomethane;
2) carrying out diazo absorption reaction on the (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride compound 1 solution and diazomethane in a microchannel reactor to obtain a compound 2;
3) and carrying out bromination reaction on the compound 2 and hydrobromic acid aqueous solution in a microchannel reactor to obtain the (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate compound 3.
2. The microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate according to claim 1, wherein the solvent in the N-methyl-N-nitroso-p-toluenesulfonamide solution in step 1 is selected from DMF, DMAC, DMSO, NMP, methanol, ethanol or isopropanol; the solvent in the solution of (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride compound 1 in step 2 is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene.
3. The microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate according to claim 1, wherein the diazomethane in step 1 is a gas obtained by separation in a gas-liquid separator, and the liquid is collected intensively, neutralized with acetic acid, and treated as waste liquid.
4. The microchannel reaction synthesis process of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate according to claim 1, wherein compound 2 in step 3 is directly the product of the reaction in step 2.
5. The microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate according to claim 1, wherein the (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate compound 3 in step 3 is a liquid separated by a gas-liquid separator, and the gas is a diazomethane waste gas which is a part of the diazo absorption reaction and is redundant, and is absorbed by an acetic acid aqueous solution and discharged into a tail gas treatment system.
6. The method for synthesizing the microchannel of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate according to claim 1, wherein the length of the microchannel reactor used in each step is 4m, and the total volume is 40 mL.
7. The microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate according to claim 1, wherein the flow rate of each reaction solution entering the microchannel reactor is 0.1-20 mL/min, and the retention time of each reaction solution in the microchannel reactor is 2-400 min.
8. The microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate according to claim 1, wherein the diazo reaction temperature in step 1 is-15 to 60 ℃; in the step 2, the diazo absorption reaction temperature is-15-60 ℃; the bromination reaction temperature in the step 3 is-15-60 ℃.
9. The microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate according to claim 1, wherein the concentration of the (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride compound 1 is 0.1-5 mol/L; the molar ratio and the dosage of each raw material are as follows: compound 1: N-methyl-N-nitroso-p-toluenesulfonamide: KOH: HBr ═ 1:1-3:2-6: 2-6.
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a method for preparing a key chiral intermediate of lapatinib by a microchannel.
Background
Upaatinib (ABT-494) is a high-efficiency and selective oral JAK1 inhibitor developed by AbbVie, and is used for treating various inflammations caused by human autoimmunity. In early 2018, ipatinib received FDA breakthrough therapy approval for the treatment of adult moderate-severe atopic dermatitis, approved in 8 months 2019 for the treatment of adult patients with moderate-to-severe active rheumatoid arthritis who were inadequately responsive or intolerant to methotrexate. In addition to the treatment of rheumatoid arthritis, the new drug under development is also used in multiple phase 3 clinical trials for the treatment of various inflammatory diseases such as ulcerative enteritis, psoriatic arthritis, crohn's disease, and atopic dermatitis. Therefore, the indication of the medicine is expected to be further expanded, and the empatinib is expected to be a new medicine with a heavy pound grade and obtain a great market share.
The chemical name of the empatinib is as follows: the technical synthesis route of (3S,4R) -3-ethyl-4- (3H-pyrazolo [1,2-a ] pyrrolo [2,3-e ] pyrazine-8-yl) -N- (2,2, 2-trifluoroethyl) pyrrolidine-1-formamide and the lapatinib is characterized in that the key chiral intermediate (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate is synthesized with low cost and high efficiency, and the structural formulas of the lapatinib and the key chiral intermediate are as follows:
the united states patent US2017129902A reports a synthetic method of uppatinib, the carburation bromination reaction of the key chiral acid intermediate (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-carboxylic acid uses TMS diazomethane, the reagent is expensive, the property is unstable, and low-temperature protection is needed for storage and transportation; the acyl diazo intermediate generated by the route has active property, the temperature is strictly controlled during the reaction, otherwise, the acyl diazo intermediate is easy to explode when the dosage is large, and the amplified production has larger potential safety hazard.
WO2017066775A reports an improved synthesis of key chiral intermediates of uppatinib, using the acid intermediate (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-carboxylic acid to react with trimethyl thionyl chloride under the action of carbonyldiimidazole, followed by bromination to obtain (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate. The method uses large amount of trimethyl thionyl chloride salt, has poor atom economy, utilizes potassium tert-butoxide for hydrogen extraction of the trimethyl thionyl chloride salt in the reaction, and raw materials, intermediates and generated products are easy to racemize under strong alkali conditions, so that the chiral selectivity of the products is poor, the total yield is low, and the synthesis cost is still high.
Therefore, a route with simpler steps, safe process amplification operation, lower process cost and higher yield needs to be searched for producing the empatinib key chiral intermediate.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a microchannel reaction synthesis method of an Upactinib key chiral intermediate (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidine-1-formate compound 3.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
the microchannel reaction synthesis method of (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate comprises the following steps:
1) mixing an N-methyl-N-nitroso-p-toluenesulfonamide solution and a potassium hydroxide aqueous solution, and carrying out diazo reaction in a microchannel reactor to obtain diazomethane;
2) carrying out diazo absorption reaction on the (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride compound 1 solution and diazomethane in a microchannel reactor to obtain a compound 2;
3) and carrying out bromination reaction on the compound 2 and hydrobromic acid aqueous solution in a microchannel reactor to obtain the (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-formate compound 3.
Further, the solvent in the N-methyl-N-nitroso-p-toluenesulfonamide solution in the step 1 is selected from DMF, DMAC, DMSO, NMP, methanol, ethanol or isopropanol; the solvent in the solution of (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride compound 1 in step 2 is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene.
Further, the diazomethane in the step 1 is gas obtained by separation through a gas-liquid separator, and liquid is collected intensively and then neutralized by acetic acid to be treated as waste liquid.
Further, compound 2 in step 3 is directly the product of the reaction in step 2.
Further, the (3R,4S) -benzyl 3- (2-bromoacetyl) -4-ethylpyrrolidinyl-1-carboxylate compound 3 in the step 3 is liquid separated by a gas-liquid separator, and gas is excess diazomethane waste gas of the diazo absorption reaction part and is absorbed by acetic acid aqueous solution and then discharged into a tail gas treatment system.
Further, the length of the microchannel reactor used in each step is 4 meters, and the total volume is 40 mL.
Furthermore, the flow rate of each reaction liquid entering the microchannel reactor is 0.1-20 mL/min, and the retention time of each reaction liquid in the microchannel reactor is 2-400 minutes.
Further, the diazotization reaction temperature in the step 1 is-15-60 ℃; in the step 2, the diazo absorption reaction temperature is-15-60 ℃; the bromination reaction temperature in the step 3 is-15-60 ℃.
Preferably, the concentration of the (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride compound 1 is in the range of 0.1-5 mol/L; the mol ratio of the raw materials is as follows: compound 1: N-methyl-N-nitroso-p-toluenesulfonamide: KOH: HBr ═ 1:1-3:2-6: 2-6.
The reaction principle used in the invention is as follows:
reacting (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formyl chloride 1 with diazomethane generated in situ in a microchannel reactor, and then brominating with hydrogen bromide in a microchannel to obtain an intermediate 3; the micro-channel reaction technology capable of realizing continuous production can enable diazomethane to be applied to amplification production, greatly reduce the danger of the diazomethane and diazo intermediates, and enable the recarburization bromination reaction to be carried out stably and quantitatively. The improvements greatly reduce the potential safety hazard of process production, improve the route efficiency, reduce the process cost and facilitate the improvement of the chiral purity of the product. The route is simple to operate, the total yield is high, the purity of the obtained product is high, and the route is suitable for large-scale production.
Drawings
FIG. 1 is a schematic diagram of a synthesis process of a microchannel reaction production technique in an embodiment of the present invention.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
The microchannel reaction technology provided by the invention comprises a microchannel reaction pump, a mixer, a gas-liquid separator and a microchannel reactor system module which are all purchased from Bayer-Elverdet micro technology company.
Example 1
As shown in FIG. 1, N-methyl-N-nitroso-p-toluenesulfonamide (42.85g,200mmol) was prepared as a 200mL DMF solution (0.8 mol/L); compound 1(29.58g,100mmol) was prepared as a 200mL tetrahydrofuran solution (0.5 mol/L); preparing 200mL of 2.0mol/L potassium hydroxide aqueous solution; preparing 30mL of 20.0mol/L hydrobromic acid aqueous solution;
setting a pump 1 and a pump 2, wherein the flow rate of the pump 3 is 5.0mL/min, and the flow rate of the pump 4 is 0.75 mL/min; the temperature of the microchannel reactor 1 is 25 ℃, and the retention time is 4 min; the reaction temperature of the micro-channel reactor 2 is 25 ℃, and the retention time is 8 min; the reaction temperature of the micro-channel reactor 3 is 25 ℃, and the retention time is 6.96 min; pumping each reaction solution into a reaction system by a pump, collecting the reaction solution at the outlet of the reactor, and sampling and detecting. HPLC results show a product purity of 96.3% in the liquid phase.
The crude solution was collected and added 296mL of water, extracted 3 times with 148mL of ethyl acetate, the combined organic phases were washed 1 time with 148mL of 5% sodium bicarbonate solution, 1 time with 148mL of saturated brine, concentrated, slurried with n-heptane and filtered to give compound 3(25.82g, 97.0% purity, 70.7% yield).
The solvent A for dissolving N-methyl-N-nitroso-p-toluenesulfonamide and the solvent B for dissolving acid chloride were changed according to the conditions of example 1, and the results are shown in examples 2 to 10:
examples
Solvent A
Solvent B
Yield of
Purity of the product
2
DMAC
THF
74.9％
98.3％
3
Methanol
THF
64.8％
95.6％
4
NMP
THF
75.2％
98.7％
5
Isopropanol (I-propanol)
THF
77.5％
98.4％
6
DMSO
DCM
68.3％
96.2％
7
DMSO
Acetonitrile
73.5％
98.3％
8
DMSO
Toluene
68.5％
94.2％
9
Ethanol
2-Me-THF
72.3％
97.9％
10
DMAC
2-Me-THF
69.2％
97.1％
Example 11
As shown in FIG. 1, N-methyl-N-nitroso-p-toluenesulfonamide (42.85g,180mmol) was prepared as a 200mL DMSO solution (0.8 mol/L); compound 1(29.58g,100mmol) was prepared as a 200mL tetrahydrofuran solution (0.5 mol/L); preparing 200mL of 2.0mol/L potassium hydroxide aqueous solution; preparing 30mL of hydrobromic acid aqueous solution of 15.0 mol/L;
setting a pump 1 and a pump 2, wherein the flow rate of the pump 3 is 5.0mL/min, and the flow rate of the pump 4 is 0.75 mL/min; the temperature of the microchannel reactor 1 is 25 ℃, and the retention time is 4 min; the reaction temperature of the micro-channel reactor 2 is 25 ℃, and the retention time is 8 min; the reaction temperature of the micro-channel reactor 3 is 25 ℃, and the retention time is 6.96 min; pumping each reaction solution into a reaction system by a pump, collecting the reaction solution at the outlet of the reactor, and sampling and detecting. HPLC results show a product purity of 98.4% in the liquid phase.
The crude solution was collected and added 296mL of water, extracted 3 times with 148mL of ethyl acetate, the combined organic phases were washed 1 time with 148mL of 5% sodium bicarbonate solution, 1 time with 148mL of saturated brine, concentrated, slurried with n-heptane and filtered to give compound 3(28.11g, 98.6% purity, 78.7% yield).
The feed concentration of Compound 1 and the ratio of N-methyl-N-nitroso-p-toluenesulfonamide (Diazald), potassium hydroxide and hydrobromic acid were adjusted as in example 11 and the results are shown in examples 12-20:
example 22
As shown in FIG. 1, N-methyl-N-nitroso-p-toluenesulfonamide (34.28g,160mmol) was prepared as a 200mL DMSO solution (0.8 mol/L); compound 1(29.58g,100mmol) was prepared as a 200mL tetrahydrofuran solution (0.5 mol/L); preparing 200mL of 1.2mol/L potassium hydroxide aqueous solution; preparing 30mL of 10.0mol/L hydrobromic acid solution;
setting a pump 1 and a pump 2, wherein the flow rate of the pump 3 is 5.0mL/min, and the flow rate of the pump 4 is 0.75 mL/min; the temperature of the microchannel reactor 1 is 23 ℃, and the retention time is 4 min; the reaction temperature of the micro-channel reactor 2 is 25 ℃, and the retention time is 8 min; the reaction temperature of the micro-channel reactor 3 is 25 ℃, and the retention time is 6.96 min; pumping each reaction solution into a reaction system by a pump, collecting the reaction solution at the outlet of the reactor, and sampling and detecting. HPLC results show a product purity of 98.4% in the liquid phase.
The crude solution was collected and added 296mL of water, extracted 3 times with 148mL of ethyl acetate, the combined organic phases were washed 1 time with 148mL of 5% sodium bicarbonate solution, 1 time with 148mL of saturated brine, concentrated, slurried with n-heptane and filtered to give compound 3(27.99g, 98.6% purity, 77.9% yield).
The microchannel reaction flow rate, reactor residence time and temperature of reactors 1,2,3 were changed as in example 22, and the results are shown in examples 11-23: