CN115417803B - Synthesis method of Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid - Google Patents
Synthesis method of Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid Download PDFInfo
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Abstract
The invention discloses a synthesis method of a Martinib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, which relates to the technical field of drug synthesis and solves the technical problems of poor reaction selectivity, harsh reaction conditions and low optical purity of a target product in the existing Wu Pa Tinib intermediate synthesis process, and the synthesis method comprises the following steps: 1-Boc-3-pyrrolidone and DMF-DMA to generate a compound A; compound A and methyl magnesium bromide generate compound B; asymmetric reduction of the compound B to obtain a compound C; asymmetric catalytic reduction of the compound C to obtain a compound D; the compound D is subjected to substitution reaction of hydroxyl and nucleophilic substitution reaction of cyano, and the configuration is absolutely reversed to obtain a compound E; hydrolyzing cyano and an upper Cbz protecting group by the compound E to obtain a crude product F; chiral resolution of the crude product F to obtain a target product; the synthesis method has the advantages of easily available raw materials, good reaction selectivity and high optical purity of the target product.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to the technical field of synthesis of a Wupattinib intermediate.
Background
Wu Pati Nib (Upadacitinib) is a novel JAK1 inhibitor developed by Abovine. In month 8 2019, lapatinib has acquired a global first in the united states for the treatment of moderate to severe active Rheumatoid Arthritis (RA) adult patients who have an inadequate or intolerant response to Methotrexate (MTX). In 12 2019, upadacrinib obtained european union approval for the treatment of moderate to severe RA adult patients who are either insufficiently responsive or intolerant to one or more disease modifying antirheumatic drugs (DMARDs). In RA, the dose approved by the Upattinib is 15mg.
Ibovine is currently being developed to treat a variety of inflammatory diseases including psoriatic arthritis (PsA), RA, axial spinal arthritis (axSpA), crohn's Disease (CD), atopic Dermatitis (AD), ulcerative Colitis (UC), giant Cell Arteritis (GCA). Industry is very good at Wu Pati Ni business prospect. The medical market research agency, evaluatePharma, previously issued report predictions that the global sales of Rinvoq in 2024 would reach $ 25.7 billion, becoming the 5 th popular antirheumatic worldwide.
WO2011068881 reports a synthetic method for the synthesis of Wu Pati ni chiral intermediate (3 r,4 s) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid using alkynoate compound 1 as starting material, reducing the triple bond as double bond by catalytic hydrogenation with lindra catalyst to give compound 2, compound 2 reacting with compound 3 to give racemate compound 4. Compound 4 is chemically resolved to give intermediate (3 r,4 s) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid. The synthetic route is as follows:
the raw material ethyl 2-valerate used in the process cannot be industrially obtained in the market, and the process reports that the 3-carboxyl and 4-ethyl have no chiral selectivity in the cyclization process, so that the subsequent chiral resolution and chiral purity improvement are not facilitated.
WO2017066775 reports a synthesis method for synthesizing Wu Pati-Ni chiral intermediate (3R, 4S) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid, which takes CBZ-glycine ethyl ester as a raw material, and reacts with ethyl acrylate under alkaline conditions to obtain a compound 1, wherein the compound 1 reacts with trifluoromethanesulfonic anhydride to obtain an OTf substituted intermediate 2, the intermediate 2 reacts with ethylboric acid under alkaline conditions under palladium catalysis to obtain an intermediate 3, the intermediate 4 after the intermediate 3 is hydrolyzed under alkaline conditions is subjected to catalytic reduction by a chiral catalyst of the intermediate 4 and salification by dicyclohexylamine to improve chiral purity, and finally (3R, 4S) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid with qualified optical purity is obtained, the synthesis route is as follows:
in this synthetic route, the starting material ethyl acrylate used was initially set up for reference at 2017, 10, 27, the carcinogen list published by the world health organization International cancer research institute, and ethyl acrylate was the class 2B carcinogen. When the intermediate 2 is synthesized, in order to activate the hydroxyl of the intermediate 1, trifluoro-sulfonic anhydride is used, and has great pollution to water body and is extremely unfriendly to the environment and human body. During the synthesis of the intermediate 3, the Pd catalyst participates in the coupling reaction, and the reaction needs strict nitrogen protection, so that the reaction conditions are more severe, and the industrial production is not facilitated.
CN111217819 reports a synthetic method for synthesizing Wu Pati-Ni chiral intermediate (3 r,4 s) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid, which uses intermediate 1 as a raw material, intermediate 1 is obtained by phosphorus trichloride chlorination, intermediate 1 and ethyl magnesium chloride are coupled through Ni catalyst to obtain intermediate 2, intermediate 2 is obtained by chiral catalytic reduction and salification to obtain (3 r,4 s) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid, the synthetic route is as follows:
in the synthesis process, the reagent phosphorus oxychloride used in the first step of chlorination can generate a large amount of sewage containing phosphorus and acidity, and is not friendly to the environment. And in the reaction process, the generated hydrogen chloride can carry out addition reaction on double bonds to produce impurities. The pH of the reaction system is strong acid, which is unfavorable for the stability of Cbz protecting groups. And ethyl magnesium chloride reacts with the ester group in intermediate 2 to form the corresponding impurity.
Patent CN 109369659B reports a synthetic route. The route uses carbonyl intermediate 1 as a starting material and reacts with Grignard reagent to obtain hydroxyl intermediate 2. And then, obtaining an intermediate 3 through sulfuric acid dehydration and alkaline hydrolysis. In the patent, a researcher directly obtains a chiral carboxylic acid intermediate through hydrogenation of a chiral Ru metal catalyst, and the synthetic route is as follows:
in the process of the patent, when the ethyl magnesium bromide performs nucleophilic addition to carbonyl, the ethyl magnesium bromide also performs nucleophilic addition reaction with ester groups in molecules, and the selectivity of the reaction is extremely poor.
Disclosure of Invention
The invention aims at: the invention provides a synthesis method of a Martinib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, aiming at solving the technical problems of poor reaction selectivity, harsh reaction conditions and low optical purity of a target product in the existing synthesis process of the Wu Pa tinib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid.
The invention adopts the following technical scheme for realizing the purposes:
the synthesis method of Wu Pa tenib intermediate (3R, 4S) -1-carbobenzoxy-4-ethylpyrrolidine-3-carboxylic acid comprises the following steps:
(1) Reacting 1-Boc-3-pyrrolidone with DMF-DMA to generate a compound A;
(2) Reacting the compound A with methyl magnesium bromide under the protection of nitrogen to generate a compound B; in this step, compound A forms a six-membered ring intermediate in the reaction with methyl magnesium bromide, and has the following structural formula:
because of the structural characteristics, redundant methyl magnesium bromide in the reaction system cannot react with carbonyl, so that the reaction selectivity of the synthesized compound B is improved, and impurities generated by the reaction of the methyl magnesium bromide and the ketocarbonyl are reduced;
(3) The compound B is subjected to asymmetric reduction of carbonyl into hydroxyl to obtain a compound C; the step adopts the reduction reaction of Corey-Bakshi-Shibata for asymmetric reduction of carbonyl to directly obtain a 3S chiral center with the 3-position being S configuration, wherein the chiral purity can reach 99 percent, and the EE value can reach 97 percent;
(4) The compound C is subjected to asymmetric catalytic reduction of double bonds to obtain a compound D;
(5) Under alkaline conditions, the compound D reacts with methylsulfonyl chloride or p-toluenesulfonyl chloride to produce an intermediate product, and the structural formula is as follows:
then nucleophilic substitution reaction is carried out on the intermediate product and a cyano reagent, and absolute inversion is carried out on the configuration to obtain a compound E; in the step, the substitution reaction of hydroxyl uses SN2 reaction, the 3-position 3S chiral center is absolutely turned over to a 3R configuration, namely, an S configuration OMs group is turned over to an R configuration cyano group, which is beneficial to the improvement of the optical purity of a target product;
(6) The compound E is firstly hydrolyzed into carboxyl under acidic condition and simultaneously removes Boc protecting group to obtain an intermediate product, and the structural formula is as follows:
then reacts with Z-OSU or Z-Cl to obtain crude compound F;
(7) The crude compound F is recrystallized or chemically resolved to obtain a high chiral Marpatinib intermediate (3R, 4S) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid;
the structural formulas of the compound A, the compound B, the compound C, the compound D, the compound E and the compound F are as follows:
the synthetic route of the invention is as follows:
further, in the synthesis of the compound A, the reaction temperature is 60-70 degrees, the reaction time is 8-12 hours, the solvent is any one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl riddle, chloroform and dichloromethane, and tetrahydrofuran is preferably used.
Further, in the synthesis of the compound A, the volume ratio of the solvent to the 1-Boc-3-pyrrolidone is 1:5, and the molar ratio of the 1-Boc-3-pyrrolidone to the DMF-DMA is 1:1.5.
Further, in the synthesis of the compound B, the reaction temperature is-10 to-15 degrees, the reaction time is 3 to 4 hours, the solvent is any one of tetrahydrofuran, diethyl ether and 2-methyltetrahydrofuran, and tetrahydrofuran is preferably used.
Further, in the synthesis of the compound B, the volume ratio of the solvent to the compound A is 1:10, and the molar ratio of the compound A to the methyl magnesium bromide is 1:1.5.
Further, in the synthesis of compound C, the asymmetric reduction system is selected from the S-2-methyl-CBS and borane tetrahydrofuran system, or the S-2-methyl-CBS and borane tetrahydrofuran system has an S/R ratio of approximately 99:2, and the S/R ratio of the S-2-methyl-CBS and borane tetrahydrofuran system is only 76:24, preferably the S-2-methyl-CBS and borane tetrahydrofuran system is used.
Further, in the synthesis of the compound D, the asymmetric reduction system adopts methanol as a solvent and triethylamine as a base, (S) -SegphosRu (OAc) 2 As a catalyst.
Further, in the synthesis of the compound E, the alkali selected under the alkaline condition is any one of triethylamine, N-diisopropylethylamine, potassium carbonate, sodium carbonate and sodium bicarbonate, preferably triethylamine; the solvent is selected from any one of dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran and DMF, preferably tetrahydrofuran; the cyano reagent is selected from any one of sodium cyanide, potassium cyanide and trimethylcyanogen, and preferably trimethylcyanogen is used.
Further, in the synthesis of the compound F, the acid selected for hydrolysis is concentrated hydrochloric acid, aqueous hydrogen bromide solution or dilute sulfuric acid, preferably concentrated hydrochloric acid; after the hydrolysis reaction is completed, the pH of the reaction is required to be adjusted to 7-8, and alkali is continuously used for keeping the pH at 7-8 in the reaction process with Z-OSU or Z-Cl, wherein the alkali can be any one of triethylamine, N, N-diisopropylethylamine, potassium carbonate and sodium carbonate, and sodium bicarbonate is preferably used.
Further, R-a-phenethylamine, dicyclohexylamine or (R) -1- (1-naphthyl) ethylamine is preferably used as the chemical resolution reagent, and (R) - (+) -1- (1-naphthyl) ethylamine is preferably used as the solvent for chemical resolution, and is any one of methanol, ethanol, isopropanol, acetonitrile and acetone, preferably acetonitrile.
Meaning of each abbreviation in the present invention:
DMF-DMA: n, N-dimethylformamide dimethyl acetal;
(S)-SegphosRu(OAc) 2 : diacetyl [ (R) - (+) -5,5 '-bis (diphenylphosphine) -4,4' -bis-1, 3-benzodioxolane]Ruthenium (II);
(S) -2-methyl-CBS: (S) -2-methyl-CBS-oxazoloborane;
Z-OSU: n-benzyloxycarbonyloxy succinimide;
Z-Cl: benzyl chloroformate.
The beneficial effects of the invention are as follows:
1. the invention adopts the 1-boc-3-pyrrolidone which is simple and easy to obtain as the raw material, and obtains the target compound (3R, 4S) -1- ((benzyloxycarbonyl) -4-ethyl pyrrolidine-3-carboxylic acid through 6 steps of reaction, the reaction selectivity is good, the reaction condition is simple, the industrial production is facilitated, the optical purity of the target product is high, and the EE value can reach 99.6 percent.
2. In the invention, a six-membered ring intermediate state is formed in the reaction process of the compound A and the methyl magnesium bromide, so that redundant methyl magnesium bromide in a reaction system cannot react with carbonyl, thereby improving the reaction selectivity of the synthesized compound B and reducing the generation of impurities by the reaction of the methyl magnesium bromide and the ketocarbonyl.
3. In the process of synthesizing the intermediate C, the invention adopts the reduction reaction of Corey-Bakshi-Shibata by asymmetric reduction of carbonyl to directly obtain the 3S chiral center with the 3-position being S configuration, the chiral purity reaches 99 percent, the EE value reaches 97 percent, and in the subsequent synthesis of the compound E, the substitution reaction of hydroxyl uses the SN2 reaction to lead the 3-position 3S chiral center to be absolutely turned into 3R configuration, thereby being beneficial to the improvement of the optical purity of the target product, and finally (3R, 4S) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid with the EE value more than 99 percent can be obtained only by the salifying reaction of the crude product.
Drawings
FIG. 1 is a diagram of Compound A 1 H-NMR spectrum;
FIG. 2 is a diagram of Compound B 1 H-NMR spectrum;
FIG. 3 is a compound C 1 H-NMR spectrum;
FIG. 4 is a diagram of Compound D 1 H-NMR spectrum;
FIG. 5 is a diagram of Compound F 1 H-NMR spectrum.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments.
The raw materials used in the following examples were commercial raw materials available on the market.
Example 1
Synthesis of Compound A
100g of 1-Boc-3-pyrrolidone was dissolved in 500mL of tetrahydrofuran, and 64g of DMF-DMA was added. The reaction solution is heated to 70 ℃ and reacted for 8 to 10 hours. After completion of the TLC detection, tetrahydrofuran was removed by concentration under reduced pressure, the concentrated residue was dissolved in 500mL of ethyl acetate, the organic phase was washed with 3M dilute hydrochloric acid, saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure to give an oil, which was 98.5g of a yellow solid recrystallized from methyl tert-butyl ether in 76% yield. The purity is 99.3 percent.
1 H NMR(400MHz,CDCl3)δ7.32-7.28(d,J＝16Hz,1H),4.59-4.54(d,J＝20Hz,2H),3.87-3.82(d,J＝20Hz,2H),3.11(s,6H),1.49(s,9H)。
Example 2
Synthesis of Compound B
90g of Compound A was dissolved in 900mL of tetrahydrofuran, kept at a temperature of-20 to-15℃and taken out of 187mL of 3M solution of methylmagnesium bromide in tetrahydrofuran under nitrogen protection, and slowly dropped into the reaction solution. After the dripping is finished, the temperature is kept between-20 and-15 ℃ for 3 to 4 hours. After completion of the TLC detection reaction, 100mL of a 10% aqueous ammonium chloride solution was added dropwise to the reaction solution. The reaction solution was extracted with ethyl acetate, the organic phase was once washed with saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure to give a red oily substance, which was subjected to column chromatography using a mixed solvent of ethyl acetate and petroleum ether 1:6 (V: V) to give 50.6g of a yellow oily substance in 64% yield. HPLC purity 98.3%.
1 H NMR(400MHz,CDCl3)δ6.78(s,1H),4.32(s,2H),3.93-3.90(d,J＝12Hz,2H),1.87-1.85(d,J＝8.0Hz,3H),1.49(s,9H)。
Example 3
Synthesis of Compound C
355mL of borane tetrahydrofuran solution is taken, the temperature of the reaction solution is controlled at minus 30 ℃, and the mixture is slowly dripped into 355 mLS-2-methyl-CBS toluene solution. After 30 minutes, 50g of compound B was dissolved in 250mL of tetrahydrofuran, and the mixture was slowly dropped into the reaction solution under nitrogen protection at a temperature of-30 ℃. After the reaction is completed by TLC detection, 500mL of 10% ammonium chloride aqueous solution and 500mL of ethyl acetate are slowly added, the organic phase is washed twice with 1N hydrochloric acid and once with 10% sodium bicarbonate and once with 10% brine, and dried and concentrated to obtain oily substance, and the crude oily substance is washed with ethyl acetate: petroleum ether=10:1 (V: V) column chromatography gives 31g of oil in 61% yield with GC purity of 95.6%. Chiral purity 98.6%.
1 H NMR(400MHz,CDCl3):δ5.72-5.71(br,1H),4.57(s,1H),4.13-4.09(d,J＝16Hz,1H),3.99-3.95(d,J＝16Hz,1H),3.62-3.59(m,1H),3.44-3.40(m,1H),1.69-1.68(d,J＝4Hz,3H),1.50-1.48(d,J＝8Hz,9H)。
Example 4
Synthesis of Compound D
Taking Compound C100g of Compound C was dissolved in 500mL of methanol, and (S) -segphosRu (OAc) was added 2 0.3g, 61.6g of triethylamine, and the above solution was slowly put in an autoclave and replaced with hydrogen gas 3 times, then the pressure was kept at 3 to 4MPa, and the reaction was carried out at 70 to 75℃for 2 to 3 hours. After the completion of the reaction, which was monitored by TLC, nitrogen was purged 3 times, and the catalyst was removed by filtration. Concentrating under reduced pressure to remove methanol, adding ethyl acetate, and adding 10% salt into the organic phaseWater and 10% aqueous citric acid, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a yellow oil, and the crude oil was chromatographed on a column of ethyl acetate: petroleum ether=6:1 (V: V) to give 82.7g of a colorless oil in 82% yield, 93.6% GC purity, 96.4% chiral purity.
1 H NMR(400MHz,CDCl3):δ3.54-3.41(m,2H),3.28-3.21(m,1H),2.87-2.83(m,1H),2.04-1.95(m,2H),1.46(s,9H),1.42-1.36(m,2H),0.95-0.91(t,J＝16Hz,3H)。
Example 5
Synthesis of Compound E
50g of compound D is dissolved in 200mL of dichloromethane, 70.5g of triethylamine is added, the reaction temperature is controlled to be less than-5 ℃, and 39.9g of methylsulfonyl chloride is slowly added dropwise. After the completion of the dropwise addition, the reaction was carried out at this temperature for 4 to 6 hours. After completion of TLC detection, 23 trimethylcyanosilane was added to the reaction solution, and the reaction was continued for 8-10 hours. After completion of the TLC monitoring reaction, the reaction was quenched by adding 100mL of 5% aqueous sodium hypochlorite solution, the organic phase was separated, and the organic phase was washed once more with 5% aqueous sodium hypochlorite solution (the organic phase and aqueous phase had to be tested with KI potassium to confirm complete cyanide destruction). The organic phase is then washed successively with 3M dilute hydrochloric acid, 10% aqueous sodium chloride and water. Drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain oily substance. The oil was used directly in the next reaction without purification.
Synthesis of crude Compound F
The above oil was dissolved in 50mL of tetrahydrofuran, 100mL of concentrated hydrochloric acid was added, the reaction was heated to reflux for 8 to 10 hours, after TLC monitoring the completion of the reaction, the reaction temperature was lowered to room temperature, the reaction was adjusted to pH 8 to 9 with 10% aqueous sodium bicarbonate solution, 57.9g of Z-OSU was slowly added, the reaction was kept at pH 8 to 9 with 10% aqueous sodium bicarbonate solution during the reaction, after TLC monitoring the completion of the reaction, the aqueous phase was washed once with ethyl acetate, adjusted to pH 2 to 3 with 6M hydrochloric acid, and the aqueous phase was extracted 2 to 3 times with ethyl acetate, the organic phases were combined, washed once with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give 36g of oil, yield 56%. HPLC purity 94.6%, chiral purity 98.4%.
Example 6
Resolution of Compound F
Dissolving 20g of crude F in 100mL of acetonitrile, adding 12.3g of (R) -1- (1-naphthyl) ethylamine under stirring, heating to 75-80 ℃ for reaction for 2-3 hours, slowly cooling to 25-30 ℃ for reaction for 4 hours, filtering, drying to obtain a white solid, adding 300mL of water and 300mL of ethyl acetate into the white solid, regulating the pH to 2-3 by using citric acid, separating an organic phase, washing the organic phase with 5% of citric acid aqueous solution for 2 times, washing the organic phase with 10% of sodium chloride aqueous solution for one time, drying, concentrating to obtain oily matter, recrystallizing the oily matter with a mixed solvent of ethyl acetate and petroleum ether to obtain 23.2g of white solid with 99.2% of HPLC purity and 99.6% of EE value. Yield: 86%.
1 H NMR(400MHz,CDCl3)δ11.01(br,1H),7.36-7.29(m,5H),5.19-5.10(m,2H),3.82-3.73(m,1H),3.66-3.52(m,2H),3.33-3.24(m,1H),3.14-3.08(m,1H),2.35-2.34(br,1H),1.56-1.48(m,1H),1.42-1.37(m,1H),0.97(t,J＝16Hz,3H).
Example 7
Resolution of Compound F
Dissolving 20g of crude F in 100mL of acetonitrile, adding 8.7g of R-alpha-phenethylamine under stirring, heating to 75-80 ℃ for reaction for 2-3 hours, slowly cooling to 25-30 ℃ for reaction for 4 hours, filtering, drying to obtain a white solid, adding the white solid into 300mL of water and 300mL of ethyl acetate, regulating the PH to 2-3 by using citric acid, separating an organic phase, washing the organic phase for 2 times by using 5% citric acid aqueous solution, washing the organic phase once by using 10% sodium chloride aqueous solution, drying, concentrating to obtain oily matter, recrystallizing the oily matter by using a mixed solvent of ethyl acetate and petroleum ether to obtain 14g of white solid, wherein the HPLC purity is 98.7%, the EE value is 99.2%, and the yield is 70%.
Example 8
Resolution of Compound F
Dissolving 20g of crude F in 100mL of acetonitrile, adding 13.3g of dicyclohexylamine under stirring, heating to 75-80 ℃ for reaction for 2-3 hours, slowly cooling to 25-30 ℃ for reaction for 4 hours, filtering and drying to obtain a white solid, adding the white solid into 300mL of water and 300mL of ethyl acetate, regulating the PH to 2-3 by using citric acid, separating an organic phase, washing the organic phase for 2 times by using 5% citric acid aqueous solution, washing the organic phase for one time by using 10% sodium chloride aqueous solution, drying and concentrating to obtain oily matter, recrystallizing the oily matter by using a mixed solvent of ethyl acetate and petroleum ether to obtain 17.4g of white solid, wherein the HPLC purity is 99.5%, the EE value is 98.7%, and the yield is 87%.
Claims (9)
1. A method for synthesizing Wu Pa tenib intermediate (3 r,4 s) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, characterized by comprising the steps of:
(1) Reacting 1-Boc-3-pyrrolidone with N, N-dimethylformamide dimethyl acetal to generate a compound A;
(2) Reacting the compound A with methyl magnesium bromide under the protection of nitrogen to generate a compound B;
(3) The compound B is subjected to asymmetric reduction of carbonyl into hydroxyl to obtain a compound C, and an asymmetric reduction system adopts a (S) -2-methyl-CBS-oxazaborolidine and borane tetrahydrofuran system when the compound C is synthesized;
(4) The compound C is subjected to asymmetric catalytic reduction of double bonds to obtain a compound D;
(5) Under alkaline condition, the compound D reacts with methylsulfonyl chloride or p-toluenesulfonyl chloride to produce an intermediate product, and then nucleophilic substitution reaction is carried out with a cyano reagent, and the configuration is absolutely turned over to obtain a compound E;
(6) Hydrolyzing cyano into carboxyl under an acidic condition, simultaneously removing Boc protecting group, and reacting with N-benzyloxycarbonyloxy succinimide or benzyl chloroformate to obtain a crude compound F;
(7) The crude compound F is recrystallized or chemically resolved to obtain a high chiral Marpatinib intermediate (3R, 4S) -1- ((benzyloxycarbonyl) -4-ethylpyrrolidine-3-carboxylic acid;
the structural formulas of the compound A, the compound B, the compound C, the compound D, the compound E and the compound F are as follows:
。
2. the method for synthesizing Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as claimed in claim 1, wherein the reaction temperature is 60-70℃and the reaction time is 8-12 hours when synthesizing compound A, and the solvent is any one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl riddle, chloroform and methylene chloride.
3. The method for synthesizing Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as defined in claim 2, wherein the volume ratio of solvent to 1-Boc-3-pyrrolidone is 1:5 and the molar ratio of 1-Boc-3-pyrrolidone to N, N-dimethylformamide dimethyl acetal is 1:1.5 when synthesizing compound A.
4. The method for synthesizing Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as defined in claim 1, wherein the reaction temperature is-10 to-15℃and the reaction time is 3-4 hours when the compound B is synthesized, and the solvent is any one of tetrahydrofuran, diethyl ether and 2-methyltetrahydrofuran.
5. The method for synthesizing Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as defined in claim 4 wherein the volume ratio of solvent to compound A is 1:10 and the molar ratio of compound A to methylmagnesium bromide is 1:1.5 when synthesizing compound B.
6. The process for the synthesis of (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as a tenib intermediate Wu Pa as claimed in claim 1, wherein the asymmetric reduction system is based on diacetyl [ (R) - (+) -5,5 '-bis (diphenylphosphine) -4,4' -bis-1, 3-benzodioxolane ] ruthenium (II) as catalyst using methanol as solvent and triethylamine as base.
7. The method for synthesizing Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as defined in claim 1, wherein in the synthesis of compound E, the alkaline condition is selected from any one of triethylamine, N-diisopropylethylamine, potassium carbonate, sodium carbonate and sodium bicarbonate, the solvent is selected from any one of dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran and N, N-dimethylformamide, and the cyano reagent is selected from any one of sodium cyanide, potassium cyanide and trimethylsilicon cyanide.
8. The process for the synthesis of (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as a tenib intermediate Wu Pa as claimed in claim 1, wherein the acid selected for hydrolysis in the synthesis of compound F is concentrated hydrochloric acid, aqueous hydrogen bromide or dilute sulfuric acid, and the pH is adjusted to 7-8 and maintained after completion of the hydrolysis reaction.
9. The method for synthesizing Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as defined in claim 1, wherein the chemical resolution reagent is selected from R-a-phenethylamine, dicyclohexylamine or (R) -1- (1-naphthyl) ethylamine.
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| CN109705011A (en) * | 2019-01-18 | 2019-05-03 | 浙江师范大学 | A kind of crow pa replaces the synthetic method and intermediate of Buddhist nun's intermediate |
| WO2020202183A1 (en) * | 2019-03-29 | 2020-10-08 | Mylan Laboratories Limited | The process for the preparation of upadacitinib and its intermediates |
| CN114315679A (en) * | 2022-01-21 | 2022-04-12 | 杭州新博思生物医药有限公司 | Preparation method of Upactinib chiral intermediate |
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| CN109705011A (en) * | 2019-01-18 | 2019-05-03 | 浙江师范大学 | A kind of crow pa replaces the synthetic method and intermediate of Buddhist nun's intermediate |
| WO2020202183A1 (en) * | 2019-03-29 | 2020-10-08 | Mylan Laboratories Limited | The process for the preparation of upadacitinib and its intermediates |
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