CN111072543A - Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound - Google Patents
Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound Download PDFInfo
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Abstract
The embodiment of the invention discloses a preparation method and application of a (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound, and relates to the technical field of drug synthesis. According to the invention, (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid is synthesized by taking glycine ethyl ester as a raw material through amino-added protective group, ring closure, substitution, coupling, catalytic hydrogenation, hydrolysis and deprotection in sequence. The target product synthesized by the reaction has higher yield and chiral purity, and simultaneously has the advantages of simple and easily obtained raw materials, simple synthetic route, mild reaction conditions, simple separation and purification operation and low synthesis cost.
Description
Technical Field
The embodiment of the invention relates to the technical field of drug synthesis, and particularly relates to a preparation method and application of a (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound.
Background
Upatinib (Uptacetitinib) is a once-daily JAK1 selective inhibitor developed by Alberwein, approved by the FDA in 2019 and marketed in 8 months for treating rheumatoid arthritis. JAK kinase (Janus kinase) is a non-receptor tyrosine kinase family in cells, mediates signals generated by cytokines and is transmitted through a JAK-STAT signal channel, and comprises four members of JAK1, JAK2, JAK3 and Tyk2, and plays an important role in signal transduction of members of a cytokine receptor superfamily. JAKs play an important role in the pathophysiological processes of immune-mediated diseases and can be used for the treatment of some autoimmune diseases such as atopic dermatitis, rheumatoid arthritis, psoriasis, ulcerative colitis and the like.
Wherein, (3R,4S) -4-ethyl pyrrolidine-3-carboxylic acid is a key chiral raw material for preparing the lapatinib, and the chemical structure of the chiral raw material is shown as the formula (I).
At present, the following synthetic methods are mainly used for preparing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid:
1. in the patent US 20110311474A 1, ethyl 2-pentynoate is used as a starting material, and a target compound is obtained through a liner reduction reaction, a cyclization reaction, a chiral resolution reaction and a catalytic reaction. The synthetic route is shown as a formula (II), the starting material is expensive, the highly toxic N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine is used for carrying out the ring closing reaction, and in addition, the target compound is obtained by utilizing a chiral resolution mode, so that the yield of the whole route is low, the atom utilization rate is low, and the cost is high.
2. WO 2019016745A 1 takes ethyl 2-pentynoate as a starting material, and a target compound is obtained through hydrolysis, condensation, reduction, cyclization, hydrolysis and reduction reactions. The synthetic route is shown as a formula (III), the starting materials in the route are expensive, the highly toxic N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine is used for carrying out cyclization, and in addition, the chiral special compound is synthesized by utilizing a chiral auxiliary agent, but the document does not report the chiral purity of the product.
3. Patent WO 2019016745A 1 takes diethyl malonate as a starting material, and a target compound is obtained through condensation, miceal addition, reduction-cyclization, substitution, resolution and catalytic hydrogenation, wherein the synthetic route is shown as a formula (IV), and the synthetic route is longer, chiral resolution is used, the yield is lower, so that the product is expensive and the atom utilization rate is low.
4. In WO 2017066775A 1, N-CBZ-glycine ethyl ester is used as a starting material, and a target compound is obtained through Michael addition-condensation, esterification, metal coupling, chiral reduction and hydrolysis reaction. The synthetic route is shown as a formula (V), the route uses trifluoromethanesulfonic anhydride which is a strong corrosive reagent, is not environment-friendly, uses triethylboronic acid which is a highly toxic and spontaneous combustion-prone corrosive liquid, and is not easy to operate. And as a medical intermediate, the use of trifluoromethanesulfonic anhydride introduces sulfonate potentially genotoxic impurities.
Disclosure of Invention
Therefore, the embodiment of the invention provides a preparation method and application of a (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound, so as to solve the problems of low yield, high cost and the like caused by chiral resolution due to the need of using a highly toxic or strongly corrosive reagent in the existing synthetic method.
In order to achieve the above object, the embodiments of the present invention provide the following technical solutions:
according to the first aspect of the embodiments of the present invention, the embodiments of the present invention provide a method for preparing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compounds, the synthetic route is as follows:
wherein R is1Is Bn, COOEt, COOMe, COOn-Pr, COOi-Pr, COOn-Bu or Boc;
R2is iodine, bromine or chlorine. Preferably, R2Is bromine or chlorine.
Specifically, the method comprises the following steps:
1) taking glycine ethyl ester, a halogenated reagent and triethylamine as raw materials, and preparing a compound 1 through nucleophilic substitution reaction;
2) taking a compound 1, ethyl acrylate and lithium tert-butoxide as raw materials, and carrying out a closed-loop reaction to obtain a compound 2;
3) taking the compound 2 as a raw material, and preparing a compound 3 through nucleophilic substitution reaction;
4) taking a compound 3, a vinyl boron anhydride pyridine complex, palladium acetate and potassium carbonate as raw materials, and carrying out coupling reaction under the protection of nitrogen to obtain a compound 4;
5) the compound 4, triethylamine and di-acetic acid [ (S) - (-) -5,5 '-bi [ di (3, 5-xylyl) phosphino ] -4, 4' -di-1, 3-benzodioxole ] ruthenium (II) are used as raw materials, and the compound 5 is prepared by catalytic hydrogenation reaction;
6) the compound 5 is taken as a raw material, and a target compound 6, namely (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid, is prepared through hydrolysis and deprotection reaction.
In the step 1), the halogenated reagent comprises bromotoluene, chlorotoluene, methyl chloroformate, methyl bromoformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate and tert-butyl chloroformate.
In the step 2), the reaction temperature is-5-30 ℃.
In the step 4), the reaction temperature is 80-120 ℃, and the reaction time is 6-10 h.
In the step 5), the reaction temperature is 60-80 ℃, and the reaction time is 3-8 h.
In step 6), when R is1When being Bn, through Pd/C, H2The benzyl protecting group can be removed;
when R is1When the compound is COOEt, COOMe, COOn-Pr, COOi-Pr, COOn-Bu or Boc, the hydrolysis and deprotection reaction can be completed under the alkaline condition.
Further, the method comprises the steps of:
1) weighing glycine ethyl ester, dissolving the glycine ethyl ester in dichloromethane, reducing the temperature to 0 ℃, sequentially dropwise adding triethylamine and methyl chloroformate, heating to room temperature after adding, continuing to react for 3-6 h, adding dilute hydrochloric acid, separating liquid, sequentially washing an organic phase with saturated saline water and water, drying anhydrous sodium sulfate, filtering, and concentrating to obtain a compound 1;
2) weighing a compound 1, dissolving in tetrahydrofuran, adding ethyl acrylate, reducing the temperature to 0 ℃, adding lithium tert-butoxide in batches, heating to room temperature after the addition, continuing to react for 1-4 h, adjusting the pH to be neutral by using acetic acid, evaporating the solvent under reduced pressure, extracting with isopropyl ether, drying, concentrating, recrystallizing with isopropyl ether-n-hexane, and separating to obtain a compound 2;
3) weighing triphenylphosphine, dissolving the triphenylphosphine in toluene, reducing the temperature to 0 ℃, slowly and dropwise adding a toluene solution of liquid bromine and a toluene solution of triethylamine and a compound 2 in sequence, heating the mixture to room temperature after the addition is finished, continuing to react for 4-8 h, quenching the reaction by using a sodium bisulfite solution, extracting, drying an organic layer, and evaporating the solvent under reduced pressure to obtain a compound 3;
4) weighing a compound 3, a vinyl boron anhydride pyridine complex, palladium acetate and potassium carbonate, dissolving in dioxane under the protection of nitrogen, heating to 100 ℃, reacting for 8-10 h, evaporating under reduced pressure to remove a solvent, adding ethyl acetate, sequentially washing with saline water and water, drying, and distilling under reduced pressure to obtain a compound 4;
5) weighing a compound 4, triethylamine and a diacetate [ (S) - (-) -5,5 '-bis [ di (3, 5-xylyl) phosphino ] -4, 4' -di-1, 3-benzodioxole ] ruthenium (II) and dissolving in methanol, adding hydrogen into a reaction kettle, heating to 66 ℃, reacting for 4-6 h, cooling to room temperature, filtering and concentrating to obtain a compound 5;
6) weighing a compound 5, dissolving in a sodium hydroxide solution, stirring at room temperature for 0.5-3 h, adjusting the pH to 2-4 with dilute hydrochloric acid, adding ethyl acetate for extraction, taking an organic layer, drying, filtering, and concentrating under reduced pressure to obtain a target compound 6, namely (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid.
According to a second aspect of the embodiments of the present invention, the embodiments of the present invention provide the use of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compounds prepared by the above method for preparing a medicament having a structure of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid.
The embodiment of the invention has the following advantages:
according to the invention, (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid is synthesized by taking glycine ethyl ester as a raw material through amino-added protective group, ring closure, substitution, coupling, catalytic hydrogenation, hydrolysis and deprotection in sequence. The target product synthesized by the reaction has higher yield and chiral purity, and simultaneously has the advantages of simple and easily obtained raw materials, simple synthetic route, mild reaction conditions, simple separation and purification operation and low synthesis cost.
Detailed Description
The present invention is described in terms of particular embodiments, other advantages and features of the invention will become apparent to those skilled in the art from the following disclosure, and it is to be understood that the described embodiments are merely exemplary of the invention and that it is not intended to limit the invention to the particular embodiments disclosed. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.
Examples
The preparation method of the (3R,4S) -4-ethyl pyrrolidine-3-carboxylic acid compound comprises the following steps:
(1) synthesis of Compound 1
The reaction equation is as follows:
dissolving 73.8g of glycine ethyl ester in 500ml of dichloromethane in a 1000ml reaction bottle, dropwise adding 144.8g of triethylamine at 0 ℃, continuously dropwise adding 74.52g of methyl chloroformate after the dropwise adding is finished, heating to room temperature after the dropwise adding is finished, continuously reacting for 3 hours, adding 100ml of hydrochloric acid aqueous solution (1M) into the reaction solution, separating, washing an organic phase with saturated saline water and water sequentially, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain the compound 1 which is directly used for the next reaction.
(2) Synthesis of Compound 2
The reaction equation is as follows:
directly dissolving the compound 1 obtained in the step (1) in 400ml of tetrahydrofuran, then adding 72g of ethyl acrylate, reducing the temperature to 0 ℃, adding 57.6g of lithium tert-butoxide in batches, heating to room temperature after the addition is finished, continuing to react for 1h, adjusting the pH to 7 by using acetic acid after the reaction is finished, removing the solvent by reduced pressure evaporation, extracting by using isopropyl ether, drying, removing the solvent by reduced pressure evaporation, and adding isopropyl ether: recrystallization from n-hexane (volume ratio 1: 2) gave compound 2(123.84g, 80.4% yield in ethyl glycinate).
Structural characterization of compound 2:1H-NMR(CDCl3)1.25(br，m，3H)，3.20～4.50(m，6H)，3.65(br，s，3H)，9.9(br，1H)；
m/z：216(M+1)+；
IR(cm-1)：1640，1706，1720，1772。
(3) synthesis of Compound 3
The reaction equation is as follows:
26.2g of triphenylphosphine was dissolved in 100ml of toluene, the temperature was reduced to 0 ℃, a toluene solution containing 16g of liquid bromine (16 ml of toluene was added thereto) was slowly dropwise, after completion of the addition, a toluene solution containing 10.1 g of triethylamine and 21.5g of compound 2 (30 ml of toluene) was added dropwise to the solution, the temperature was raised to room temperature, stirring was continued for 4 hours, the reaction was completed, the reaction was quenched with a sodium bisulfite solution, extraction was performed, the organic layer was dried, and the solvent was distilled off under reduced pressure to obtain compound 3(20.85g, yield 75.3%).
(4) Synthesis of Compound 4
The reaction equation is as follows:
under the protection of nitrogen, 27.8g of compound 3, 24g of vinyl boronic anhydride pyridine complex, 1.4g of palladium acetate and 13.8g of potassium carbonate were dissolved in 100ml of dioxane, the temperature was raised to 100 ℃, reaction was carried out for 8 hours, after the reaction was completed, the solvent was distilled off under reduced pressure, 150ml of ethyl acetate was added, and the mixture was washed with brine and water in this order, dried, and the solvent was distilled off under reduced pressure to obtain compound 4(16.43g, yield 72.7%).
(5) Synthesis of Compound 5
The reaction equation is as follows:
8g of compound 4, 4.2g of triethylamine and 30mg of [ (S) - (-) -5,5 '-bis [ di (3, 5-xylyl) phosphino ] -4, 4' -di-1, 3-benzodioxole ] ruthenium (II) diacetate were dissolved in 100ml of methanol, hydrogen (500psi) was added to the reaction kettle, the temperature was raised to 66 ℃ and after 5 hours of reaction, the temperature was lowered to room temperature, filtered and concentrated to obtain compound 5, which was directly used in the next step.
(6) Synthesis of Compound 6
The reaction equation is as follows:
directly dissolving the compound 5 obtained in the step (5) in 100ml of a sodium hydroxide solution with the mass fraction of 10%, stirring at room temperature for 1h, adjusting the pH to 3 by using dilute hydrochloric acid, adding ethyl acetate for extraction, taking an organic layer for drying, filtering, and concentrating under reduced pressure to obtain a compound 6, namely a target compound (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid (3.85g, the yield is 77% calculated by using the compound 4; the HPLC purity is not less than 99%, and the HPLC chiral purity is not less than 99%).
Structural characterization of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid:1H-NMR(CD3OD)δ0.98(m，3H)，1.39～1.42(m，1H)，1.65～1.70(m，1H)，2.34～2.39(m，1H)，2.56～2.62(m，1H)，2.80～2.88(m，1H)，3.36～3.48(m，3H)；
m/z：144(M+1)+。
although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (9)
1. A preparation method of (3R,4S) -4-ethyl pyrrolidine-3-carboxylic acid compounds is characterized in that the synthetic route is as follows:
wherein R is1Is Bn, COOEt, COOMe, COOn-Pr, COOi-Pr, COOn-Bu or Boc;
R2is iodine, bromine or chlorine.
2. The method for producing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compounds according to claim 1, wherein R is2Is bromine or chlorine.
3. The method for producing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acids according to claim 1, comprising the steps of:
1) taking glycine ethyl ester, a halogenated reagent and triethylamine as raw materials, and preparing a compound 1 through nucleophilic substitution reaction;
2) taking a compound 1, ethyl acrylate and lithium tert-butoxide as raw materials, and carrying out a closed-loop reaction to obtain a compound 2;
3) taking the compound 2 as a raw material, and preparing a compound 3 through nucleophilic substitution reaction;
4) taking a compound 3, a vinyl boron anhydride pyridine complex, palladium acetate and potassium carbonate as raw materials, and carrying out coupling reaction under the protection of nitrogen to obtain a compound 4;
5) the compound 4, triethylamine and di-acetic acid [ (S) - (-) -5,5 '-bi [ di (3, 5-xylyl) phosphino ] -4, 4' -di-1, 3-benzodioxole ] ruthenium (II) are used as raw materials, and the compound 5 is prepared by catalytic hydrogenation reaction;
6) the compound 5 is taken as a raw material, and a target compound 6, namely (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid, is prepared through hydrolysis and deprotection reaction.
4. The method of claim 3, wherein the halogenating agent is bromotoluene, chlorotoluene, methyl chloroformate, methyl bromoformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate or tert-butyl chloroformate.
5. The method for producing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compounds according to claim 3, wherein the reaction temperature in the step 2) is-5 to 30 ℃.
6. The method for producing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acids according to claim 3, wherein the reaction temperature in step 4) is 80-120 ℃ and the reaction time is 6-10 hours.
7. The method for producing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acids according to claim 3, wherein the reaction temperature in step 5) is 60-80 ℃ and the reaction time is 3-8 hours.
8. The method for producing (3R,4S) -4-ethylpyrrolidine-3-carboxylic acids according to claim 3, comprising the steps of:
1) weighing glycine ethyl ester, dissolving the glycine ethyl ester in dichloromethane, reducing the temperature to 0 ℃, sequentially dropwise adding triethylamine and methyl chloroformate, heating to room temperature after adding, continuing to react for 3-6 h, adding dilute hydrochloric acid, separating liquid, sequentially washing an organic phase with saturated saline water and water, drying anhydrous sodium sulfate, filtering, and concentrating to obtain a compound 1;
2) weighing a compound 1, dissolving in tetrahydrofuran, adding ethyl acrylate, reducing the temperature to 0 ℃, adding lithium tert-butoxide in batches, heating to room temperature after the addition, continuing to react for 1-4 h, adjusting the pH to be neutral by using acetic acid, evaporating the solvent under reduced pressure, extracting with isopropyl ether, drying, concentrating, recrystallizing with isopropyl ether-n-hexane, and separating to obtain a compound 2;
3) weighing triphenylphosphine, dissolving the triphenylphosphine in toluene, reducing the temperature to 0 ℃, slowly and dropwise adding a toluene solution of liquid bromine and a toluene solution of triethylamine and a compound 2 in sequence, heating the mixture to room temperature after the addition is finished, continuing to react for 4-8 h, quenching the reaction by using a sodium bisulfite solution, extracting, drying an organic layer, and evaporating the solvent under reduced pressure to obtain a compound 3;
4) weighing a compound 3, a vinyl boron anhydride pyridine complex, palladium acetate and potassium carbonate, dissolving in dioxane under the protection of nitrogen, heating to 100 ℃, reacting for 8-10 h, evaporating under reduced pressure to remove a solvent, adding ethyl acetate, sequentially washing with saline water and water, drying, and distilling under reduced pressure to obtain a compound 4;
5) weighing a compound 4, triethylamine and a diacetate [ (S) - (-) -5,5 '-bis [ di (3, 5-xylyl) phosphino ] -4, 4' -di-1, 3-benzodioxole ] ruthenium (II) and dissolving in methanol, adding hydrogen into a reaction kettle, heating to 66 ℃, reacting for 4-6 h, cooling to room temperature, filtering and concentrating to obtain a compound 5;
6) weighing a compound 5, dissolving in a sodium hydroxide solution, stirring at room temperature for 0.5-3 h, adjusting the pH to 2-4 with dilute hydrochloric acid, adding ethyl acetate for extraction, drying an organic layer, filtering, and concentrating under reduced pressure to obtain a target compound 6, namely (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid.
9. An application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compounds prepared by the method of any one of claims 1 to 8 in preparation of drugs with a (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid structure.
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