WO2019062027A1 - Green preparation method for n-substituted-l-pyroglutamic acid ester - Google Patents

Abstract

The present invention provides a green preparation method for N-substituted-L-pyroglutamic acid ester (I), comprising: using L-glutamic acid (II) as a starting material, and preparing L-glutamic acid diester hydrochloride (III) by means of an esterification reaction in the presence of an acidic reagent; and then subjecting L-glutamic acid diester hydrochloride (III) to N-substituted protective reaction with an N-substituent protective reagent by means of a one-pot method in the presence of a base and a solvent, introducing an N-substituted protective group, and heating is performed for dealcoholization cyclization in molecules to obtain N-substituted-L-pyroglutamic acid ester (I). The present invention has the advantages of cheap and easily available raw materials, classic reaction types, short process route, simple and convenient operation, small amount of waste water, green and environment-friendly production process, high reaction yield, and low product costs. 5R-benzyloxyaminopiperidine-2S-formate, 5R-benzyloxyaminopiperidine-2S-carboxylate oxalate, and avibactam can be prepared from N-substituted-L-pyroglutamic acid ester (I) prepared in the present invention.

Description

Green preparation method of N-substituted-L-pyroglutamic acid ester Technical field

The invention relates to a green preparation method of N-substituted-L-pyroglutamic acid ester, belonging to the field of pharmaceutical biochemical industry.

Background technique

N-substituted-L-pyroglutamic acid ester (I) is an important chemical and pharmaceutical intermediate. In the field of medicine, N-substituted-L-pyroglutamic acid ester can be used to prepare novel extended-spectrum β- The amidase inhibitor ababatan, patents CN103649051A, CN105294690A, US20140275001 all use a N-substituted-L-pyroglutamic acid ester (I) to prepare ababatam. The structural formula of N-substituted-L-pyroglutamic acid ester (I) and avivatan is as follows:

The existing N-substituted-L-pyroglutamic acid ester (I) is prepared by reacting pyroglutamic acid with benzyl chloride, an organic base, 1,2-dichloroethane (CN105732454A method) or bromine. The benzyl, organic base and acetone are reacted (CN105130870A method) to obtain L-pyroglutamic acid ester, which is further protected to obtain N-substituted-L-pyroglutamic acid ester. See Reaction Route 1.

The above methods all use stimulating bromobenzyl or benzyl chloride as raw materials, long reaction time, low production efficiency, large amount of waste water; additionally, the price of pyroglutamic acid is higher, and pyroglutamic acid needs high temperature from glutamic acid (150 -160 ° C) melt preparation, inconvenient operation, post-processing is cumbersome, requires multiple decolorization, decolorization process produces a large amount of wastewater, the yield is only 75%; and the above process requires three operation steps in the preparation process, the process route is long, which is not conducive to green production .

Summary of the invention

In view of the deficiencies of the prior art, the present invention provides a green preparation method of N-substituted-L-pyroglutamic acid ester (I). The raw material of the invention is cheap and easy to obtain, the reaction type is classic, the process route is short, and the operation is simple. The amount of waste water is small, the production process is green and environmentally friendly, the reaction yield is high, and the product cost is low.

The compound numbers in this specification are identical to the structural formula numbers and have the same reference relationship.

The technical solution of the present invention is as follows:

A method for preparing N-substituted-L-pyroglutamic acid ester, comprising the steps of:

(1) using L-glutamic acid (II) as a starting material, in the presence of an alcohol and an acidic reagent, esterification reaction to prepare L-glutamic acid diester hydrochloride (III);

Wherein R in the formula III is a C _1-6 saturated aliphatic group or an alkyl-substituted phenyl group.

(2) The L-glutamic acid diester hydrochloride (III) obtained in the step (1) is subjected to an N-substituted protection reaction with an N-substituent protecting agent in the presence of a base and a solvent to introduce an N-substituted protecting group, By dealcoholation ring to obtain N-substituted-L-pyroglutamic acid ester (I);

Wherein R in the formula I is the same as R in the formula III, and PG is in a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an ethyloxycarbonyl group, an allyloxycarbonyl group or a phenyloxycarbonyl group. One.

According to a preferred embodiment of the present invention, the alcohol of the step (1) is one of a C _1-6 saturated fatty alcohol, an aromatic alcohol or an alkyl-substituted aromatic alcohol.

Preferably, the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, tert-amyl alcohol, hexanol, benzyl alcohol, ortho One of methylbenzyl alcohol or p-methylbenzyl alcohol; further preferably, the alcohol is one of benzyl alcohol, ethanol, tert-butanol or methanol.

According to a preferred embodiment of the invention, the mass ratio of the alcohol to L-glutamic acid (II) in step (1) is from 8 to 30:1.

According to a preferred embodiment of the present invention, the acidic reagent in the step (1) is one of thionyl chloride, triphosgene or diphosgene.

Preferably, the molar ratio of the thionyl chloride to L-glutamic acid (II) is 2.0-10.0:1; the esterification reaction temperature is 40-85 ° C; further preferably, the esterification reaction temperature It is 60-85 ° C. The reaction time is 1-8 hours.

Preferably, the molar ratio of the triphosgene to L-glutamic acid (II) is 0.33-2.5:1; the esterification reaction temperature is 50-100 ° C; further preferably, the esterification reaction temperature is 60 -80 ° C. The reaction time is 1-8 hours.

Preferably, the molar ratio of the diphosgene to the L-glutamic acid (II) is from 0.5 to 3.5:1; the esterification reaction temperature is from 50 to 100 ° C; further preferably, the esterification reaction temperature is 60-80 ° C. The reaction time is 1-8 hours.

According to a preferred embodiment of the invention, the molar ratio of the acidic reagent to L-glutamic acid (II) in step (1) is from 0.33 to 10.0:1.

According to the preferred embodiment of the present invention, the esterification reaction temperature in the step (1) is from 30 to 100 ° C; preferably, the esterification reaction temperature is from 40 to 85 ° C.

According to a preferred embodiment of the invention, the esterification reaction time in step (1) is from 1 to 8 hours.

According to the preferred embodiment of the present invention, the base in the step (2) is an inorganic base or an organic base; the inorganic base is potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, calcium hydrogencarbonate, potassium acetate, One or a combination of two or more of sodium acetate, calcium acetate, sodium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide or sodium benzylate; the organic base is triethylamine, three-positive One or a combination of two or more of butylamine, diisopropylethylamine or pyridine.

According to a preferred embodiment of the invention, the molar ratio of the base to the L-glutamic acid diester hydrochloride (III) in step (2) is from 1.0 to 2.0:1.

According to the preferred embodiment of the present invention, the solvent in the step (2) is 1,2-dichloroethane, 1,1,2-trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane, One or a combination of two or more of benzene, toluene or xylene.

According to a preferred embodiment of the invention, the mass ratio of the solvent to the L-glutamic acid diester hydrochloride (III) in the step (2) is from 4 to 20:1.

According to the preferred embodiment of the present invention, the N-substituent protecting agent in the step (2) is di-tert-butyl dicarbonate, benzyl chloroformate, ethyl chloroformate, allyl chloroformate, tert-butyl chloroformate. Or one of phenyl chloroformate.

According to a preferred embodiment of the present invention, the molar ratio of the N-substituent protecting agent to the L-glutamic acid diester hydrochloride (III) in the step (2) is from 1.0 to 2.0:1.

According to a preferred embodiment of the present invention, the N-substituted protection reaction temperature in the step (2) is from -20 to 80 ° C; preferably, the N-substituted protection reaction temperature is from 20 to 50 ° C.

According to a preferred embodiment of the invention, the N-substituent protection reaction time in step (2) is from 2 to 10 hours.

According to a preferred embodiment of the present invention, the dealcoholization ring-closing reaction temperature in the step (2) is from 60 to 120 ° C; preferably, the dealcoholization ring-closing reaction temperature is from 70 to 105 ° C.

According to a preferred embodiment of the invention, the dealcoholation ring closure reaction time of step (2) is from 2 to 8 hours.

The invention is described as the following reaction route (Scheme 2):

Technical features and beneficial effects of the present invention:

1. The present invention uses L-glutamic acid (II) as a starting material to prepare L-glutamic acid diester hydrochloride (III) by esterification in the presence of an alcohol and an acidic reagent; The N-substituent protecting reagent is introduced into the N-substituted protecting group, and the in-molecular dealcoholation is carried out by heating, and the "one-pot method" is carried out to obtain N-substituted-L-pyroglutamic acid ester (I).

2. Compared with the prior art, the invention does not use bromine or benzyl chloride, and is harmless and environmentally friendly; the invention uses L-glutamic acid (II) as a starting material, and the raw materials are cheap and easy to obtain, and the reaction type is classic. The invention has the advantages of short process route, simple operation and low product cost; the invention does not need to wash the product, the amount of waste water is small, and the organic raw materials such as the solvent used can be recycled and reused, environmentally friendly, can effectively reduce the cost; and the reaction yield is high, The total yield is as high as 93.4%.

Detailed ways

The invention is described in detail below with reference to the examples, but the invention is not limited thereto.

% in the examples are percentages by mass unless otherwise specified.

The reaction process and product purity were monitored by gas phase or liquid chromatography, and the optical purity (area ratio %) was measured by a liquid chromatograph equipped with a chiral column (ES-OVS, 150 mm × 4.6 mm, Agilent), and the calculation was performed. Rate and ee% value.

Example 1: Preparation of L-glutamic acid dibenzyl ester hydrochloride (III ₁ )

Add 280 g of benzyl alcohol, 14.7 g (0.10 mol) of L-glutamic acid, 30.0 g (0.25) to a 500 ml four-necked flask equipped with a stirring, thermometer and reflux condenser (connected to a 30% aqueous sodium hydroxide absorption unit). Molyl) thionyl chloride, heated, reacted at 80-85 ° C for 5 hours, cooled to 20 ~ 25 ° C, nitrogen exchange system hydrogen chloride gas, after 30 minutes of replacement, distillation of excess thionyl chloride and benzyl alcohol, and then To the residue was added 120 g of methyl tert-butyl ether, which was beaten, filtered, and dried to give 35.9 g of white solid L-glutamic acid dibenzyl ester hydrochloride. The liquid phase purity was 99.8%, and the yield was 98.7%.

Example 2: Preparation of L-glutamic acid dibenzyl ester hydrochloride (III ₁ )

Add 280 g of benzyl alcohol, 14.7 g (0.10 mol) of L-glutamic acid, 30.0 g (0.15) to a 500 ml four-necked flask equipped with a stirring, thermometer and reflux condenser (connected to a 30% aqueous sodium hydroxide absorption unit). Mohr) Double phosgene, heated, reacted at 70 to 75 ° C for 6 hours, cooled to 20 to 25 ° C, and replaced with hydrogen chloride gas in a nitrogen system for 30 minutes. Excess diphosgene and benzyl alcohol were distilled off, and then 120 g of methyl tert-butyl ether was added to the residue, beaten, filtered, and dried to obtain 35.5 g of a white solid L-glutamic acid dibenzyl ester hydrochloride. The purity was 99.7%, and the yield was 97.6%.

Example 3: Preparation of L-glutamic acid diethyl ester hydrochloride (III ₂ )

Add 300 g of ethanol, 14.7 g (0.10 mol) of L-glutamic acid, 25.0 g (0.08 mol) to a 500 ml four-necked flask equipped with a stirring, thermometer and reflux condenser (connected to a 30% aqueous sodium hydroxide absorption unit). The triphosgene is heated, reacted at 70 to 75 ° C for 5 hours, cooled to 20 to 25 ° C, and replaced with hydrogen chloride gas in a nitrogen gas system for 30 minutes. Excess triphosgene and ethanol were distilled off, and then 100 g of methyl tert-butyl ether was added to the residue, beaten, filtered, and dried to obtain 23.5 g of a white solid L-glutamic acid diethyl ester hydrochloride. The liquid phase purity was 99.7. %, the yield was 98.0%.

Example 4: Preparation of L-glutamic acid dimethyl ester hydrochloride (III ₃ )

Add 300 g of methanol, 14.7 g (0.10 mol) of L-glutamic acid, 30.0 g (0.25 mol) to a 500 ml four-necked flask equipped with a stirring, thermometer and reflux condenser (connected to a 30% aqueous sodium hydroxide absorption unit). The thionyl chloride is heated, reacted at 60-63 ° C for 7 hours, cooled to 20-25 ° C, replaced with hydrogen chloride gas in the nitrogen system, and after 30 minutes of replacement, the excess thionyl chloride and methanol are distilled off and then left to the remainder. 100 g of methyl tert-butyl ether was added, beaten, filtered, and dried to obtain 20.8 g of a white solid L-glutamic acid dimethyl ester hydrochloride. The liquid phase purity was 99.5%, and the yield was 98.1%.

Example 5: Preparation of N-tert-Butoxycarbonyl-L-pyroglutamic acid benzyl ester (I ₁ )

To a 500 ml four-necked flask equipped with a stirring, a thermometer and a reflux condenser, 18.2 g (0.05 mol) of L-glutamic acid dibenzyl ester hydrochloride prepared in Example 1, 150 g of toluene, 7.8 g (0.06 mol) was added. Diisopropylethylamine, 12.0 g (0.055 mol) of di-tert-butyl dicarbonate, heated, reacted at 30-35 ° C for 4 hours, reacted at 90-95 ° C for 5 hours, cooled to 20-25 ° C, filtered, distilled The solvent was recovered from the filtrate, and 50 g of methyl tert-butyl ether was added to the residue to recrystallize, filtered, and dried to give 15.1 g of white powder solid N-tert-butyloxycarbonyl-L-pyroglutamic acid benzyl ester. 99.9%, the yield was 94.6%.

The nuclear magnetic data of the obtained product are as follows: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (9H, s), 2.01 (1H, m), 2.30 (1H, m), 2.49 (1H, m), 2.58 (1H, m), 4.63 (1H, t), 5.20 (2H, m), 7.36 (5H, m).

Example 6: Preparation of N-tert-Butoxycarbonyl-L-pyroglutamic acid benzyl ester (I ₁ )

To a 500 ml four-necked flask equipped with a stirring, a thermometer and a reflux condenser, 18.2 g (0.05 mol) of L-glutamic acid dibenzyl ester hydrochloride prepared in Example 2, 150 g of 1,1,2-three was added. Ethyl chloride, 7.8 g (0.06 mol) of diisopropylethylamine, 8.2 g (0.06 mol) of t-butyl chloroformate, reacted at 25-30 ° C for 5 hours, reacted at 80-85 ° C for 5 hours, cooled to 20 ° The solvent was distilled off at 25 ° C, and the filtrate was evaporated. The residue was crystallized from 50 g of methyl tert-butyl ether, and filtered, and dried to give 14.7 g of white powder solid N-tert-butyloxycarbonyl-L-pyroglutamic acid Benzyl ester, liquid phase purity 99.8%, yield 92.0%.

Example 7: Preparation of N-tert-Butoxycarbonyl-L-pyroglutamic acid ethyl ester (I ₂ )

To a 500 ml four-necked flask equipped with a stirring, a thermometer and a reflux condenser, 12.0 g (0.05 mol) of L-glutamic acid diethyl ester hydrochloride prepared in Example 3, 120 g of 2-methyltetrahydrofuran, 8.5 was added. Grams (0.06 mol) potassium carbonate, 8.2 g (0.06 mol) t-butyl chloroformate, react at 25-30 ° C for 5 hours, 75-80 ° C for 7 hours, cool to 20-25 ° C, filter, distill the filtrate to recover solvent To the residue was added 40 g of methyl tert-butyl ether to recrystallize, filtered and dried to give 11.5 g of white powdery solid N-tert-butyloxycarbonyl-L-pyroglutamic acid ethyl ester. The yield was 89.3%.

The nuclear magnetic data of the obtained product are as follows: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (3H, t), 1.46 (9H, s), 2.02 (1H, m), 2.31 (1H, m), 2.48 (1H, m), 2.59 (1H, m), 4.16 (2H, q), 4.61 (1H, m).

Example 8: Preparation of N-benzyloxycarbonyl-L-pyroglutamic acid benzyl ester (I ₃ )

To a 500 ml four-necked flask equipped with a stirring, a thermometer and a reflux condenser, 18.2 g (0.05 mol) of L-glutamic acid dibenzyl ester hydrochloride prepared in Example 1, 150 g of 1,1,2-three was added. Ethyl chloride, 6.1 g (0.06 mol) of triethylamine, 10.5 g (0.06 mol) of benzyl chloroformate, reacted at 35 to 40 ° C for 4 hours, reacted at 100 to 105 ° C for 3 hours, cooled to 20 to 25 ° C, and filtered. The solvent was distilled off, and 50 g of methyl tert-butyl ether was added to the residue to recrystallize, filtered, and dried to give 16.2 g of white powder solid N-benzyloxycarbonyl-L-pyroglutamic acid benzyl ester. 99.3%, the yield was 91.7%.

The nuclear magnetic data of the obtained product are as follows: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.06 (1H, m), 2.34 (m, 1H), 2.50 (m, 1H), 2.61 (1H, m), 4.72 (1H, m), 5.12 (2H, s), 5.21 (s, 2H), 7.40-7.20 (m, 10H).

Comparative Example 1: Preparation of N-tert-Butoxycarbonyl-L-pyroglutamic acid benzyl ester (I ₁ )

To a 500 ml four-necked flask equipped with a stirring, a thermometer and a reflux condenser, 11.0 g (0.03 mol) of L-glutamic acid dibenzyl ester hydrochloride prepared in Example 1, 90 g of toluene, 4.7 g (0.036 mol) was added. Diisopropylethylamine, 7.2 g (0.033 mol) of di-tert-butyl dicarbonate, heated, reacted at 30-35 ° C for 4 hours, reacted at 50-55 ° C for 8 hours, cooled to 20-25 ° C, filtered, distilled The solvent was recovered from the filtrate, and 30 g of methyl tert-butyl ether was added to the residue to recrystallize, filtered, and dried to give 2.2 g of white powdery solid N-tert-butyloxycarbonyl-L-pyroglutamic acid benzyl ester. 99.1%, the yield was 23.0%.

It can be seen from the present comparative examples that the temperature of the dealcoholization ring reaction has a great influence on the yield of the final product, and the temperature of the dealcoholization ring is too low, which causes a sharp drop in the yield of the final product.

Claims (10)

A method for preparing N-substituted-L-pyroglutamic acid ester, comprising the steps of: (1) using L-glutamic acid (II) as a starting material, in the presence of an alcohol and an acidic reagent, esterification reaction to prepare L-glutamic acid diester hydrochloride (III);

Wherein R in the formula III is a C _1-6 saturated aliphatic group or an alkyl substituted phenyl group; (2) The L-glutamic acid diester hydrochloride (III) obtained in the step (1) is subjected to an N-substituted protection reaction with an N-substituent protecting agent in the presence of a base and a solvent to introduce an N-substituted protecting group, By dealcoholation ring to obtain N-substituted-L-pyroglutamic acid ester (I);

Wherein R in the formula I is the same as R in the formula III, and PG is in a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an ethyloxycarbonyl group, an allyloxycarbonyl group or a phenyloxycarbonyl group. One. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the alcohol in the step (1) is a C _1-6 saturated aliphatic alcohol, an aromatic alcohol or an alkyl substituted aromatic alcohol. a kind Preferably, the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, tert-amyl alcohol, hexanol, benzyl alcohol, ortho One of methylbenzyl alcohol or p-methylbenzyl alcohol; further preferably, the alcohol is one of benzyl alcohol, ethanol, tert-butanol or methanol; Preferably, the mass ratio of the alcohol to L-glutamic acid (II) in the step (1) is from 8 to 30:1. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the acidic reagent in the step (1) is one of thionyl chloride, triphosgene or diphosgene. Species Preferably, the molar ratio of the thionyl chloride to L-glutamic acid (II) is 2.0-10.0:1; the esterification reaction temperature is 40-85 ° C; further preferably, the esterification reaction temperature 60-85 ° C; Preferably, the molar ratio of the triphosgene to L-glutamic acid (II) is 0.33-2.5:1; the esterification reaction temperature is 50-100 ° C; further preferably, the esterification reaction temperature is 60 -80 ° C; Preferably, the molar ratio of the diphosgene to the L-glutamic acid (II) is from 0.5 to 3.5:1; the esterification reaction temperature is from 50 to 100 ° C; further preferably, the esterification reaction temperature is 60-80 ° C. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the molar ratio of the acidic reagent to L-glutamic acid (II) in the step (1) is 0.33 10.0:1. The method for producing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the esterification reaction temperature in the step (1) is from 30 to 100 ° C; preferably, the esterification The reaction temperature is 40-85 °C. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the base in the step (2) is an inorganic base or an organic base; and the inorganic base is potassium carbonate or carbonic acid. Sodium, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, calcium hydrogencarbonate, potassium acetate, sodium acetate, calcium acetate, sodium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide or sodium benzylate One or a combination of two or more; the organic base is one or a combination of two or more of triethylamine, tri-n-butylamine, diisopropylethylamine or pyridine; Preferably, the molar ratio of the base to the L-glutamic acid diester hydrochloride (III) in the step (2) is from 1.0 to 2.0:1. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the solvent in the step (2) is 1,2-dichloroethane, 1,1,2- One or a combination of two or more of trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane, benzene, toluene or xylene; Preferably, the mass ratio of the solvent to the L-glutamic acid diester hydrochloride (III) in the step (2) is from 4 to 20:1. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the N-substituent protecting agent in the step (2) is di-tert-butyl dicarbonate or chloroformic acid. a benzyl ester, ethyl chloroformate, allyl chloroformate, t-butyl chloroformate or phenyl chloroformate; Preferably, the molar ratio of the N-substituent protecting agent and the L-glutamic acid diester hydrochloride (III) in the step (2) is from 1.0 to 2.0:1. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the N-substituted protection reaction temperature in the step (2) is -20-80 ° C; preferably, The N-substituted protection reaction temperature is 20-50 °C. The method for preparing N-substituted-L-pyroglutamic acid ester according to claim 1, wherein the dealcoholization ring-closing reaction temperature in the step (2) is 60-120 ° C; preferably, the The dealcoholization ring reaction temperature is 70-105 °C.