CN115197115A - Preparation method and application of chiral 5-oxopyrrolidine-3-formic acid - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical chemistry and organic chiral compound preparation, and particularly relates to a preparation method and application of chiral 5-oxopyrrolidine-3-formic acid, wherein the method takes dimethyl itaconate (CAS: 617-52-7) and R (+) -p-methoxy methylbenzylamine (CAS: 22038-86-4) as starting raw materials to react to prepare a pair of diastereoisomers, and then the two diastereoisomers are separated by common silica gel column chromatography to obtain the two diastereoisomers; then the two diastereoisomers are respectively used for continuing chemical reaction, and two target chiral compounds (R) -A and (S) -A with two configurations can be obtained by ester hydrolysis and nitrogen protecting group removal, or nitrogen protecting group removal and ester hydrolysis.

Description

A kind of preparation method and application of chiral 5-oxopyrrolidine-3-carboxylic acid

technical field

The invention belongs to the technical field of medicinal chemistry and organic chiral compound preparation, in particular to a preparation method and application of a chiral 5-oxopyrrolidine-3-carboxylic acid.

Background technique

5-oxopyrrolidine-3-carboxylic acid (chemical structure is as follows: A), is an important class of pharmaceutical intermediates, such as N-alkyl or benzyl substituted 5-oxopyrrolidine-3-carboxylic acid is synthesized and prepared Neiraracetam is an essential intermediate raw material; Neiraracetam is a new drug with pyrrolidone structure (Nebracetam), which can improve brain energy metabolism and neurotransmission function, and significantly improve the dysfunction of cholinergic system in the brain; and The chiral R/S configuration of 5-oxopyrrolidine-3-carboxylic acid can be used to prepare novel pyrrolidone derivatives.

The chemical name of 5-oxopyrrolidine-3-carboxylic acid can also be named as 2-pyrrolidone-4-carboxylic acid. In patent CN104447733A, researchers put 1-benzyl-2-pyrrolidinone-4-carboxylic acid ( 1-benzyl-5-oxopyrrolidine-3-carboxylic acid) with 5-arylaminoacyl-2-aminothiazole, the main pharmacophore fragment of the protein kinase inhibitor antineoplastic drug Dasatinib Coupling gave 1-benzyl-2-pyrrolidinone-4-amide compounds with the following chemical structures:

The 2-pyrrolidone-4-amide compounds with dasatinib pharmacophore can effectively regulate the signal transduction of tyrosine kinase, inhibit the proliferation of undesirable cells and the growth of blood vessels, and have obvious anti-tumor activity.

In conclusion, 5-oxopyrrolidine-3-carboxylic acid (2-pyrrolidone-4-carboxylic acid) is a key intermediate in the synthesis of nootropics and antitumor compounds, and chiral R or S-configuration 5-oxopyrrolidine-3-carboxylic acid will have important practical value and broad application prospects in the field of medicinal chemistry, so it is necessary to provide a chiral R or S configuration 5-oxopyrrole Preparation method and application of alkane-3-carboxylic acid.

SUMMARY OF THE INVENTION

In order to solve the above technical problems, the present invention provides a preparation method and application of chiral 5-oxopyrrolidine-3-carboxylic acid, which introduces a chiral center, and each chiral intermediate product is easy to separate and purify, and has high optical purity.

In order to achieve the technical effect of solving the above-mentioned technical problems, the present invention is realized by the following technical methods: a preparation method of chiral 5-oxopyrrolidine-3-carboxylic acid, which is characterized in that, specifically comprises the following steps:

S1. Heating reaction with starting material dimethyl itaconic acid (CAS: 617-52-7) and R(+)-p-methoxymethylbenzylamine (CAS: 22038-86-4) at 180 °C .

As a preference, since the two raw materials are liquid, no other organic solvent is used, and at the same time, the methanol (CH ₃ OH) generated by the reaction is separated with a water separator to promote the reaction to proceed more completely; the reaction substrate is dimethyl itaconic acid. The equivalent molar ratio of ester and R(+)-p-methoxymethylbenzylamine was 1:1; the reaction product was a mixture of a pair of diastereomers.

S2. Separate a pair of diastereomers generated by the first step reaction by using a common silica gel column chromatography separation method.

The chemical names of the two isolated chiral compounds are (1R, 3R)-1-(1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid methyl ester (the former product in the above reaction formula) and (1R, 3S)-1-(1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid methyl ester (reaction above The latter products in the formula), their respective chemical yields exceed 60%, and their d.e. values are all greater than 90% by high pressure liquid chromatography (HPLC) analysis.

Preferably, the eluent used in column chromatography is preferably petroleum ether (60-90°C) and ethyl acetate, and the ratio (volume ratio) is 3:1, 2:1, 1:1, 1:2 in turn; Ether (60-90 ℃) can also use the running range of 30-60 ℃, or use n-hexane instead; the silica gel used in column chromatography can be 100-200 mesh or 200-300 mesh, preferably 200-300 mesh.

S3. The two diastereomers separated in the above step continue to react through ester hydrolysis and removal of the protective group on the nitrogen, or first remove the protective group on the nitrogen and then hydrolyze the ester to obtain the target molecules of the two configurations. Compounds (R)-A and (S)-A.

Preferably, the two diastereomers obtained by column separation in S2 are oily substances, and the molar ratio to lithium hydroxide (LiOH) is 1:1~1:1.5, and the reaction uses mixed solvent methanol and water. (volume ratio 1:1), the reaction temperature is room temperature 20-25°C, the reaction time is generally 2-3 hours, and the chemical yield of the hydrolysis reaction exceeds 85%; the names of the two products are (1R, 3R)- 1-(1-(4-Methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid and (1R, 3S)-1-(1-(4-methoxyphenyl) Ethyl)-5-oxopyrrolidine-3-carboxylic acid; since these two carboxylic acid intermediates are solid, their optical purity can be increased by recrystallization.

Preferably, the carboxylic acid products are also diastereomers of each other, and are respectively reacted with the rare earth compound ceric amine nitrate (Ce(NH ₄ ) ₂ (NO ₃ ) ₆ ) to remove the protective group on N ( (3R) 5-oxopyrrolidine-3-carboxylic acid and (3S) 5-oxopyrrolidine-3-carboxylic acid are generated; molar ratio of chiral carboxylic acid substrate to ceric amine nitrate It is 1:1~1:2, preferably 1:1.5; the solvent is acetonitrile and water (volume ratio 1:1), the reaction temperature is room temperature 20-25°C, and the reaction time is 0.5~1.5 hours, preferably 1 hour.

Preferably, the product (1R, 3R) or (1R, 3S)-1-(1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate in the S2 Methyl acid can also be reacted with ceric amine nitrate in acetonitrile and water to remove the protecting group on N to obtain two configurations (3R or 3S) of chiral 5-oxopyrrolidine-3-carboxylate methyl ester , which are also two solids that can be purified by recrystallization to improve their optical purity; the chemical reaction conditions are the same as described in (2). Then, the methyl ester was hydrolyzed with lithium hydroxide in methanol and water to obtain two target products (3R) 5-oxopyrrolidine-3-carboxylic acid and (3S) 5-oxopyrrolidine-3-carboxylic acid, respectively. ; The chemical reaction conditions are the same as those described in (1); the chemical yields are also similar.

Another object of the present invention is to provide an application of chiral 5-oxopyrrolidine-3-carboxylic acid.

The beneficial effects of the present invention are:

1. The method of the present invention uses the chiral compound R(+)-p-methoxymethylbenzylamine (CAS: 22038-86-4) as a raw material for the first time, and introduces a chiral center after reacting with dimethyl itaconic acid carbon atom; and the para-methoxy group of the benzene ring increases the polarity of the intermediate product, which is beneficial to the post-processing and the purification and separation of diastereomers, which is innovative to a certain extent.

2. A chiral diastereomer generated in the first step reaction can be easily separated by ordinary silica gel column chromatography, avoiding the use of tedious and expensive methods and reagents such as other chiral separation or chiral preparative chromatography. , and the optical purity (d.e value) of both chiral intermediates exceeds 90%.

3. (1R, 3R) or (1R, 3S)-1-(1-(4-methoxyphenyl) obtained by hydrolyzing methyl ester with lithium hydroxide (LiOH) for the first chiral compound after separation and purification )ethyl)-5-oxopyrrolidine-3-carboxylic acid is solid, and its optical purity (d.e value) can be improved by recrystallization and purification. Similarly, the two-configuration chiral (3R/3S)-5-oxopyrrolidine-3-carboxylate methyl ester obtained by reacting with ceric amine nitrate to remove the protecting group on N is also a solid, which can also be easily obtained by Purified by recrystallization to increase its optical purity (e.e. value). This effectively ensures the optical purity of the final product (3R)/(3S)-5-oxopyrrolidine-3-carboxylic acid.

4. The synthetic process route of the present invention is novel, the raw materials and reagents are cheap and easy to obtain, the post-processing is convenient, the reaction conditions are mild, and the chemical yield is high; especially, the chiral center is cleverly introduced, and each chiral intermediate product is easy to be separated and purified, and has High optical purity; wide application value and potential in chiral drug synthesis.

Description of drawings

In order to illustrate the technical solutions of the embodiments of the present invention more clearly, the following briefly introduces the accompanying drawings used in the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained from these drawings without any creative effort.

Fig. 1 is the chemical structure schematic diagram of;

Figure 2 is the chemical reaction of dimethyl itaconic acid (CAS: 617-52-7) and R(+)-p-methoxymethylbenzylamine (CAS: 22038-86-4) heated at 180 °C Mode;

Fig. 3 is the chemical reaction formula that adopts common silica gel column chromatography separation method to obtain;

Figure 4 shows that the two diastereomers continue to react through ester hydrolysis and removal of the protecting group on the nitrogen, or the target chiral compound (R) with two configurations can be obtained by first removing the protecting group on the nitrogen and then hydrolyzing the ester. Chemical formulas of -A and (S)-A.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1

15.85 g of dimethyl itaconic acid (0.1 mol) and 15.12 g of R(+)-p-methoxymethylbenzylamine (0.1 mol) were weighed into a round-bottomed flask, and heated in a silicone oil bath at 180 °C. The reaction was carried out for 2-3 hours, and the methanol produced by the reaction was separated with a water separator; the two raw material points of thin layer plate spotting (TLC) disappeared, and the separated methanol was about 3.5-4.0 ml, and the reaction was terminated at this time; the reaction oily residue After cooling, directly use 200-300 mesh ordinary silica gel for column chromatography separation, and use petroleum ether (60-90 ° C) and ethyl acetate as eluents in turn, and the volume ratio (ethyl acetate: petroleum ether) is sequentially from 1:3 , 1:2, 1:1, 2:1 gradient elution, respectively collect the fluorescent point product above and the fluorescent point product below on TLC, evaporate the solvent under reduced pressure rotary evaporator to obtain 8.7 g of the product with less polar above, and the yield is 8.7 g. 62.8%; the lower polar product is 9.5 g, and the yield is 68.6%.

Determination of d.e. value of optical purity, using C-18 ordinary chromatographic column with n-hexane and methanol as mobile phase, the d.e. value of diastereomers measured by high pressure liquid chromatography (HPLC) is 93.56 for less polar products, respectively %, more polar products 95.23%. It is worth pointing out that we cannot compare the less polar or more polar products in chromatography (TLC & HPLC) with their absolute configuration products, i.e. 1-(1-(4-methyl) of (1R, 3R) or (1R, 3S). oxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate methyl ester corresponds.

Hydrogen nuclear magnetic resonance spectroscopy ( ¹ HNMR-CDCl ₃ ) structure identification: (1), less polar product: δ(ppm): 1.50(d, 3H), 2.63-2.78(m, 2H), 3.09(q, 1H) ), 3.18(t, 1H), 3.52(dd, 1H), 3.72(s, 3H), 3.80(s, 3H), 5.44(q, 1H), 6.86(d, 2H), 7.22(d, 2H) . (2) Product with higher polarity: δ(ppm): 1.51(d, 3H), 2.63-2.78(m, 2H), 3.08-3.22(m, 2H), 3.52(m, 1H), 3.65( s, 3H), 3.80(s, 3H), 5.45(q, 1H), 6.86(d, 2H), 7.22(d, 2H) The chemical shifts of atoms are obviously different, the less polar is 3.72 ppm, and the more polar is 3.65 ppm, which is a remarkable sign of distinguishing two chiral diastereomers in ¹ HNMR spectrum.

Example 2

Take 4.8 g (17.3 mmol) of methyl 1-(1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate, the less polar product of the reaction in the previous step, with 20 mL After dissolving the oil in methanol, add 20 mL of water and stir evenly. Weigh 0.65 g (27.1 mmol) of LiOH. If the amount of lithium hydroxide is small, the solid can be added slowly. If the amount is large, it can be dissolved in an appropriate amount of water and added dropwise; After -4 hours, the TLC spot plate detected the disappearance of the substrate point to terminate the reaction; the reaction solution was adjusted to pH 5~6 with 10% hydrochloric acid, the methanol was evaporated, an appropriate amount of water was added, and then extracted three times with ethyl acetate, and the organic layers were combined with saturated common salt. Wash once with water and water, dry with anhydrous sodium sulfate or anhydrous magnesium sulfate, and rotate the organic solvent to dryness to obtain a light yellow solid; the solid is recrystallized with a mixed solvent (n-hexane:tetrahydrofuran=1:1) as a white crystal, Set for filtration, concentrate the mother liquor to separate out solid crystals again, filter, combine, dry, and weigh a total of 4.1 grams, with a chemical yield of 89.9%.

Hydrogen nuclear magnetic resonance spectrum ( ¹ HNMR-CDCl ₃ ), δ(ppm): 1.50(d, 3H), 2.70-2.84(o&qq, 2H), 3.09-3.16(m, 1H), 3.18-3.23(t, 1H) , 3.56-3.60(q, 1H), 3.78(s, 3H), 5.45(q, 1H), 5.78(br, 1H, COOH), 6.87(d, 2H), 7.22(d, 2H). Carbon NMR Spectrum ¹³ CNMR (CD Cl ₃ ), δ (ppm): 16.10, 34.38, 35.86, 44.48, 48.94, 55.26, 114.01, 128.34, 131.27, 159.05, 172.41, 176.21.

The same reaction method, conditions and post-processing operation, 4.5 grams of methyl carboxylate isomers with higher polarity are hydrolyzed by lithium hydroxide to obtain 3.8 grams of white solid carboxylic acid products of another configuration, and the chemical yield is 88.9%. . Hydrogen nuclear magnetic resonance spectrum ( ¹ HNMR-CDCl ₃ ), δ(ppm): 1.51(d, 3H), 2.69-2.84(m, 2H), 3.08-3.13(m, 1H), 3.18-3.24(m, 1H) , 3.52-3.60(m, 1H), 3.80(s, 3H), 5.44(q, 1H), 6.40(br, 1H, COOH), 6.86(d, 2H), 7.22(d, 2H). Carbon NMR Spectrum ¹³ CNMR (CD Cl ₃ ), δ (ppm): 16.43, 34.56, 35.89, 44.68, 49.02, 55.38, 114.01, 128.34, 131.47, 159.13, 172.62, 176.32.

Example 3

Take about 2.5 g (9 mmol) of either of the two chiral isomers in Example 1, add 40 mL of acetonitrile and 40 mL of water to dissolve and stir evenly, weigh 8.1 g (15 mmol) of cerium nitrate and add it in batches, stir at room temperature The reaction was carried out for about 1 hour, the color of the reaction solution changed from brown-red to red-yellow to bright yellow, the TLC dot plate detected the disappearance of the raw material point, then ₃₀ mL of NaHCO aqueous solution was added to terminate the reaction, part of acetonitrile was evaporated under reduced pressure, and an appropriate amount of water was added with ethyl acetate. Extracted three times, combined the organic layers and washed twice with water, dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and rotary evaporated the organic solvent to dryness to obtain a gum; the gum was separated by flash silica gel column chromatography, first with petroleum ether (60 -90℃) and ethyl acetate (5:1) as eluent, collect the product with strong fluorescent point above, evaporate to dryness and send it to ¹ HNMR (CDCl ₃ ) to identify the by-product p-methoxyacetophenone; finally, use ethyl acetate Ester: dichloromethane (volume ratio 1:1) eluted the following product point (iodine color development), after the combination, the solvent was evaporated to dryness to obtain about 1.05 g of white solid, the yield was 81.4%, and it was identified as the product by the nuclear magnetic resonance spectrum structure. (3R/3S)-5-oxopyrrolidine-3-carboxylate methyl ester.

Hydrogen nuclear magnetic resonance spectrum ( ¹ HNMR-CDCl ₃ ), δ(ppm): 2.54-2.70(o, 2H), 3.12-3.40(q, 1H), 3.59-3.67(m, 2H), 3.75(s, 3H) , 6.96(br, 1H, NH). Carbon NMR ( ¹³ CNMR, CD Cl ₃ ), δ(ppm): 33.15, 38.77, 44.40, 52.45, 173.16, 176.66.

Example 4

The product (1R, 3R) or (1R, 3S)-1-(1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid in Example 2 was used in Example 3 The ceric amine nitrate is oxidized to remove the protecting group on N, and the chiral target product (3R)/(3S)-5-oxopyrrolidine-3-carboxylic acid (gum) is obtained. And the product in Example 3 (3R/3S)-5-oxopyrrolidine-3-carboxylate methyl ester takes the lithium hydroxide in Example 2 to hydrolyze the methyl ester, and also obtains the chiral target product (3R)/ (3S)-5-Oxopyrrolidine-3-carboxylic acid (gum).

In the description of this specification, description with reference to the terms "one embodiment," "example," "specific example," etc. means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one aspect of the present invention. in one embodiment or example. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

The above-disclosed preferred embodiments of the present invention are provided only to help illustrate the present invention. The preferred embodiments do not exhaust all the details, nor do they limit the invention to only the described embodiments. Obviously, many modifications and variations are possible in light of the content of this specification. These embodiments are selected and described in this specification in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can well understand and utilize the present invention. The present invention is to be limited only by the claims and their full scope and equivalents.

Claims (6)

1. a preparation method of chiral 5-oxopyrrolidine-3-carboxylic acid, is characterized in that, specifically comprises the following steps: S1. It is prepared by reacting dimethyl itaconic acid (CAS: 617-52-7) and R(+)-p-methoxymethylbenzylamine (CAS: 22038-86-4) as starting materials for diastereomers; S2, separate and obtain these two diastereomers by ordinary silica gel column chromatography; S3. Continue the chemical reaction with these two diastereomers, respectively, through ester hydrolysis and removal of the protective group on the nitrogen, or first remove the protective group on the nitrogen and then hydrolyze the ester to obtain two chiral configuration targets respectively. Compounds (3R)-5-oxopyrrolidine-3-carboxylic acid ((R)-A) (CAS: 428518-37-0) and (3S)-5-oxopyrrolidine-3-carboxylic acid ((S) -A) (CAS:30948-17-5). 2. the preparation method of a kind of chiral 5-oxopyrrolidine-3-carboxylic acid according to claim 1, is characterized in that: in described S1, two starting raw material reaction conditions are heated at temperature 180 ℃ for 2 -3 hours and fractional distillation of the methanol formed. 3. the preparation method of a kind of chiral 5-oxopyrrolidine-3-carboxylic acid as claimed in claim 1, is characterized in that: two diastereomers that generate after two raw materials react in the described S2 The purification and separation method used for the structure is ordinary silica gel column chromatography, and the eluents used in the column chromatography are preferably petroleum ether (60-90 ° C) and ethyl acetate, and the volume ratio is 3:1, 2:1, 1 : 1, 1: 2; petroleum ether (60-90 ℃) can also use the sliding range of 30-60 ℃, or use n-hexane instead; the silica gel used in column chromatography can be 100-200 mesh or 200-300 mesh , preferably 200-300 mesh. 4. the preparation method of a kind of chiral 5-oxopyrrolidine-3-carboxylic acid according to claim 1, is characterized in that: the hydrolysis method of methyl carboxylate in the described S3 adopts lithium hydroxide (LiOH) , the molar ratio of methyl carboxylate and lithium hydroxide (LiOH) is 1:1~1:1.5, the solvent is methanol and water, the volume ratio is 1:1, the reaction temperature is room temperature 20-25℃, and the reaction time is generally 2- 3 hours. 5. the preparation method of a kind of chiral 5-oxopyrrolidine-3-carboxylic acid according to claim 1, is characterized in that: the removal of protecting group on nitrogen atom in described S3 has used rare earth compound cerium nitrate Amine (Ce(NH ₄ ) ₂ (NO ₃ ) ₆ ), the molar ratio of chiral carboxylic acid substrate and ceric nitrate amine is 1:1~1:2, the solvent is acetonitrile and water, the volume ratio is 1:1, the reaction The temperature is room temperature 20-25°C, and the reaction time is 0.5-1.5 hours. 6. The preparation method of a chiral 5-oxopyrrolidine-3-carboxylic acid according to claim 1, which discloses the application of a chiral 5-oxopyrrolidine-3-carboxylic acid.

Images