CN112679407A - Preparation method of chiral 5-substituted proline compound - Google Patents
Preparation method of chiral 5-substituted proline compound Download PDFInfo
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- CN112679407A CN112679407A CN202110283863.4A CN202110283863A CN112679407A CN 112679407 A CN112679407 A CN 112679407A CN 202110283863 A CN202110283863 A CN 202110283863A CN 112679407 A CN112679407 A CN 112679407A
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Abstract
The invention discloses a preparation method of a chiral 5-substituted proline compound, which comprises the following steps: s1: carrying out format reaction; s2: carrying out reduction reaction; s3: acylation reaction; s4: and (4) performing hydrolysis reaction. The preparation method of the chiral 5-substituted proline compound has the advantages of simple synthetic route, simplicity and easiness in operation, low cost, mild reaction, easiness in amplification production, easiness in obtaining raw materials and high yield, and the chirality is formed by generating dominant conformations through reduction reaction.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a chiral 5-substituted proline compound.
Background
The invention aims to provide a simple and feasible route with low cost for synthesizing a chiral 5-substituted proline compound intermediate to synthesize novel medicines for treating diabetes, epilepsy, virus, hypertension and the like. The invention adopts a reducing agent with low price, raw materials, auxiliary materials and the like, has simple operation and is easy to be amplified to a kilogram level.
Disclosure of Invention
The present invention is directed to a method for preparing chiral 5-substituted proline compounds, which solves the problems set forth in the background art.
The synthetic route of the invention is as follows:
the first step is as follows:
the second step is that:
the third step:
the fourth step:
wherein: r is: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methoxybenzyl, 3-nitrobenzyl, preferably tert-butoxy, benzyloxy; r1Is hydrogen radical, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methoxybenzyl, 3-nitrobenzyl, vinyl, allyl, preferably hydrogen radical, methyl.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of chiral 5-substituted proline compounds comprises the following steps in sequence:
s1: format reaction: dissolving the compound 1 in a solvent, cooling to-40 ℃, adding a Grignard reagent, reacting for 2 hours, heating to-23 to-17 ℃, reacting for 12 hours, quenching with saturated ammonium chloride, extracting with ethyl acetate, drying an organic phase with anhydrous magnesium sulfate, filtering to obtain a filtrate, concentrating to dryness, dissolving an oily substance with dichloromethane, adding a deprotection reagent, stirring for reaction, and concentrating to dryness to obtain an oily substance, namely a deprotected compound 2;
s2: reduction reaction: adding the compound 2 obtained in the step into an alcohol solvent, adding a reducing agent for reduction reaction, quenching, and concentrating to dryness to obtain an oily level compound 3;
s3: acylation reaction: adding the compound 3 obtained in the step into a reaction solvent, then adding triethylamine, finally adding acyl chloride or acid anhydride, reacting for 5 hours at 20-40 ℃, washing the reaction solution with dilute hydrochloric acid and saturated salt solution after the reaction is finished, and then concentrating and drying to obtain an oily substance, namely a compound 4;
s4: and (3) hydrolysis reaction: dissolving the compound 4 obtained in the step into an ethanol solution, adding an aqueous solution of an inorganic alkaline reagent, heating to 60-80 ℃ for reaction, adjusting the pH to 2-3 with hydrochloric acid after the reaction is finished, separating out solids, and filtering to obtain a compound 5.
Preferably, in step S1, the solvent is tetrahydrofuran, and the deprotection reagent is one of hydrochloric acid, sulfuric acid, trifluoroacetic acid and methanesulfonic acid, preferably trifluoroacetic acid.
In any of the foregoing schemes, preferably, in step S2, the reducing agent is one of sodium borohydride, sodium triethylborohydride, sodium acetylborohydride, and lithium aluminum hydride, preferably sodium borohydride, and the alcohol solvent is one of methanol, ethanol, isopropanol, n-propanol, n-butanol, and tert-butanol, preferably ethanol.
In any of the above schemes, preferably, in step S3, the reaction solvent is one of tetrahydrofuran, dichloromethane and 1, 2-dichloroethane, preferably dichloromethane.
In any of the above embodiments, in step S4, the inorganic alkaline reagent is preferably one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide, and is preferably lithium hydroxide.
The invention has the technical effects and advantages that: the preparation method of the chiral 5-substituted proline compound has the advantages of simple synthetic route, simplicity and easiness in operation, low cost, mild reaction, easiness in amplification production, easiness in obtaining raw materials and high yield, and the chirality is formed by generating dominant conformations through reduction reaction.
Detailed Description
The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. 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.
Example 1:
the first step is as follows: dissolving N-Boc-L-pyroglutamic acid (5.0 g, 19.43 mmol) in tetrahydrofuran solution (100 mL), cooling to-40 ℃, adding Grignard reagent (21 mL, 1M, 21.38 mmol), reacting for 2h, slowly heating to-20 ℃ +/-3 ℃ for reaction for 12h, quenching the reaction by saturated ammonium chloride solution (100 mL), extracting by ethyl acetate (200 mL), drying the organic phase by anhydrous magnesium sulfate, filtering to obtain filtrate, concentrating to dryness, dissolving the oily substance by dichloromethane (100 mL), adding trifluoroacetic acid (3.81 g, 38.87 mmol), stirring for reaction, and concentrating to dryness to obtain oily substance which is deprotected imine intermediate B and directly using in the next reaction.
The second step is that: adding the imine intermediate B into 50 mL of ethanol, adding sodium borohydride (1.46 g, 38.66 mmol) in batches under stirring, then stirring strongly for 2h, after the TLC controlled reaction is finished, quenching the reaction by using saturated ammonium chloride solution (50 mL), extracting by using ethyl acetate (200 mL), drying an organic phase by using anhydrous magnesium sulfate, filtering to obtain a filtrate, and concentrating to dryness to obtain an intermediate C with an oily substance in a cis form, wherein the intermediate C is directly used for the next reaction.
The third step: adding the cis-form intermediate C into dichloromethane (50 mL), then adding triethylamine (3.86 g, 38.16 mmol), finally adding Boc anhydride (5.00 g, 22.90 mmol), then keeping at 20-30 ℃ for reaction for 5h, washing the reaction liquid with dilute hydrochloric acid and saturated saline solution after the reaction is finished, and then concentrating to dryness to obtain 4.20 g of oily matter which is an acylated product D and directly used for the next reaction.
The fourth step: dissolving an acylated product D (4.0 g, 15.54 mmol) into 20 mL of ethanol solution, adding an aqueous solution (10 mL) of lithium hydroxide (1.12 g, 46.63 mmol), heating to 60-80 ℃ for reaction, adjusting the pH to 2-3 with hydrochloric acid after the reaction is finished, separating out solids, and filtering to obtain 3.23 g of (2R,5R) -N-Boc-5-methylproline (compound 5) serving as a carboxyl compound, wherein the purity of the carboxyl compound is 97.3 percent, and the total yield of the four steps is 72.5 percent.
Wherein the structural formula of the imine intermediate B is as follows:(ii) a The structural formula of cis-form intermediate C is:(ii) a The structural formula of the acylation product D is as follows:。
example 2: preparation of (2R,5R) -N-Boc-5-cyclopropyl-proline ethyl ester
The first step is as follows:
dissolving N-Boc-L-pyroglutamic acid (5.0G, 19.43 mmol) in tetrahydrofuran solution (100 mL), cooling to below-40 ℃, then adding methyl Grignard reagent (21 mL, 1M, 21.38 mmol), reacting for 2h, slowly heating to-20 ℃ +/-3 ℃ for reacting for 12h, quenching the reaction by saturated ammonium chloride solution (100 mL), extracting by ethyl acetate (200 mL), drying the organic phase by anhydrous magnesium sulfate, filtering to obtain filtrate, concentrating to dryness, dissolving the oily substance by dichloromethane (100 mL), adding trifluoroacetic acid (3.81G, 38.87 mmol), stirring for reacting, concentrating to dryness to obtain oily substance which is deprotected intermediate G, and directly using in the next reaction.
The second step is that:
adding the intermediate G into 50 mL of ethanol, adding sodium borohydride (1.46G, 38.66 mmol) in batches under stirring, then stirring strongly for 2H, after the TLC controlled reaction is finished, quenching the reaction by using saturated ammonium chloride solution (50 mL), extracting by using ethyl acetate (200 mL), drying an organic phase by using anhydrous magnesium sulfate, filtering to obtain a filtrate, and concentrating to dryness to obtain an intermediate H with an oily substance in a cis form which is directly used for the next reaction.
The third step:
adding the intermediate H into dichloromethane (50 mL), then adding triethylamine (3.86 g, 38.16 mmol), finally adding Boc anhydride (5.00 g, 22.90 mmol), then keeping at 20-30 ℃ for reaction for 5H, washing the reaction liquid with dilute hydrochloric acid and saturated saline solution after the reaction is finished, and then concentrating to dry to obtain 4.20 g of oily matter serving as the intermediate I which is directly used for the next reaction.
The fourth step:
dissolving (3.80 g, 13.41 mmol) the intermediate I into 20 mL ethanol solution, adding a water (10 mL) solution of lithium hydroxide (0.96 g, 40.23 mmol), heating to 60-80 ℃ for reaction, adjusting the pH to 2-3 with hydrochloric acid after the reaction is finished, separating out solids, and filtering to obtain 3.00 g of compound J (2R,5R) -N-Boc-5-cyclopropyl-proline ethyl ester with the purity of 98.5%, wherein the total yield of the four steps is 60.5%.
Wherein the structural formula of the intermediate G is as follows:(ii) a The structural formula of the intermediate H is as follows:(ii) a The structural formula of the intermediate I is as follows:(ii) a The structural formula of compound J is:。
although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (5)
1. A preparation method of chiral 5-substituted proline compound is characterized by comprising the following steps: the method comprises the following steps in sequence:
s1: format reaction: dissolving the compound 1 in a solvent, cooling to-40 ℃, adding a Grignard reagent, reacting for 2 hours, heating to-23 to-17 ℃, reacting for 12 hours, quenching with saturated ammonium chloride, extracting with ethyl acetate, drying an organic phase with anhydrous magnesium sulfate, filtering to obtain a filtrate, concentrating to dryness, dissolving an oily substance with dichloromethane, adding a deprotection reagent, stirring for reaction, and concentrating to dryness to obtain an oily substance, namely a deprotected compound 2;
s2: reduction reaction: adding the compound 2 obtained in the step into an alcohol solvent, adding a reducing agent for reduction reaction, quenching, and concentrating to dryness to obtain an oily level compound 3;
s3: acylation reaction: adding the compound 3 obtained in the step into a reaction solvent, then adding triethylamine, finally adding acyl chloride or acid anhydride, reacting for 5 hours at 20-40 ℃, washing the reaction solution with dilute hydrochloric acid and saturated salt solution after the reaction is finished, and then concentrating and drying to obtain an oily substance, namely a compound 4;
s4: and (3) hydrolysis reaction: dissolving the compound 4 obtained in the step into an ethanol solution, adding an aqueous solution of an inorganic alkaline reagent, heating to 60-80 ℃ for reaction, adjusting the pH to 2-3 with hydrochloric acid after the reaction is finished, separating out solids, and filtering to obtain a compound 5;
the synthetic route is as follows:
the first step is as follows:
the second step is that:
the third step:
the fourth step:
wherein: r is: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methoxybenzyl, 3-nitrobenzyl; r1Hydrogen radical, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methoxybenzyl, 3-nitrobenzyl, vinyl and allyl.
2. A process according to claim 1 for the preparation of a chiral 5-substituted proline compound, characterized in that: in step S1, the solvent is tetrahydrofuran, and the deprotection reagent is one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, and methanesulfonic acid.
3. A process according to claim 1 for the preparation of a chiral 5-substituted proline compound, characterized in that: in step S2, the reducing agent is one of sodium borohydride, sodium triethylborohydride, sodium acetylborohydride, and lithium aluminum hydride, and the alcohol solvent is one of methanol, ethanol, isopropanol, n-propanol, n-butanol, and tert-butanol.
4. A process according to claim 1 for the preparation of a chiral 5-substituted proline compound, characterized in that: in step S3, the reaction solvent is one of tetrahydrofuran, dichloromethane, and 1, 2-dichloroethane.
5. A process according to claim 1 for the preparation of a chiral 5-substituted proline compound, characterized in that: in step S4, the inorganic alkaline agent is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.
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