CN115490606A - Method for preparing medical intermediate from 2-chloromethylene-diethyl malonate - Google Patents
Method for preparing medical intermediate from 2-chloromethylene-diethyl malonate Download PDFInfo
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- CN115490606A CN115490606A CN202211213895.8A CN202211213895A CN115490606A CN 115490606 A CN115490606 A CN 115490606A CN 202211213895 A CN202211213895 A CN 202211213895A CN 115490606 A CN115490606 A CN 115490606A
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- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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- C07C231/00—Preparation of carboxylic acid amides
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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Abstract
The invention discloses a method for preparing a medical intermediate from 2-chloromethylene-diethyl malonate, belongs to the technical field of organic compound preparation, and relates to preparation of 2-amino-2- (chloromethyl) -monoethyl malonate and (Boc) 2 Reacting O in an organic solvent under the action of an alkaline reagent to generate 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl)Yl) -malonic acid monoethyl ester; reacting 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester with benzene in an organic solvent under the action of a catalyst to generate 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester; the protection group of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester is removed and then reacted with acetic acid to produce 2-acetamido-2-benzylmalonic acid monoethyl ester.
Description
Technical Field
The invention belongs to the technical field of organic compound preparation, and particularly relates to a method for preparing a medical intermediate from 2-chloromethylene-diethyl malonate.
Background
The synthesis process of 2-acetamido-2-benzyl malonic acid monoethyl ester is one kind of intermediate of monoamino inhibitor, and the downstream product includes the reaction with alcohol to prepare corresponding amino acid compound or amino alcohol compound.
The prior synthesis method of the 2-acetamido-2-benzyl malonic acid monoethyl ester comprises the steps of taking the 2-acetamido-2-benzyl malonic acid ethyl ester as a raw material, and obtaining a target product through selective deesterification, wherein the route has expensive initial raw materials, higher production cost and poorer economy; and the other method is that diethyl aminomalonate is used as a raw material and subjected to amino protection, substitution, monoester removal, amino protecting group removal and acetylation to obtain a target product, so that the method has the advantages of multiple reaction steps, large reagent consumption, high recovery difficulty and poor economic benefit.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: aiming at the defects, the invention provides the preparation method of the monoamino inhibitor intermediate 2-acetamido-2-benzyl malonic acid monoethyl ester, the method has simple steps, avoids the byproduct generated by monoester removal when diethyl ester derivatives are used as raw materials, and has the advantages of few steps, mild reaction conditions, good yield and good economic benefit.
The invention discloses 2-amino-2- (chloromethyl) -malonic acid monoethyl ester shown as the following formula:
the invention discloses a preparation method of the 2-amino-2- (chloromethyl) -malonic acid monoethyl ester, which comprises the following steps: adding 2-chloromethylene-diethyl malonate and ammonia into a reactor containing a catalyst, reacting for 1-4 hours at 10-30MPa and 200-400 ℃, removing monoester of the product in a solvent under the action of alkali, and separating and purifying by column chromatography to obtain 2-amino-2- (chloromethyl) -monoethyl malonate (compound I).
Preferably, in the preparation of the compound I, 2-chloromethylene-diethyl malonate and ammonia are added into a reactor containing a catalyst to react for 1 to 4 hours at 10 to 30MPa and 200 to 400 ℃, the monoester of the product is removed in a solvent containing alkali at the temperature of minus 5 ℃ to 20 ℃, the product is washed, rotary evaporated to remove water and is separated and purified by column chromatography to obtain 2-amino-2- (chloromethyl) -monoethyl malonate (compound I).
More preferably, 2-chloromethylene-malonic acid diethyl ester and ammonia are present in a molar ratio of 1:1-2, the catalyst is silico-aluminum potassium zeolite, the solvent is methanol, the alkali is sodium hydroxide, the usage amount of the alkali is 10-25wt% of the product, and the usage amount of the product is 20-40wt% of the solvent.
The invention aims to provide a method for synthesizing a mono-amino inhibitor intermediate, namely, 2-acetamido-2-benzylmalonic acid monoethyl ester, which has the advantages of simple steps, few steps, mild reaction conditions, high yield and high economic benefit, avoids by-products generated by removing monoester when diethyl ester derivatives are used as raw materials.
The technical scheme adopted by the invention for realizing the purpose is as follows:
a synthetic method of monoamino inhibitor intermediate 2-acetamido-2-benzylmalonic acid monoethyl ester comprises the following steps:
s1, 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and (Boc) 2 Reacting O in an organic solvent in the presence of an alkaline reagent to generate 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (a compound II), wherein the organic solvent is at least one of dichloromethane, methanol, tetrahydrofuran and 1, 4-dioxane;
s2, reacting 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) with benzene in an organic solvent under the action of a catalyst to generate 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III);
and S3, removing a protective group from the monoethyl 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonate, and reacting the monoethyl 2-acetamido-2-benzylmalonate with acetic acid to generate monoethyl 2-acetamido-2-benzylmalonate. The invention takes 2-chloromethylene-diethyl malonate as initial reactant, and finally generates the monoamine inhibitor intermediate 2-acetamido through the reaction of a series of reagentsThe improvement of the present invention is achieved by reacting 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) with (Boc) 2 Dissolving O in an organic solvent, reacting under the action of an alkaline reagent to generate 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II), and then selecting a proper solvent to dissolve the 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) and reacting with benzene under the action of a catalyst to generate the 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III).
Preferably, the basic agent is DMAP.
Preferably, the basic agent is used in a molar amount of 160-240% of the molar amount of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester used.
Preferably, the catalyst is aluminum trichloride.
Preferably, the catalyst is used in a molar amount of 150-200% of the molar amount of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester used.
Preferably, (Boc) 2 The molar amount of O used is 100 to 120% of the molar amount of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester used.
Preferably, benzene is used in a molar amount of 100-120% of the molar amount of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester used.
Preferably, the organic solvent in S2 is at least one of acetone, cyclohexanone, acetonitrile, DMF.
Preferably, the synthetic route of the monoethyl 2-acetamido-2-benzylmalonate is as follows:
preferably, S1 is prepared by adding (Boc) to the system starting with 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) 2 And reacting the protected amino group in an organic solvent in the presence of a base to obtain 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II).
Preferably, in the preparation of compound II, 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and (Boc) 2 Adding O into an organic solvent, adding an alkaline reagent, and reacting at the temperature of 0-40 ℃ to obtain 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II).
More preferably, in the preparation of the compound II, the organic solvent is at least one of dichloromethane, methanol, tetrahydrofuran and 1, 4-dioxane.
More preferably, in the preparation of compound II, 2-amino-2- (chloromethyl) -malonic acid monoethyl ester is used in an amount of 5-30wt% based on the organic solvent.
More preferably, in the preparation of compound II, (Boc) 2 The molar amount of O used is 100 to 120% of the molar amount of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester used.
More preferably, in the preparation of compound II, the basic agent is DMAP and the molar amount of the basic agent is 160-240% of the molar amount of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester.
Preferably, in S2, 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound ii) is subjected to substitution reaction with benzene in the presence of a catalyst in an organic solvent to give 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound iii). The reaction temperature is the reflux temperature of the corresponding organic solvent.
Preferably, in the preparation of compound III, compound II and benzene are added into an organic solvent, a catalyst is added, and reflux reaction is carried out to obtain 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III).
More preferably, in the preparation of compound III, the organic solvent is at least one of acetone, cyclohexanone, acetonitrile and DMF.
More preferably, in the preparation of compound III, compound II is used in an amount of 45 to 75wt% based on the organic solvent.
More preferably, in the preparation of compound III, benzene is used in a molar amount of 100 to 120% of the molar amount of compound II.
More preferably, in the preparation of compound III, the catalyst is aluminum trichloride, and the molar amount of the catalyst used is 150-200% of the molar amount of compound II.
Preferably, S3 is divided into the preparation of the compounds IV, V.
Preferably, in S3, the amino protecting agent Boc group is removed from 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound iii) in an organic solvent in trifluoroacetic acid or hydrogen chloride conditions to give 2-amino-2-benzyl-malonic acid monoethyl ester (compound iv); and 2-amino-2-benzyl-malonic acid monoethyl ester (a compound IV) and acetic acid are subjected to condensation reaction to obtain 2-acetamido-2-benzyl malonic acid monoethyl ester (a compound V).
Preferably, in the preparation of the compound IV, the compound III is added into an organic solvent, an acidic reagent is added, and the Boc group of the amino protective agent is removed at the temperature of 0-40 ℃ to obtain 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV).
More preferably, in the preparation of compound iv, the organic solvent is dichloromethane and/or acetone.
More preferably, in the preparation of the compound IV, the compound III is used in an amount of 30-60wt% based on the organic solvent.
More preferably, in the preparation of compound IV, the acidic reagent is trifluoroacetic acid and/or hydrogen chloride, and the molar amount of the acidic reagent used is 150-300% of the molar amount of compound III used.
Preferably, in the preparation of the compound V, the compound IV and acetic acid are added into an organic solvent and react at the temperature of 35-65 ℃ to obtain the 2-acetamido-2-benzylmalonic acid monoethyl ester (compound V).
More preferably, in the preparation of compound v, the organic solvent is DMF and/or n-butanol.
More preferably, in the preparation of the compound V, the compound IV is used in an amount of 40-65wt% based on the organic solvent.
More preferably, in the preparation of compound V, acetic acid is used in a molar amount of 120-200% of the molar amount of compound IV.
The invention adopts 2-amino-2- (chloromethyl) -malonic acid monoethyl ester to obtain 2-acetamido-2-benzylmalonic acid monoethyl ester through amino protection, substitution, deamination protection and condensation, thereby having the following beneficial effects: the method avoids the by-product generated by removing the monoester when the diethyl ester derivative is taken as the raw material, has less steps and mild reaction conditions; the method has the advantages of high yield of each step, simple and convenient purification method, convenient operation and convenient industrial production; the method has the advantages of easily obtained raw materials, less byproducts, purification and reutilization of the recovered solvent, and good economic benefit. Therefore, the method for synthesizing the monoamino inhibitor intermediate 2-acetamido-2-benzyl malonic acid monoethyl ester has the advantages of simple steps, few steps, mild reaction conditions, high yield and high economic benefit, and by-products generated by monoester removal when diethyl ester derivatives are used as raw materials are avoided.
Drawings
FIG. 1 is a graph of the overall yield of compound III;
FIG. 2 is a graph of the overall yield of Compound V.
Detailed Description
The technical solution of the present invention is further described in detail below with reference to the following detailed description and the accompanying drawings:
the reactions were monitored by TLC in each reaction in the examples of the invention.
Example 1:
a synthetic method of monoamino inhibitor intermediate 2-acetamido-2-benzylmalonic acid monoethyl ester comprises the following steps:
preparation of compound i: adding 0.5M 2-chloromethylene-diethyl malonate and 0.75M ammonia into a reactor containing 30g of silicoaluminophosphate zeolite catalyst, reacting at 20MPa and 300 ℃ for 3 hours, and adding 30g of productRemoving monoester in 125mL methanol containing 6g sodium hydroxide at 5 ℃, washing, rotary steaming to remove water, separating and purifying by column chromatography to obtain 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) with the yield of 36.0%, 1 H NMR(400MHz，MeOD)δ1.26(t， 3H)， 3.03(s， 2H)，3.2-3.5(s， 2H)， 3.55-3.80(m，2H)，11.09（s， 1H）。
preparation of compound ii: 100g of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and 117.15g of (Boc) 2 O was dissolved in 500mL of methylene chloride, 99.94g of DMAP was added to the system at 25 ℃ and after the reaction, the solvent was distilled off under reduced pressure, and the organic phase after extraction was dried, filtered and concentrated to give 145.14g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) in 96.0% yield.
Preparation of compound iii: 145.14g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) and 39.10g of benzene were added to 300mL of acetone, 98.16 g of an aluminum trichloride catalyst were used at the reflux temperature of the solvent, the reaction was terminated, quenched with alkali, extracted, and the organic phase was distilled to give 129.98g of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) in 78.5% yield.
Preparation of Compound IV: 129.98g of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) is added into 300mL of acetone solution, 65.89g of trifluoroacetic acid is added into the system, the reaction temperature is 25 ℃, after the reaction is finished, extraction, washing and drying of an organic phase through sodium bicarbonate are carried out, and the Boc group of an amino protective agent is removed, so that 88.94g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) is obtained, and the yield is 97.3%.
Preparation of Compound V: 88.94g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) and 27.01g of acetic acid are added into 200ml of DMF, the reaction temperature is controlled at 60 ℃, after condensation reaction, the organic phase is washed by dilute hydrochloric acid, the water phase is extracted, the organic phase is separated, dried, concentrated and purified to obtain 99.47g of 2-acetamido-2-benzyl malonic acid monoethyl ester (compound V), and the reaction yield is 95.0%.
Example 2:
a synthetic method of monoamino inhibitor intermediate 2-acetamido-2-benzylmalonic acid monoethyl ester comprises the following steps:
preparation of compound i: 0.5M 2-chloromethylene-diethyl malonate and 0.75M ammonia are added into a reactor containing 30g of silicoaluminophosphate zeolite catalyst, the reaction is carried out for 3 hours under 20MPa at 300 ℃,30g of product is subjected to monoester removal in 125mL of methanol containing 6g of sodium hydroxide at 5 ℃, washing and rotary evaporation are carried out to remove water, and the separation and purification are carried out by column chromatography to obtain 2-amino-2- (chloromethyl) -ethyl malonate (compound I), wherein the yield is 36.0%.
Preparation of compound ii: 100g of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and 122.73g of (Boc) 2 O was dissolved in 500mL of tetrahydrofuran, 124.92g of DMAP was added to the system, the reaction temperature was 25 ℃, the solvent was evaporated under reduced pressure after the reaction, and the organic phase after extraction was dried, filtered and concentrated to obtain 148.47g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II), with a yield of 98.2%.
Preparation of compound iii: 148.47g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) and 41.17g of benzene were charged in 300mL of DMF, 117.15g of an aluminum trichloride catalyst were added at the reflux temperature of the solvent, the reaction was terminated, quenched with an alkali, extracted, and the organic phase was distilled to give 143.12g of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) in a yield of 84.5%.
Preparation of Compound IV: 143.12g 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) is added into 300mL dichloromethane solution, 84.64g trifluoroacetic acid is added into the system, the reaction temperature is 0 ℃, after the reaction is finished, extraction is carried out, an organic phase is washed by sodium bicarbonate and dried, and an amino protective agent Boc group is removed, thus obtaining 99.65g 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV), with the yield of 99.0%.
Preparation of Compound V: 99.65g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) and 40.35g of acetic acid are added into 200ml of DMF, the reaction temperature is controlled at 60 ℃, after condensation reaction, the organic phase is washed by dilute hydrochloric acid, the water phase is extracted, the organic phase is separated, dried, concentrated and purified to obtain 114.72g of 2-acetamido-2-benzyl malonic acid monoethyl ester (compound V), and the reaction yield is 97.8%.
Example 3:
a synthetic method of monoamino inhibitor intermediate 2-acetamido-2-benzyl malonic acid monoethyl ester comprises the following steps:
preparation of compound i: 0.5M 2-chloromethylene-diethyl malonate and 0.75M ammonia are added into a reactor containing 30g of silicoaluminophosphate zeolite catalyst, the reaction is carried out for 3 hours under 20MPa at 300 ℃,30g of product is subjected to monoester removal in 125mL of methanol containing 6g of sodium hydroxide at 5 ℃, washing and rotary evaporation are carried out to remove water, and the separation and purification are carried out by column chromatography to obtain 2-amino-2- (chloromethyl) -ethyl malonate (compound I), wherein the yield is 36.0%.
Preparation of compound ii: 100g of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and 128.31g of (Boc) 2 O was dissolved in 500mL of 1, 4-dioxane, 149.90g of DMAP was added to the system, the reaction temperature was 0 ℃ and after the reaction was completed, the solvent was distilled off under reduced pressure, and after the extraction, the organic phase was dried, filtered and concentrated to obtain 149.18g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II), with a yield of 96.7%.
Preparation of compound iii: 149.8 g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) and 43.34g of benzene were added to 300mL of acetonitrile, 134.53g of an aluminum trichloride catalyst were used, the reaction temperature was the reflux temperature of the solvent, the reaction was terminated, and after quenching with alkali, extraction and organic phase distillation were carried out to give 139.72g of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III), with a yield of 82.1%.
Preparation of Compound IV: 139.72g of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) is added into 300mL of dichloromethane solution, 94.44g of trifluoroacetic acid is added into the system, the reaction temperature is 0 ℃, after the reaction is finished, extraction is carried out, an organic phase is washed by sodium bicarbonate and dried, and amino protecting agent Boc group is removed, so that 96.20g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) is obtained, and the yield is 97.9%.
Preparation of Compound V: 96.20g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) and 48.69g of acetic acid are added into 200mL of n-butyl alcohol, the reaction temperature is controlled to be 60 ℃, after condensation reaction, an organic phase is washed by dilute hydrochloric acid, an aqueous phase is extracted, the organic phase is separated, dried, concentrated and purified to obtain 109.29g of 2-acetamido-2-benzyl malonic acid monoethyl ester (compound V), and the reaction yield is 96.5%.
Example 4:
a synthetic method of monoamino inhibitor intermediate 2-acetamido-2-benzyl malonic acid monoethyl ester comprises the following steps:
preparation of compound i: 0.5M 2-chloromethylene-diethyl malonate and 0.75M ammonia are added into a reactor containing 30g of silicoaluminophosphate zeolite catalyst, the reaction is carried out for 3 hours under 20MPa at 300 ℃,30g of product is subjected to monoester removal in 125mL of methanol containing 6g of sodium hydroxide at 5 ℃, washing and rotary evaporation are carried out to remove water, and the separation and purification are carried out by column chromatography to obtain 2-amino-2- (chloromethyl) -ethyl malonate (compound I), wherein the yield is 36.0%.
Preparation of compound ii: 100g of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and 120.50g of (Boc) 2 O was dissolved in 500mL of methanol, 124.92g of DMAP was added to the system, the reaction temperature was 0 ℃ and after the reaction, the solvent was distilled off under reduced pressure, and the organic phase after extraction was dried, filtered and concentrated to obtain 148.17g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) with a yield of 98.0%.
Preparation of compound iii: 148.17g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) and 41.09g of benzene were added to 300mL of cyclohexanone, 116.91g of an aluminum trichloride catalyst were added at the reflux temperature of the solvent, the reaction was completed, quenched with an alkali, extracted, and the organic phase was distilled to give 142.83g of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) in 84.5% yield.
Preparation of Compound IV: 142.83g 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) is added into 300mL dichloromethane solution, 37.05g hydrogen chloride is introduced into the system, the reaction temperature is 25 ℃, after the reaction is finished, extraction, washing and drying of an organic phase by sodium bicarbonate are carried out, and 98.74g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) is obtained after removal of an amino protecting agent Boc group, and the yield is 98.3%.
Preparation of Compound V: 98.74g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) and 37.48g of acetic acid are added into 200mL of n-butanol, the reaction temperature is controlled at 45 ℃, after condensation reaction, the organic phase is washed by dilute hydrochloric acid, the aqueous phase is extracted, the organic phase is separated, dried, concentrated and purified to obtain 112.98g of 2-acetamido-2-benzyl malonic acid monoethyl ester (compound V), and the reaction yield is 97.2%.
Example 5:
a synthetic method of monoamino inhibitor intermediate 2-acetamido-2-benzylmalonic acid monoethyl ester comprises the following steps:
preparation of compound i: 0.5M 2-chloromethylene-diethyl malonate and 0.75M ammonia are added into a reactor containing 30g of silicoaluminophosphate zeolite catalyst, the reaction is carried out for 3 hours under 20MPa at 300 ℃,30g of product is subjected to monoester removal in 125mL of methanol containing 6g of sodium hydroxide at 5 ℃, washing and rotary evaporation are carried out to remove water, and the separation and purification are carried out by column chromatography to obtain 2-amino-2- (chloromethyl) -ethyl malonate (compound I), wherein the yield is 36.0%.
Preparation of compound ii: 100g of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and 120.50g of (Boc) 2 O was dissolved in 500mL of methanol, 124.92g of DMAP was added to the system, the reaction temperature was 0 ℃ and after the reaction, the solvent was distilled off under reduced pressure, and the organic phase after extraction was dried, filtered and concentrated to obtain 148.18g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) with a yield of 98.0%.
Preparation of compound iii: 148.17g of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) and 41.09g of benzene were added to 300mL of cyclohexanone, 116.91g of an aluminum trichloride catalyst were added at the reflux temperature of the solvent, the reaction was terminated, quenched with an alkali, extracted, and the organic phase was distilled to give 142.82g of 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) in 84.5% yield.
Preparation of Compound IV: 142.82g 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III) is added into 300mL dichloromethane-acetone solution, 43.22g hydrogen chloride is introduced into the system, the reaction temperature is 25 ℃, after the reaction is finished, extraction is carried out, an organic phase is washed by sodium bicarbonate and dried, and an amino protective agent Boc group is removed, so that 98.94g 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) is obtained, wherein the yield is 98.5%. The dichloromethane-acetone solution is formed by mixing dichloromethane and acetone, and the dichloromethane-acetone solution contains 20wt% of acetone.
Preparation of Compound V: 98.94g of 2-amino-2-benzyl-malonic acid monoethyl ester (compound IV) and 37.56g of acetic acid are added into 200mL of n-butanol, the reaction temperature is controlled at 45 ℃, after condensation reaction, the organic phase is washed by dilute hydrochloric acid, the aqueous phase is extracted, the organic phase is separated, dried, concentrated and purified to obtain 113.21g of 2-acetamido-2-benzyl malonic acid monoethyl ester (compound V), and the reaction yield is 97.2%.
The organic solvent of each of the above examples can be recovered and reused.
The overall yield is the product of the yields of intermediates from the start of the preparation of compound i to the desired product.
The results of the overall yields of compound iii prepared starting from compound i in the various examples of the invention are shown in fig. 1, where a is example 1, b is example 2, c is example 3, d is example 4, e is example 5, and the overall yield of compound iii prepared by the method of example 2 is highest.
The overall yield results for the preparation of compound v starting from compound i in the various examples of the invention are shown in fig. 2, where a is example 1, b is example 2, c is example 3, d is example 4, e is example 5, the process of example 2 gives the highest utilization of compound i (compound 1) and the overall yield of the final product is the highest.
The above embodiments are merely illustrative, and not restrictive, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also belong to the scope of the present invention, and the protection scope of the present invention should be defined by the claims.
Claims (10)
1. 2-amino-2- (chloromethyl) -malonic acid monoethyl ester, represented by the following formula:
2. a process for the preparation of monoethyl 2-amino-2- (chloromethyl) -malonate according to claim 1, comprising: adding 2-chloromethylene-diethyl malonate and ammonia into a reactor containing a catalyst, reacting for 1-4 hours at 10-30MPa and 200-400 ℃, removing monoester of the product in a solvent under the action of alkali, and separating and purifying by column chromatography to obtain 2-amino-2- (chloromethyl) -monoethyl malonate (compound I).
3. A preparation method of a monoamino inhibitor pharmaceutical intermediate comprises the following steps:
s1, 2-amino-2- (chloromethyl) -malonic acid monoethyl ester (compound I) and (Boc) according to claim 1 2 Reacting O in an organic solvent in the presence of an alkaline reagent to generate 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (a compound II), wherein the organic solvent is at least one of dichloromethane, methanol, tetrahydrofuran and 1, 4-dioxane;
s2, reacting 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester (compound II) with benzene in an organic solvent under the action of a catalyst to generate 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonic acid monoethyl ester (compound III);
and S3, removing a protecting group from the monoethyl 2-benzyl-2- ((tert-butoxycarbonyl) amino) -malonate, and reacting with acetic acid to generate monoethyl 2-acetamido-2-benzylmalonate.
4. The method for preparing a monoamine inhibitor pharmaceutical intermediate according to claim 3, wherein: the alkaline agent is DMAP.
5. The method for preparing a monoamine inhibitor pharmaceutical intermediate according to claim 3, wherein: the molar amount of the alkaline reagent is 160-240% of the molar amount of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester.
6. The method for preparing a monoamine inhibitor pharmaceutical intermediate according to claim 3, wherein: the catalyst is aluminum trichloride.
7. The method for preparing a monoamine inhibitor pharmaceutical intermediate according to claim 3, wherein: the molar amount of the catalyst used is 150 to 200% of the molar amount of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester used.
8. The method for preparing a monoamine inhibitor pharmaceutical intermediate according to claim 3, wherein: said (Boc) 2 The molar amount of O used is 100 to 120% of the molar amount of 2-amino-2- (chloromethyl) -malonic acid monoethyl ester used.
9. The method for preparing a monoamine inhibitor pharmaceutical intermediate according to claim 3, wherein: the benzene was used in a molar amount of 100 to 120% based on the molar amount of 2- ((tert-butoxycarbonyl) amino) -2- (chloromethyl) -malonic acid monoethyl ester.
10. The method for preparing a mono-amino inhibitor pharmaceutical intermediate according to claim 3, wherein the method comprises the following steps: the organic solvent in S2 is at least one of acetone, cyclohexanone, acetonitrile and DMF.
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| CN101133022A (en) * | 2004-07-12 | 2008-02-27 | 拜尔农作物科学股份公司 | Substituted 2-pyrrolidone derivatives as fungicides and insecticides |
| CN106946724A (en) * | 2017-04-07 | 2017-07-14 | 苏州汉德创宏生化科技有限公司 | The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2 |
| CN108752253A (en) * | 2018-06-27 | 2018-11-06 | 深圳市茵诺圣生物科技有限公司 | A kind of polynary aza-cyclic Non-natural chiral amino acid and its synthetic method |
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| CN101133022A (en) * | 2004-07-12 | 2008-02-27 | 拜尔农作物科学股份公司 | Substituted 2-pyrrolidone derivatives as fungicides and insecticides |
| CN106946724A (en) * | 2017-04-07 | 2017-07-14 | 苏州汉德创宏生化科技有限公司 | The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2 |
| CN108752253A (en) * | 2018-06-27 | 2018-11-06 | 深圳市茵诺圣生物科技有限公司 | A kind of polynary aza-cyclic Non-natural chiral amino acid and its synthetic method |
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