CN116120252A - Preparation method of ramipril key intermediate derivative - Google Patents

Preparation method of ramipril key intermediate derivative Download PDF

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CN116120252A
CN116120252A CN202211653944.XA CN202211653944A CN116120252A CN 116120252 A CN116120252 A CN 116120252A CN 202211653944 A CN202211653944 A CN 202211653944A CN 116120252 A CN116120252 A CN 116120252A
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formula
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ramipril
cyclopentanone
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李坚军
张诺
周章兴
杨伟强
朱兴一
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a preparation method of ramipril key intermediate derivatives, which is (E) -2- ((5-oxo-2-phenyl oxazole-4 (5H) -ethylene) methyl) cyclopent-1-alkene-1-yl substituent acid ester, and the preparation method comprises the following steps: taking hippuric acid as raw material, cyclizing with 2- [ (dimethylamino) methylene]-1-cyclopentanone and carboxylic acid to prepare ramipril key intermediate (azlactone) derivatives. The invention is applicable to C 1 ‑C 5 Aliphatic, aromatic and heteroaromatic acids, with moderate to good yields to azlactone derivatives, has the advantages of low cost and availability of raw materials, low cost, relatively friendly environment, simple operation and the like, and accords with the concept of green pharmacy.

Description

Preparation method of ramipril key intermediate derivative
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of a ramipril key intermediate derivative for treating hypertension.
Background
Hypertension, also known as arterial hypertension, is a multifactorial chronic disease that is manifested mainly by elevated arterial pressure in the systemic circulation, which can burden the heart during blood circulation and can cause a series of complications such as stroke, myocardial infarction, heart failure, aneurysms, chronic kidney disease. Clinically first-line antihypertensive drugs include dihydropyridine calcium channel blockers, thiazines diuretics, angiotensin II receptor antagonists, beta receptor blockers and angiotensin converting enzyme inhibitors (Angiotensin converting enzyme inhibitor, ACEI), which are an irreplaceable product, ramipril has been attracting attention as an excellent representative of the ACEI family.
Ramipril (Ramipril), chemical name (S) -2- [ N- (1-ethoxycarbonyl-3-phenyl-propyl) alanyl ] -2-azabicyclo [3.3.0] octane-3-carboxylic acid, a long-acting non-sulfhydryl ACEI drug developed by the company Sainophenanthrene-Anvant (sanofi-aventis), under the trade name Ramite (Triatec), marketed in France and the United states, respectively, around the beginning and after nineties of the twentieth century. Is used for treating moderate and primary hypertension, renal hypertension and moderate and malignant congestive heart failure in clinic, and can reduce the incidence rate of diabetic complications. Ramipril has the structural formula shown below:
Figure BDA0004011674800000021
(Z) -4- (2-chlorocyclopent-1-enyl) methylene) -2-phenyloxazol-5 (4H) one is a key intermediate for the synthesis of ramipril, while (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl substituent acid ester is a key intermediate derivative for the synthesis of ramipril, the structural formula of which is shown in (I):
Figure BDA0004011674800000022
the existing synthesis method of the intermediate mainly comprises the following steps:
in 2007 Philip a et al developed a novel and effective method for rapid synthesis of Erlenmeyer azlactone under mild conditions. The method first synthesizes a more stable intermediate by self-concentrating hippuric acid, and reacts with aliphatic aldehyde (< 2 minutes) under neutral alumina adsorption and microwave irradiation. The process is simple to operate and short in reaction time, but uses alumina as a catalyst for the reaction and requires microwave irradiation (Tetrahedron, 2009,65,2935-2938.).
Figure BDA0004011674800000023
In 2017, abdulhamid Fadavi et al developed a simple and efficient method for the direct synthesis of aliphatic, (hetero) aromatic oxazol-5-ones and 4-arylmethyl oxazolones from carboxylic acids in one pot. The method has the advantages of mild reaction conditions, high yield, simple operation and the like, but uses Vilsmeier reagent, has low safety and is not friendly to the environment (Comptes Rendus Chimie,2018,21,9-13).
Figure BDA0004011674800000031
Aims at the problems of low yield, environment friendliness, poor safety and the like in the synthesis method. The invention develops a synthetic process route of ramipril key intermediate with cheap and easily obtained raw materials, low cost, environmental protection and simple operation.
Disclosure of Invention
The invention aims to provide a method for preparing ramipril key intermediate (E) -2- ((5-oxo-2-phenyl oxazole-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl substituent acid ester by taking hippuric acid as a starting material, which has the characteristics of simple process, convenient operation, good yield, low cost and the like.
The key intermediate derivative is (E) -2- ((5-oxo-2-phenyl oxazole-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl substituent acid ester shown in a formula (I), and is prepared by reacting cyclopentanone shown in a formula (II) with DMF-DMA to obtain an intermediate 2- [ (dimethylamino) methylene ] -1-cyclopentanone (III), wherein hippuric acid shown in a formula (IV) is subjected to self condensation to generate an intermediate 2-phenyl-5-oxazolone (V); then, the intermediate (III) and the intermediate (V) are reacted with carboxylic acid in the presence of condensing agent to obtain the catalyst, which is characterized by comprising the following steps:
(1) Taking cyclopentanone and DMF-DMA shown in a formula (II) as starting materials, adding the starting materials into a solvent A, heating the starting materials for reaction, cooling and concentrating the reaction product after the reaction is finished to remove the solvent A, thereby obtaining a compound of which the intermediate is shown in a formula (III);
(2) Adding a compound shown in a formula (IV) into a solvent B, performing self-condensation reaction under the action of a condensing agent A, concentrating to remove the solvent B after the reaction is finished, and adding absolute ethyl alcohol for recrystallization to obtain a compound shown in a formula (V);
(3) Adding a compound shown in a formula (III) and a compound shown in a formula (V) into a solvent C, adding an acid A and a condensing agent B for three-component reaction, and recrystallizing to obtain the compound shown in the formula (I);
the reaction equation is as follows:
Figure BDA0004011674800000041
wherein R is C 1 ～C 5 Alkanes, substituted aromatic hydrocarbons, substituted heteroaromatic hydrocarbons, and the like.
The preparation method of the ramipril key intermediate derivative is characterized in that the mass ratio of DMF-DMA in the step (1) to cyclopentanone shown in the formula (II) is 1.0-3.0:1, preferably 1.0-1.5:1; solvent A is N, N-dimethylformamide, benzene or toluene, preferably N, N-dimethylformamide or toluene; the reaction temperature is 60-150 ℃, preferably 80-120 ℃; the reaction time is 8 to 20 hours, preferably 10 to 20 hours.
The preparation method of the ramipril key intermediate derivative is characterized in that the mass ratio of the condensing agent A in the step (2) to the compound shown in the formula (III) is 0.8-3.0:1, preferably 1.0-2.5:1; condensing agent A is EDCI, DCC, DIC, TBTU, HOBT or CDI, preferably EDCI or DCC; solvent B is dichloromethane, tetrahydrofuran, acetonitrile, chloroform, 1, 2-dichloroethane, ethyl acetate or methyl acetate, preferably dichloromethane or 1, 2-dichloroethane; the reaction temperature is 20-25 ℃; the reaction time is 0.5 to 6 hours, preferably 2 to 4 hours.
The preparation method of the ramipril key intermediate derivative is characterized in that the mass ratio of the acid A in the step (3) to the compound shown in the formula (V) is 1.0-4.0:1, preferably 1.0-2.0:1; the mass ratio of the compound represented by the formula (III) to the compound represented by the formula (V) is 1.0 to 4.0:1, preferably 1.0 to 2.0:1; the mass ratio of the condensing agent B to the compound represented by the formula (V) is 0.8-2.0:1, preferably 1.0-1.5:1; condensing agent B is EDCI, DCC, DIC or thionyl chloride, preferably thionyl chloride or DCC; the solvent C is dichloromethane, tetrahydrofuran or acetonitrile, preferably dichloromethane and tetrahydrofuran; the reaction temperature is 25 ℃; the reaction time is 0.5 to 6 hours, preferably 1 to 3 hours; solvent D is n-hexane.
By adopting the technology, compared with the prior art, the invention has the beneficial effects that:
(1) The method is simple to operate, raw materials hippuric acid and cyclopentanone are cheap and easy to obtain, and can react to generate a more stable intermediate under heating or room temperature, so that azlactone derivatives can be obtained with moderate to good yields;
(2) The invention is environment-friendly, does not need Vilsmeier reagent, uses carboxylic acid instead, increases the expansibility of the substrate, and has mild reaction conditions;
(3) The method has the advantages of short reaction period, less three wastes, higher product yield and purity, and suitability for industrial production.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the scope of the invention is not limited thereto.
Example 12 preparation of- [ (dimethylamino) methylene ] -1-cyclopentanone (III)
Into a 50mL three-necked flask were charged cyclopentanone (3.00 g,35.66 mmol), DMF-DMA (4.25 g,35.66 mmol) and toluene 25.0mL. Heating in an oil bath, heating to 100 ℃, and reacting for 14.0h under stirring. After completion of the TLC detection, the reaction was cooled and the solvent was removed by rotary evaporation under reduced pressure to give 4.35g of 2- [ (dimethylamino) methylene ] -1-cyclopentanone (III) as a tan to brown oil in 79% yield and 90.5% purity by HPLC.
EXAMPLE 22 preparation of- [ (dimethylamino) methylene ] -1-cyclopentanone (III)
Into a 50mL three-necked flask were charged cyclopentanone (3.00 g,35.66 mmol), DMF-DMA (5.10 g,42.80 mmol) and toluene 25.0mL. Heating in an oil bath, heating to 90 ℃, and reacting for 18.0h under stirring. After completion of the TLC detection, the reaction was cooled and the solvent was removed by rotary evaporation under reduced pressure to give 4.81g of 2- [ (dimethylamino) methylene ] -1-cyclopentanone (III) as a tan to brown oil in 85% yield and 87.2% purity by HPLC.
Example 32 preparation of- [ (dimethylamino) methylene ] -1-cyclopentanone (III)
Into a 50mL three-necked flask were charged cyclopentanone (3.00 g,35.66 mmol), DMF-DMA (6.37 g,53.50 mmol) and toluene 25.0mL. Heating in an oil bath, heating to 80 ℃, and reacting for 16.0h under stirring. After completion of the TLC detection, the reaction was cooled and the solvent was removed by rotary evaporation under reduced pressure to give 4.48g of 2- [ (dimethylamino) methylene ] -1-cyclopentanone (III) as a tan to brown oil in a yield of 81% and HPLC purity of 89.3%.
Example 42 preparation of- [ (dimethylamino) methylene ] -1-cyclopentanone (III)
Into a 50mL three-necked flask were charged cyclopentanone (3.00 g,35.66 mmol), DMF-DMA (6.37 g,53.50 mmol), and N, N-dimethylformamide (25.0 mL). Heating in an oil bath, heating to 100 ℃, and reacting for 14.0h under stirring. After completion of the TLC detection, the reaction was cooled and the solvent was removed by rotary evaporation under reduced pressure to give 4.71g of 2- [ (dimethylamino) methylene ] -1-cyclopentanone (III) as a tan to brown oil in 84% yield and 88.4% purity by HPLC. Example 52 preparation of- [ (dimethylamino) methylene ] -1-cyclopentanone (III)
Into a 50mL three-necked flask were charged cyclopentanone (3.00 g,35.5 mmol), DMF-DMA (10.62 g,89.16 mmol) and benzene 25.0mL. Heating in an oil bath, heating to 80 ℃, and reacting for 20.0h under stirring. After completion of the TLC detection, the reaction was cooled and the solvent was removed by rotary evaporation under reduced pressure to give 4.75g of 2- [ (dimethylamino) methylene ] -1-cyclopentanone (III) as a tan to brown oil in 83% yield and 86.6% purity by HPLC.
Example 62 preparation of- [ (dimethylamino) methylene ] -1-cyclopentanone (III)
Into a 50mL three-necked flask were charged cyclopentanone (3.00 g,35.5 mmol), DMF-DMA (12.75 g,106.99 mmol) and N, N-dimethylformamide (25.0 mL). Heating in an oil bath, heating to 110 ℃, and reacting for 8.0h under stirring. After completion of the TLC detection, the reaction was cooled and the solvent was removed by rotary evaporation under reduced pressure to give 4.64g of 2- [ (dimethylamino) methylene ] -1-cyclopentanone (III) as a tan to brown oil in 86% yield and 91.9% purity by HPLC.
Example 72 preparation of phenyl-5-oxazolone (V)
N-benzoylglycine (1.70 g,9.49 mmol), DCC (2.35 g,11.39 mmol) and dichloromethane (20.0 mL) were placed in a 50mL two-necked flask, and stirred at 20-25℃for 2.0h. After the TLC detection reaction was completed, the filtrate was collected, concentrated under reduced pressure, and recrystallized by adding absolute ethanol to give 1.45g of 2-phenyl-5-oxazolone (V) as a yellow solid, the yield was 91%, and the HPLC purity was 96.2%.
EXAMPLE 82 preparation of phenyl-5-oxazolone (V)
N-benzoylglycine (1.70 g,9.49 mmol), EDCI (1.82 g,10.42 mmol) and dichloromethane (20.0 mL) were added into a 50mL two-necked flask, stirred at 20-25 ℃ for 0.5h, after TLC detection reaction was completed, filtered, the filtrate was collected, concentrated under reduced pressure, and then added with absolute ethyl alcohol to recrystallize to obtain 1.42g of yellow solid 2-phenyl-5-oxazolone (V) with a yield of 89% and an HPLC purity of 95.6%.
Example 92 preparation of phenyl-5-oxazolone (V)
N-benzoylglycine (1.70 g,9.49 mmol), DIC (0.96 g,7.59 mmol) and acetonitrile (20.0 mL) were put into a 50mL two-necked flask, stirred at 20-25℃for 6.0h, after the TLC detection reaction was completed, filtered, the filtrate was collected, concentrated under reduced pressure, and then recrystallized by adding absolute ethanol to give 1.20g of 2-phenyl-5-oxazolone (V) as a yellow solid, yield 93%, HPLC purity 94.8%
Example 102 preparation of phenyl-5-oxazolone (V)
N-benzoylglycine (1.70 g,9.49 mmol), TBTU (4.57 g,14.23 mmol) and 1, 2-dichloroethane (20.0 mL) were put into a 50mL two-necked flask, stirred at 20-25℃for 3.0h, after the completion of the reaction by TLC, filtered, the filtrate was collected, concentrated under reduced pressure, and recrystallized by adding absolute ethanol to give 1.25g of 2-phenyl-5-oxazolone (V) as a yellow solid in 79% yield and 96.6% HPLC purity
Example 112 preparation of phenyl-5-oxazolone (V)
N-benzoylglycine (1.70 g,9.49 mmol), HOBT (3.85 g,28.47 mmol) and 1, 2-dichloroethane (20.0 mL) were put into a 50mL two-necked flask, stirred at 20-25℃for 3.0h, after TLC detection of the reaction was completed, filtered, the filtrate was collected, concentrated under reduced pressure, and recrystallized by adding absolute ethanol to give 1.29g of 2-phenyl-5-oxazolone (V) as a yellow solid, yield 80% and HPLC purity 95.2%
Example 12 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl benzoate (I-a)
Figure BDA0004011674800000091
Into a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer was charged 2- [ (dimethylamino) methylene]1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL of dichloromethane, refluxing benzoic acid (2 g,16.38 mmol) in 8mL of thionyl chloride for 3.5h, removing thionyl chloride to give crude benzoyl chloride, dissolving crude benzoyl chloride (1.41 g,10.06 mmol) in 5mL of dichloromethane, slowly dropwise adding to the flask at room temperature, keeping the temperature of the reaction solution at 20-25℃after the completion of the dropwise addition, stirring at 20-25℃for 2.0h, adding pre-chilled n-hexane at 0℃after the completion of TLC detection, pulping for 10min, and suction filtering to give yellow solid 4- [2- (benzoyloxy) -1-cyclopentenyl)]Methylene group]2.89g of (E) -2-phenyl-5 (4H) -oxazolone (I-a), 78% yield and 97.8% purity. 1 H NMR(400MHz,CDCl 3 )δ8.24–8.04(m,4H),7.71–7.64(m,1H),7.62–7.48(m,5H),7.26(s,1H),3.17(t,J＝7.3Hz,2H),2.95(t,J＝7.7Hz,2H),2.18(p,J＝7.7Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ167.89,163.31,161.75,160.68,134.04,132.86,132.69,130.31,128.85,128.76,128.65,128.01,125.89,124.49,123.28,32.31,30.20,20.80.
Example 13 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl benzoate (I-a)
Into a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer were charged 2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (3.24 g,20.12 mmol) and 20mL tetrahydrofuran. The preparation of benzoyl chloride in example 13 was carried out as described in example 12, benzoyl chloride (1.70 g,12.07 mmol) was dissolved in 5mL tetrahydrofuran and slowly added dropwise to the flask at room temperature, the reaction mixture was kept at 20-25℃and stirred for 1.5H at 20-25℃after the completion of the reaction, and after TLC detection, pre-chilled n-hexane was added at 0℃for 10min to obtain 4- [2- (benzoyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-a) 2.84g as a yellow solid, in 77% yield and 97.7% HPLC purity.
Example 14 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl benzoate (I-a)
Into a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer were charged 2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (2.43 g,15.09 mmol) and 20mL acetonitrile. The preparation of benzoyl chloride in example 14 was carried out as described in example 12, benzoyl chloride (5.66 g,40.23 mmol) was dissolved in 5mL of acetonitrile and slowly added dropwise to the flask at room temperature, the reaction mixture was kept at 20-25℃and stirred for 3.0H at 20-25℃after completion of the dropwise addition, and after completion of the TLC detection reaction, pre-chilled n-hexane was added at 0℃for 10min and suction filtration was carried out to obtain 4- [2- (benzoyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-a) 2.80g in 76% yield and 97.8% HPLC purity as a yellow solid.
Example 15 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl benzoate (I-a)
2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL of methylene chloride were added to a 50mL two-necked flask with magnetic stirring and thermometer, benzoic acid (1.70 g,12.07 mmol) and DCC (2.49 g,12.07 mmol) were dissolved in 5mL of methylene chloride and slowly added dropwise to the flask at room temperature to ensure that the reaction solution temperature was controlled at 20-25℃and stirred at 20-25℃for 6.0H after completion of TLC detection, pre-chilled n-hexane was added at 0℃for 10min and suction filtration was performed to give 4- [2- (benzoyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-a) as a yellow solid, 2.60g, yield 70% and HPLC purity 97.2%.
Example 16 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl benzoate (I-a)
2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (3.24 g,20.12 mmol) and 20mL tetrahydrofuran were added to a 50mL two-necked flask with magnetic stirring and thermometer, benzoic acid (1.23 g,10.06 mmol) and EDCI (1.54 g,8.05 mmol) were dissolved in 5mL tetrahydrofuran and slowly added dropwise to the flask at room temperature to ensure the reaction temperature to be controlled at 20-25℃and stirred at 20-25℃for 1.5H after completion of TLC detection, and after completion of the reaction pre-chilled n-hexane was added at 0℃for 10min, suction filtration gave 4- [2- (benzoyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-a) as a yellow solid, 2.67g, with a yield of 72% and HPLC purity of 97.4%.
Example 17 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl benzoate (I-a)
2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (2.43 g,15.09 mmol) and 20mL of acetonitrile were added to a 50mL two-necked flask with magnetic stirring and thermometer, benzoic acid (1.72 g,14.08 mmol) and DIC (2.54 g,20.12 mmol) were dissolved in 5mL of acetonitrile and slowly dropped into the flask at room temperature to ensure that the reaction solution temperature was controlled to 20-25℃and stirred at 20-25℃for 3H after the completion of TLC detection, pre-chilled n-hexane was added at 0℃for beating 10min, and then 4- [2- (benzoyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-a) was obtained as a yellow solid in 2.64g, yield of 71% and HPLC purity of 97.1%.
Example 18 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl-4-methoxybenzoate (I-b)
Figure BDA0004011674800000131
Into a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer was charged 2- [ (dimethylamino) methylene]-1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL dichloromethane. Preparation of 4-Methoxybenzoyl chloride in example 18 referring specifically to example 12, 4-methoxybenzoyl chloride (1.72 g,10.06 mmol) was dissolved in 5mL of dichloromethane and slowly dropped into the flask at room temperature to ensure that the temperature of the reaction solution was controlled at 20-25℃and stirred at 20-25℃for 2.0h after the completion of the TLC detection reaction, pre-chilled n-hexane was added at 0℃for beating for 10min, and suction filtration was performed to obtain 4- [2- (p-methoxybenzoyloxy) -1-cyclopentenyl as a yellow solid]Methylene group]3.54g of (E) -2-phenyl-5 (4H) -oxazolone (I-b) with a yield of 88% and an HPLC purity of 97.3%. 1 H NMR(400MHz,CDCl 3 )δ8.16–8.05(m,4H),7.62–7.47(m,3H),7.27(s,1H),7.05–6.97(m,2H),3.92(s,3H),3.16(t,J＝7.6Hz,2H),2.94(t,2H),2.16(p,J＝7.7Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ167.96,164.31,162.97,161.58,161.16,132.80,132.50,132.44,128.84,127.97,125.92,124.21,123.53,120.87,114.08,55.57,32.40,30.14,20.82.
Example 19 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl-4-methoxybenzoate (I-b)
2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL of methylene chloride were added to a 50mL two-necked flask with magnetic stirring and thermometer, 4-methoxybenzoic acid (1.53 g,10.06 mmol) and DCC (2.08 g,10.06 mmol) were dissolved in 5mL of methylene chloride and slowly dropped into the flask at room temperature to ensure that the temperature of the reaction solution was controlled to 20-25℃and the dropping was completed, stirred at 20-25℃for 3 hours, after TLC detection was completed, pre-chilled n-hexane was added at 0℃and slurried for 10 minutes, and a yellow solid of 4- [2- (p-methoxybenzoyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-b) was obtained by suction filtration in 3.24g with a yield of 81% and HPLC purity of 97.9%.
Example 20 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl-4-nitrobenzoate (I-c)
Figure BDA0004011674800000141
Into a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer was charged 2- [ (dimethylamino) methylene]-1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL dichloromethane. Preparation of 4-nitrobenzoyl chloride in example 20 with specific reference to example 12, 4-nitrobenzoyl chloride (1.87 g,10.06 mmol) was dissolved in 5mL of dichloromethane and slowly added dropwise to the flask at room temperature to ensure that the reaction solution temperature was controlled at 20-25℃and stirred at 20-25℃for 2.0h after the completion of TLC detection, and then pre-chilled n-hexane was added at 0℃for beating for 10min, followed by suction filtration to give 4- [2- (p-nitrobenzoyloxy) -1-cyclopentenyl as a yellow solid]Methylene group]2.93g of (E) -2-phenyl-5 (4H) -oxazolone (I-c) in a yield of 70% and with a HPLC purity of 97%. 1 H NMR(400MHz,CDCl 3 )δ8.43–8.31(m,4H),8.14–8.06(m,2H),7.64–7.57(m,1H),7.53(dd,J＝8.4,6.9Hz,2H),7.18(s,1H),3.19(t,J＝7.4Hz,2H),2.95(t,J＝7.8Hz,2H),2.20(p,J＝7.7Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ167.75,162.24,161.51,159.24,151.14,134.02,133.35,133.09,131.42,128.90,128.11,125.70,125.10,123.87,122.40,32.12,30.26,20.73.
Example 21 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl-4-nitrobenzoate (I-c)
2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL of methylene chloride were added to a 50mL two-necked flask with magnetic stirring and thermometer, 4-nitrobenzoic acid (6.72 g,40.23 mmol) and EDCI (3.86 g,20.12 mmol) were dissolved in 5mL of methylene chloride and slowly dropped into the flask at room temperature to ensure that the temperature of the reaction solution was controlled to 20-25℃and the dropping was completed, stirred at 20-25℃for 3H, after TLC detection was completed, pre-chilled n-hexane was added at 0℃for beating 10min, and a yellow solid of 4- [2- (p-nitrobenzoyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-c) was obtained by suction filtration in 2.68g with a yield of 64% and a purity of 97.2% HPLC.
Example 22 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl-2-methylbenzoate (I-d)
Figure BDA0004011674800000161
Into a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer was charged 2- [ (dimethylamino) methylene]-1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL dichloromethane. The procedure for preparing 2-methylbenzoyl chloride in example 22 is specifically described in example 12, 2-methylbenzoyl chloride (1.55 g,10.06 mmol) is dissolved in 5mL of dichloromethane and slowly dropped into a flask at room temperature, the temperature of the reaction solution is controlled to be 20-25 ℃, the mixture is stirred for 2.0h at 20-25 ℃, after TLC detection reaction is completed, pre-chilled n-hexane is added at 0 ℃ for pulping for 10min, and suction filtration is carried out to obtain yellow solid 4- [2- (o-methylbenzoyl) -1-cyclopentenyl)]Methylene group]3.15g of (E) -2-phenyl-5 (4H) -oxazolone (I-d) with a yield of 82% and an HPLC purity of 97.7%. 1 H NMR(400MHz,CDCl 3 )δ8.24–8.01(m,3H),7.63–7.56(m,1H),7.56–7.45(m,3H),7.41–7.31(m,2H),7.25(s,1H),3.17(t,J＝7.5Hz,2H),2.93(t,J＝8.0Hz,2H),2.68(s,3H),2.18(p,J＝7.6Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ167.98,163.79,161.66,160.97,141.74,133.27,132.87,132.58,132.14,131.46,128.87,128.00,127.48,126.13,125.87,124.59,123.49,32.34,30.21,22.04,20.82.
Example 23 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl-2-methylbenzoate (I-d)
2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL of methylene chloride were added to a 50mL two-necked flask with a magnetic stirrer and thermometer, 2-methylbenzoic acid (1.37 g,10.06 mmol) and DCC (2.07 g,10.06 mmol) were dissolved in 5mL of methylene chloride and slowly dropped into the flask at room temperature to ensure that the temperature of the reaction solution was controlled to 20-25℃and the reaction solution was stirred at 20-25℃for 2.0H after completion of TLC detection, pre-chilled n-hexane was added at 0℃for 10min and suction filtration to give 4- [2- (o-tolyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-d) as a yellow solid, 2.84g, with a yield of 74% and a purity of 97.7% by HPLC.
Example 24 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl 6-chloronicotinic acid ester (I-E)
Figure BDA0004011674800000171
Into a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer was charged 2- [ (dimethylamino) methylene]-1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL dichloromethane. Preparation of 6-Chloroficosyl chloride in example 24 referring specifically to example 12, 6-Chloroficosyl chloride (1.77 g,10.06 mmol) was dissolved in 5mL of dichloromethane and slowly added dropwise to the flask at room temperature, the reaction solution temperature was kept at 20-25℃and stirred at 20-25℃for 2.0h after the completion of the dropwise addition, and after TLC detection the reaction was completed, pre-chilled n-hexane was added at 0℃for beating for 10min, and suction filtration was performed to obtain 4- [2- (o-methylbenzyloxy) -1-cyclopentenyl as a yellow solid]Methylene group]3.01g of (E) -2-phenyl-5 (4H) -oxazolone (I-d) was obtained in 74% yield and 97.4% purity by HPLC. 1 H NMR(400MHz,CDCl 3 )δ9.13(s,1H),8.41–8.31(m,1H),8.17–8.06(m,2H),7.64–7.57(m,1H),7.57–7.48(m,3H),7.16(s,1H),3.17(t,J＝7.4Hz,2H),2.93(t,J＝7.9Hz,2H),2.19(p,J＝7.6Hz,2H). 13 CNMR(101MHz,CDCl 3 )δ167.77,162.20,161.32,159.15,156.82,151.79,140.00,133.31,133.11,128.92,128.11,125.67,125.14,124.56,123.74,122.43,32.15,30.25,20.70.
Example 25 preparation of (E) -2- ((5-oxo-2-phenyloxazol-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl 6-chloronicotinic acid ester (I-E)
2- [ (dimethylamino) methylene ] -1-cyclopentanone (1.40 g,10.06 mmol), 2-phenyl-5-oxazolone (1.62 g,10.06 mmol) and 20mL of methylene chloride were added to a 50mL two-necked flask with a magnetic stirrer and thermometer, 6-chloronicotinic acid (1.90 g,12.07 mmol) and DCC (2.07 g,10.06 mmol) were dissolved in 5mL of methylene chloride and slowly dropped into the flask at room temperature to ensure that the temperature of the reaction solution was controlled to 20-25℃and the reaction solution was stirred at 20-25℃for 5.0H after completion of TLC detection, pre-chilled n-hexane was added at 0℃for 10min and suction filtration to give 4- [2- (o-methylbenzyloxy) -1-cyclopentenyl ] methylene ] -2-phenyl-5 (4H) -oxazolone (I-f) as a yellow solid, 2.85g, with a yield of 70% and a HPLC purity of 97.5%.
Finally, it should be noted that the above-mentioned embodiments are only for illustrating the technical solution of the present invention and not for limiting the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention, and it should be covered by the scope of the claims of the present invention.

Claims (9)

1. A preparation method of ramipril key intermediate derivative, wherein the key intermediate derivative is (E) -2- ((5-oxo-2-phenyl oxazole-4 (5H) -ethylene) methyl) cyclopent-1-en-1-yl substituent acid ester, and the structural formula is shown as formula (I), and the preparation method is characterized in that: firstly, reacting cyclopentanone shown in a formula (II) with N, N-dimethylformamide dimethyl acetal (DMF-DMA) to prepare an intermediate 2- [ (dimethylamino) methylene ] -1-cyclopentanone shown in a formula (III); then in the presence of a condensing agent A, the hippuric acid shown in the formula (IV) is condensed by itself to generate an intermediate 2-phenyl-5-oxazolone shown in the formula (V); finally, the intermediate 2- [ (dimethylamino) methylene ] -1-cyclopentanone shown in the formula (III), 2-phenyl-5-oxazolone shown in the formula (V) and carboxylic acid are subjected to a three-component reaction in the presence of a condensing agent B to obtain a target product ramipril key intermediate derivative, wherein the characteristic process is as follows:
Figure FDA0004011674790000011
wherein: r is C 1 ～C 5 Alkanes, substituted aromatic hydrocarbons and substituted heteroaromatic hydrocarbons.
2. The preparation method of ramipril key intermediate derivative according to claim 1, which is characterized by comprising the following steps:
(1) Taking cyclopentanone and DMF-DMA shown in a formula (II) as starting materials, adding the starting materials into a solvent A, heating the starting materials for reaction, cooling and concentrating the reaction product after the reaction is finished to remove the solvent A, thereby obtaining an intermediate 2- [ (dimethylamino) methylene ] -1-cyclopentanone shown in a formula (III);
(2) Adding hippuric acid shown in the formula (IV) into a solvent B, performing self-condensation reaction under the action of a condensing agent A, concentrating to remove the solvent B after the reaction is finished, and adding absolute ethyl alcohol for recrystallization to obtain 2-phenyl-5-oxazolone shown in the formula (V);
(3) Adding 2- [ (dimethylamino) methylene ] -1-cyclopentanone shown in formula (III) and 2-phenyl-5-oxazolone shown in formula (V) into a solvent C, adding carboxylic acid and a condensing agent B for three-component reaction, concentrating after the reaction structure to remove the solvent C, and adding the solvent D for recrystallization to obtain the compound shown in formula (I), namely the ramipril key intermediate derivative.
3. The process for the preparation of a key intermediate derivative of ramipril according to claim 2, characterized in that the ratio of DMF-DMA in step (1) to cyclopentanone of formula (ii) is 1.0-3.0:1, preferably 1.0-1.5:1; solvent A is N, N-dimethylformamide, benzene or toluene, preferably N, N-dimethylformamide or toluene.
4. The process for the preparation of a key intermediate derivative of ramipril according to claim 2, characterized in that the reaction temperature of step (1) is 60-150 ℃, preferably 80-120 ℃; the reaction time is 8 to 20 hours, preferably 10 to 20 hours.
5. The process for the preparation of a key intermediate derivative of ramipril according to claim 2, characterized in that the mass ratio of condensing agent a in step (2) to the substance of hippuric acid of formula (iv) is 0.8-3.0:1, preferably 1.0-2.5:1; condensing agent A is EDCI, DCC, DIC, TBTU, HOBT or CDI, preferably EDCI or DCC; solvent B is dichloromethane, tetrahydrofuran, acetonitrile, chloroform, 1, 2-dichloroethane or ethyl acetate, preferably dichloromethane or 1, 2-dichloroethane.
6. The process for the preparation of a key intermediate derivative of ramipril according to claim 2, characterized in that the reaction temperature of step (2) is 20-25 ℃; the reaction time is 0.5 to 6 hours, preferably 2 to 4 hours.
7. The process for the preparation of a key intermediate derivative of ramipril according to claim 2, characterized in that the ratio of the amount of 2- [ (dimethylamino) methylene ] -1-cyclopentanone of formula (iii) to the amount of 2-phenyl-5-oxazolone of formula (v) in step (3) is 1.0-4.0:1, preferably 1.0-2.0:1.
8. The process for the preparation of a key intermediate derivative of ramipril according to claim 2, characterized in that the ratio of the amount of condensing agent B in step (3) to the amount of 2-phenyl-5-oxazolone of formula (v) is 0.8-2.0:1, preferably 1.0-1.5:1; condensing agent B is EDCI, DCC, DIC or thionyl chloride, preferably thionyl chloride or DCC; solvent C is dichloromethane, tetrahydrofuran or acetonitrile, preferably dichloromethane or tetrahydrofuran.
9. The process for the preparation of a key intermediate derivative of ramipril according to claim 2, characterized in that the reaction temperature in step (3) is 20-25 ℃; the reaction time is 0.5 to 6 hours, preferably 1 to 3 hours; solvent D is n-hexane.
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