阅读说明：本技术 一种雷米普利的制备方法 (Preparation method of ramipril ) 是由 王海波 提文利 刘忠 于 2020-04-23 设计创作，主要内容包括：本发明提供了一种雷米普利的制备方法,将传统的苄基保护(S,S,S)-2-氮杂双环[3,3,0]辛烷-3-羧酸盐酸盐上的羧基改为叔丁氧羰基(Boc)保护N-[1-(S)-乙氧羰基-3-苯丙基]-L-丙氨酸上的氨基,经缩合反应得雷米普利关键中间体,然后在稀盐酸作用下脱去保护基得到雷米普利这一策略,解决了现有技术中由于采用苄基保护(S,S,S)-2-氮杂双环[3,3,0]辛烷-3-羧酸盐酸盐上的羧基而最后不得不使用危险系数较高的Pd-C/H-(2)催化氢化再脱去苄基这一技术缺陷。同时降低了成本,更适合工业化生产。(The invention provides a preparation method of ramipril, which protects (S, S, S) -2-azabicyclo [3,3,0] by traditional benzyl]Changing carboxyl on octane-3-carboxylate into tert-butyloxycarbonyl (Boc) to protect N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]The amino on the L-alanine is condensed to obtain the ramipril key intermediate, and then the protecting group is removed under the action of dilute hydrochloric acid to obtain the ramipril, thereby solving the problem that the benzyl protection (S, S, S) -2-azabicyclo [3,3,0] is adopted in the prior art]The carboxyl group of the octane-3-carboxylate and finally the Pd-C/H with a higher risk factor have to be used 2 Catalytic hydrogenation and then removing benzyl. Meanwhile, the cost is reduced, and the method is more suitable for industrial production.)

1. A process for the preparation of ramipril, characterized in that said process is as follows:

2. the method of claim 1, wherein the method comprises the steps of:

step 1: dissolving N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine in an organic solvent, adding triethylamine and di-tert-butyl dicarbonate, stirring for reaction at room temperature, concentrating under reduced pressure after the reaction is finished, adding ethyl acetate for dissolution, standing at low temperature for crystallization to obtain N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine protected by white crystal amino;

step 2: adding the N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine protected by the amino group obtained in the step 1, an organic solvent, a condensing agent, Hobt and triethylamine into a reaction kettle, slowly adding (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylic acid hydrochloride while stirring at the temperature of 10-15 ℃, after the addition is finished, carrying out heat preservation and stirring reaction, carrying out centrifugal filtration, controlling the temperature of 10-15 ℃, slowly adding dilute hydrochloric acid into the filtrate, carrying out heat preservation and stirring, carrying out centrifugal filtration, separating liquid, collecting an organic phase, washing, carrying out decompression concentration on the organic phase to obtain an oily substance, adding ethyl acetate to dissolve the oily substance, and carrying out standing and crystallization at a low temperature to obtain ramipril.

3. The preparation method of claim 2, wherein the mass-to-volume ratio of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to organic solvent in step 1 is 50-300: 1, mg/ml.

4. The method according to claim 2, wherein the amount of di-tert-butyl dicarbonate used in step 1 is 1 to 2 times the mass of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.

5. The method according to claim 2, wherein the amount of triethylamine in step 1 is 0.36 to 0.72 times the mass of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.

6. The method according to claim 2, wherein the organic solvent in step 2 is chloroform, dichloromethane, diethyl ether or toluene.

7. The method according to claim 2, wherein the condensing agent in the step 2 is DCC, DIC or EDC.

8. The method according to claim 2, wherein the mass ratio of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to the condensing agent, Hobt and triethylamine in step 2 is 1: 0.6-1: 0.35-0.6: 0.5 to 1.

9. The method according to claim 2, wherein the (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate in step 2 is used in an amount of 0.5 times the mass of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.

10. The method according to claim 1, wherein the low temperature in step 2 is 0 to 10 ℃.

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a preparation method of ramipril.

Background

Ramipril (Ramipril), the chemical name of which is (2s,3as,6as) -1- { (2s) -2- { [ (1s) -1- (ethoxycarbonyl) -3-phenylpropyl ] amino } propionyl } -octahydrocyclopenta [ b ] pyrrole-2-carboxylic acid, is a long-acting and potent Angiotensin Converting Enzyme Inhibitor (ACEI) developed by the German Hoechst company, is suitable for moderate and severe essential hypertension and moderate and malignant congestive heart failure patients, is firstly marketed in France in 1989, and has the characteristics of quick drug effect, long acting time, high tissue specificity, low toxic and side effects and the like.

At present, many methods for preparing ramipril are reported, but most of the methods basically adopt benzyl to protect carboxyl on (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate to obtain (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate hydrochloride, then the hydrochloride is condensed with N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine or analogues thereof to form a key intermediate of ramipril, and then the target product ramipril is obtained by removing a protecting group benzyl group through catalytic hydrogenation. For example, European patent EP0079022(1983) reports a synthesis method as shown in formula I, wherein a carboxyl group on (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate is protected by benzyl, the carboxyl group is subjected to resolution and condensation with N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine, and then the protecting group is removed by Pd/C catalytic hydrogenation to obtain ramipril, wherein Pd/C used for removing the protecting group by hydrogenation is inflammable substances, and the danger coefficient in hydrogenation reaction is high. Therefore, the process has high requirements on reaction equipment and operation, high danger coefficient and unsuitability for large-scale industrial production, and the reaction route is as follows:

chinese patent CN101326151 reports another preparation method of ramipril, as shown in formula ii, which also uses benzyl group to protect carboxyl group on (S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate, and also uses Pd/C in the hydrodebenzyl stage. Therefore, the method is not suitable for large-scale industrial production, and the reaction route is as follows:

although patent CN101855207A reports that ramipril is obtained directly by coupling reaction without any protection of the secondary amine of the reactant, it is found by analysis that the coupling reaction needs to be activated by acid halogenation reaction before proceeding, it is well known that the acid halogenation reaction is not in accordance with the concept of green chemistry, and the secondary amine of the reactant is not protected, and self-condensation impurities are easily generated, and the reaction of the route needs to be carried out under the condition of extremely low temperature of-40 ℃, and such harsh reaction conditions are difficult to be realized in the scale-up production stage. Therefore, the development of a new route which has high reaction efficiency, mild reaction conditions and less generated impurities and is suitable for industrial production is still significant.

Disclosure of Invention

The invention provides a preparation method of ramipril, which changes carboxyl on the traditional benzyl protection (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate into tert-butyloxycarbonyl (Boc) protection N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -amino on L-alanine, and obtains the key intermediate of ramipril through condensation reaction, then removing the protecting group under the action of dilute hydrochloric acid to obtain ramipril, and solves the technical defect that in the prior art, the carboxyl on (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate is protected by benzyl and the benzyl is removed by catalytic hydrogenation with Pd-C/H2 with higher danger coefficient. Meanwhile, the cost is reduced, and the method is more suitable for industrial production.

The specific technical content of the invention is as follows:

step 1: dissolving N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine in an organic solvent, adding triethylamine and di-tert-butyl dicarbonate, stirring for reaction at room temperature, concentrating under reduced pressure after the reaction is finished, adding ethyl acetate for dissolution, standing at low temperature for crystallization to obtain N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine protected by white crystal amino;

step 2: adding the N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine protected by the amino group obtained in the step 1, an organic solvent, a condensing agent, Hobt and triethylamine into a reaction kettle, slowly adding (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylic acid hydrochloride while stirring at the temperature of 10-15 ℃, after the addition is finished, carrying out heat preservation and stirring reaction, carrying out centrifugal filtration, controlling the temperature of 10-15 ℃, slowly adding dilute hydrochloric acid into the filtrate, carrying out heat preservation and stirring, carrying out centrifugal filtration, separating liquid, collecting an organic phase, washing, carrying out decompression concentration on the organic phase to obtain an oily substance, adding ethyl acetate to dissolve the oily substance, and carrying out standing and crystallization at a low temperature to obtain ramipril.

Preferably, the organic solvent in step 1 is chloroform, dichloromethane, diethyl ether or toluene, preferably dichloromethane.

Preferably, the mass volume ratio of the N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to the organic solvent in the step 1 is 50-300: 1, mass in g, volume in L; preferably 100 to 200: 1, mass in g, volume in L.

Preferably, the dosage of the di-tert-butyl dicarbonate in the step 1 is 1-2 times, preferably 1.2-1.5 times of the mass of the N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.

Preferably, the dosage of the triethylamine in the step 1 is 0.36 to 0.72 time, preferably 0.5 to 0.6 time of the mass of the N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.

Preferably, the reaction time in the step 1 is 1.5 to 3 hours, preferably 2 to 2.5 hours.

Preferably, the low temperature in the step 1 is 0-10 ℃, and preferably 5-10 ℃.

Preferably, the organic solvent in step 2 is chloroform, dichloromethane, diethyl ether or toluene, preferably dichloromethane.

Preferably, the mass-to-volume ratio of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to the organic solvent in the step 2 is 50-200: 1, mass in g, volume in L; preferably 50-100: 1, mass in g, volume in L.

Preferably, the condensing agent in step 2 is DCC (dicyclohexylcarbodiimide), DIC (N, N' -diisopropylcarbodiimide), or EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride); preferably EDC.

Preferably, the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine described in step 2 is present in a molar ratio to the condensing agent, Hobt and triethylamine of 1: 1.1-1.8: 1-1.7: 1.8-3.8, preferably 1: 1.3-1.5: 1.1-1.4: 2.3 to 3.

Preferably, the amount of the (S, S, S) -2-azabicyclo [3,3,0] octane-3-carboxylate in the step 2 is 0.3 to 0.8 times, preferably 0.5 times, the mass of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.

Preferably, the reaction time in the step 2 is 5 to 8 hours, preferably 6 to 7 hours.

Preferably, the low temperature in the step 2 is 0-10 ℃, and preferably 5-10 ℃.

Preferably, the time of the heat preservation stirring in the step 2 is 0.5-2 h, and preferably 1 h.

Compared with the prior art, the invention has the following technical effects:

the invention uses tert-butyloxycarbonyl (Boc) protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]-L-alanine is used as an initiator, a ramipril key intermediate is obtained through condensation reaction, then the protecting group is removed under the action of dilute hydrochloric acid to obtain ramipril, and the method solves the problem that benzyl protection (S, S, S) -2-azabicyclo [3,3,0] is adopted in the prior art to protect]The carboxyl group of the octane-3-carboxylate and finally the Pd-C/H with a higher risk factor have to be used₂The catalytic hydrogenation is carried out to remove benzyl, and the method has the technical defects of mild reaction conditions, high reaction yield and less generated impurities, and is suitable for industrial large-scale production.

Detailed Description

The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.

The product prepared by the method can be measured according to Chinese pharmacopoeia standards, and the specific method comprises the following steps:

performing high performance liquid chromatography (general pharmacopoeia 0512) test, using octadecylsilane chemically bonded silica as filler (Nucleosil C18 column, 4.0mm × 250mm,3 μm or equivalent chromatographic column), and column temperature is 65 deg.C. Mobile phase A sodium perchlorate buffer (2.0 g sodium perchlorate, 0.5ml triethylamine, 800ml water dissolved, pH adjusted to 3.6 with phosphoric acid) -acetonitrile (800: 200). And mobile phase B, sodium perchlorate buffer solution (2.0 g of sodium perchlorate is taken, 0.5ml of triethylamine is added, 300ml of water is added for dissolution, the pH value is adjusted to 2.6 by phosphoric acid) -acetonitrile (300: 700), gradient elution is carried out according to the following table, and the detection wavelength is 210 nm.

Example 1

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]dissolving-L-alanine (279g) in dichloromethane (2L), adding triethylamine (139.5g) and di-tert-butyl dicarbonate (362g) under stirring, stirring at room temperature for 2 hours after the addition is finished, concentrating the reaction solution under reduced pressure at 35-45 ℃, adding ethyl acetate (1L), standing at 5 ℃ for crystallization for 24 hours, performing suction filtration, washing the filter cake with N-heptane (80mL) to obtain white crystals, wherein the yield is 94.6% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl group)]-L-alanine), HPLC purity 99.7%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]Adding (300g) L-alanine, dichloromethane (4L), EDC (250g), Hobt (120g) and triethylamine (180g) into a reaction kettle, controlling the temperature to be 10-15 ℃, and slowly adding (S, S, S) -2-azabicyclo [3,3,0] under stirring]Octane-3-carboxylic acid hydrochloride (150g), finishing feeding, carrying out heat preservation reaction for 6h, after the reaction is finished, carrying out centrifugal filtration to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, carrying out heat preservation stirring for 1h, carrying out centrifugal filtration to obtain a filtrate, separating liquid, collecting an organic phase, washing the organic phase with 1L saturated sodium bicarbonate solution once, then washing with purified water for three times (1L each time), carrying out reduced pressure concentration on the organic phase at 35-45 ℃ to obtain an oily substance, then adding ethyl acetate (1.2L) for dissolution, standing at 5 ℃ for crystallization for 24h, carrying out centrifugal filtration to obtain ramipril, wherein the yield is 93.5% (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl protected by amino group)]-L-alanine), HPLC purity 99.5%, MS-ESI M/z 416.46(M + H)⁺。

Example 2

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]-L-alanine (279g) in dichloromethane (2L) and triethylamine (167g) and bis (methanol) were added with stirringDi-tert-butyl carbonate (418g), stirring at room temperature for 2.5 hours after the feeding is finished, after the reaction is finished, concentrating the reaction liquid under reduced pressure at 35-45 ℃, adding ethyl acetate (1L), standing at 10 ℃ for crystallization for 24 hours, performing suction filtration, washing a filter cake with N-heptane (80mL) to obtain white crystals, wherein the yield is 92.5% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl group)]-L-alanine), HPLC purity 99.5%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]Adding (300g) L-alanine, dichloromethane (4L), EDC (287g), Hobt (150g) and triethylamine (240g) into a reaction kettle, controlling the temperature to be 10-15 ℃, and slowly adding (S, S, S) -2-azabicyclo [3,3,0] under stirring]Octane-3-carboxylic acid hydrochloride (150g), finishing feeding, keeping the temperature and stirring for 7h, after the reaction is finished, centrifugally throwing and filtering to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing adding, keeping the temperature and stirring for 1h, centrifugally throwing and filtering to obtain a filtrate, separating liquid, collecting an organic phase, washing the organic phase once with 1L saturated sodium bicarbonate solution, then washing with purified water for three times (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain an oily substance, then adding ethyl acetate (1.2L) for dissolving, standing and crystallizing at 10 ℃ for 24h, centrifugally throwing and filtering to obtain ramipril, wherein the yield is 92.7% (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl protected by amino group)]-L-alanine), HPLC purity 99.3%, MS-ESI M/z 416.46(M + H)⁺。

Example 3

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]dissolving-L-alanine (279g) in dichloromethane (1.4L), adding triethylamine (100g) and di-tert-butyl dicarbonate (279g) under stirring, stirring at room temperature for 2.5 hours after the addition is finished, concentrating the reaction solution under reduced pressure at 35-45 ℃, adding ethyl acetate (0.5L), standing and crystallizing at 5 ℃ for 24 hours, performing suction filtration, washing the filter cake with N-heptane (80mL) to obtain white crystals with the yield of 92.3 percent (by using N- [1- (S) -ethoxycarbonyl-3-phenylpropyl group)]-L-alanine), HPLC purity 99.1%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]-L-alanine (300g), dichloromethane (3L), EDC (210g), Hobt (105g) and triethylamine (150g) were added to the reaction vessel under controlSlowly adding (S, S, S) -2-azabicyclo [3,3,0] at the temperature of 10-15 ℃ under stirring]Octane-3-carboxylic acid hydrochloride (90g), finishing feeding, keeping the temperature and stirring for 6.5h, after the reaction is finished, centrifugally filtering to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing adding, keeping the temperature and stirring for 1h, centrifugally filtering to obtain a filtrate, separating liquid, collecting an organic phase, washing the organic phase once with 1L saturated sodium bicarbonate solution, then washing with purified water for three times (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain an oily substance, then adding ethyl acetate (1.2L) for dissolving, standing at 5 ℃ for crystallization for 24h, centrifugally filtering to obtain ramipril, wherein the yield is 95.5% (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl protected by amino group)]-L-alanine), HPLC purity 99.3%, MS-ESI M/z 416.46(M + H)⁺。

Example 4

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]dissolving-L-alanine (279g) in dichloromethane (2.8L), adding triethylamine (200.8g) and di-tert-butyl dicarbonate (558g) under stirring, stirring at room temperature for 2 hours after the addition is finished, concentrating the reaction solution under reduced pressure at 35-45 ℃, adding ethyl acetate (1L), standing at 10 ℃ for crystallization for 24 hours, performing suction filtration, washing the filter cake with N-heptane (80mL) to obtain white crystals, wherein the yield is 92.6% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl group)]-L-alanine), HPLC purity 99.2%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]adding-L-alanine (300g), dichloromethane (6L), DIC (227g), Hobt (180g) and triethylamine (300g) into a reaction kettle, controlling the temperature to be 10-15 ℃, and slowly adding (S, S, S) -2-azabicyclo [3,3,0] under stirring]Octane-3-carboxylate (240g), finishing feeding, carrying out heat preservation reaction for 6h, after the reaction is finished, carrying out centrifugal filtration to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, carrying out heat preservation stirring for 1h, carrying out centrifugal filtration to obtain a filtrate, separating liquid, collecting an organic phase, washing the organic phase once with 1L saturated sodium bicarbonate solution, washing with purified water for three times (1L each time), carrying out reduced pressure concentration on the organic phase at 35-45 ℃ to obtain an oily substance, adding ethyl acetate (1.2L) for dissolution, standing at 10 ℃ for crystallization for 24h, and carrying out centrifugal filtration to obtain the productRamipril, yield 91.5% (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl protected with amino group)]-L-alanine), HPLC purity 99.1%, MS-ESI M/z 416.46(M + H)⁺。

Example 5

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]dissolving-L-alanine (279g) in dichloromethane (2L), adding triethylamine (139.5g) and di-tert-butyl dicarbonate (362g) under stirring, stirring at room temperature for 2 hours after the addition is finished, concentrating the reaction solution under reduced pressure at 35-45 ℃, adding ethyl acetate (1L), standing at 0 ℃ for crystallization for 24 hours, performing suction filtration, washing the filter cake with N-heptane (80mL) to obtain white crystals, wherein the yield is 91.3% (by N- [1- (S) -ethoxycarbonyl-3-phenylpropyl group)]-L-alanine), HPLC purity 98.5%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]adding-L-alanine (300g), dichloromethane (4L), DCC (268g), Hobt (120g) and triethylamine (180g) into a reaction kettle, controlling the temperature to be 10-15 ℃, and slowly adding (S, S, S) -2-azabicyclo [3,3,0] under stirring]Octane-3-carboxylic acid hydrochloride (150g), finishing feeding, carrying out heat preservation reaction for 6h, after the reaction is finished, carrying out centrifugal filtration to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, carrying out heat preservation stirring for 1h, carrying out centrifugal filtration to obtain a filtrate, separating liquid, collecting an organic phase, washing the organic phase with 1L saturated sodium bicarbonate solution once, then washing with purified water for three times (1L each time), carrying out reduced pressure concentration on the organic phase at 35-45 ℃ to obtain an oily substance, then adding ethyl acetate (1.2L) for dissolution, standing at 0 ℃ for crystallization for 24h, carrying out centrifugal filtration to obtain ramipril, wherein the yield is 91.4% (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl protected by amino group)]-L-alanine), HPLC purity 98.7%, MS-ESI M/z 416.46(M + H)⁺。

Example 6

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]dissolving-L-alanine (279g) in dichloromethane (2L), adding triethylamine (139.5g) and di-tert-butyl dicarbonate (362g) under stirring, stirring at room temperature for 2 hours after the addition is finished, concentrating the reaction solution under reduced pressure at 35-45 ℃, adding ethyl acetate (1L), standing at 15 ℃ for crystallization for 24 hours, performing suction filtration, and washing a filter cake with n-heptane (80mL)Washing to obtain white crystal with yield of 82.5% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl)]-L-alanine), HPLC purity 99.0%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]Adding (300g) L-alanine, dichloromethane (4L), EDC (250g), Hobt (120g) and triethylamine (180g) into a reaction kettle, controlling the temperature to be 10-15 ℃, and slowly adding (S, S, S) -2-azabicyclo [3,3,0] under stirring]Octane-3-carboxylic acid hydrochloride (150g), finishing feeding, carrying out heat preservation reaction for 6h, after the reaction is finished, carrying out centrifugal filtration to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, carrying out heat preservation stirring for 1h, carrying out centrifugal filtration to obtain a filtrate, separating liquid, collecting an organic phase, washing the organic phase with 1L saturated sodium bicarbonate solution once, then washing with purified water for three times (1L each time), carrying out reduced pressure concentration on the organic phase at 35-45 ℃ to obtain an oily substance, then adding ethyl acetate (1.2L) for dissolution, standing at 15 ℃ for crystallization for 24h, carrying out centrifugal filtration to obtain ramipril, wherein the yield is 83.3% (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl protected by amino group)]-L-alanine), HPLC purity 99.1%, MS-ESI M/z 416.46(M + H)⁺。

Example 7

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]dissolving-L-alanine (279g) in chloroform (2L), adding triethylamine (223.2g) and di-tert-butyl dicarbonate (474g) under stirring, stirring at room temperature for 2 hours after the addition is finished, concentrating the reaction solution under reduced pressure at 35-45 ℃, adding ethyl acetate (1L), standing at 10 ℃ for crystallization for 24 hours, performing suction filtration, washing the filter cake with N-heptane (80mL) to obtain white crystals, wherein the yield is 88.6% (by N- [1- (S) -ethoxycarbonyl-3-phenylpropyl group)]-L-alanine), HPLC purity 98.2%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]adding-L-alanine (300g), chloroform (4L), DIC (252g), Hobt (240g) and triethylamine (360g) into a reaction kettle, controlling the temperature to be 10-15 ℃, and slowly adding (S, S, S) -2-azabicyclo [3,3,0] under stirring]Octane-3-carboxylic acid hydrochloride (150g), finishing feeding, carrying out heat preservation reaction for 6h, after the reaction is finished, carrying out centrifugal filtration to obtain filtrate, controlling the temperature to be 10-15 ℃, and slowly adding the filtrate intoSlowly adding 2M dilute hydrochloric acid (1L), keeping the temperature and stirring for 1h after the addition is finished, centrifugally spin-filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once with 1L saturated sodium bicarbonate solution, then washing with purified water for three times (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily matter, then adding ethyl acetate (1.2L) to dissolve the oily matter, standing the organic phase at 10 ℃ for crystallization for 24h, centrifugally spin-filtering to obtain ramipril, wherein the yield is 86.2 percent (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl phenyl protected by amino group)]-L-alanine), HPLC purity 97.5%, MS-ESI M/z 416.46(M + H)⁺。

Example 8

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]dissolving-L-alanine (279g) in toluene (2L), adding triethylamine (83.7g) and di-tert-butyl dicarbonate (220g) under stirring, stirring at room temperature for 2 hours after the addition is finished, concentrating the reaction solution under reduced pressure at 35-45 ℃, adding ethyl acetate (1L), standing at 5 ℃ for crystallization for 24 hours, performing suction filtration, washing the filter cake with N-heptane (80mL) to obtain white crystals, wherein the yield is 82.6% (by N- [1- (S) -ethoxycarbonyl-3-phenylpropyl group)]-L-alanine), HPLC purity 99.0%, MS-ESI M/z 379.16(M + H)⁺。

The obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl]adding-L-alanine (300g), toluene (4L), DCC (206g), Hobt (90g) and triethylamine (120g) into a reaction kettle, controlling the temperature to be 10-15 ℃, and slowly adding (S, S, S) -2-azabicyclo [3,3,0] under stirring]Octane-3-carboxylic acid hydrochloride (150g), finishing feeding, carrying out heat preservation reaction for 6h, after the reaction is finished, carrying out centrifugal filtration to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, carrying out heat preservation stirring for 1h, carrying out centrifugal filtration to obtain a filtrate, separating liquid, collecting an organic phase, washing the organic phase with 1L saturated sodium bicarbonate solution once, then washing with purified water for three times (1L each time), carrying out reduced pressure concentration on the organic phase at 35-45 ℃ to obtain an oily substance, then adding ethyl acetate (1.2L) for dissolution, standing at 5 ℃ for crystallization for 24h, carrying out centrifugal filtration to obtain ramipril, wherein the yield is 83.5% (N- [1- (S) -ethoxycarbonyl-3-phenylpropyl protected by amino group)]-L-alanine), HPLC purity 97.8%, MS-ESI M/z 416.46(M + H)⁺。