TW476761B - A process for preparing the derivative of a dipeptide and (R)-Α-hydroxy benzoic acid ester and pharmaceutically acceptable salts thereof - Google Patents

Abstract

A process for preparing a compound of formula (I) which is a derivative of a dipeptide and (R)-Α-hydroxy benzoic acid ester and pharmaceutically acceptable salts thereof, wherein n is an integer of from 0 to 3; X represents hydrogen, C1-C10alkyl or halogen; R1 and R5 can be the same or different, and each represents hydrogen, or C1-C10alkyl unsubstituted or substituted with the following groups: hydroxy, mercapto, C1-C10alkylthio, carboxyl, amido, unsubstituted or substituted phenyl, or R2 is hydrogen, or C1-C6alkyl which is unsubstituted or substituted by phenyl; R3 is hydrogen, or C1-C10alkyl which is unsubstituted or substituted by phenlyl; R4 is hydrogen or C1-C10alkyl, or R4 and R5 together form a ring through C, N or S; comprising the following steps: (a) protecting the carboxy group of dipepide with a protective group; (b) forming a leaving group on the hydroxy group of (R)-Α-hydroxy benzoic acid of formula (II), wherein X, n and R2 are as defined in the compounds of formula (I); (c) carrying out a SN2 reaction between the products of steps (a) and (b); and (d) deprotecting the product thus obtained.

Description

Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 476761 A7 B7 V. Description of the invention (1) Background of the invention Due to the gradual increase in the elderly population, the number of patients with high blood I has also increased relatively in recent years. The sales volume of the drug can be seen. Among the top 100 best-selling drugs in the world's sales rankings in 1995, the total sales of cardiovascular drugs reached US $ 16.17 billion, of which angiotensin-converting enzyme (ACE) inhibitor sales accounted for 36% of them, equivalent to 5.75 billion US dollars. The main drugs of angiotensin-converting enzyme inhibitors on the market include Vesotec ® produced by Merck, which is a phenyl butyrate propionate, commonly known as Enalapril Maleate, Annual sales amounted to USD 2.4 billion; Prinivil®, produced by Merck, is a lysine derivative of phenylbutyric acid and propionate, commonly known as Lisinopril, which is sold throughout the year The amount is USD 375 million; and Zestenl ® produced by Zeneca, which is also an lysine derivative of propyl butyrate and propionate, ---------------- --- S-- Commonly known as lisinopril (1 ^ 111〇1: 11), the annual sales amount is 850 million US dollars. Xian, Yi-Yixin The future of the cardiovascular drug market is still very promising. In the previous technique, the synthesis of phenylbutyric acid such as Enalapril, Enalaprilat, Enalapril Maleate, Lisopnl, etc. There are many literatures on biology. For example, European Patent No. 0 012 401 requests a method for the preparation of pit-based bimonthly peptide derivatives, which mainly includes the following steps: first protecting the amine group or carboxyl group of the amino acid, and then Coupling is performed in the presence of a Schiff base, and the protective product is removed from the resulting product. The disadvantage of this method is that the obtained carbonylalkyl bispeptide derivative is a mixture of optical isomers, and additional separation must be performed. P: \ PTS \ MLS \ M \ 46671.DOC — 4 ~ This paper is applicable to the standard China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

、 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs P: \ PTS \ MLS \ M \ 46671.DOC — 5 — This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 public celebration) 476761 V. Invention Explanation (2 yI to the desired mono-optical isomer is not only time consuming, increased cost, and easy to reduce yield. U.S. Patent No. 4,374,829 discloses the use of bis-peptide and 2-keto Phenylbutyric acid is a kind of proto-amination reaction, which uses specific reductive amination reagents such as sodium borocyanide, platinum / carbon, and Raleigh nickel. As with the above cited case, the f-method reaction is completed. A mixture of optical isomers is also obtained, and it is still necessary to reuse separation methods such as official column chromatography to be able to separate the desired single optically active compound. 'It is less suitable for large-scale industrial production.', Journal of Organic Chemistry (J.〇 rg. Chem) 1988, Bian 836 first used phosgene to enter the coupling reaction of bis-peptide, and then the obtained bis-peptide was reductively aminated with 2-ketophenylbutyrate and reacted, and then The presence of hydrogenation catalysts such as in ethanol solutions and Raleigh nickel A low-pressure catalytic hydrogenation reaction is carried out. This technique reveals a major disadvantage, that is, the final product is a mixture of optical isomers, which must be subjected to additional separation steps before obtaining the desired single optically active compound, which is not suitable for Mass production in industry. Chinese Journal of Chemistry (J. Chmese · Chem · Soc ·) 1991, 1 487 first used acetylation reaction with enzyme (such as lipase) to obtain (R > i ^ ethyl 醯The nitrile is separated and hydrolyzed to form the esters of galenyl; the hydrolyzed product M isomer is then subjected to SN 2 nucleophilic substitution reaction to obtain enalapril. According to the example of this document, the enzyme reaction The time is up to 12 days, and the silica gel column chromatography is used to separate the products. Chinese Journal of Medicinal Chemistry (Chinese. J. Med. Chem.) 1995, 5 (3) 218 Reveals the use of α-aminopropyl The acid and conjugated esters undergo a Michael addition reaction (Michad addition), and then the difference in the solubility of the components is used to isolate the desired monomer.

P: \ PTS \ HLS \ H \ 46671.DOC (Please read the notes on the back before filling this page)

1T 476761 A7 B7 V. Description of the invention (3 Optically active compounds; The isolated single optically active compound is then coupled with proline to obtain the final product, enalapril. The procedure disclosed in this document is slightly complicated It is less suitable for large-scale production in industry. Therefore, it is still necessary to develop a simpler, more suitable for large-scale production in industry and obtain higher yields of bis-peptide and perylene benzoate. Derivatives and methods for synthesizing pharmaceutically acceptable salts thereof. SUMMARY OF THE INVENTION The present invention relates to a novel derivative of bis-peptide of the general formula (I) and fluorene 1-hydroxybenzoate using SN2 reaction and its pharmaceutically acceptable How to accept salt, (Please read the precautions on the back before filling this page) R1 R4

rR5 COOR3 (I) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

COOR2 includes the following steps: (1) protecting the carboxyl portion of the bis-peptide with a protecting group; (2) the following. (R) -α-benzoate hydroxy group formation-leaving group represented by formula (II), where (II) where X, η and R2 are as defined in the compound of formula (I); (i) subjecting step (ii) to the product of step (ii) to undergo SN2 reaction; and (d) removing the protecting group of the resulting product.

P: \ PTS \ MLS \ M \ 46671.DOC This paper size is applicable to China National Standard (CNS) 8 4 specifications (210X297 mm) 476761 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (4) According to the method of the present invention, a compound having a single optical rotation can be directly obtained without omitting the optical separation treatment of the product in the prior art, so it is very suitable for large-scale industrial production. After the reaction is completed, the protective group of the product can be Complete removal at one time is quite simple for industrial large-scale production. The scope of application is quite wide, and different types of starting materials can be changed according to the needs to produce different products as desired. The compound prepared by the method of the present invention can be used as an angiotensin-converting enzyme inhibitor for treating hypertension such as essential hypertension, renal hypertension, renal vascular hypertension, and malignant hypertension. And cardiovascular diseases such as congestive heart failure. Brief Description of the Drawings Figure 1 is an HPLC chart of standard lisinopril defined in the United States Pharmacopoeia; Figure 2 is a HPLC chart of the first specific example-Lisinopril-prepared according to the method of the present invention Figure 3 is an HPLC chart of the standard Enalapnl Maleate set in the United States Pharmacopoeia; Figure 4 is a second specific embodiment prepared according to the method of the present invention-Enalapnl Maleate- HPLC chart; Figure 5 is a HPLC chart of a third specific embodiment-Enalapril prepared according to the method of the present invention; and Figure 6 is a fourth specific example-Enapril prepared according to the method of the present invention Column (Enalaprilat)-HPLC profile. P: \ PTS \ MLS \ M \ 46671.DOC 1 7 A paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) 11 ^ / 6761 Μ B7 V. Description of the invention (5) ^ ~~ The present invention claims a double peptide of formula (1) and (R > α-hydroxybenzoate) which can be used as angiotensin converting enzyme inhibitor. Novel preparation method of derivatives and their pharmaceutically acceptable salts:

Wherein 'n is an integer from 0 to 3; X represents hydrogen, CpCi 〇 alkyl or halogen; R1 and R5 may be the same or different, they are hydrogen or Ci-Cio alkane unsubstituted or substituted by Group: light group, hydrogen thio group, Ci-C4 thiothio group HN— several groups, fluorenylamino group, C = NH, amino group nh2 substituted or unsubstituted phenyl group, or ch2-ch—II nh2 oh

.N (Please read the notes on the back before filling this page)

Printed by the Consumers' Cooperative of the China ’s Prospective Bureau of the Ministry of Economic Affairs as R 'or unsubstituted or substituted with phenyl Ci-Cg pit base; R is oxygen' or unsubstituted or substituted with phenyl C; [- C 10 pit group; R4 is hydrogen or CpCio alkyl group, or R4 and R5 can be connected to form a ring through C, N or S; includes the following steps: (a) the carboxyl portion of the bis-peptide is protected by a protecting group; The leaving group of ⑻-α-hydroxybenzoate represented by the following formula (Π) is a leaving group,

P ： \ PTS \ HLS \ M \ 46671.DOC This paper size is applicable to Chinese National Standard (CNS) Α4 size (2Η) × 297mm 幷 / O / bl A7 V. Description of the invention (6

0H

COOR2 (Π) where X, η and R2 are as defined in the compound of formula (1): (i) subjecting step (ii) to the product of step (ii) to perform SN2 reaction; (d) removing the protecting group of the resulting product. The method of the present invention can be applied to the preparation of derivatives of bis-peptide and (R) w-hydroxybenzoate and their pharmaceutically acceptable salts known in any conventional art, preferably those having the following formula (I): ： --------- 0 ^ — ^. (Please read the notes on the back before filling in this I)

, 11 wherein 'η is an integer from 0 to 3, preferably 2; X represents hydrogen, Ci-C! Alkyl or halogen; R1 and R5 may be the same or different, and they are hydrogen or unsubstituted or Ci-C10 alkyl substituted with the following groups: hydroxyl, hydrogenthio, Cl-C4 alkylthio, HN --- carboxyl, amido, pNH, amine, Ch2-CH1, ~~,

NH2 in2 OH substituted or unsubstituted phenyl, or; preferably hydrogen Η P: \ PTS \ MLS \ M \ 46671.DOC-g — this paper ruler; ΐ applicable Zhongguanjia standard (CNS) A4 specification (Others: 7 public directors) —0 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 476761 A7 B7 V. Description of the invention (7) HN— or Ci-Cg alkyl, which is unsubstituted or substituted with the following groups ... Ch2 ~ ch- > substituted or unsubstituted phenyl hn ^ n nh2 oh or

, · Best hydrogen or unsubstituted or Ci-Q alkyl substituted by phenyl printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs; R2 is hydrogen, or unsubstituted or substituted phenyl CpCs Alkyl; preferably hydrogen, or an unsubstituted or phenyl substituted C1-C4 alkyl group; more preferably hydrogen, C alkyl or fluorenyl; R3 is hydrogen, or unsubstituted or phenyl substituted Ci_Ci〇 Tiger group; preferably hydrogen, or Ci-Cg alkyl group which is unsubstituted or substituted with phenyl group; more preferably hydrogen series, third butyl or fluorenyl group; R4 is hydrogen or Ci-Cio group Or, R4 and R5 may be connected to form a ring via c, N or s, 'preferably a nitrogen or Ci-Cg group' or 0 and r5 may be connected to form a ring via c. The dipeptide used in step ⑻ of the method of the present invention can be purchased directly in the commercial field, or it can be prepared in any manner known to those skilled in the art, for example, through the following steps: (1) In an aqueous test solution, the amine group Acid to form N α protecting group, (η) in the presence of coupling reagents and amines, the amino acid with N α protecting group in step (i) and another amino group with the same or different carboxy protecting spirit The acid is coupled, and (iii) the resulting product is removed from the protecting group with an acidic aqueous solution.

P: \ PTS \ MLS \ M \ 46671.DOC -10-This paper size is applicable to China National Standard (CNS) 8-4 specifications (2ι〇 × 297 male sauce) ▼ pack--1. (Please read the precautions on the back first Refill this page) Order 476761 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (8) The test solution in the above step (i) can be an aqueous solution of metal test or soil test metal. An aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide, magnesium hydroxide or calcium hydroxide, more preferably an aqueous solution of sodium hydroxide or magnesium hydroxide, and most preferably an aqueous solution of sodium hydroxide. The concentration of the alkaline solution may be between 0.5 and 1.5 N, preferably between 0.8 and 1.2 N, and most preferably 1.0 N. The N α protecting group attached to the amino acid may be any known in the art, such as N-methylamino, N-thirdbutoxycarbonyl or N-fluorenyloxycarbonyl, preferably N-third Butoxycarbonyl. In Scheme I, N-tert-butoxycarbonyl is used as the protecting group attached to the amino acid as an example. Another amino acid with the same or different carboxy-protecting group can be purchased directly in commerce, usually in the form of, for example, the hydrochloride salt; the carboxyl group on it can also be protected by any skilled person in any known manner, For example, a CpCio alkoxy group or a benzyloxy group can be prepared; the benzyl group is exemplified in the flow chart I. The coupling reagent in the above step 可 can be any user known in the amino acid coupling reaction, such as bis (2-oxo-3-azazolidinyl) phosphonium chloride (BOP-C1), dicyclohexylcarbonyl Diamidine (DCC), diphenoxyphosphonium azide (DPPA), 1- (3-dimethylaminopropyl) -3-ethylcarbonyldiamidine hydrochloride (EDC) or Carbonyl diimidazole (CDI); bis (2-oxo-3-humidazolidinyl) phosphonium halide (BOP-C1) is preferred. Further, the amino acid for preparing the bis-peptide required in the present invention may be, for example, lysine, α-aminopropionic acid or proline. In Scheme I, lysine and proline are used as examples. The acidic aqueous solution that can be used in the above step (iii) may be hydrofluoric acid, hydrogen acid, hydrobromic acid, sulfuric acid, riding acid, acetic acid, or three-track acetic acid; preferably P: \ PTS \ MLS \ M \ 46671 .DOC ~ 11 One paper size is applicable to Chinese National Standard (CNS) M specifications (210X: 297 mm) (Please read the precautions on the back before filling this page): Packing-、 11 476761 A7 __B7__ V. Invention Explanation (9) Hydrogen acid or trifluoroacetic acid aqueous solution; the most preferred is trifluoroacetic acid aqueous solution. The carboxyl group of the bis-peptide in the step 方法 of the method of the present invention can be made into a protecting group in any manner known to those skilled in the art, for example, it can be made into a d-Cio alkyl group or a fluorenyloxy group. Scheme I: Preparation of double peptides 〇 R1, human

BuO N 、 C〇OH Η HN +

Hydrochloride 1 -------- ^ (Please read the notes on the back before filling in this 肓) Coupling Reagent Amine

cooch2- BuO

Trifluoroacetic acid

* Step (b) in the method of the present invention printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics is a known step, usually in the presence of a base, so that ⑻-a-hydroxybenzoate represented by formula (II) The hydroxyl group forms a leaving group. Wherein the test may be, for example, triethylamine, p-bito, morphine, and preferably p-bito. The (R) -α-hydroxybenzoate-α-hydroxy group-forming leaving group may be selected from: -OTf (for example, from trifluoromethanesulfonic anhydride), -〇Ts (for example, from tolyl citric acid) , -OBs (for example, from p-bromophenyl acid), -OMs (for example, from methyl tranexamic acid) 'and a group of functins; the leaving group is preferably a 12-

P: \ PTS \ HLS \ M \ 46671.DOC This paper size is applicable to Chinese National Standard (CNS) A4 specification (21〇 > < 297mm) 476761 A7 B7 5. Description of the invention (10 is _〇Tf or- 〇Ms. In the following scheme II, trifluoromethanesulfonate_〇Tf is used as an example of the leaving group. Scheme II: ⑻W via phenylbenzoic acid activation reaction

Inspection (please read the note J · on the back side and fill in * * 丨 |: write this page) The SN2 reaction in step (C) is performed at a temperature between -20 ° C and room temperature. 10 to (TC); and can be selected from, for example, tetrahydrofuran, dichloromethane, acetonitrile, and dihumane, preferably using dichloromethane or tetrahydrofuran as the solvent. The product obtained in step ⑹ The protecting group can be removed in any conventional manner, for example, a hydrogenolysis method, and an acidic or alkaline hydrolysis method can be used; preferably, a cliffing method is used. The following flowchart m illustrates the present invention by a hydrogenolysis method: deprotection If the hydrogenolysis method is used, the hydrogenolysis catalyst can be 5 or 3 specifications

Pd / C, the amount can be 2 to 10% by weight of the starting material, preferably 3 to ^%, and most preferably 5%; it can also be added, such as vinegar I to shorten the hydrogenolysis reaction j time. The method of the present invention may optionally include a stepping horse transformed into a salt form (e) ', which may be carried out according to any method known to those skilled in the art. For example, you can add an appropriate solvent to i (for example, cis-butadiene-bistellurium-bismuth <acetonitrile solution), and __P: \ PTS \ MLS \ M \ 4 6671.DOC_ Yifei 'paper standards are applicable to Chinese national standards (CNS) ---_, 1T Φ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 476761 A7 B7 V. Description of the invention (η) After the solution is heated to complete dissolution, it is filtered while hot, and then recrystallized with acetonitrile solution , And left at room temperature for a sufficient period of time, the final product in the form of salts (for example, in the form of maleate) can be precipitated. Flowchart III: SN2 reaction, hydrogenolysis and purification into salt form Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the notes on the back before filling this page)

1T ip The following examples are to further confirm the feasibility of the present invention, to make the technical content requested by the present invention more specific, and to make it clear for the skilled person and can be implemented accordingly, but it is not intended to limit the present invention. What you should get P: \ PTS \ MLS \ M \ 46671.DOC-14-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 476761 Α7 Β7 V. Description of the invention (l2) Scope of protection . Various changes and improvements of the present invention that can be achieved by other skilled artisans based on the indications of known arts should fall within the scope of the present invention. Specific Example HPLC operating condition column: LiChrospher 100RP-8 (5 μπι) 250 χ 4 mm Eluent: 96/4 A / B isocratic @ 1.8 ml / min A two 0.02M NaH2P04 / H20 B = CH3CN, pH = 5.0 (but pH = 6.8 in Figure 5) Detector: UV 210nm Temperature · 50 ° C Example 1 (Please read the note 4 on the back first, then fill and install! I write this page) t-BOC- Lys- (Z) -Pro-OBzl was prepared by combining 2.0 g (5.26 mmol) of BooLys (Z) -〇H and 1.34 g (5.26 mmol) of bis (2-oxo-3-π) Critical base) Phosphorus chloride is placed in the reaction flask, and 6 ml of Qijiakeng is added. Stir at room temperature: After 15 minutes, the solution is white and cloudy. • Transfer the reaction flask to the ice bath, and Add 1.53 g (6.3 mmol) of H-Pr0-OBzl · HC1, and prepare a mixed solution of 2.9 ml (21.0 mmol) of triethylamine in 6 ml of dichloromethane, slowly dripping Into the aforementioned reaction bottle in an ice bath, a fuming phenomenon will occur at this time. After the addition, the solution is white and cloudy; continue to stir the resulting solution; stir for 1 hour, and then concentrate to remove the dichloromethane *. Extraction step, followed by extraction with 30 ml of ethyl acetate and distilled water, and then washing the organic layer with saturated saline once; after drying, filtering and concentrating, a yellow viscous liquid was obtained; For column chromatography, the eluent used was: 2) Ethyl acetate / P: \ PTS \ MLS \ M \ 16671.DOC-15-This paper size applies the Chinese National Standard (CNS) M specifications (210X297 (Mm), 1T -0 Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed 476761 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of the invention (13) n-hexane solution to obtain 2.11 g of a pale yellow viscous liquid (product (71%). The hNMRCCDClicO analysis data of the product are as follows: 7.34 (s, 10H), 5.40-5.28 (m, m), 5.12-5.06 (m, 5H), 4.61-4.56 (m, 1H), 4.45-4.42 (m, 1H), 3.70-3.60 (m, 2H), 3.26-3.06 (m, 2H), 2.19-2.17 (m, 1H), 1.98-1.96 (m, 3H), 1.26 (s, 15H). Example 2 Preparation of BOC-A 丨 a-Pro-OBzl The preparation method is the same as that described in Example 1, except that 2.0 g (10.6 mmol) of Boc-Ala-ΟΗ and 3.07 g (12.7 mmol) H-Pro-OBzl · HC1 was used as the starting material. At the end of the reaction, 3.2 g of a white viscous liquid was obtained (80% yield). The iHNMR (CDClid) analysis data of the product are as follows: 7.27 (s? 5H), 5.37-5.33 (m? 1H)? 5.18 ^ 5.06 (ABq? J-12.2 Hz5 2H)? 4.60-4.55 (m, lH), 4.47- 4.40 (m, lH), 3.69-3.54 (m, 2H), 2.25-2.13 (m, lH), 2.02-1.90 (m, 3H), 1.40 (s, 9H), 1.27 (d, J = 6.8 Hz, 3H). Example 3 Preparation of H-Lys (Z) -Pro-OBz and CF3COOH 2.11 g. (3.72 mmol): (600) ^ (2)-? 1: 0-〇83 was placed in a reaction flask, Add an appropriate amount of dichloromethane so that the reaction can be agitated, then place the reaction flask in an ice bath, and slowly inject 2.87 ml (37.2 mmol) of trifluoroacetic acid solution into the reaction bottle with a syringe. At that time, the color of the solution will change from white and transparent to yellow; after the addition is complete, the reaction mixture is continuously stirred overnight; after that, a concentration step is performed to remove excess trifluoroacetic acid in the mixture, or isopropyl ether may be added to dilute it, and then It was removed during concentration; 2.16 g of a yellow viscous liquid was obtained with a yield of 100%. P: \ PTS \ HLS \ M \ 46671.DOC — 16 — ’(Please read the notes on the back of the 4 items before filling and loading — I: write this page)

、 1T it This paper size is applicable to China National Standard (CNS) A4 specification (210X: 297 mm) 476761 A7

The analysis data of ^ NMI ^ CDCkd) printed by employees' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are as follows: 7.33-7.23 (m, 1GH), 5.11 · 5.03 (η, 5H), 4.59_4.55 (m, 1H), 4.39 _4.19 (m, 1H), 3.70-3.42 (m? 2H)? 3.14-3.10 (m? 2H)? 2.38 ^ 2.05 (m3 1H), 2.06-1.72 (m? 5H)? 1.56-1.42 (m, 4H). Example 4 Preparation of H-Ala-Pro-OBzl · CF3COOH The preparation method is the same as that in Example 3, but changed to 3.2 g (850 mm) BOC-Ala-ProOBzl and 6.55 ml (85 mmol) Ear) of trifluoroacetic acid as a starting material, the reaction ended in 3.32 g of a yellow sticky liquid (yield 100%). The iHNMI ^ CDCkcO analysis data of the product are as follows: 7.40-7.25 (m, 5H), 5.17 and 5.03 (ABq, &gt; 12.2 Hz, 2H), 4.56-4.50 (m, 1.H), 4.28-4.25 (m, 1H ), 3.62-3.45 (m, 2H), 2.25_2.22 (m, 1H), 2.04-1.92 (m, 3H), 1.42 ((1, J = 7.0 Hz, 3H). Example 5 (R)- Preparation of 4-phenyltrifluoromethylsulfone oxyacetate 3.73 ml (22.2 mmol) of trifluoromethanesulfonic anhydride was dissolved in 7 ml of dichloromethane, and the reaction flask was transferred to an ice bath In addition, another 50 grams (18.5 millimoles) of stilbene-4-phenyl-2-hydroxybutyrate dissolved in 12 ml of dichloromethane was prepared and mixed slowly. Add to the above reaction bottle, and the color of the solution will change from colorless and transparent to yellow at this time; then prepare 1:79 ml (222 millimoles) of bite dissolved in 7 ml of methane gas and put it in the addition funnel "Then slowly drop into the flask containing the reaction mixture in the ice bath, smoke will occur at this time. After the addition is complete, continue the whole mixture for 1 hour"; Turned burgundy with P: \ PTS \ MLS \ H \ 4 667l.DOC-17 — This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 public holiday) (Please read the precautions on the back before filling this page) Binding-Order i # 476761 A7 B7 V. Description of the invention ( is) Production of white sulfonate pyridine salt solids produced by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs; after the reaction is completed, the solution is filtered to remove the white salts, and then extracted with 25 ml of isopropyl ether and distilled water, and then The organic layer was washed once with distilled water; after drying, filtering, and concentrating, 7.50 g of a wine-red liquid was obtained (yield: 100%). The iHNMRCDCkd of the product was analyzed as follows: 7.37-7.10 (m, 10H ), 5.23-5.16 (m, 3H), 2.76-2.68 (m, 2H), 2.37-2.26 (m, 2H). Example 6 Preparation of (R) -4-phenyltrifluorofluorenylsulfone oxybutyric acid ethyl ester The preparation method was the same as that in Example 5, except that 5.0 g (24 mmol) of (R) was used instead. 4-phenyl-2-Ethyl butyric acid ethyl ester and <84 ml (28.8 mmol) trifluoromethanesulfonic anhydride were used as starting materials. At the end of the reaction, 8.16 g of a red-brown liquid was obtained with a yield of 100%. The .½ NMR (CDCI3, β) analysis data of the product are as follows: 7.32-7.17 (m, 5Η), 5.14 (t, J = 6.0 Ηζ, 1Η), 4.27 (q, &gt; 7.0 Ηζ, 2Η), 2.82-2.74 (m, 2H), 2.38-2.27 (m, 2H), 1.3l (t, J = 7.0 Hz, 3H). Example 7 Preparation of N2-[(S) Phenyloxycarbonyl each phenylpropyl] -Nε-benzyloxycarbonyl-L · ionamidinyl-L-proline phenyl methyl ester 2.16 g (3.72 mmol) ) Of H-Lys (Z) -Pr0-〇Bzl · CF3COOH, dissolved in 4 ml of dichloromethane, then the flask containing the above mixture was placed in an ice bath, and 2.05 g ( 5.11 mmol) The compound prepared in Example 5 was dissolved in 2 ml of digas methane, and a solution of 1.4 ml (10.2 mmol) of triethylamine in 4 ml of digas A was prepared, respectively. Place in two addition funnels and slowly drip into the reaction bottle at the same time, because the addition of triethylamine will cause

P: \ PTS \ MLS \ M \ 46671.DOC — 18 — This paper size applies to the Chinese National Standard (CNS) M specification (2 丨 〇 &gt; &lt; 297 mm) (Please read the precautions on the back before filling in this Page) Equipment, 11 it / υ / υ 丄 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs—19 I. Description of the Invention (l6 ίΐΓ: Elephant; After the addition is complete, the reaction mixture is continued at C. Take two 'and then concentrate. Read out the two gaseous scorch burners in the mixture and extract them with 40¾ liters of ethyl acetate and distilled water.

The organic layer was then washed with distilled water — F ^ θ death / person. After drying, filtering and concentrating, a red sticky body could be inserted; it could be transferred by column chromatography. The extraction solution used was: &quot; 2 ethyl acetate / n-hexane solution, and separated 210 g of a pale yellow viscous liquid with a yield of 79%. The 1H NMR (CDCl3, d) analysis data of the product are as follows: 7.34 7.09 (m, 20 H), 5.12-5.01 (m, 7H), 4.56-4.52 (ιη, 1H), 3.76-3.56 (m, 1H) ), 3.38-3.16 (m, 5H), 2.65-2.58 (m, 2H), 2.08-1.84 (m, 7H), 1.4H.22 (m, 5H). Example 8 Preparation of N-[(S) -l-fluorenyloxyphenylphenylpropanyl-propylaminofluorenyl cardiac proline phenylmethyl ester] The preparation method is the same as that described in Example 7, but changed to 45 Grams (3.71 millimoles) of H-Ala-Pro-OBz CF3COOH, and 1.97 grams (4.89 millimoles) of the compound obtained in Example 5 were used as starting materials. After the reaction was completed, 114 grams of a pale yellow viscous liquid was obtained. The yield was 58%. The 4 NMR (CDCI3, β) analysis data of the product are as follows: 7.39-7.09 (m, 15Η), 5.21-5.04 (m, 4Η), 4.56-4.46 (m, 1Η), 3.43-3.40 (m, 2Η), 3.31 -3.24 (m, 2H)? 2.63-2.59 (m, 2H)? 2.05-1.88 (m, 6H), 1.22-1.18 (d, J = 6.8 Hz, 3H). Example 9 N2-((S) Small Preparation of ethoxycarbonyl phenylpropylbenzene L-propylaminofluorenyl-L-proline phenylmethyl ester

P: \ PTS \ MLS \ M \ 4 66 &quot; 71 .D0C The M-scale scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1. J0 reference ----- 丨 order ----- -mil (Please read the notes on the back before filling this f) 476761 A7

The printing and preparation method of the employee consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is the same as that in Example 7, but changed to 3.07 g (7.87 mmol) of H-AIa-Pro-OBz CFgCOOH and 3.11 g (9.15 mmol) Ear) The compound obtained by the implementation of He 6 was used as a starting material. After the reaction was completed, 20 g of a pale yellow viscous liquid was obtained with a yield of 55%. The 4 NMR (CDCI3, β) analysis data of the product are as follows: 7.35-7 · 13 (m, 10Η), 5.20 and 5.09 (ABq, J = 12.2 Ηζ, 2Η), 4.62-4.57 (m, 1Η) 4.17 (q , J 2 7 · 0 Ηζ, 2Η), 3.60-3.49 (m, 3Η), 3.23 (t, J = 6.6 Ηζ, 1Η), 2.73-2.63 (m, 2H), 2.21-1.88 (m, 6H), 1.31-1.22 (m, 6H). Example 1 Preparation of 0 2-((S) -1-Carboxyphenylphenyl] -L. Aminopyridine Cardioproline [Lisinopril] 3.32 g (4.61 mmol) Ear) The compound of Example 7 was dissolved in 50 ml of methanol, and 200 mg of 10% Pd / C (5% by weight) was added to give 200 mg of activity (5% by weight), and the foregoing reaction mixture was subjected to hydrogenation. In the bottle, the hydrogenation reaction was carried out by pipetting at parr until the hydrogen pressure was maintained at 40 psi. After the reaction was completed, 'Celite was filtered and the methanol was removed by concentration' to obtain 2.0 g of a pale yellow solid with a yield of 100%; and then recrystallization was performed with ethanol / ethyl acetate. , Can obtain white powder with higher purity. The melting point is 150-152T: (literature 159-160 ° C) 20 ["] 1 :) 25.3. ((: 1.0, 乂 6〇11) (literature 値, 23.3.) Η NMR of the product ( CD3OD, β) analysis data are as follows: 7.33-7.17 (m? 5H), 4.69 (t, J = 6.0 Hz, 0.5H), 4.52-4.49 (m, 1H)? 4.24 (t, J = 6.0 Hz, 0.5H ), 3.83 (t, J = 6.0 Hz, 0.5H), 3.74-3.54 (m, 2H), 3.42 (t? J-6.0 Hz, 0.5H), 3.05- 2.85 (m, 2H), 2.79-2.74 ( m, 2H), 2.27-1.85 (m, 7H), 1.85-1.71 (m, 5H). P: \ PTS \ MLS \ M \ 4 667l. DOC — 2 0 — This paper standard applies to Chinese National Standard (CNS) A4 specification (210x297 mm) IJ equipment I: ------ Order ------ (Please read the precautions on the back before filling out this page} 476761 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______B7 V. Description of the invention (18) The HPLC analysis results of this compound are shown in Figure 2. From the data in Figure 2, it can be seen that the lisinopril prepared according to the method of the present invention has the standard lisinopril adopted by the United States Pharmacopoeia. (Shown in Fig. 1) A similar analysis data of PLC. Example 1 1 N-[(S) -l-Retyl-3-phenylpropyl] -L-propylamine-L-proline [I Naples ( Enalaprilat)] The preparation method is the same as that in Example 10, but 2.58 g (4.89 mmol) of the compound of Example 8 is used, 150 mg of 10% Pd / C (5% by weight) and 150 mg of activated carbon (Weight 5%) is the reactant, the reaction product is a light yellow solid (170 g, yield 100%); recrystallized with acetone to obtain a white solid powder. Melting point 148-151 ° C (Reference 値149-151 ° C) ... 20. K] D = -50.6 ° (ClAMeOH) (literature 値 is -51. ~ -56.) The 4 NMR (CD30D, d) analysis of the product is as follows: 7.34- 7.17 (m, 5H), 4.79-4.59 (m, 1H), 4.33 (q, J = 6.4 Hz, 0.7H), 4.16 (q, J = 6.4 Hz, 0.3H), 3.84-3.69 (m, 1H), 3.64-3.50 (m, 2H), 2.88-2.74 (m, 2H), 2.37-2,15 (111, 3H), 2.06-2.02 (m, 3H), 1.61-1.55 (m, 3H). Example 1 Preparation of 2 N-[(S) -1-ethoxyphenylphenyl] -L-propylamine-L-cholic acid [Enalapril] Preparation method and Example 10 Same as described above, but changed to 2.0 g (4.3 mmol) of the compound of Example 9, 100 mg of 10% Pd / C (5% by weight), and 100 mg of active compound (5% by weight). As a reactant, the reaction product was a pale yellow solid (1.56 g, 96% yield). _ 9 Ί-P: \ PTS \ MLS \ M \ 46671.DOC The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). Loading 丨 Bull (Please read the precautions on the back before filling in this Page) Order 476761 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (19) Melting point 85-90 ° C 20 WD = -47.8 ° (C 1.0, MeOH) yNMRCCDsOD of the product, ^) analysis data As follows: 7.34, 7.16 (m, 5H), 4.65_4.55 (m, 0.5H), 4.52_4.48 (m, 0.5H), 4.36-4.22 (m, 2.7H), 4.12 (q, J = 7.0 Hz, 0.3H), 3.96 (t, J = 6.0Hz, 1H), 3.64-3.58 (m, 2H), 2.88-2.68 (m, 2H), 2.37-2.21 (m, 4H), 2.11-1 91 (ιη, 2H), 1.61-1.55 (m, 3H), 1.33 (t, wind 2 Hz, 3H) 〇 Example 1 3 N2-[(S) -1-ethoxyl-3-phenylpropyl Preparation of [L-propyl] -L-propylamine-L-cholic acid [Enalapril Maleate] 308 mg (2.66 mmol) of maleic acid was placed in a reaction flask 6 ml of acetonitrile was added, and the solution was heated to 80. At this time, the solution was mainly white and transparent; another 1.0 g (2.66 mmol) of enalapril and 3 耄 were prepared. A mixed solution of acetonitrile (white turbid liquid), slowly pour this mixed solution into the reaction bottle containing the maleic acid, diacid / acetonitrile solution, and continue heating and stirring at the same temperature for 1 hour. After the reaction is complete, the solution is Filter while hot and let the filtrate cool at room temperature to precipitate a pale blue solid. The solid precipitate is filtered off and rinsed with 10 ml of ether to obtain 117 g of a light-monitored solid. Yield 90% . Because the above products are easy to deliquesce, it can be recrystallized with ethyl wax to obtain a white solid powder which is easier to preserve. Melting point is 135-140 ° C (literature 143-144.5 ° C) Γ 20 [a] D; 40.4 (Cl. 0, MeOH) (documents 値 -41.0. ~ -43.5.) IHNMR ^ CDWDj analysis of the product The data are as follows: 7.34-7.20 (m, 5H), 6.31 (s, 2H), 4.65-4.55 (m, 0.5H), 4.55 «4.45 (m, 0.5H), P: \ PTS \ MLS \ M \ 46671 .DOC — 22 — $ Paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 male D —---- ^ ------ m- · ------ order ------ (Please read the notes on the back before filling this page) 476761 A7 B7 V. Description of the invention (20) 4.34-4.26 (m, 2.5H), 4.12 (q, J = 7.0 Hz, 0.5H), 3.97 (q, J = 5.6Ηζ, 1Η), 3.58-3.43 (m, 2H), 2.81-2.71 (m, 2H), 2.32-2.26 (m, 4H), 1.62-1.56 (m, 3H), 1.32 (t, J = 7.0 Hz, 3H) 〇 The HPLC analysis results of this compound are shown in FIG. 4. From the data in FIG. 4, it can be seen that the enalapril mele according to the method of the present invention has the standard enalapril set by the US Pharmacopoeia A similar HPLC analysis data of Meilie (shown in Figure 3). Hit! (Please read the precautions on the back before filling this page)

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Claims (1)

476761 No. 8611 :: 187 Chinese Shen Qing Chinese reading special trip Fan Jue ^. ———- No. 87 Patent Application Zero Xiangfan Miscellaneous Method for preparing bis-peptide of formula ⑴ and (R &gt; α-hydroxybenzylic acid, its pharmaceutically acceptable salt, brewed derivative and C00R3 (I) wherein η is an integer from 0 to 3; X represents hydrogen, C1-C4 alkyl or halogen; R1 and R5 may be the same or different, and they are hydrogen or unsubstituted or substituted with the following groups: Cp C6 alkyl: C4 C4 alkylthio, amine, substituted or unsubstituted phenyl; R2 is hydrogen, or Cl = C4 alkyl unsubstituted or substituted with phenyl; R3 is hydrogen, or Unsubstituted or substituted phenyl C4 alkyl; R is hydrogen or CpC6 alkyl, or R4 and R5 can be connected to form a ring via c * N; Include the following steps: ⑻ The carboxyl portion of the bis-peptide Protected with a protecting group; ⑸ formed as a leaving group in the hydroxyl group of the (R) _a phenylbenzoate represented by the following formula (Π), 0H COOR2 (Π) where X, η and R2 are as defined in the compound of formula ①; (c) subjecting step ii to the product of step ii to perform SN2 reaction; and (d) removing the protecting group of the resulting product. ; t. ¾¾ Note on filling in this page) • I. Α8 Β8 C8 D8 Wherein the scope of patent application in the derivative of formula (I) 2. According to the method of the first scope of patent application, where formula (1) is derived R1 and R5 are hydrogen or Cl_e6 alkyl group which is unsubstituted or substituted with amine group or phenyl group. 3. The method according to item 1 of the scope of patent application, wherein R2 in the derivative of formula (I) is hydrogen, (: B (4 alkyl or benzyl). 4. The method R3 is based on the scope of patent application 1, Is hydrogen, third butyl or benzyl. 5. The method according to item 1 of the scope of patent application, wherein R4 in the derivative of formula (I) is hydrogen or CVC6 alkyl, and R4 and R5 are connected via c or N Ring formation. 6. The method according to item i of the scope of patent application, wherein step ⑸ is in the presence of a base to make the radical of (R) -α-light benzoate into a leaving group. 7. According to the application The method according to item 6 of the patent, wherein the base is triethylamine, pyridine or morpholine. 8. The method according to item 丨 of the application, wherein the leaving group in step 选自 is selected from -0Tf (may be From trifluoromethanesulfonic anhydride) '_ 〇Ts (can be derived from tolylsulfonic acid), -0Bs (can be derived from p-bromophenylsulfonic acid), _〇Ms (can be derived from methylsulfonic acid), and! | The group formed. 9. The method according to item 丨 of the scope of patent application, wherein the leaving group in step 系 is -OTf or -OMs. 讥 According to the scope of patent application The method according to item 1, wherein the sn2 reaction in step 系 is performed at a temperature between -20 ° C and room temperature. Η · The method according to item 1 in the patent application range, wherein the sn2 reaction in step ㈡ is from -10 to 0 ° C. 12. According to the method of the scope of application for the patent application, the method of step 2 of the sn2 anti- "Sweep Wiii (CNS) A4g (21〇χ29) gy (Please read the precautions on the back before filling (This page) Order printed by the Consumers' Cooperative of the Central Bureau of Quasi-Economic Bureau of the Ministry of Economic Affairs 476761 A8 B8 C8 D8 6. The scope of patent application should be carried out in a solvent selected from the group consisting of tetrahydrofuran, dichloromethane, acetonitrile, dioxane and 2-hexane. 13. The method according to item 1 of the scope of patent application, wherein the SN2 reaction in step ㈡ is performed in a solvent of dichloromethane or tetrahydrofuran. 14. The method according to item 1 of the scope of patent application, further comprising a salt as needed Steps for purification of similar forms ⑹ (Please read the precautions on the back before filling out this page) Printed by Yuman National Standard (CNS) A4 (210X297Y)