TWI239956B - A process for preparing N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride - Google Patents

Abstract

A process for preparing N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride of formula (I) is to react N-[l-(S)-ethyoxy carbonyl-3-phenylpropyl]-L-alanine with XCOOR, wherein X is halogen atom, R is C1-C6 alkyl, to obtain a N-alkoxycarbonyl compound, then reacting with an acyl group activation reagent, finally contact with water. The compound of formula (I) is a key intermediate of ACE inhibitors.

Description

1239956 A7 B7 V. Description of the invention ([Field of the invention] The present invention relates to a method for producing a derivative of an anterior derivative having the effect of inhibiting Angiotensin Converting Enzyme (hereinafter referred to as ACE); further, the present invention The invention relates to N- [1- (S) -Ethylacet-3-phenylpropyl] -L-aminopropionic acid-N-quinic acid liver (! ^-[1_ (S) -ethyoxycarbonyl-3- [Manufacturing method of phenylpropyl] -L-alanine N-carboxy-anhydride (hereinafter referred to as NEPA-NCA). [Background of the invention] Hypertension is the most common cardiovascular disease. In order to treat hypertension, the demand for antihypertensive drugs is increasing, so A simpler and more convenient manufacturing method is needed to produce compounds with ACE inhibitory effects as antihypertensive agents. Among them, Enalapril Maleate is the following formula (II): (Please read first (Notes on the back, please fill out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

V eight

COOH

COOH (II) is a commonly known antihypertensive agent. Its preparation method is that NEPA-NCA of formula (I) and L-proline (L-proline) are condensed under alkaline conditions. Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1239956 A7 B7 V. Description of the invention (2) Should be 'A to N- [1- (S)-: @ @ 基 -3-phenylpropyl] -L-aminopropionic acid-N-choline, commonly known as Enalapril:

Enalapril is finally added with maleic acid to obtain amino acid salt compounds, namely enalapril maleate of formula (II). This method has been disclosed in patents such as EP2 15335. 0 Makes NEPA-NCA different from The condensation reaction of amino acids under similar conditions can be used to synthesize other commonly used ACE inhibitors, such as Ramipil, Trandolapril, Delapril, Imidapril, and Quinapril HC1. Conventional methods for manufacturing NEPA-NCA compounds of formula (I), (III) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

(III) N- [1- (S) _ethylsulfonyl-3-benzyl] -L-aminopropionic acid (N- [l_ (S) -ethyoxy carbonyl-3-phenylpropyl] -L-alanine , Hereinafter referred to as NEPA) stored in phosgene, diphosgene or triphosgene 4 This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 1239956 A7 B7 V. Explanation of the invention (3) Please read the reaction below, this method has been disclosed in jp57175152A, US4496541 and EP215335. Although the phosgene process has a high yield, phosgene is a gas with a mother nature. Based on industrial safety considerations, special designs must be used to avoid the leakage of phosgene; while double phosgene and triple phosgene are liquid or Solid, but the vapour generated during heating is extremely toxic, so you need to be careful when handling it. In addition, the treatment of waste gas and waste generated during the process is also very difficult, and it is easy to cause harm to the environment, so it belongs to industrial applications. A difficult private system. Other preparation methods replacing direct use of phosgene have also been developed, as described in U.S. Pat. No. 5,359,086, using N, N, -carbonyldiimidazole (N, N'_Carbonyldiimidazole) to replace phosgene; However, N, N, _carbonyl diimide is expensive, and if it is to be recycled, it needs to be regenerated using phosgene, which is not suitable for industrial use. The present invention discloses a process that does not require the use of highly toxic reagents such as phosgene, has low toxicity, low risk, and is easy to operate, which can overcome all the shortcomings of the conventional techniques. [Summary of the Invention] The object of the present invention is to provide a method for producing NEPA-NC A without using highly toxic reagents such as phosgene or diphosgene. Another object of the present invention is to provide a method for manufacturing NEPA-NCA which is safe and has low manufacturing difficulty. Another object of the present invention is to provide a paper with a high economic value, suitable for 5 paper sizes, applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 1239956 A7 B7 V. Description of the invention (4) Industrial production use NEPA- NCA manufacturing method. The present invention relates to a method for producing NEPA-NCA of the following formula: ch3 Η! ,, Η ch2. Αν ο ο ο (I) which is based on the N- [1_ (S) -ethyl ester group of formula (III) -3_phenylpropyl] -L-aminopropionic acid (referred to as NEPA).

I ch2, ch2

ch3 h ^ h N ^ 'COOH

H Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (HI) and XCOOR compounds of formula (V): XCOOR (V) where X is a halogen atom and R / is a 0-06 alkyl group, forming an N-alkyl ester compound (N-alkoxycarbonyl), and then reacted with acid-based activating reagent, and finally obtained by interaction with water. The method of the present invention can also be applied to other starting materials having an amino acid structure to synthesize corresponding N-carboxyanhydride compounds. -------- 5 ----! ---------- Order --------- line (please read the precautions on the back before filling this page) Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 1239956 A7 B7 V. Description of the invention (5) Various starting materials with amino acid structure, such as Η Η Ν

• COOH Η ΗI Ν

•, COOH

ΗI 〇 \ person „COOH Η

Strict

" COOH Η

ΗI

„COOH

I

ΗI

Γ h3c

Ν ,, COOH Ν ..COOHS ~ V S

ch3

or

. " • Ν Η ch2-cooh -------- „—: —-------- Order --------- line -0 ^-(Please read the first Note: Please fill in this page again.) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics. [Detailed description of the invention] The present invention provides a NEPA-NCA manufacturing method. The synthetic reaction formula is roughly as follows: The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1239956 A7 B7 V. Description of the invention (6) H3C, CH2, 0po Jk; ^, (: H2 / \ 〆C00H H (III) XCOOR (V) organic solvent Η3% Η2 / 〇R, 0 (IV) '0 hydrazone activating reagent water organic solvent ^ n-CH2, ch2

0 ch3 Η I Η N Ο

: 0 (I) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where X is a halogen atom and R is a Ci-C6 alkyl group. First, NEPA of formula (III) is reacted with compound (V) in an organic solvent to form an N-alkyl ester-based compound of formula (IV), and then reacted with a fluorenyl activating reagent, and finally obtained by reacting with water. The aforementioned organic solvent refers to an aprotic solvent, and examples thereof include dichloromethane, dichloroethane, toluene, ethylacetate, hexane, Cyclohexane or heptane, of which dichloromethane, dichloroethane or toluene is preferred, and dichloroethane is the most preferred. Compound (V), in which X is a halogen atom system including a gas atom, a bromine atom, and an iodine atom, the most preferable of which is a chlorine atom; wherein, the CPC6 alkyl system includes a straight chain or a branch, examples are: A Base, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl and hexyl, etc. 8 This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1239956 Α7 _____ Β7 _____ 5. Description of the invention (7) Among them, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or Third butyl. The aforementioned fluorenyl activating reagent may be acyl chlorination reagent 'such as thionyl chloride or phosphorus pentachloride, hepatic acid or acid halide compounds (such as ethyl alcohol ( acetyl chi〇ride)), among which preferred is sulfenyl chloride, acetic anhydride or acetyl chloride. In the present invention, the reaction temperature between EPA and the compound (V) is not too limited, and it ranges from room temperature to 120. (: Both are applicable, mainly depending on the organic solvent selected; the reaction time is also not too limited, and the preferred reaction time is 0-5 to 3 hours. N-alkyl ester compounds (IV) and fluorenyl groups are activated The reaction of reagents has a reaction temperature range of -10 ° C to 120 ° C and a reaction time of 2 to i 4 hours, which mainly depends on the selected reagents. The method of the present invention has low toxicity, low risk and Advantages such as ease of operation 0 [Preferred Embodiments of the Invention] The present invention will be described in more detail with reference to the following examples, but will not limit the scope of the present invention. Unless otherwise stated, the examples used in the examples The percentages are based on weight, and the temperature is in degrees Celsius. ^ Unit. Example 1: Add 27.9 grams of ΝΡΑ and 90 ml to the reactor. The standard is applicable to the standard _tsuka standard (CNS) A4 coffee χ 297 public love_ Gas Bake, then ^^ -------- Order --------- line (Please read the precautions on the back before filling this page) 123 妁 56 A7 R7 V. Description of the invention (8 ) (Please read the note 2 on the back before filling this page) Force 13.1 grams of ethyl chloroformate and 10. 0 g of triethylamine was stirred at room temperature until the reaction was completed. After the organic layer was washed twice with 50 ml of water, the pH was adjusted to 3 to 4 with hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and stored. The filtrate. 13.1 g of sulfenyl chloride was added to the reactor, and 5 ~ 10. (:, The previous filtrate was slowly dripped in, and then stirred at room temperature until the reaction was completed, the organic layer was washed with 50 ml of water After two times, it was dried and filtered with magnesium sulfate, and the crude product was obtained after concentration under reduced pressure. Finally, recrystallization was performed to obtain N- [1- (S) -ethylethyl-3-phenylpropyl]- White crystals of L-aminopropionic acid-N-carboxy anhydride, the total yield is 70% 〇 Product melting point: 68 ° C; W-NMRCCDCh): dl.26 (t, 3H), β 1.53 (d, 3Η), c? 2.22 ~ 2.48 (m, 2Η), d 2.66 ~ 2.84 (m, 2Η), β 3.39 (q, old), j 4.20 (d, 2H), (T4.33 (d, 1H), and d 7.15 ~ 7.34 (m, 5H) 〇 Example 2: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 27.9 g of NEPA and 60 ml of dichloroethane were added to the reactor, and then 13.1 g of ethyl chloroformate and 9.6 were added. G Polyethylpyridine, at room temperature Stir until the reaction is complete. After washing the organic layer twice with 50 ml of water, adjust the pH to 3 to 4 with hydrochloric acid. Take the organic layer and dry it with magnesium sulfate. After filtration, save the filtrate and liquid. Add 10.2 g of ethyl to the reactor Chlorine, and slowly drip the previous filtrate at 5 ~ 10 ° C, and then stir at room temperature until the reaction is complete. The organic layer was washed twice with 50 ml of water, and then dried and filtered with magnesium sulfate. Concentrated to obtain 10 paper sizes applicable to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 1239956 A7 B7 V. Description of the invention (9) The crude product can be obtained after the final ◦ recrystallization, N- [1 -(S) -Ethyl-3- (Please read the note on the back first? Please fill in this page again) White crystals of phenylpropyl] 丄 -aminopropionic acid carboxylic anhydride, the total yield is 91% 〇 Product melting point: 68 ° C; W-NMR ^ CDCls): 〇M.26 (t, 3H ), D 1.53 (d, 3H), J 2.22 ~ 2.48 (m, 2H), d 2.66 ~ 2.84 (m, 2H), d 3.39 (q, 1H), d 4.20 (d, 2H), cT4.33 ( d, 1H) and d 7.15 ~ 7.34 (m, 5H). Example 3: In the reactor, 1.2 liters of dichloroethane and 560 g of NEPA were added, and 23 7.6 g of ethyl chloroformate was added. After stirring for half an hour, 230 ml of a 10M aqueous sodium hydroxide solution was added to the reactor and stirred for an additional hour. After the reaction is completed, add 188.4 g of acetam chloride, and react at 85 ~ 95 ° C for 2 hours. Then add 800 ml of water to keep the temperature at 70 ~ 80 ° C. After the reaction is completed, the organic layer is extracted. A crude product was obtained after concentration under reduced pressure. Recrystallize after taking it. Payable 1 ^-[1- (8) -ethyl @@ 基 -3-phenylpropyl] -L-aminopropionic acid-N-carboxylic acid anhydride, the total yield is 82% . The melting point of the printed product of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs: 68 ° C; W-NMRCCDCIJ: d 1.26 (t, 3H), d 1.53 (d, 3H), 2.22 ~ 2.48 (m, 2H), β 2.66 ~ 2.84 (m, 2H), 3.39 (q? 1H), d 4.20 (d, 2H), cM.33 (d, 1H), and β 7.15 to 7.34 (m, 5H). Example 4: 27.9 g of ΝΡΑ and 60 ml of toluene were added to the reactor, and then 11 paper sizes were applied to the Chinese National Standard (CNS) A4 (210 X 297 mm) 1239956 A7 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Preparation of B7 V. Description of the invention (10) Add 13.1 g of ethyl chloroformate, and after reacting for one hour, add 12 6 g of fluorenyl chloride at room temperature. Continue until the reaction is complete. After washing twice with milliliter of water, it was then dried and filtered with sulphuric acid. The crude product was obtained after concentration under reduced pressure. Finally, it was recrystallized to obtain N- [1- (S) -ethylethyl-3-phenylpropyl]. -L-aminopropionic acid-N-carboxylic acid anhydride was white crystals with a total yield of 53%. Product melting point: 68 ° C; W-NMRCCDCL): d 1.26 (t, 3H), β 1.53 (d, 3H), d 2.22 ~ 2.48 (m, 2H), d 2.66 ~ 2.84 (m, 2H), 3.39 (q5 1H), d 4.20 (d, 2H), d 4.33 (d, 1H), and β 7.15 to 7.34 (m, 5H). Example 5: Add 27.9 g of NEPA and 90 ml to the reactor Dichloroacetamidine, and then 13.1 g of ethyl chloroformate were added. After the reaction for one hour, 10 ml of a 10 M aqueous sodium hydroxide solution was added to the reactor and stirred for another half an hour. After the reaction was completed, 5.1 g of acetic anhydride was added. After the salt was filtered off, 13.1 g of sulfenyl chloride was added, and then stirred at room temperature until the reaction was completed. The organic layer was washed with 20 ml of water and depressurized. The crude product was obtained after concentration. Finally, recrystallization was performed to obtain white crystals of N- [1- (S) -ethylethyl-3-phenylpropyl] -L-aminopropionic acid-N-carboxylic acid anhydride, with a total yield of 63%. Product melting point: 68 ° C; e-NMR ^ CDCh): J 1.26 (t, 3H), d 1.53 (d, 3H), β 2.22 ~ 2.48 (m, 2H), d 2.66 ~ 2.84 (m, 2H), d 3.39 (q, 1H), d 4.20 (d, 2H), β 4.33 (d, 1H), and j 7.15 ~ 7.34 (% 5H) 〇 The above shows that the technical idea disclosed in this invention Reached the invention 12 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------- 7--Ί -------- Order ------- -^ (Please read the notes on the back before filling this page)

I 239956 A7 B7 V. Description of the invention (| (Purpose, novelty, progress, and industrial availability, and in line with the requirements of the invention patent. However, those disclosed above are the preferred embodiments, and all local details Those who change or modify and derive from the technical ideas of this case and are easily inferred by those who are familiar with the technology, do not depart from the patent scope of this case. (Please read the precautions on the back before filling this page) Order ---- ----- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 13 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

A8S8D8 1239956 6. Scope of patent application 6. The method according to item 4 of the scope of patent application, wherein the aprotic organic solvent is dichloroethane. 7. The method according to item 1 of the scope of patent application, wherein the compound (IV) is composed of N- [1- (S) -ethylethyl-3-phenylpropyl] -L-aminopropyl of the following formula (III) Acid ~ / 〇 丫 v 2 ~ CH2〆 ^ N COOH I i H (ΠΙ) is obtained by reacting an XCOOR compound XCOOR (V) with the following formula (V) in an organic solvent; wherein X is a chlorine atom and R is Methyl or ethyl. 8. The method according to item 7 of the scope of patent application, wherein the compound (v) is ethyl chloroformate. 9. The method of claim 7 in which the reaction is performed in an organic solvent containing at least one aprotic solvent. 10. The method of claim 9 in which the aprotic organic solvent is selected from the group consisting of dichloromethane, dichloroethane, toluene, ethyl acetate, hexane, cyclohexane, or heptane. 11. The method of claim 9 in which the aprotic organic solvent is dichloroethane. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 issued) (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -------- -Line —-------- A8B8C8D8 Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs f: printed by cooperatives 1239956 Sixth, the scope of patent application 12.-a compound, as shown in the following formula (IV): COOH (IV) where R is the Ci_C6 courtyard. 13. The compound as claimed in claim 12, wherein R is methyl, ethylpropyl, isopropyl, butyl, isobutyl, or tertiary butyl. 14. The compound as claimed in claim 12 wherein R is ethyl. This paper size applies to China National Standard (CNS) A4 (210 X 297)