KR810001043B1 - Process for the preparation of amino acid esters - Google Patents

Abstract

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Description

Preparation of amino acid esters

-메틸-3,4-디하이드록시 페닐 알라닌 유도체의 제조방법에 관한 것이다.The present invention provides novel compounds useful for the treatment of hypertension, in particular of general formula (1)

A method for producing a -methyl-3,4-dihydroxy phenyl alanine derivative.

Food,

n is 0,1,2 or 3

m is 0,1,2 or 3

A ₁ and A ₂ are each hydrogen or a lower alkanoyl group.

R ₁ and R ₂ are each hydrogen or alkyl having 1-3 carbon atoms,

R ₃ is selected from the group consisting of the following (A) and (B).

(A) a monocycle or bicyclic heterocycle group (each of the heterocycle group) containing one or two heteroatoms and 3-12 hexcarbon atoms selected from N and S wherein at least one is N Ring contains 5-6 members) and

(B) X -R ₄ groups

Wherein X is -O-, -S-, or -NH-,

R ₄ is an acyl group of a monocycle carboxylic acid containing up to 21 carbon atoms and containing (1) a hydrocarbon group or (2) one or more heteroatoms in an organic non-cycle or ring.

The present invention also includes pharmaceutically acceptable acid addition salts of the compounds of the general formula (1).

-메틸-3,4-디하이드록시페닐 알라닌으로 고혈압을 바람직하게 치료하는 것이 본 분야에 공지되어 있다. D-형을 제거하여 독성을 감소시키고 효과를 증가시켰다(미국특허 제3,344,023호 및 영국특허 제936,074호 참조).

-메틸-3,4-디하이드록시페닐 알라닌의 L-이성체는 보통 L-

-메틸도파 또는 메틸도파로 부른다. 또한 L- 또는 DL-

-메틸-3,4-디하이드록시페닐 알라닌의 알킬 에스테르도 비경구적 투여로 고혈압의 응급 치료에 유용함이 공지되어 있다(미국특허 제3,230,143호 참조). 특수 구조를 가진 DL 또는 L-

-메틸-3,4-디하이드록시페닐 알라닌의 기타 에스테르 및 유도체들도 고혈압의 치료에 또한 유용하며 어떤 신규 화합물들보다 높은 활성을 가지므로 공지 화합물보다 낮은 투여량이 필요함을 알게 되었다.It has been proposed in the art that various alanine compounds are useful for the treatment of hypertension (see US Pat. No. 2,868,818). In addition, since the D-form of the compound is therapeutically inactive and only L-form is therapeutically active, L-

It is known in the art to preferably treat hypertension with -methyl-3,4-dihydroxyphenyl alanine. Elimination of D-form reduced toxicity and increased effects (see US Pat. No. 3,344,023 and UK Pat. No. 936,074).

L-isomers of -methyl-3,4-dihydroxyphenylalanine are usually L-

It is called methyldopa or methyldopa. Also L- or DL-

Alkyl esters of -methyl-3,4-dihydroxyphenyl alanine are also known to be useful for the emergency treatment of hypertension by parenteral administration (see US Pat. No. 3,230,143). DL or L- with special structure

It has been found that other esters and derivatives of -methyl-3,4-dihydroxyphenyl alanine are also useful in the treatment of hypertension and require lower dosages than known compounds as they have higher activity than any new compound.

Accordingly, it is an object of the present invention to provide novel classes of compounds that are effective in treating hypertension, and another object is to provide a group of compounds that are more effective in treating hypertension. Another object is to provide a method for preparing any compound, and another object relates to a method for treating hypertension by using a new compound, and to provide a novel composition useful for treating hypertension. Other objects will be apparent from the description of the process of the invention.

In a preferred embodiment of the invention n and m are 0 or 1; R ₁ and R ₂ are hydrogen or methyl; R ₃ is a heterocycle ring of the following general formula which may be substituted by a lower alkyl group of 1-3 carbon atoms,

Or R ₅ is XR ₄ wherein X is —0- or —NH—, R ₄ is an acyl group from an alkanoic acid containing 2-5 carbon atoms, and R ₅ and R ₆ are hydrogen.

The present invention also encompasses esters of the L-isomers of amino acids having the general formula (1) 'following the complete isomerization of D isomer or a pharmaceutically acceptable acid addition salt thereof.

Food,

n, m, R ₁ , R ₂ and R ₃ are as described above.

즉, 좌선성 형태일지라도, L-배열은 입체 배열에 관한 것이지 광학적 회전에 관한 것이 아니다. 또한 흑종의 경우에 R₁과 R₂가 상이할 때 그들이 부착된 탄소원자가 또한 부재 탄소원자이므로 L 이나 D배열이 존재할 수 있다는 사실에 특히 주의하여야 한다.Regarding the L-isomer, it should be noted that the subsidiary carbon atom contains amino and methyl groups in the acid portion of the molecule, and this part of the molecule is called L-array. In this case, the L-stereoscopic arrangement of the optical isomers

That is, even in the left linear form, the L-array is about stereoscopic alignment and not about optical rotation. Also, in the case of melanoma, particular attention should be paid to the fact that when R ₁ and R ₂ are different, the carbon atoms to which they are attached are also absent carbon atoms and therefore L or D arrangements may be present.

이성체로 표시되므로 그들의 입체 배열은 결정되지 않았다. 여하튼

및

이성체 모두 그들의 입체 배열에 관계없이 활성이 있다.As pointed out later, the two isomers of this part of the compound are active and these stereoisomers are separated, but they And

Since they are represented as isomers, their conformation has not been determined. anyway

And

Both isomers are active regardless of their conformation.

Also provided is a method of treating hypertension of an animal in hypertension consisting of administering to the animal a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof:

Food,

n, m, A ₁ , A ₂ , R ₁ , R ₂ and R ₃ are as described above.

In treating hypertension, the compounds of the present invention are generally administered in an amount of about 0.005-300 mg / kg, preferably about 0.05-100 mg / kg, in the body weight of the animal. In a more suitable embodiment the compound is administered in an amount of about 0.1-25 mg / kg of body weight. In this regard, the dosage should be adjusted according to the activity of the compound, the response required to reduce blood pressure and the body weight of the animal. Within this range, there is a tendency to be provided at lower dosages than more effective compounds and at higher dosages than lower activity compounds.

Animal under hypertension, comprising administering to the animal a therapeutically effective amount of an isomer ester of an amino acid having the general formula (1) 'or a pharmaceutically acceptable acid addition salt thereof A method for treating hypertension is provided.

Food,

n, m, R ₁ , R ₂ and R ₃ are as described above.

When the L-isomer of the compound of the present invention is actually present in the absence of the D isomer, the required dose of the L isomer is about half of the racemate dose since the D isomer is not therapeutically active.

Since the compound of the present invention changes to some extent, the racemate of the less active compound needs to be administered several times, and in general, the compound can be administered within the above dose.

According to the invention there is also provided a pharmaceutical composition consisting of an inert, pharmaceutically acceptable diluent and a compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof.

Food,

n, m, A ₁ , A ₂ , R ₁ , R ₂ and R ₃ are as described above.

In a single dosage form of the compositions of the invention the active compound is generally present in the composition in an amount of 1-2,000 mg, more preferably in an amount of 5-1,000 mg. In a more preferred embodiment the active ingredient is present in an amount of 10-500 mg. A single dosage form of the compound is administered in a single, slow acting single dose, or in small amounts, several times a day, generally 2-8 times.

Pharmaceutical compositions comprising an inert pharmaceutically acceptable diluent according to the invention and an ester of an isomer of an amino acid having the general formula (1) 'and then a pharmaceutically acceptable acid addition salt thereof are completely released. Is provided.

Food,

n, m, R ₁ , R ₂ and R ₃ are as described above.

There is a need for reduced dosages of the L isomers in which the D isomer is completely free when compared to racemate in the method of treatment. However, the difference in activity of various compounds requires different dosages, for example, some compounds are much more active than others, so their racemates require less than L isomers of less reactive compounds. It is in the said range.

According to the present invention, a compound of the following general formula (1) or an acid addition salt thereof is provided by esterifying a compound of the following general formula (3) with an acid derivative of the following general formula (2) or an acid addition salt thereof.

Food,

n, m, A ₁ , A ₂ , R ₁ , R ₂ and R ₃ are as described above.

Y is -COOH, -CO halogen or -carboxylic acid salt,

X ₁ is a hydroxyl, alkali metal —0-, halogen or substituted —SO ₃ — group.

If necessary, stereoisomers can be separated by (1) fractional crystallization of one stereoisomer from a solution or (2) forming a porous isomer with optically active acids to crystallize one of the porous isomers from the solution.

Acid derivatives of the general formula

Or an acid addition salt thereof is esterified with a compound of the following general formula (3) under ordinary reaction conditions to provide a process for preparing the following general formula (1) 'compound.

Food,

Y is -COOH, -CO halogen or -carboxylic acid salt,

n, m, R ₁ , R ₂ and R ₃ are as described above.

X is a hydroxyl, alkali metal -0-, halogen or substituted -SO ₃ -group.

In a preferred embodiment of the invention the process is carried out with the amino acid portion of the molecule being in a L-stereo array.

표시 (-CH ₂ ) n ＂and＂ (-CH ₂ ) m ＂indicate that n and m are 0 or 1

Branched chain alkylene groups such as;

In an embodiment of R ₃ , in formula R ₃ , at least one contains N ... 5-6 member atoms, the predicate may contain one or two nitrogen atom rings, any sulfur atom and 3-12 carbon atom rings. It means the compound containing. The compound also includes one or two rings of 5-6 members which may be substituted with halogen, hydroxyl, amino or other groups in each ring.

의 아실기를 의미한다. 실시예에서 지적한 바와 같이 R기는 알킬기, 헤테로싸이클기나 또는 이와 같은 기타기이며, 이 R기의 성질은 한계성이 없고 광범위하게 변화될 수 있다.＂R ₄ contains up to 21 carbon atoms … The predicate, which is an acyl group of a monocycle carboxylic acid, is a general formula wherein R ₄ is a hydrocarbon having one or less heteroatoms containing a total of 1-21 carbon atoms, or R is an acyclic or monocyclic group.

Means acyl. As pointed out in the examples, the R groups are alkyl groups, heterocycle groups, or other such groups, and the properties of these R groups are not limiting and can vary widely.

The term “pharmaceutically acceptable acid addition salts” is a well known expression in the art and includes compounds prepared by the reaction of free bases with inorganic or organic acids, such as salts of hydrochloride, hydrobromide, sulfuric acid, etc. It includes.

The phrase “isomer of amino acid in which the D isomer is actually free” means that the D isomer is present in an amount of no greater than 10%. However, it is preferred that the D isomer is not actually present in the composition. In the following examples, when the L isomer is pointed out, the compound has an L configuration of 100% (ie at least 99%).

The term “protecting group” refers to any group protecting an amino or hydroxyl group, and suitable protecting groups for nitrogen atoms include carbobenzyloxy, paramethoxycarbenzyloxy, trifluoroacetyl, HCl and the like. Suitable protecting groups for hydroxyl groups include diphenyl ketal for hydroxyl groups and acetyl and carbobenzyloxy for each such group as well as other groups. Substituents in the quenched -SO ₃ -group may be any group as the group is easily separated during the esterification reaction and the nature of this group is not limiting.

The term “reducing group” means any group which may be substituted by a hydrogen atom or partially or completely saturated by hydrogen, such groups as —CH═CH—, —C≡C—, —halogen, NO ₂ , --CN, etc.

의 화합물과 같은 활성화된 카복실산 유도체를 의미한다.The expression “acylating agent” is a general formula wherein carboxylic anhydride (including mixed anhydride) or R ₈ is an organic group and X ₂ is an easily removable group such as halogen, P-nitrophenoxy, phenoxy and the like.

It means an activated carboxylic acid derivative such as a compound of.

It is sometimes desirable to separate this mixture into L and D isomers when the racemic compound is formed according to the synthesis of the present invention. These isomers may be separated at any time in the synthesis, which is usually preferred before the final product is formed. In another example (when R ₁ and R ₂ are different groups and the acid moiety is L configuration), a porous isomeric mixture is formed as a final product which can be crystallized or separated directly by crystallization to form simple derivatives. However, when a single isomer is desired, it is more preferable to start with the desired isomer (ie L isomer). Perforated isomers of the racemic mixtures formed according to the invention for separation can also be prepared. In this case, optically active acids such as tartaric acid, 10-camphor sulfonic acid, malic acid, pyroglutamic acid, menthoxyacetic acid and the like can be used. The choice of a particular mountain is a necessity and obvious to those skilled in this field.

The compounds of the present invention may be used in the form of compositions which are preferably administered in unit dosage form such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions. To prepare solid compositions such as tablets, the basic active ingredient is conventionally used, such as corn starch, lactose, sugar, sorbitol, talc, stearic acid, magnesium stearate, calcium phosphate, gums and fractionally similar substances such as pharmaceutical diluents or carriers. Mix with purified ingredients. Tablets or pills of the new composition may be plated or prepared in doses that provide the benefits of sustained release or scheduled continuity of the enclosed drug, e.g. tablets or pills may consist of an internal preparation and an external preparation. The preparation ingredients are stacked on top of the internal preparation ingredients. The two components prevent degradation in the stomach and retard the internal components from completely passing or liberating into the duodenum, allowing them to separate in the intestine. Various materials for enteric coatings can be used and include such mixtures of many polymeric or polymeric acids with shellac, shellac and cetyl alcohol, cellulose acetate and the like. Particularly advantageous enteric coatings include styrene maleic acid copolymers with supporting materials that contribute to the enteric properties of the coating. The compounds are also useful when administered in the form of suppositories or as penetration enhancers such as dimethyl sulfoxide.

Liquid forms that can be mixed to administer the novel compositions of the present invention include edible oils such as cottonseed oil, sesame oil, coco palm oil, peanuts, as well as emulsions suitably sweetened with pensions and similar pharmaceutical excipients. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymatic cellulose, methylcellulose polyvinylpyrrolidone, gelatin. Sterile suspensions or solutions are required for parenteral use, and isotonic preparations containing suitable preservatives are preferred for injectable solutions.

As used herein, a single dosage form refers to physically discrete units suited as unitary dosages for warm-blooded animals, each unit being combined with a desired pharmaceutical diluent, carrier, or excipient in a predetermined amount so as to obtain the desired therapeutic effect. Contains the active substance. The specification of the novel unit dosage forms of the present invention is directed to the field of preparing active substances for the treatment of mixed race animals as described in detail herein (a) the nature of the active substance and the particular therapeutic effect to be achieved. It is indicated according to inherent limitations. Examples of suitable single oral dosage forms according to the invention include tablets, capsules, pills, powders, packages, granules, oblaart, cachets, one full spoon, one drop full, ampoules, vials, isolated drainage of any of the above. And other forms described herein.

Hereinafter, the present invention will be described in detail with reference to Examples. All parts are parts by weight. The pressure reduction used in the following examples is 15-25 mmHg (unless otherwise indicated) at 25-35 ° C. and the resulting product is sometimes a solvent compound when reduced pressure is carried out to remove the solvent. Therefore, all solvents are referred to in the form of “concentrated” products even if all solvents have been removed except those bound to the product.

Example 1

Preparation of 2-acetamidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride

의 에틸 에테르 가하였다. 형성된 침전을 500㎖의 에틸 에테르로 세척하고, 6

의 10% 에탄올-90% 에틸 아세테이트(용량에 의한), 150㎖의 포화 탄산나트륨 용액 및 100g의 탄산나트륨과 함께 진탕하였다. 유기 추출액을 무수 황산 마그네슘 상에서 건조시키고 여과하여 감압하에 농축시키면 아세트아미도 에틸 에스테르의 유리 염기가 얻어진다. 이 염기를 300㎖의 이소프로판올 중의 15g의 푸마르산으로 처리하고 충분한 에틸 에테르를 가하면 푸마레이트염이 침전되었다. 푸마레이트 염을 이소프로판올로부터 충분한 에틸 에테르를 가하여 한번 더 침전시킨 다음 200㎖의 10% 에탄올-90% 에텔 아세테이트(용량에 의한), 200㎖의 포화탄산나트륨 용액 및 20g 고체 탄산나트륨과 함께 진탕하여 전과 같이 유리 염기로 다시 전환시켰다. 유리 염기는 100㎖의 무수 에탄올에 용해시키고 10㎖의 9.6N 염산을 가하고 1

의 에틸 에테르를 가하여 침전시킴으로서 하이드로클로라이드염으로 전환시켰다. 위에서 실시한 바와 같이 에탄올-에틸 에테르로부터 세번 침전시킨 후 박층 크로마토그래피 [50% 메탄올-50% 벤젠(용량에 의한)으로 전개한 형광 실리카겔판]에서 Rf=0.57인 15.1g(15%)의 2-아세트아미도 에틸 L-3-(3,4-다하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드염이 얻어졌다.88.3 g (0.30 mole) of L-3- (3,4-dihydroxyphenyl) -2-methylalany hydrochloride ethanol solvate (by concentrating the ethanol solution of hydrochloride under reduced pressure) and 146.4 g ( 1.42 mol) of N-acetylethanolamine was heated to 104-108 ° C. 84.8 g (0.713 mol) of thionyl chloride were added over 15 minutes with stirring. The reaction mixture develops severe foam during the addition. After the addition was complete the reaction mixture was stirred for 18 h at 104-108 ° C. and additional 42.4 g (0.357 mole) of thionyl chloride was added over 7 min. The reaction mixture was stirred at 104-108 ° C. for 3 h and then cooled to 30 ° C. and concentrated under reduced pressure to give a viscous oil. This oil was slurried with 100 mL of chloroform to remove chloroform under reduced pressure. This was repeated three more times and the oil was washed with 100 ml of benzene and decanted. The residue was dissolved in 700 ml of isopropanol and 6

Ethyl ether was added. The precipitate formed was washed with 500 ml of ethyl ether, 6

Was shaken with 10% ethanol-90% ethyl acetate (by volume), 150 ml of saturated sodium carbonate solution and 100 g of sodium carbonate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the free base of acetamido ethyl ester. This base was treated with 15 g of fumaric acid in 300 mL of isopropanol and sufficient ethyl ether was added to precipitate the fumarate salt. The fumarate salt was precipitated once more by adding sufficient ethyl ether from isopropanol and then shaken with 200 ml of 10% ethanol-90% ether ether (by volume), 200 ml of saturated sodium carbonate solution and 20 g of solid sodium carbonate to free as before. Switch back to base. The free base is dissolved in 100 ml of absolute ethanol and 10 ml of 9.6N hydrochloric acid is added 1

Was converted to the hydrochloride salt by precipitation of ethyl ether. 15.1 g (15%) of 2-1 with Rf = 0.57 in thin layer chromatography [fluorescence silica gel plate developed by 50% methanol-50% benzene (by volume)] after three precipitations from ethanol-ethyl ether as described above Acetamido ethyl L-3- (3,4-polyhydroxyphenyl) -2-methylalanine hydrochloride salt was obtained.

Assay for C ₁₄ H ₂₀ N ₂ O ₅ HCl:

Theoretical: C, 50.52; H, 6. 36; N, 8.41

Found: C, 50.49; H, 6.69; N, 8.49

Example 2

Preparation of 3-acetamidopropyl L-3- (3,4-dihydroxyphenyl) -2-methylalanineate hydrogen oxalate hydrate

(Sesqui) 수화물에 가하고 혼합물을 증기욕에서 가열하였다. 2시간동안 가열 후 혼합물을 25㎖의 벤젠에 용해된 7.5㎖의 디메틸포름아미드로 희석하고 가스 발생이 정지될 때까지 증기욕에서 교반하였다. 100㎖의 벤젠을 가하고 조잡한 아황산 에스테르를 여과하여 제거하고, 100㎖의 벤젠, 100㎖의 클로로포름 및 100㎖의 에테르로 세척하고 감압하에 건조시키면 융점이 199℃(분해)인 280g의 아황산 에스테르 중간물질이 얻어졌다. 13.7g의 조잡하 아황산 에스테르 중간물질, 24.98g(0.212몰)의 N-아세틸프로판올아민 및 무수 디메틸포름아미드의 혼합물을 증기욕에서 20시간 동안 교반하고 냉각시켰다. 반응 혼합물을 200㎖씩의 에틸 에테르로 6번, 200㎖씩의 염화메틸렌으로 4번 세척하고, 감압하에 건조시켰다. 잔류하는 반-고체 물질을 200㎖의 20% 에탄올-30% 에틸 아세테이트(용량에 의한), 20㎖의 포화 탄산나트륨 용액 및 20g의 고체 탄산나트륨과 함께 교반하였다. 유기 추출액을 무수 황산 마그네슘 상에서 건조시키고 여과한 후 여액을 50㎖의 에탄올 중의 3.2g의 옥살산 용액에 가하였다. 감압하에 용매를 제거한 다음 잔유물을 500㎖의 에탄올에 용해시키고 500㎖의 에틸 에스테르를 가하면 침전이 생긴다. 생성물을 다시 50㎖의 에탄올에 용해시키고 500㎖의 에틸 아세테이트를 가하여 침전시키면 박층 크로마토그래피 [25% 메탄올-75% 클로로포름(용량에 의한)으로 전개한 형광 실리카겔판]에서 Rf=0.45인 3-아세트아미도프로필 L-3-(3,4-다하이드록시페닐)-2-메틸알라니네이트 하이드로겐 옥살레이트 수화물이 얻어졌다.250 g L-3- (3,4-dihydroxyphenyl) -2-methylalanine at 25 ° C. with 275 ml of thionyl chloride

It was added to Sesqui hydrate and the mixture was heated in a steam bath. After heating for 2 hours the mixture was diluted with 7.5 ml dimethylformamide dissolved in 25 ml benzene and stirred in the steam bath until gas evolution ceased. 100 ml of benzene is added and the crude sulfurous acid ester is filtered off, washed with 100 ml of benzene, 100 ml of chloroform and 100 ml of ether and dried under reduced pressure to 280 g of sulfite ester intermediate having a melting point of 199 ° C. (decomposition). Was obtained. A mixture of 13.7 g of crude sulfite ester intermediate, 24.98 g (0.212 mol) of N-acetylpropanolamine and anhydrous dimethylformamide was stirred and cooled in a steam bath for 20 hours. The reaction mixture was washed 6 times with 200 mL of ethyl ether and 4 times with 200 mL of methylene chloride and dried under reduced pressure. The remaining semi-solid material was stirred with 200 mL of 20% ethanol-30% ethyl acetate (by volume), 20 mL of saturated sodium carbonate solution and 20 g of solid sodium carbonate. The organic extract was dried over anhydrous magnesium sulfate and filtered and the filtrate was added to 3.2 g of oxalic acid solution in 50 ml of ethanol. After removal of the solvent under reduced pressure, the residue is dissolved in 500 ml of ethanol and 500 ml of ethyl ester is added to precipitate. The product was again dissolved in 50 ml of ethanol and precipitated by addition of 500 ml of ethyl acetate. 3-acetic with Rf = 0.45 in thin layer chromatography [fluorescence silica gel plate developed by 25% methanol-75% chloroform (by volume)]. Amidopropyl L-3- (3,4-polyhydroxyphenyl) -2-methylalanineate hydrogen oxalate hydrate was obtained.

Analysis of C ₁₅ H ₂₂ N ₂ O ₅ ㆍ C ₂ H ₂ O ₄ ㆍ H ₂ O:

Theoretic value: C, 48.80; H, 6. 26; N, 6.69

Found: C, 48.73; H, 6. 85; N, 6.68

Example 3

Preparation of 2-methylthioethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanineate hydrogen oxalate

275 ml of thionyl chloride was added 250 g of L-3- (3,4-dihydroxyphenyl) -2-methylalanineate at 25 ° C. to the hydrate and the mixture was heated in a steam bath for 2 hours, followed by a thick reaction. The mixture was diluted with 7.5 ml dimethylformamide in 25 ml benzene and stirred in a steam bath until gas evolution ceased. 100 ml of benzene was added and filtered to recover crude sulfurous acid ester, washed with 100 ml of benzene, 100 ml of chloroform and 100 ml of ether and dried under reduced pressure. 280 g of sulfite ester intermediate having a melting point of 199 ° C (decomposition) Obtained. A mixture of 30 g crude sulfurous acid ester, 34.6 g (0.375 mol) 2-dihydroxyethyl methylsulfide and 6 g anhydrous dimethylformamide was stirred and cooled in a steam bath for 28 hours. The reaction mixture was washed four times with 100 ml of ethyl ether and three times with 100 ml of methylene chloride and the remaining material was washed with 250 ml of 20% ethanol-80% ethyl acetate (by volume) and 30 ml of saturated sodium carbonate. The solution was stirred with 60 g of solid sodium carbonate and filtered. The insoluble material was washed three times with 250 mL of 20% ethanol-80% ethyl acetate (by volume), combined with the original ethanol-ethyl acetate extract and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. A total of 2.3 g product was eluted with 25% methanol-75% chloroform (by volume) mixture. This product was added to 1.3 g of oxalic acid solution in 25 ml of ethanol and then converted to the oxalate salt by precipitation with sufficient ethyl ether. Three more precipitations were carried out using ethanol to dissolve the product and ethyl ether to precipitate and the melting point was 85-90 ° C. (decomposition) and thin layer chromatography [25% methanol-75% chloroform (by volume)] Electric fluorescent silica gel plate] to obtain 300 mg of 2-methylthioethyl L-3- (3,4-polyhydroxyphenyl) -2-methylalanine hydrogen oxalate having a uniform Rf = 0.83.

Analysis of C ₁₃ H ₁₉ NO ₄ ㆍ C ₂ H ₂ O ₄ :

Theoretic value: C, 47.99; H, 5. 64; N, 3.73

Found: C, 48.00; H, 6. 10; N, 4.07

Example 4

Segmentation of racemized pivaloyloxymethyl 3- (3,4-dihydroxyphenyl) -2-methylalaninate by direct recrystallization

Racemized pivaloyloxymethyl 3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride was prepared as in Example 23.

30 g of racemized pivaloyloxymethyl 3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride was slurried at 100C in 100 ml of 1.0N hydrochloric acid and the excess solid was filtered off. . The saturated solution was aged at 35 ° C. with pivaloyloxymethyl D-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride hydrate and the mixture was cooled to 20 ° C. in 30 minutes to 20 ° C. It was left for 30 minutes at. The separated material was separated by filtration, washed twice with 5 ml cold water and dried at 0.1-0.5 mm and 20-15 ° C. for 20 hours, and pivaloyloxymethyl D-3- (3,4-dihydroxyphenyl) 2-Methylalanine hydrochloride hydrate was obtained.

The mother liquor from the previous step was heated to 35 ° C. and aged at 35 ° C. with pivaloyloxymethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride and the mixture was stirred for 30 minutes. Cool to 20 ° C. over and leave at 20 ° C. for half hour. The precipitate was separated by filtration, washed twice with 5 ml of cold water, dried at 0.1-0.5 mm and 20-25 ° C. and then pivaloyloxymethyl L-3- (3,4-dihydroxyphenyl) -2-methyl Alanine hydrochloride hydrate was obtained.

Example 5

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드 이수화물(

-이성체)의 제조A. By Discrimination

Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride dihydrate (

Isomers)

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드 (

-및

- 이성체 혼합물)을 50㎖의 (따뜻한) 95% 에탄올(5% 물)에 용해시키고, 무수 에테르로 엷은 혼탁액이 되도록 희석하여 결정화가 일어나도록 숙성시키고 긁어 주었다. 5-10℃에서 12시간동안 냉각시킨 후 침전 고체를 회수하여 70℃에서 건조시켰다. 95% 에탄올-5% 물-에틸에테르(용량에의한)로부터 부가적인 유사한 재결정화를 행하였더니 123-126℃(분해)에서 용융하는 물질이 얻어졌다. 95% 에탄올로부터의 최종 재결정은 융점이 129-131℃(분해)(70℃에서 철야 건조한)이고, 박층 크로마토그래피 [형광 실리카겔판, 50% 메탄올-50% 벤진(용량에 의한) 용매]에서 균일한, Rf=0.7인 이수화물로서

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸 알라니네이트 하이드로클로라이드 (

-이성체)이 얻어졌다.10 g of Example 2

Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride (

-And

Isomeric mixture) was dissolved in 50 ml (warm) 95% ethanol (5% water), diluted with anhydrous ether to a light turbid solution, aged and scratched to crystallization. After cooling at 5-10 ° C. for 12 hours, the precipitated solid was recovered and dried at 70 ° C. An additional similar recrystallization from 95% ethanol-5% water-ethyl ether (by volume) resulted in a material which melted at 123-126 ° C. (decomposition). Final recrystallization from 95% ethanol has a melting point of 129-131 ° C. (decomposition) (dry overnight at 70 ° C.) and homogeneous in thin layer chromatography [fluorescent silica gel plate, 50% methanol-50% benzine (by volume) solvent] As dihydrate with Rf = 0.7

-Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methyl alanate hydrochloride (

Isomers).

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드 이수화물(

-이성체)의 제조B.

Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride dihydrate (

Isomers)

-이성체가 풍부한

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드 이수화물

-이성체의 첫번째 결정화로부터의 모액을 15-20㎜ 및 40-45℃에서 농축시켰다. 잔사를 20㎖이 따팀한 95% 에탄올(5%물)에 용해시키고 엷은혼탁액이 되도록 에틸 아세테이트로 희석하여 숙성시키고 긁어 주었더니

-이성체가 풍부한

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸 알라니네이트 하이드로클로라이드 수화물의

-이성체가 침전되었다. 95% 에탄올(5% 문) 및 에틸 아세테이트로부터 부가적으로 침전시켰더니 에틸 아세테이트 용매화물로서 Rf=0.7 [박층 크로마토그래피, 형광 실리카겔판, 50% 메탄올-50% 벤젠(용량에 의한) 용매]인

-이성체가 얻어졌다.Equivalent

Isomer-rich

Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride dihydrate

The mother liquor from the first crystallization of the isomers was concentrated at 15-20 mm and 40-45 ° C. The residue was dissolved in 20 ml of warm 95% ethanol (5% water), diluted with ethyl acetate to give a light turbidity, and aged.

Isomer-rich

Of succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methyl alanate hydrochloride hydrate

Isomers precipitated out. Additional precipitation from 95% ethanol (5% door) and ethyl acetate gave Rf = 0.7 [thin layer chromatography, fluorescent silica gel plate, 50% methanol-50% benzene (by volume) solvent] as ethyl acetate solvate.

Isomers were obtained.

Example 6

Preparation of Pivaloyloxymethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride

0.95 g (4.0 mmol) L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesqui hydrate and 0.61 g (4.06 mmol) pivaloyloxy in 5 ml of dimethyl sulfoxide The methyl chloride solution was stirred at 20-25 ° C. for 23 hours. The solution was diluted with 10 ml of distilled water, passed through a 5 g weakly basic anion exchange resin column on a basic cycle, eluted with a water fraction, and then combined with the fraction showing the positive ferric chloride test. Was added to the column. Unreacted L-3- (3,4-dihydroxyphenyl) -2-methylalanine was eluted with distilled water until a negative ferric chloride test was obtained and the ester was eluted with 1N acetic acid. When 50 ml of the ester fraction (pH 3.2) was acidified with 1N hydrochloric acid to pH = 2.0 and lysified at 0.1-0.3 mm for 20 hours, pivaloyloxymethyl L-3- (3, 4-dihydroxyphenyl) -2-methylalanine hydrochloride was obtained.

Analysis of C ₁₆ H ₂₃ NO ₆ ㆍ HCl 1/3 HC ₂ H ₄ O ₂

Theoretical: C, 52.11; H, 6.69; N, 3.58

Found: C, 52.11; H, 6. 49; N, 3.73

Example 7

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드의 제조

Preparation of Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride

-클로로에틸)-숙신이미드의 용액을 20-25℃에서 23시간 동안 교반하였다. 10㎖의 증류수로 용액을 희석하여 염기성 싸이클상의 5g의 약염기성 음이온 교환수지를 포함한 컬럼을 통과시키고 물 유분으로 용출시킨 후 양성염화 제2철 시험을 나타내는 유분을 합쳐서 산성 싸이클상의 3g의 약산성 양이온 교환수지에 컬럼에 가하였다. 음성 염화 제2철 시험을 얻을 때까지 비 반응된 L-3-(3,4-디하이드록시페닐)-2-메틸알라닌을 증류수로 용출시킨 다음 에스테르를 1N 아세트산으로 용출시켰다. 55㎖의 에스테르 유분(pH 3.2)을 pH=2.0이 되도록 1N 염산으로 처리하고 0.1-0.3㎜에서 20시간 친액화하였더니

-숙신이미도 에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드 아세트산 용매화물이 얻어졌다.0.95 g (4.0 mmol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesquihydrate with 5 mL of dimethyl sulfoxide and 0.65 g (4.0 mmol) of N- (

A solution of -chloroethyl) -succinimide was stirred at 20-25 ° C. for 23 hours. Dilute the solution with 10 ml of distilled water, pass through a column containing 5 g of weakly basic anion exchange resin on the basic cycle, elute it with water fraction, and combine the fractions representing the ferric chloride test to add 3 g of weakly acidic cation exchange on the acid cycle. The resin was added to the column. Unreacted L-3- (3,4-dihydroxyphenyl) -2-methylalanine was eluted with distilled water until a negative ferric chloride test was obtained and then the ester was eluted with 1N acetic acid. 55 ml of ester fraction (pH 3.2) was treated with 1N hydrochloric acid to pH = 2.0 and lyophilised at 0.1-0.3 mm for 20 hours.

Succinimido ethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride acetic acid solvate was obtained.

Analysis of C ₁₆ H ₂₀ N ₂ O ₆ ㆍ HCl 1/3 C ₂ H ₄ O ₂

Theoretical: C, 50.96; H, 5.73; N, 7.13

Found: C, 50.48; H, 6. 13; N, 6.77

Example 8

Preparation of 3-acetamidepropyl L-3- (3,4-dihydroxyphenyl) -2-methylalanineate hydrogen oxalate hydrate

275 mL of thionyl chloride was added to 250 g of L-3- (3,4-dihydroxyphenyl) -2-methylalaninate sesquihydrate at 25 ° C. and heated in a steam bath. After heating for 2 hours, the concentrated reaction mixture was diluted with 7.5 ml dissolved in 25 ml of benzene to dimethylformamid and stirred in a steam bath until gas evolution ceased. 100 ml of benzene was added and the crude sulfurous acid ester was recovered by filtration, washed with 100 ml of benzene, 100 ml of chloroform and 100 ml of ether, dried under reduced pressure, and 280 g of sulfite ester intermediate having a melting point of 199 ° C. (decomposition). Was obtained.

A mixture of 13.7 g crude sulfurous acid ester intermediate, 24.98 g (0.212 mol) N-acetylpropanolamine and 2 g anhydrous dimethylformamide was stirred and cooled in a steam bath for 20 hours. The reaction mixture was washed 6 times with 200 mL of ethyl ether and 4 times with 200 mL of methylene chloride and dried under reduced pressure. The remaining semi-solid material was stirred with 200 mL of 20% ethanol-80% ethyl acetate (by volume), 20 mL of saturated sodium carbonate solution and 20 g of solid sodium carbonate. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was added to a 3.2 g oxalic acid solution in 50 mL of ethanol. The solvent was removed under reduced pressure, dissolved in 50 mL of ethanol and precipitated by addition of 500 mL of methether. The product was again dissolved in 50 ml of ethanol and precipitated by addition of 500 ml of ethyl acetate and precipitated by thin layer chromatography [Fluorescence silica gel plate developed with 25% methanol-75% by chloroform (by volume)] with Rf = 0.45. Acetamidopropyl L-3- (3,4-polyhydroxyphenyl) -2-methylalaninate hydrogen oxalate hydrate was obtained.

Analysis of C ₁₅ H ₂₂ N ₂ O ₅ ㆍ C ₂ H ₂ O ₄ ㆍ H ₂ O

Theoretic value: C, 48.80; H, 6. 26; N, 6.69

Found: C, 48.73; H, 6. 85; N, 6.68

Example 9

Preparation of 2-acetamidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride

의 에틸 에테르에 가하였다. 형성된 침전을 500㎖의 에틸 에테르로 세척하고, 6

의 10% 에탄올-90% 에틸 아세테이트(용량에 의한), 150㎖의 포화 탄산나트륨 용액 및 100g의 탄산나트륨과 함께 진탕하였다. 유기 추출액을 무수 황산 마그네슘 상에서 건조하고 여과하여 감압하에 농축시키면 아세트아미도 에틸 에스테르의 유리 염기가 얻어졌다. 이 염기를 300㎖의 이소프로판올 중의 15g의 푸마르산으로 처리하고 에틸 에테르를 충분히 가하여 침전시켰다. 푸마레이트 염을 이소프로판올로부터 에틸 에테르를 충분히 가하여 한번 더 침전시킨 후 200㎖의 10% 에탄올-90% 에텔 아세테이트(용량에 의한), 200㎖의 포화탄산나트륨 용액 및 20g 고체 탄산나트륨과 함께 진탕하여 상기와 같이 유리염기로 전환시켰다. 유리염기를 100㎖의 무수 에탄올에 용해시키고 10㎖의 9.6N 염산을 가하고 1

의 에틸 에테르를 가하여 침전시킴으로서 하이드로클로라이드 염으로 전환시켰다. 상기 실시한 바와 같이 에탄올-에틸 에테르로부터 3번 침전시킨 후 박층 크로마토그래피 [50% 메탄올-50% 벤젠(용량에 의한)로 전개한 형광 실리카겔판]에서 Rf=0.57인 2-아세트아미도에틸 L-3-(3,4-다하이드록시페닐)-2-메틸 알라니네이트 하이드로클로라이드가 얻어졌다.88.3 g (0.30 mole) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride ethanol solvate (by concentration of ethanol solution of hydrochloride under reduced pressure) and 146.4 g (1.42 mole) ) Slurry of N-acetylethanolamine was heated to 104-108 ° C. under nitrogen and 84.8 g (0.713 mol) of thionyl chloride was added over 15 minutes with stirring. The reaction mixture was foamed vigorously during the addition and stirred for 18 hours at 104-108 ° C. after the addition was complete. Additional 42.4 g (0.357 mole) thionyl chloride was added in 7 minutes. The reaction mixture was stirred at 104-108 ° C. again for 3 and a half hours, then cooled to 30 ° C. and concentrated under reduced pressure to give a viscous oil. This oil was slurried with 100 mL of chloroform and the chloroform was removed under reduced pressure. This was repeated three more times and the oil was washed with 100 ml of benzene and decanted. The residue was dissolved in 700 ml of isopropanol and 6

To ethyl ether. The precipitate formed was washed with 500 ml of ethyl ether, 6

Was shaken with 10% ethanol-90% ethyl acetate (by volume), 150 ml of saturated sodium carbonate solution and 100 g of sodium carbonate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the free base of acetamido ethyl ester. This base was treated with 15 g of fumaric acid in 300 ml of isopropanol and precipitated by sufficient addition of ethyl ether. The fumarate salt was precipitated once more with sufficient addition of ethyl ether from isopropanol, followed by shaking with 200 ml of 10% ethanol-90% ether ether (by volume), 200 ml of saturated sodium carbonate solution and 20 g of solid sodium carbonate as above. Converted to free base. Free base is dissolved in 100 ml of absolute ethanol and 10 ml of 9.6N hydrochloric acid is added 1

Of ethyl ether was added to precipitate and converted to the hydrochloride salt. 2-acetamidoethyl L- with Rf = 0.57 in thin layer chromatography [fluorescent silica gel plate developed by 50% methanol-50% benzene (by volume)] after three precipitations from ethanol-ethyl ether as described above. 3- (3,4-polyhydroxyphenyl) -2-methyl alanate hydrochloride was obtained.

Analysis of C ₁₄ H ₂₀ N ₂ O ₅ ㆍ HCl

Theoretical: C, 50.52; H, 6. 36; N, 8.41

Found: C, 50.49; H, 6.69; N, 8.49

Example 10

A. Preparation of L-3- (3,4-diacetoxyphenyl) -2-methyl alaninate hydrochloride

To a mixture of 320 ml of glacial acetic acid and 24 ml of acetyl chloride, 69.4 g (0.291 mol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesqui hydrate were added in portions and the temperature of the reaction mixture Raising to near 50 ℃ makes clear solution. At this temperature additional 85 ml of acetyl chloride was added for 10 minutes and the resulting clear pale yellow solution was left at 20-25 ° C. for 14 hours. 400 ml of anhydrous ethyl ether is added for 15 minutes and a white solid begins to precipitate when the addition is almost complete. The mixture was stirred at 20-25 ° C. for 30 minutes at 5-10 ° C. for 1 hour and then cooled at −10 ° C. for 2 hours. The solids were collected by filtration, suspended in 150 ml of 30% acetic acid -70% ethyl ether (by volume), filtered and washed with 500 ml of ethyl ether. After drying at 70 ° C. for 2 hours, 83.7 g (88%) of L-3- (3,4-diacetoxyphenyl) -2-methylalanine hydrochloride was obtained.

B. Preparation of L-3- (3,4-diacetoxyphenyl) -2-methyl alanyl hydrochloride

6.60 g (0.020 mole) of L-3- (3,4-diacetoxyphenyl) -2-methylalanine hydrochloride and 40 ml of thionyl chloride was stirred at 60 ° C. for 2 hours until solution It was. Excess thionyl chloride was removed at 15-20 mm and 40-45 ° C. 50 mL of methylene chloride was added and the mixture was reconcentrated at 15-20 mm and 40-50 ° C. and this was repeated once more with another 50 mL of methylene chloride. After drying for 30 minutes at 0,2-0.5 mm and 40 ° C., L-3- (3,4-diacetoxyphenyl) -2-methylalanyl chloride was obtained.

C. Preparation of Succinimidomethyl L-3- (3,4-dihydroxyphenyl) -2-methyl alaninate hydrochloride hydrate

A solution of 3.50 g (10 mmol) of L-3- (3,4-diacetoxyphenyl) -2-methylalanyl chloride hydrochloride in 20 ml of chloroform was charged at 3.87 g (in 20 ml of chloroform at 25 ° C). 30 mmol) of N-hydroxymethyl succinimide and stirred at reflux for 20 hours to remove almost all chloroform at 15-20 mm and 30-40 ° C. The residue was diluted with 10 mL of 1N hydrochloric acid and extracted twice with 20 mL of ethyl ether. The aqueous extract was stirred at 20-25 ° C. under nitrogen for 5 hours. After lyophilization at 0.1-0.3 mm for 20 hours the residue was treated with 50 ml of 10% ethanol-90% ethyl acetate (by volume) solution, 5 ml of saturated sodium carbonate solution and 5 g of solid sodium carbonate. After filtration the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated at 15-20 mm and 30-40 ° C. The residue was redissolved in 25 ml of absolute ethanol, treated with 5 ml of 9.6 N ethanol anhydrous hydrogen chloride solution and concentrated under reduced pressure to give thin layer chromatography [Fluorescent silica gel plate, 30% methanol-70% benzine (by volume) solvent] Succinimidomethyl L-3- (3,4-polyhydroxyphenyl) -2-methylalaninate hydrochloride hydrate having a uniform Rf of 0.5 was obtained.

Example 11

A. Preparation of N-carboxy Anhydride of L-3- (3,4-dihydroxyphenyl) -2-methyl alanine

25 minutes until the phosgene gas is saturated through a mixture of 9.0 g (0.038 mol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesqui hydrate in 500 ml tetrahydrapran. Foamed. The temperature of the reaction mixture rose to 45 ° C. during the addition. The solution was stirred for another 50 minutes with nitrogen gas blowing and the insoluble material was removed by filtration through a pad with diatom and the fish solution was concentrated to an oil at 15-20 mm pressure and 30-35 ° C. The residue was dissolved in 75 ml of ethyl acetate and hexane was added to clouding point. After cooling at 0-5 ° C. for several days, the precipitated solid was collected by filtration and dried at 25 ° C. under a 0.1-0.3 mm pressure. N- of L-3- (3,4-dihydroxyphenyl) -2-methylalanine Carboxy anhydride was obtained.

B. Preparation of Succinimidomethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride hydrate

2.37 g (10 mmol) of N-carboxy anhydride of L-3- (3,4-dihydroxyphenyl) -2-methylalanine and 1.29 g (10 mmol) of N-hydroxymethyl succinimide The solution was heated at reflux until all the N-carboxy anhydride reacted. After concentration at 15-20 mm pressure and 30-40 ° C., the residue was extracted with 50 ml of benzene and 50 ml of ethyl acetate. The insoluble solid was shaken with 50 ml of 10% ethanol-90% ethyl acetate (by volume) mixture and 10 ml of saturated sodium carbonate solution. After filtration, the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 25 ml of absolute ethanol again, treated with 5 ml of 9.5 N ethanol anhydrous hydrogen chloride solution and concentrated under reduced pressure. Thin layer chromatography [Fluorescent silica gel plate, 30% methanol-70% benzine (by volume)] Solvent], a succinimidomethyl L-3- (3,4-polyhydroxypepe) -2-ylmethylalaninate hydrochloride hydrate having a uniform Rf of 0.5 was obtained.

Example 12

A. Preparation of L-3- (3,4-diacetoxyphenyl) -2-methyl alanine hydrochloride

To a mixture of 320 ml of glacial acetic acid and 24 ml of acetyl chloride was added 69.4 g (0.291 moles) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesqui hydrate in portions. At this time, when the reaction temperature is approximately 50 ℃, a clear solution is obtained. At this temperature again 85 ml of acetyl chloride was added over 10 minutes. The resulting clear pale yellow solution was left at 20-25 ° C. for 14 hours. 400 ml of anhydrous ethyl ether was added over 15 minutes. A white solid precipitated when the addition was almost complete. The mixture was stirred at 20-25 ° C. for 30 minutes at 5-10 ° C. for 1 hour and then cooled at −10 ° C. for 2 hours. The solids were collected by filtration, suspended in 150 ml of 30% acetic acid-70% ethyl ether (by volume), filtered, washed with 500 ml of ethyl ether and dried at 70 ° C. for 2 hours, and the melting point was 196.0-197.0 ° C. 83.7 g (88%) of L-3- (3,4-diacetoxyphenyl) -2-methylalanine hydrochloride were obtained.

-숙신이미도에틸 L-3-(3,4-디아세톡시페닐)-2-메틸알라니네이트 하이드로클로라이드의 제조B.

Preparation of Succinimidoethyl L-3- (3,4-diacetoxyphenyl) -2-methylalanine hydrochloride

-클로로에틸)-숙신이미드의 용액을 20-25℃에서 20-24시간 교반하였다. 20㎖의 메틸 에테르와 함께 수분간 교반하여 디메틸 설폭사이드를 제거한 다음 에틸 에테르를 따라내었다. 이 추출 공정을 3번 실시하고, 잔사를 10㎖의 무수 에탄올에 용해시킨 다음 과량의 에틸 에테르를 가하여 생성물을 침전시켰다. 이 침전 공정을 2번 반복하면 순수한

-숙신이미도에틸 L-3-(3,4-디아세톡시페닐)-2-메틸알라니네이트 하이드로클로라이드가 얻어졌다.1.66 g (5 mmol) L-3- (3,4-diacetoxyphenyl) -2-methylalanine hydrochloride in 5 mL dimethyl sulfoxide, 0.51 g (5 mmol) triethylamine and 0.81 g (5 mmol) N- (

The solution of -chloroethyl) -succinimide was stirred at 20-25 ° C. for 20-24 hours. Stirring with 20 ml of methyl ether for several minutes to remove dimethyl sulfoxide and then decanted ethyl ether. This extraction process was carried out three times, and the residue was dissolved in 10 ml of absolute ethanol and excess ethyl ether was added to precipitate the product. If you repeat this precipitation process twice,

Succinimidoethyl L-3- (3,4-diacetoxyphenyl) -2-methylalaninate hydrochloride was obtained.

Example 13

A. Preparation of N- (1-chloroethyl) -maleimide

의 사염화탄소 중의 49.2g(0.40몰)의 N-비닐말레이미드 용액에 첨가한 혼합물을 교반하면서 20-30℃에서 염화수소로 6시간 동안 포화시켰다. 24시간 후 혼합물을 1.5시간 동안 염화수소로 다시 포화시키고, 48시간 후 용액을 따라낸 다음 검상, 잔사를 100㎖씩의 사염화탄소로 10번 세척하고 합친 추출액을 10g의 규조토로 슬러리화하고 여과한 후 여액을 감압하에 거의 400㎖까지 농축하였다. N-(1-클로로에틸)-말레이미드를 여과하여 20-30℃에서 건조시켰다.5.20 g (0.020 mole) of ditin chloride

The mixture added to a 49.2 g (0.40 mole) N-vinyl maleimide solution in carbon tetrachloride was saturated with hydrogen chloride at 20-30 ° C. for 6 hours with stirring. After 24 hours, the mixture was saturated again with hydrogen chloride for 1.5 hours, after 48 hours, the solution was decanted, and the gums were washed 10 times with 100 ml of carbon tetrachloride, and the combined extracts were slurried with 10 g of diatomaceous earth, filtered and the filtrate Was concentrated to nearly 400 ml under reduced pressure. N- (1-chloroethyl) -maleimide was filtered off and dried at 20-30 ° C.

-말레이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드의 제조B.

Preparation of maleimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride

-말레이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드가 얻어졌다.0.95 g (4.0 mmol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesqui hydrate and 0.64 g (4.0 mmol) of N- (α in 5 ml of dimethyl sulfoxide The -chloroethyl) -maleimide solution was stirred at 20-25 ° C for 23 h. The solution was diluted with 10 ml of distilled water, passed through a column containing 5 g of weakly basic anion exchange resin on the basic cycle, eluted with water fraction and combined with the fractions representing the positive ferric chloride test, and 3 g of weakly acidic cation on the acid cycle. It was added to a column of exchange resin. Unreacted L-3- (3,4-dihydroxyphenyl) -2-methylalanine was eluted with distilled water until a negative ferric chloride test was obtained and then the ester was eluted with 1N acetic acid. 55 ml (PH 3.2) of ester fraction was treated with 1N hydrochloric acid to make PH2 and lyophilised at 0.1-0.3 mm for 20 hours.

-Maleimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride was obtained.

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드의 제조C.

Preparation of Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride

-말레이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드 용액을 1당량의 수소가 흡수될때 까지 대기압 및 25℃에서 1.0g의 탄소상에 담지된 10% 팔라듐 촉매로 수소화하였다. 촉매를 여과하고 여액을 감압하에 30-40℃에서 증발시킨 다음 잔사를 50㎖의 10% 에탄올-90% 에틸아세테이트(용량에 의한) 용액을 용해시키고 5㎖의 포화 탄산나트륨 용액 및 대략 5g의 무수탄산 나트륨과 10분간 교반하였다. 여과 후 여액을 무수 황산 마그네슘상에서 건조시키고 여과하여 감압하에 증발 건조시켰다. 잔사를 20㎖의 무수 클로로포름에 용해시키고 용액을 빙욕에서 냉각하여 염화수소로 15분간 포화시켰다. 고체를 회수하여 25㎖의 무수 에테르에 3번 현탁시켜 세척하고 질소하에, 20-25℃에서 밀폐된 플라스크내에 25㎖의 메틸 아세테이트에서 철야 슬러리화하였다. 불용성 고체를 여과하여 제거하고 30㎖의 헥산과 2시간 동안 교반하고 진공 건조기내의 염화칼슘상에서 건조시켰더니, 박층 크로마토그래피 [형광 실리카겔판, 50% 메탄올-50% 벤젠(용량에 의한) 용매]에서 관찰된, Rf=0.7인

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드를

-및

이성체의 혼합물로써 얻어졌다.(1.0 g (2.7 mmol) in 25 mL of absolute ethanol

The maleimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride solution was supported on 1.0 g of carbon at atmospheric pressure and 25 ° C. until 1 equivalent of hydrogen was absorbed. Hydrogenated with 10% palladium catalyst. The catalyst was filtered off and the filtrate was evaporated under reduced pressure at 30-40 ° C. and the residue dissolved in 50 ml of 10% ethanol-90% ethylacetate (by volume) solution and 5 ml of saturated sodium carbonate solution and approximately 5 g of anhydrous acidic acid. Stir with sodium for 10 minutes. After filtration the filtrate was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 20 mL of anhydrous chloroform and the solution was cooled in an ice bath and saturated with hydrogen chloride for 15 minutes. The solid was recovered, suspended, suspended three times in 25 ml of anhydrous ether and slurried overnight in 25 ml of methyl acetate in a closed flask at 20-25 ° C. under nitrogen. The insoluble solid was removed by filtration and stirred with 30 ml of hexane for 2 hours and dried over calcium chloride in a vacuum drier, observed in thin layer chromatography [fluorescent silica gel plate, 50% methanol-50% benzene (by volume) solvent]. , Rf = 0.7

-Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride

-And

Obtained as a mixture of isomers.

Example 14

Finely mix the fine powder ingredients into 1,000 hard hard gelatin capsules containing 200 mg of succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride, respectively. Made with capsules.

Example 15

refine

-숙신이미도에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드 이수화물(

-이성체)를 각각 포함한 1,000개의 정제는다음 성분으로부터 제조하였다.100 mg

Succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride dihydrate (

1,000 tablets each comprising an isomer) were prepared from the following ingredients.

The finely divided components were mixed well and then refined by a slug process.

Example 16

Hard Gelatin Capsules

-피발로일옥시에틸 L-3-(3,4-디하이드록시페닐)-2-메틸알라니네이트 하이드로클로라이드를 포함한 5,000개의 두쪽의 경질 젤라틴 캡슐을 다음 성분들로부터 제조하였다.400 mg each

5,000 two hard gelatine capsules containing pivaloyloxyethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride were prepared from the following ingredients.

The fine powder components are sufficiently mixed into capsules by conventional methods.

Example 17

Antihypertensive action

The process for evaluating the anti-hypertensive action of the active agent consists of orally or intraperitoneally administering the compound to spontaneous hypertensive rats of the Wistar-Okamoto strain. Power blood pressure for these animals was recorded continuously through the indwelling aortic catheter injected through the tail artery. Animals were allowed to exercise freely in metabolic cages during the measurement.

메틸도파보다 더 작용성을 나타냈다.Oral administration of the compounds of the present invention showed a pronounced anti-hypertensive action and also when tested in the intestine. In some instances the compounds are actually L-

It was more functional than methyldopa.

Claims (1)

As described above in the text, a process for preparing a compound of formula (1) consisting of esterifying an acid derivative of formula (2) with a compound of formula (3):

Food, n is 0,1,2 or 3 m is 0,1,2 or 3 A ₁ and A ₂ are each hydrogen or a lower alkanoyl group. R ₁ and R ₂ are each hydrogen or alkyl having 1-3 carbon atoms, R ₃ is selected from the group consisting of the following (A) and (B). (A) a monocycle or bicyclic heterocycle group (each of the heterocycle group) containing one or two heteroatoms and 3-12 hexane atoms selected from N and S wherein at least one is N Ring contains 5-6 members) and (B) X -R ₄ groups Wherein X is -O-, -S-, or -NH-, R ₄ is an acyl group of a monocycle carboxylic acid containing up to 21 carbon atoms and containing at most one heteroatom in (1) a hydrocarbon group or (2) an organic non-cycle or ring, Y is -COOH, -CO halogen or -carboxylic acid salt, X ₁ is a hydroxyl, alkali metal —0-, halogen or substituted —SO ₃ — group.