CS200172B2 - Process for preparing derivatives of alpha-methyl-3,4-dihydroxyphenylalanine - Google Patents

Description

(54) Preparation of derivatives of n-methyl-3,4-dihydroxyphenylalanine \

The present invention relates to a novel and useful class of compounds that can be used for the treatment of hypertension. More specifically, the present invention relates to α-methyl-3,4-dihydroxyphenylalanine derivatives.

It is known that various alanimine compounds (see US Patent No. 2,868,818) can be used in the treatment of hypertension. Furthermore, it is known that hypertension is preferably treated with N-methyl-3,4-dihydroxy-phenylalanine, since the D-form of the compound is therapeutically inert and only the L-form. is therapeutically active. Removal of the D-form thus reduces toxicity and enhances the effect (see US Patent No. 3,344,023 and GB Patent No. 936,074). The L-isomer of _1α -methyl-3,4-dihydroxyphenylalanine is commonly referred to as? -Methylphdopa or methyldopa. It is further known that alkyl esters of L- or DL-α-methyl-3,4-dihydroxyphenylalanine are useful for the treatment of urgent cases of hypertension by parenteral administration (see U.S. Patent 3,230,143). It has now been found that other esters and derivatives of DL- or N-methyl-3,4-dihydroxyphenylalahine of a certain structure are also effective for the treatment of hypertension and thus an alternative compound is available for this treatment. It has also been found that the new compounds are more active and lower dosages can be used than those used with known compounds.

The present invention relates to a process for the preparation of .alpha.-methyl-.beta.-dihydroxyphenylalanine derivatives of formula (I)

CH 2 O 1 nh _z r _z (I) wherein n is 0, 1, 2 or 3, m is 0, 1, 2 or 3,

A 1 and A 2 are independently hydrogen or - (C 2 -C 5) alkanoyl,

R 1 and R 2 are independently hydrogen or C 1 -C 3 alkyl and

R 3 is an substituent selected from the group consisting of:

a) a monocyclicocyclic or bicyclic heterocyclic radical containing from 3 to 12 carbon atoms in the nucleus having 1 or 2 heteroatoms displaced from the group consisting of N and S, at least one heteroatam being N and each ring in said heterocyclic radical containing 5 to 6 members X — Rt where X is -O-, —S- or —NH— and Rt is a radical containing up to <21 carbon atoms, namely a hydrocarbon radical or an acyl organic acyclic or monocyclic carboxylic acid containing no more than one ring or salt heteroatom with an acid, characterized in that it is an acid derivative of the general formula

CH 1 ^and I -YY-ch-cy ^ae ^ ° aetc * ch ₃ ^ o- ^ t-ch-c-co ^

AfOch _of o cc

Α-O-γ) NH JD

Hundred

NH.

or an acid salt, esterified with a compound of formula

Ri

X1 - ^ (CH2) n - C - ((- 1CH2) _{m -} R3,

R2 wherein Y is —COOH, —COhalogen, or a carboxylic acid salt of am, η, A 1, A 2, R 1, R 2 and R 3 are as defined above and Xt is hydCW 3 o ⁰ -S>

or an acid salt wherein n, m, R 1, R 2 and R 3 are as defined above, characterized in that the acid derivative of the formula

or an acid salt thereof, esterified with a compound of formula

Rt

AND

X - (CH 2) n - C - (- CH 2) _{m -} R 3,

R2 wherein Y is —COOH, —CO halogen, —carboxylic acid in salt form, am, n, R1, R2 and R3 are as defined above and X is hydroxyl, alkali metal —O--, halogen or roxyl, alkali metal —O A halogen or a substituted -SO 3 group and optionally resolved by stereoisomers 1j by fractional crystallization of one stereoisomer from solution or

2) forming a diastereoisomer with an optically active acid and crystallizing one diastereoisomer from solution.

The present invention further relates to a process for the preparation of a compound of the formula substituted-SO 3 - group. The esterification is carried out under conventional reaction conditions.

In a preferred embodiment of the process of the present invention, the process is performed with an amino acid that forms part of the molecule and which has an L-stereoconfiguration.

The terms "(- · CH ₂ ' _n " and "(—CH 2) _m " also include branched alkylene chain alkylenes such as

CH3 —CH—,

CH3 —C— a

CH3

C2H5 —CH—.

Preferably n and m are 0 or 1.

The term "monocyclic non-bicyclic 5 to 6 members" refers to compounds containing one or two ring nitrogen atoms or a ring sulfur atom and from 3 to 12 carbon atoms. The compounds further contain one or two rings with 5 or 6 members in each ring, and the rings may be substituted with groups such as halogen, hydroxyl, amino or the like.

The term "R 4 contains up to 21 carbon atoms 1 ring heteroatom" means that R 4 contains a total of 1 to 21 carbon atoms and is either a hydrocarbon radical or an acyl radical of formula ⁰ wherein R is an acyclic or monocyclic radical containing no more than 1 heteroatom. As will be shown in the examples, the R group may be an alkyl group, the h-ether heterocyclic moiety n-e and any other moiety. The type of these 'R groups' is not critical and can vary widely.

The term &quot; a salt with a pharmaceutically acceptable acid &quot; is a term commonly known and used in the art which includes those compounds prepared by reaction of the free base with a yesirganic or organic acid. It includes hydrochlorides, hydrobromides, salts with sulfuric acid and the like.

The term "amino acid L-isomer substantially free of the D-isomer" means that the D-isomer is present in an amount that does not exceed 10 ^l / o. However, it is desirable that the D-isomer is not in the mixture. In the following examples, when the designation is L-isomer, the compound is 100% (i.e., greater than 99%) in the form. L-isomer.

The term "protecting group" means any group that protects amino or hydroxyl groups during the reaction. Suitable protecting groups for the nitrogen atom include carbobenzyloxy, p-methoxycarbonylbenzyloxy, trifluoroacetyl,

HCl and the like. Suitable hydroxyl protecting groups are dienyl ketal for both hydroxyl groups and acetyl and canbobenzyloxy for individual hydroxyl groups and other residues. The substituent in the "substituted-SO 3" moiety can be any moiety as these moieties are readily cleaved during esterification and the type of moiety is not critical.

If racemic mixtures are formed during the synthesis of the present invention, it is sometimes necessary to separate the 11a La D-isomers. Isomers may be resolved at any point in the synthesis, and in many cases resolving them prior to formation of the final product is desirable. In other cases (such as when R 1 and R ²¹ are different and the acid forming part of the molecule is L-configuration, the resulting product is a mixture of diastereamiers and these can be separated directly by crystallization or by simple derivative formation and crystallization. " starting from the desired isomer (i.e., the L-isomer) when one isomer is required as the reaction product, as well as forming a diastereomer of the racemic mixture resulting from the process of the present invention for resolution, in which case an optically active acid may be used, such as tartaric acid, 10-camphorsulfonic acid, maleate acid, pyroglutamic acid, methoxyacetic acid and the like.

In the treatment of hypertension, the compounds of the present invention are generally administered in an amount of from about 0.0-05 to about 300 mg / kg body weight, preferably from about 0.05 to 10 mg / kg. In an even more preferred embodiment, the compounds are administered in an amount of from about 0.1 to about 25 µg / kg of animal body weight. It should be emphasized that the dose must be administered depending on its activity, the desired lowering of blood pressure and also the animal's n-a weight. Within the above ranges, the more active compounds are administered at lower doses and the less active compounds are administered at higher doses.

When the L-isomer of the compound of the present invention is administered without the D-isomer, the desired dose of the L-isomer is about half that of the racemate as the D-isomer is therapeutically inactive. However, the compounds of the present invention exhibit to some extent different activity and thus the racemate of the less active compound of the present invention needs to be administered at a several times higher dose than the more active compounds. Generally, the compounds are administered within the above dosage range.

In one dosage form, the composition of the present invention is generally comprised from 1 mg to 2000 mg, preferably from about 5 mg to about 10-00 mg of the active compound. According to an even more preferred feature of the present invention, from about 10 mg to 500 mg of the active compound is contained in a single dosage form. The unit dosage form of the compound may be administered as a single slow-acting dose or may be administered in several small doses throughout the day, usually in 2 to 8 individual doses,

The compounds of the present invention can be used in the form of a mixture and are preferably administered in unit dosage form such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, and the like. the basic active ingredients are mixed with conventional tableting agents such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, calcium phosphate, gums and the like, suitable as pharmaceutical diluents or carriers. Tablets or pills of the novel compositions may be coated or otherwise formulated to provide a dosage form that preferably will have a sustained effect or a predetermined progressive effect. For example, tablets or pills may contain an inner and an outer dosage component, the latter forming the shell of the former. Both components may be separated by an inner layer which serves to prevent disintegration in the stomach and allows the inner component to pass intact into the duodenum or delay the decomposition. Various materials can be used for these inner layers or coatings including a variety of polymeric acids or mixtures of polymeric acids such as shellac, shellac and cetyl alcohol, cellulose acetate and the like. Particularly suitable inner coatings are styrene-maleic acid copolymers along with known materials used for coatings . The compounds of the present invention are also useful when administered in the form of suppositories or together with a penetrating agent such as dimethyl sulfoxide.

Liquid forms in which the novel compositions of the present invention can be applied include a suitable amount of a flavored emulsion with edible oils such as cottonseed oil, sesame oil, cocoa oil, peanut oil and the like, as well as brine and the like. Suitable dispersing or suspending agents for aqueous suspensions are synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatin and the like. Sterile suspensions or solutions are required for parenteral use. Isotoric preparations containing suitable preservatives are also suitable for injectable use.

The term "single dosage form" as used herein means a physically discrete unit suitable as a unit dose for warm-blooded animals, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect together with a suitable pharmaceutical diluent or carrier. The data for the novel unit dosage forms of the present invention is dependent on:

(a) the characteristics of the active substance and the therapeutic effect which they can achieve; and

b) the limitations known to the skilled person associated with the therapeutic use of the active material in warm-blooded animals, as further described in the description. Examples of suitable oral unit dosage forms of the present invention are: tablets, capsules, pills, powder packets, granules, wafers, ampoules, vials and the like.

The invention is illustrated, but not limited, by the following examples. All parts are by weight unless otherwise stated. The term "reduced pressure" used in the following examples, 1.99 to 3.33 kPa at 25 to 35 ^Q C (unless otherwise specified). When the reduced pressure is used to remove the solvent, the product formed is often a solvate, and so in the examples the &quot; evaporated &quot; product means that all the solvent has been removed except that part of the solvent that is bound in the product.

Example 1

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

A suspension of 88.3 g (0.30 mol) of L-3- (3,4-dihydroxyphenyl) -2-methylamine hydrochloride ethanol solvate (by concentrating the ethanolic hydrochloride solution under reduced pressure) and 146.4 g (1.42 mol) of N -acetylethanolamine was heated to 104-108 ° C under nitrogen. Thionyl chloride (84.8 g, 0.713 mol) was then added with stirring over 15 minutes. The reaction mixture fumes vigorously during the addition. After the addition was complete, the reaction mixture was stirred at 104-108 ° C for 18 hours. Additional thionyl chloride, 42.4 g (0.357 mol) was added over 7 minutes. The reaction mixture was stirred at 104-108 ° C for an additional 3.5 hours, then cooled to 30 ° C and concentrated under reduced pressure to give a viscous oil. This oil was suspended in 100 ml of chloroform and the chloroform was removed under reduced pressure. Wash the oil three times with 1ΌΟ ml of benzene, which is decanted. The residue was dissolved in isopropanol (700 mL) and ethyl ether (6 L) was added. The resulting precipitate is washed with 500 ml of ethyl ether and shaken with 6 liters of a mixture of 10% ethanol and 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 in vacuo to give the free base of acetamidoester. This base is treated with 15 g of fumaric acid in 300 ml of isopropanol and the fumarate is precipitated by the addition of a sufficient amount of ethyl ether. The fumarate is then precipitated once more with isopropanol by adding sufficient ethyl ether and then converted back to the free base, as above, by shaking with 200 ml of 10% ethanol and 90% ethyl acetate (v / v), 20 ml of saturated sodium carbonate solution and 20 ml. g of sodium carbonate. The free base is converted to the hydrochloride by dissolution in 100 ml of absolute ethanol, 10 ml of 9.6 N hydrochloric acid are added, and the product is precipitated with 1 liter of ethyl ether. After precipitating from ethanol / ether three times as described above, it is obtained

15.1 g (15%) of 2-acetamidoethyl L-3- (3 _K 4-dihydroxyphenyl) -2-methylalaninate hydrochloride, Rf 0.57, silica gel thin-layer chromatography fluorescent silica gel e200172 eluent mixture 50% methanol-50 -% benzene (by volume).

Analysis for C 14 H 20 N 2 O 5 .HCl calculated: 50.52% C, 6.36% H, 8.41% N; Found: C 50.49, H 6.69, N 8.49. Example 2

Preparation of 3-acetamidopropyl L-3- (3,4-dihydiroxyphenyl) -2-methylalaninate hydrogen oxalate hydrate

Thionyl chloride, 275 ml, was added to 250 g of L-3- (3,4-dihydropyloxyphenyl) -2-methylalaninate sesquihydrate at 25 ^and C and the mixture was heated on a steam bath. After heating for 2 hours, the thick reaction mixture is diluted with 7.5 ml of dimethylformamide in 25 ml of benzene and the reaction mixture is stirred on a steam bath until gas evolution ceases. Benzene (100 ml) was added and the crude sulfuric acid ester was filtered off, washed with benzene (100 ml), chloroform (100 ml) and ether (100 ml), dried under reduced pressure to give 280 g of intermediate sulfuric acid ester, mp 199 ° C (dec. ).

A mixture of 13.7 g of crude S-sulfuric acid ester intermediate, 24.98 g (01.212 mol) of N-acetylpropanolamine and 2 g of anhydrous dimethylformamide is stirred on a steam bath for 20 hours and then cooled. The reaction mixture was washed with six 200 ml portions of ethyl ether, four 200 ml portions of methylene chloride and dried under reduced pressure. The remaining semi-solid material was stirred with 200 ml of a mixture of 20% ethanol and 80% ethyl acetate (v / v), 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 3.2 g of oxalic acid in 50 ml of ethanol were added to the filtrate. After removal of the solvents under reduced pressure, the product is precipitated by dissolving in 50 ml of ethanol and adding 500 ml of ethyl ether. The product is reprecipitated by dissolving in 50 ml of ethanol and adding 500 ml of ethyl acetate. There was obtained 3-acetamidopropyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrogen oxalate hydrate, Rf = 0.45, thin layer chromatography (fluorescent silica gel, developing a mixture of 25% methanol and 75% chloroform (v / v)). .

Analysis for C15H22N2O5.C2H2O4.H2O calculated: 48.80% C, 6.26% H, 6.69% N; found: 48.73% C, 6.85% H, 6.68% N. EXAMPLE 1 a d 3

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

Thionyl chloride (275 ml) was added to 250 g of L-3- (3,4-dihydroxyphenyl) -2-methylalaninate sesquihydrate at 25 ° C and the mixture was heated on a steam bath. ml of dimethylformamide in 25 ml of benzene and stirred with stirring on a steam bath until gas evolution ceased, 100 ml of benzene added and the crude sulfuric ester was filtered off, washed with 10 ml of benzene, 10 ml of chloroform and 100 ml of ether, dried under reduced pressure. Pressure to give 280 g of the sulfuric acid ester as an intermediate, m.p. 199 DEG C. (dec.

A mixture of 30 g of crude intermediate, sulfuric acid ester, 34.6 g (0.375 mol) of 2-hydroxyethylmethylsulfide and 6 g of anhydrous dimethylformamide was stirred on a steam bath for 28 hours and then cooled. The reaction mixture was washed with 100 mL of ethyl ether and three 100 mL portions of methylene chloride. The residual material was stirred with 250 ml of a mixture of 0% ethanol and 80% ethyl acetate (1.30 ml of a saturated solution of sodium carbonate and 60 g of solid sodium carbonate) and then filtered. % ethanol and 80% ethyl acetate (v / v), combined with the first ethanol-ethyl acetate extract and dried over anhydrous magnesium sulfate. After filtration, the solvents were removed under reduced pressure and the residue was chromatographed on silica gel for a total of 2.3 g of product. This product was converted to the oxalate by adding to a solution of 1.3 g of oxalic acid in 25 ml of ethanol and then precipitating with a sufficient amount of ethyl ether. After three further precipitation by dissolution in ethanol. and adding ether to precipitate 300 mg of 2-methylthioethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrogen oxalate which is homogeneous according to thin layer romatography [fluorescent silica gel, developing 25% methanol and 75% chloroform (v / v)], Rf = 0.83, mp 85-90 ° C. rozkl.

Analysis for C 13 H 19 NO 4 S.C 2 H 2 O 4 calculated: 47.99% C, 5.64% H, 3.73% N; Found:% C, 48.00;% H, 6.10;% N, 4.07

Preparation of pivaloyloxymethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride

A solution of 0.95 g (4.0 mmol) of L-3- (3,4-dlhydroxyphenyl) -2-methylalanine sesquihydrate and 0.91 g (4.06 mmol) of pivaloyloxymethyl chloride in 5 ml of methylsulfoxide was stirred for 23 hours at 20 DEG -25 DEG C. The solution is diluted with 10 ml of distilled water and passed through a column containing 5 g of a weakly Baisic anion exchange resin in a basic cycle, after elution of the aqueous fractions, the fractions giving positive FeCl3 test are pooled and applied to 3 g of a weakly acidic cation The unreacted L-3- (3,4-dihydroxyphenyl) -2-methylalanine was eluted with distilled water until a negative FeCl2 test was obtained, and the ester was then eluted with 1 N acetic acid.Ester fraction 50 ml (pH 3.2) The acid was acidified to pH 2.0 with 1 N hydrochloric acid and lyophilized at

The pivaloyloxymethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride is obtained as an acetic acid solvate at 20 to 20 psi for 20 hours.

Anal. Calcd for C 16 H 23 NO 6 .HCl.1 / 3 HCl 2 H 4 O 2: C, 52.11; H, 6.69; N, 3.58. Found: C 52.11, H 6.49, N 3.73. Example 5

Preparation of α-succinimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride

A solution of 0.95 g (4.0 mmol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesquihydrate and 0.65 g (4.0 mmol) of N- (α-chloroethyl) succinimide in 5 ml of dimethyl sulfoxide The solution is diluted with 10 ml of distilled water and passed through a column containing 5 g of a weakly basic anion exchange resin in a basic cycle. After elution of the aqueous fractions, the fractions giving the positive test with ferric chloride are combined and added to the column. 3 g of a weakly acidic cation exchange resin in an acid cycle The unreacted L-3- (3,4-dihydroxyphenyl) -2-methylalanine is eluted with distilled water until a negative ferric chloride test is obtained, and the ester is then eluted with 1 N acetic acid. 55 ml (pH 3.2) is then acidified with 1N hydrochloric acid to pH 2.0 and lyophilized at 13.33 Pa to 39.99 Pa for 20 hours to obtain α-succinimidoethyl L-3- (3,4). (dihydroxyphenyl) -2-methylalaninate hydrochloride as the acetic acid solvate.

Anal. Calcd for C16H20N2O6.HCl.1 / 3C2H4O2: C, 50.96; H, 5.73; N, 7.13. found: C 50.48, H 6.13, 6.77% N. Example 6 ’

3-Acetamidopropyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrogen oxalate hydrate

Thionyl chloride (275 ml) was added to 250 g of L-3- (3,4-dihydiroxyphenyl) -2-methylalaninate sesquihydrate at 25 ° C and the mixture was heated on a steam bath, after heating for 2 hours the thick reaction mixture was diluted with 7.5 ml of dimethylformamide dissolved. in 25 ml of benzene, and the reaction mixture is stirred on a steam bath until gas evolution is complete, 100 ml of benzene is added and the crude sulfuric ester is filtered off, washed with 100 ml of benzene, 100 ml of chloroform and 100 ml of ether and dried under reduced pressure. pressure, 280 g of ester 3 are obtained with sulfuric acid, mp 199 ° C (dec.

A mixture of 13.7 g of the crude sulfuric ester, 24.98 g (0.212 mol) of N-acetylpropanolamine and 2 g of anhydrous dimethylformamide was stirred on a steam bath for 20 hours and allowed to cool. The reaction mixture was washed with six 200 ml portions of methylene chloride and dried under reduced pressure. The residual semi-solid was stirred with 200 ml of a mixture of 20% ethanol and 80% ethyl acetate (v / v), 20 ml of saturated sodium carbonate solution and 20 g of solid sodium carbonate. The organic extract was dried over anhydrous magnesium sulfate, filtered. 2 g oxalic acid in 50 ml of ethanol. After evaporation of the solvents under reduced pressure, the product is precipitated by dissolving in 50 ml of ethanol and adding 500 ml of ethyl ether. The product was reprecipitated by dissolving in 50 ml of ethanol and adding 50 ml of ethyl acetate. There was thus obtained 3-acetamidopropyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrogen oxalate hydrate, Rf = 0.45, thin layer chromatography [fluorescent silica gel developing with a mixture of 25% methanol and 75% chloroform (v / v)] ].

Anal. Calcd for C15H22N2O5.C2H2O4.H2O: C, 48.80; H, 6.26; N, 6.69. Found: C 48.73, H 6.85, N 8.68. Example 7

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

Suspension 88.3 g (0.30 mol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride solvate 1i with ethanol (concentration of the ethanolic solution of hydrochloride under reduced pressure) and 146.4 g (1 N-acetylethanolamine (42 moles) was heated to 104 DEG-108 DEG C. under nitrogen and 84.8 g (0.713 mol) of thionyl chloride were then added with stirring over 15 minutes, while the reaction mixture was vigorously fuming during the addition. The reaction mixture was stirred at 104-108 ° C for 18 hours and additional thionyl chloride (42.4 g, 0.357 mol) was then added over seven minutes. The reaction mixture was stirred at 104-108 ° C for an additional 3.5 hours then cooled to room temperature. The oil is suspended in 100 ml of chloroform and the chloroform is removed under reduced pressure, the oil is washed three times with 100 ml of benzene, which is decanted, and the residue is dissolved in 700 ml. isopropanol and 6 L is added The resulting precipitate is washed with 500 ml of ethyl ether and shaken with 6 liters of a mixture of 10% ethanol and 90% ethyl acetate (v / v), 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 acetamidoethyl ester. This base is treated with 15 g of fumaric acid in 300 ml of isopropanol and the fumarate is precipitated by the addition of sufficient ethyl ether. The fumarate is precipitated once more from isopropanol by adding sufficient ethyl ether and then converted back to the free base, as previously used, by shaking with 200 ml of a mixture of 10% ethanol and 90% ethyl acetate (by volume) 20 ml of saturated sodium carbonate solution and 20 µg. solid sodium carbonate. The free base is converted to the hydrochloride by dissolving in 100 ml of absolute ethanol, adding 10 ml of 9.6 N hydrochloric acid and then precipitating with 1 liter of ether. After three precipitation from ethanol / ethyl ether as above, 2-acetamido-ethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride, Rf - 0.5.7, thin layer chromatography [fluorescent silica gel developing 50 % Methanol and 50% benzene (v / v)].

Analysis for C 14 H 20 N 2 O 5 .HCl calculated: 50.52% C, 6.36% H, 8.41% N; found: C 50.49, H 6.69, N 8.49. Example 8

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

To a mixture of 320 ml of glacial acetic acid, 24 ml of acetyl chloride, 69.4 g (0.291 mol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesquihydrate are added in one portion. The temperature of the reaction mixture rose to approximately 50 ° C to obtain a clear solution. An additional 85 ml of acetyl chloride was added at this temperature over 10 minutes. The resulting clear pale yellow solution was allowed to stand for 14 hours at 20-25%, then 400 mL of anhydrous ethyl ether was added over 15 minutes. As soon as the addition was almost complete, a white solid began to precipitate. The mixture was then stirred at 20-25 ° C for 30 minutes and then at 5-10 ° C for one hour, then cooled to -10% for two hours. The solid is filtered off, suspended in 150 ml of a mixture of 30% acetic acid and 70% ethyl ether (by volume), filtered and washed with 500 ml of ethyl ether. After drying at 70% for two hours, 83.7 grams (88%) of L-3- (3,4-diacetoxyphenyl) -2-methylalanine hydrochloride is obtained, m.p. 198.0-197.0%.

B. Preparation of L-3- (3,4-diacetoxyphenyl) -2-methylalanyl chloride hydrochloride

A mixture of L-3- (3,4-diacetoxyphenyl) -2-methylalanine hydrochloride (6.60 g, 0.020 mol) and thlonyl chloride (40 ml) was stirred for 2 hours at 00 degrees Celsius until complete dissolution at 1999.83 to 2666.44. mbar and 49-50 ° C, then removed the excess thionylchloiridu. methylene chloride, 50 ml, and the mixture was again concentrated at 1999.83 to 2666.44 Pa at ^40! to 50%. the process is repeated once with an additional 50 ml of methylene chloride After drying at 26.66 to 66.66 Pa and 40 ° C for 30 minutes, L-3- (3,4-diacetoxyphenyl) -2-methyl-aalanyl chloride is obtained.

C. Preparation of Succinimidomethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate Hydrochloride Hydrate

A solution of 3.50 g (10 mmol) of L-3- (3,4-dlacetoxyphenyl) -2-methylalanyl chloride hydrochloride in 20 ml of chloroform was added to a solution of 3.87 g (30 mmol) of N-hydroxymethylsuccinimide in 20 ml of chloroform at a temperature. Deň: 22 ° C. After stirring for 20 hours at the boiling point, most of the chloroform is evaporated at 1999.83 to 2666.44 Pa and 30 to 40 ° C. The residue is diluted with 10 ml of 1 N hydrochloric acid solution and extracted with two 20 ml portions of ethyl ether. The aqueous extract was stirred under nitrogen at 20-25 ° C for 5 hours. After lyophilization at 20 mmHg for 20 hours, the residue is treated with 50 ml of 10% ethanol / 90% ethyl acetate (v / v), 5 ml of saturated sodium carbonate solution and 5 g of solid sodium carbonate. After filtration, the filtrate is dried over anhydrous magnesium sulphate, filtered and concentrated at 30 to 40%. The residue is re-concentrated in 25 ml of absolute ethanol, treated with 5 ml of a 9.6N ethanolic hydrogen chloride solution and concentrated in vacuo to give the succinimidomethyl L-3- (3,4-dihydro-oxyphenyl) -2-methylalaninate hydrochloride hydrate, which is homogeneous by thin layer chromatography [fluorescent silica gel, 30% methanol and 70% benzene (v / v)], Rf = 0.5. Example 9

A. Preparation of L-3- (3,4- · L-3- (3,4-) -carbonylamide)

-dihydroxyphenyl] -2-methylalanine

Phosgene was bubbled through a mixture of 9.0 g (0.038 mol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesquihydrate in 500 ml of tetrahydrofuran for 25 minutes until the solution was saturated. The insoluble material is filtered through diatomaceous earth, and the filtrate is concentrated to an oil at 30 to 35 ° C. The residue is dissolved in 75 ml of ethyl acetate. After cooling to 0 to 5% for several days, the precipitated solid is filtered off, dried at 25% and 13.33 to 39.99 Pa.

There was thus obtained L-3- (3,4-dihydroxyphenyl) -2-methylalanine N-carboxyanhydride.

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

A solution of L-3- (3,4-dihydroxyphenyl) -2-methylalanine N-carboxyanhydride (2.37 g, 10 mmol) and N-hydroxymethylsuccinimide (1.29 g, 10 mmol) was heated to boiling until all N After concentration under a pressure of 1 mm Hg and at a temperature of 30 DEG-40 DEG C., the residue is extracted with 50 ml of benzene and then with 50 ml of ethyl acetate and the insoluble solid is then shaken with 50 ml of 10% w / v. ethanol and 90% ethyl acetate (by volume) and 10 ml of saturated sodium carbonate solution. After filtration, the filtrate is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue is redissolved in 25 ml of absolute ethanol. A 6 N solution of ethanolic hydrogen chloride and concentration in vacuo afforded succinimidomethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride hydrate, homogeneous by thin layer chromatography [fluorescent silica gel in a mixture of 30% methanol and 70% benzene ( v) Rf = 0.5 Example 10

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

Tin (II) chloride, 5.20 g (0.020 mol) was added to a solution of 4.9.2 (0.40 mol) n-vinylmaleimide in 1 liter of carbon tetrachloride, and the mixture was stirred and saturated with hydrogen chloride gas for 6 hours at 20-30 ° C. After 24 hours, the mixture was again saturated with hydrogen chloride for 1.5 hours. At the end of 48 hours, the solution was decanted and the gummy residue was washed with ten 100 ml portions of carbon tetrachloride. The combined extracts are treated with diatomaceous earth (10 g), filtered, and the filtrate is concentrated under reduced pressure to about 400 rolls. N- (1-chloroethyl) maleimide is filtered off and dried at 20-30 ° C.

B. Preparation of α-maleimidoethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride

A solution of 0.95 g (4.0 mmol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesquihydrate and 0.64 g (4.0 mmol) of N- (α-chloroethyl) -maleinimide in 5 ml of dimethyl sulfoxide was stirred at 210-25 ° C for 23 hours. The solution is diluted with 10 ml of distilled water and passed through a column containing 5 g of a slightly basic anion exchange resin in a basic cycle. After elution, the fractions giving the positive ferric chloride test are combined and added to the column with 3 g of a slightly acid cation exchange resin in an acid cycle. Unreacted L-3- (3,4-dihydroxyphenyl) -2-methylalanine was eluted with distilled water until negative with ferric chloride chloride, and the ester was then eluted with 1 N acetic acid. The ester fractions, 55 ml (pH 3.2), were acidified with 1N hydrochloric acid to pH 2.0 and lyophilized at 13.33 to 39.99 Pa for 20 hours to yield .alpha.-smallimidoethyl L-34 3,4-dihydroxyphenyl. -2-Methyl lalaninate hydrochloride.

Example 11

A. Preparation of α-chloroethyl 3-chloro-2,2-dimethylpropionate

Zinc chloride, 400 mg, is melted at 26.66 to 66.66 Pa and then cooled to 25 to 30 ° C under a nitrogen atmosphere. 3-Chloro-2,2-dimethylpropionyl chloride, 62 g (0.40 mol) and 19.2 g acetaldehyde (0.44 mol) were then added thereto, during the addition of acetaldehyde, which was carried out as quickly as possible. After heating for 1 hour to boiling, α-chloroethyl 3-chloro-2,2-di-methylpropionate is obtained by distillation.

B. Preparation of α- (3-chloro-2,2-dimethylpropionyloxy) ethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate (hydrochloride)

A solution of 0.95 g (4.0 mmol) of L-3- (3,4-dihydroxyphenyl) -2-methylalanine sesquihydrate and 0.81 g (4.06 mmol) of α-chloroethyl and 3-chloro-2,2- of dimethylpropionate in 5 ml of dimethyl sulfoxide is stirred at 20-25 ° C for 23 hours. The solution is diluted with 10 ml of distilled water and then passed through a column containing 5 g of an alkaline ion exchange resin. After elution of the aqueous fractions, the fractions giving the positive test were combined with ferric chloride and added to the column 3 g of a weakly acidic cation exchange resin in an acid cycle. Unreacted L-3-i (3,4-dihydroxyphenyl) -2-methylalanine was eluted with distilled water until a negative ferric chloride test was performed, and the ester was then eluted with 1 N acetic acid. The ether fractions 50 ml (pH 3.2) were acidified to pH 2.0 with 1N hydrochloric acid and lyophilized for 20 hours at 13.33 to 39.99 Pa. There was thus obtained .alpha.-chloro-2,2-dimethylpropionoyloxy) ethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride as an acetic acid solvate.

Example 12

A. Preparation of 2-hydroxyethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride

A solution of 0.95 g (4.0 mmol) of L-3- (3,4-dihydroxyphenyl) -2-methylalaninate sesquihydrate and 0.51 g (4.06 mmol) of 2-bromoethanol in 5 ml of dimethylsulfoxide is stirred 5 hours at 60 degrees Celsius and then allowed to cool and stand for 23 hours at 20-25 ° C. -Se solution diluted with 10 ml of distilled water and passed through a 5 g kolo200172 Nou weakly basic anion exchange resin in a basic cycle .. After elution with water fractions, the fractions giving a positive ferric chloride test with combined and added to ¹ 3 g column of weakly acidic cation exchanger in the acid cycle ¹ . Unreacted L-3- (3,4-dihydroxyphenyl) -2-methylalanine was eluted with distilled water until negative for ferric chloride. The ester was then eluted with 1 N acetic acid. The ester fractions, 50 mL (pH 3.2) were acidified to pH 2.0 with 1 N hydrochloric acid and lyophilized for 20 hours at 13.33 to 39.99 Pa to give 2-hydroxyethyl L-3- (3,4). (dihydroxyphenyl) -2-methylalanine ninate hydrochloride,

B. Preparation of 2-acetoxyethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate

A mixture of 1.0 g (3.4 mmol) of 2-hydroxyethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride and 50 ml of acetyl chloride is stirred at 215 DEG C. for 6 hours. Up to 2666.4 Pa and 35 ° C, the residue is dissolved in 25 ml of 1 N hydrochloric acid and stirred under a nitrogen atmosphere for 5 hours at 20-25 ° C. After 20 hours of lyophilization at 13.33 to 39.99 Pa, the residue is worked up. with 50 ml of a mixture of 10% ethanol and 90% ethyl acetate (by volume), 5 ml of saturated sodium carbonate solution and 5 g of solid sodium carbonate, filtered, dried over anhydrous magnesium sulphate, filtered and concentrated at 1999, 83 to 2666.44 Pa and 30 to 40 ^q C.

The residue is chromatographed on silica gel, eluting with a mixture of 20% methanol and 80% benzene (v / v). Recrystallization is accomplished by dissolving the ester in boiling ethyl acetate and adding sufficient cyclohexane to precipitate. Thus, the desired 2-acetoxyethyl L-3- (3,4-dihydroxy-18-phenyl) -2-methylalaninate, m.p. 114-118 ° C, dec.

Example 13

Preparation of 2-acetoxyethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate

A mixture of 1.0 g (3,4 immol) 2-hydroxyethyl L-3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride and 50 ml of methanesulfonyl chloride was stirred at 25 ° C for 6 hours. , 44 Pa and 35 ° C and dried at 40 ° C and 13.3 to 666.5 Pa to give the crude methanesulfonyl derivative, to which 10 ml of dimethylsulfoxide and

Lithium acetate (6.6 g, 10 mmol) was stirred for 6 hours at 60 DEG C. After addition of an excess of ethanolic anhydrous hydrogen chloride solution, the dimethylsulfoxide was removed by stirring three times with 50 ml of ethyl ether and decanting the ether. hydrochloric acid and stirred in a nitrogen atmosphere at 20-25 ° C for one hour After lyophilization for 20 hours at 13.33 to 39.99 Pa, the residue is mixed with 50 ml of a 10% ethanol / 90% ethyl acetate (v / v) solution. ml of a saturated solution of sodium carbonate and 5 g of solid sodium carbonate After filtration, the filtrate is dried over anhydrous magnesium sulphate, filtered and concentrated at 1999.8 to 2666.4 Pa and 30 to 40 ° C.

The residue is chromatographed on silica gel, eluting with 20% methanol and 80% benzene (v / v). The ester is recrystallized by dissolving ethyl acetate and adding sufficient cyclohexane. Thus, the desired 2-acetoxyethyl L-3- (3,4-dihydroxyphenyl) -2-methylalanine is precipitated, m.p. 114-118 ° C dec.

Claims (3)

SUBJECT (1) a hydrocarbon residue; or (1) traction crystallization of one stereoisomer from solution; or A process for the preparation of α-methyl-3,4-dihydroxyphenylalanine derivatives of the general formula I CH 0 I JI ⁵ wherein n is 0, 1, 2, · or 3, m is 0, 1, or 2 · 3 A 1 and A 2 are independently hydrogen or C 2 -C 5 alkanoyl R 1 and R 2 are independently hydrogen or C 1 -C 3 alkyl and R 3 is selected from the group consisting of a monocyclic or bicyclic heterocycle having from 3 to 12 carbon atoms and 1 or 2 ring heteroatoms selected from N or S, wherein at least one heteroatom is N and each ring of the heterocyclic radical contains 5 to 6 members and bj is X-R 1 wherein X is —O—, —S—, or —NH—, R a contains up to 21 carbon atoms and is a hydrocarbon or acyl residue of an organic acyclic or monocyclic carboxylic acid containing at most 1 ring heteroatom or a pharmaceutically acceptable salt thereof ^Chi ~ I ⁰ ^ \ CH _~! , -Č-Y or NH, or CHj A _- O-M suitable acid salts, characterized in that the acid derivative of the general formula is esterified AfO ^A ° - Ct ₃ O ° II o /, - c — C * · II II Or an acid salt thereof with a compound of formula Ri X 1 - (CH 2) n - C - 1 (- 'CH 2' - R3 R 3, R2 wherein Y is —COOH, —COhalogen, or a salt of a carboxyl group, and n, m, A1, A2, R 1, R 2, R 2, R 2, R 3, R 3, R 3, and R 3 is as defined above and Xt is hydroxyl, alkali metal -O-, halogen, or substituted -SO 3 -group and optionally resolved by stereoisomers 2] an acyl radical of an organic acyclic or imonocyclic carboxylic acid containing at most 1 ring heteroatom or an acid salt thereof, characterized in that the acid derivative or the acid salt is esterified with a compound of the formula Ri X - (- CH2) _n - C - (- CH2) _{m -} R3, R2 wherein Y is —COOH, —COhalogen or a carboxylic acid salt wherein n, m, R1, R2 and R3 are as defined above and X is a hydroxyl, alkali metal —O—, halogen or substituted —SO3 — group. 2. The process of item 1 for preparing a compound of formula Í ^H 3 í? W - (CH 2) -, C - C - O K 2 --CH 2 --CH 2 -R, where n is 0, 1, 2 or 3, m is 0, 1, 2 or 3, R 1 and R 2 are independently H or C 1 -C 3 alkyl, R 3 is selected from the group consisting of (a) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 carbon atoms and ^: 1 or 2 heteroatoms selected from N and S, wherein at least one is N and each ring of the heterocyclic radical contains 5 to 6 members; and b) a residue X - R 4 kdq X is —O—, —S—, or —NH— and R4 contains up to 21 carbon atoms and is 2) formation of diastereoisomers with an optically active acid and crystallization of one diastereoisomer from solution. 3. The process of claim 2, wherein the acid is used in said L-configuration acid derivative.