FI92393C - Process for the preparation of 1,5-benzothiazepine derivatives - Google Patents

Description

92393

METHOD FOR THE PREPARATION OF 1,5-BENZOTHIACEPINE DERIVATIVES

This invention relates to a process for the preparation of 1,5-benzothiazepine derivatives. More particularly, it relates to a process for the preparation of 1,5-benzothiazepine derivatives of the following formula (I): 5 f * - /, (I)

I 0 „R

CH CH N

XR

wherein R 1 is a lower alkyl or lower alkoxy group; R 2 is a hydrogen atom or a lower alkanoyl group; each of R3 and R4 is a lower alkyl group; and one of R 5 and R 6 is a halogen atom or a lower alkyl group and the other is a hydrogen atom, and for the preparation of their pharmaceutically acceptable acid addition salts.

1,5-Benzothiazepine derivatives (I) and their pharmaceutically acceptable acid addition salts are useful pharmaceutical compounds having excellent antihypertensive activity, cerebrovascular and coronary vasodilatory activity and / or antiplatelet activity, and compounds (I), and wherein R 2 is a hydrogen atom, myds is useful as a select product in the synthesis of other pharmaceutical compounds.

Japanese Patent Publication Nos. 225174/1984 and 202871 / -1985 (unexamined) disclose a process for preparing 1,5-benzothiazepine derivatives by reacting the corresponding N-unsubstituted 1,5-benzothiazepine derivatives with a di (lower alkyl) aminoethyl halide.

92393 2 EP-A-127 882 and 154 838 disclose a process for the preparation of 1,5-benzothiazepine derivatives which uses a propionic acid derivative which is unsubstituted in the N-position of the aminophenylthio group as a starting material and an intramolecular cycling is carried out thereon. The N-position is then subjected to amino-lower alkylation.

FI patent 77240 discloses a process for the preparation of a 1,5-benzothiazepine derivative, in which a propionic acid derivative having an acyl group in the N-position of the aminophenylthio group and subjected to intramolecular cyclization is used as a starting material. This gives a selected product having an acyl group at the N-position of the aminophenylthio group, which compound is then further reacted to give the desired compound.

U.S. Pat. No. 4,680,392 discloses a process for the preparation of caprolactam derivatives which is alkylated according to the following reaction formula: s-y rj R'NH-CH NH2 + 1-C-COR4> COOR7 R5

II VIII

rV r ryl

R8-NH-CH NH-C-COR4>. I I

I / R'-NH-Λ N-C-COR4-> COR 'R> \ 4 «V °

V

a selected product of formula (II) with a haloester of formula (VIII) to give an intermediate of formula (IV). When R 4 is OH and R 7 is OR 9, this selected product is warmed in an organic solvent such as acetonitrile in the presence of a base such as triethylamine to give a perhydroazepinone of formula (V) which is then further reacted with the desired caprolactam derivative. When R 4 is not OH and R 7 is OH, the intermediate of formula (IV) can also be cyclized to the compound of formula (V) using dicyclohexylcarbodiimide and N-hydroxysuccinimide in a suitable solvent.

As a result of various studies, the present inventors have now discovered a new and high yielding industrial process for the preparation of 1,5-benzothiazepine derivatives.

According to the present invention, 1,5-benzothiazepine derivatives (I) or pharmaceutically acceptable salts thereof can be prepared by carrying out for a propionic acid derivative of the following formula: R 2 r * a -— r Y I 1T Vor cooh _ (II) CH 2 CH 2% 4

JK

wherein the symbols have the same meaning as previously defined, or a reactive derivative thereof, for intramolecular cyclization, and if necessary converting the product into a pharmaceutically acceptable acid addition salt thereof.

In the process according to the invention, cyclization is then carried out on a starting material in which the N-position of the aminophenylthio group of the propionic acid derivative is substituted by an aminodialkyl group, and it has surprisingly been found that this reaction gives a very good yield.

In the process according to the invention, the 1,5-benzothiazepine derivative is obtained in one reaction step and in a high yield of 92393 4.

Suitable examples of the reactive derivative of compound (II) in the above reaction include the corresponding reduced alkyl esters (e.g. methyl and ethyl ester), active esters (e.g. p-nitrophenyl, 2,4-dinitrophenyl, N-hydroxybenzotriazole, phthalimide). , succinimide, piperidine, 2-pyridine, 2-pyrrolidon-1-yl and diethyl chlorophosphinate ester), mixed anhydrides (e.g. mixed anhydride of compound (II) ethoxycarboxylic, t-butoxycarboxylic) -li- and benzyloxycarboxylic acid), acid halides and acid amides (e.g. imidazole, 4-substituted imidazole and triazolamide).

The cyclization reaction of this invention can be carried out in the presence or absence of a condensing agent or an acid receptor. For example, when free propionic acid compounds are used as a starting material. (II) or a lower alkyl ester thereof, said intramolecular cyclization may be performed in a warm inert solvent. Compound (II) or a lower alkyl ester thereof can be used in free form or in salt form. Examples of these salts include ephororganic acid addition salts such as hydrochloride, hydrobromide, sulfate, perchlorate, phosphate; organic acids such as acetate, oxalate, fumarate, maleate; and the like. High-boiling organic solvents such as xylene, toluene, acetic acid, diphenyl ether and the like can be preferably used as a solvent.

The reaction is preferably carried out in a lamp room at 100 to 180 ° C. In addition, when the propionic acid compound (II) is used as the starting material, the reaction can also be carried out in the presence of a condensing agent in an inert solvent. Examples of female condensing agents are carbodiimide compounds such as N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbamide. o y o bodiimide; carbonyldiimidazole; l-methyl-2-klooripy-ridiniumjodidi; ethoxyacetylene; A mixture of 2,2'-dipyridyl disulfide and triphenylphosphine; dimethylprop-2-ynylsulfonium halide such as dimethylprop-2-ynylsulfonium chloride; and the like. As the solvent, organic solvents such as chloroform, methylene chloride, chlorobenzene, tetrahydrofuran, diethyl ether, methyl ethyl ether, dioxane, ethyl acetate, benzene, toluene, dimethylformamide, diethylformamide, diethylformamide, N-forylformamide can be used. acetonitrile, dimethyl sulfoxide and the like. It is preferred to carry out the reaction in the reaction temperature and cooling to 150 ° C.

On the other hand, the intramolecular cyclization of the active ester, acid anhydride or acid halide of compound (II) can be carried out in an inert solvent. Suitable solvents for this reaction are also those which are used in carrying out the cyclization in the presence of a condensing agent. It is preferable to carry out the reaction at a temperature of -50 to 60 ° C. In addition, when an acid halide is used as the reactive derivative of the compound (II), it is preferable to carry out the reaction in the presence of an acid-receiving agent at a temperature of -30 to 50 ° C. Examples of acid-accepting agents include organic bases such as pyridine, collidine, lutidine, triethylarino, N-methylmorpholine and the like; and inorganic bases such as alkali metal carbonate (e.g., sodium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, etc.), and the like.

The 1,5-benzothiazepine derivative (I) of the present invention thus obtained can be easily converted into its pharmaceutically acceptable acid addition salt, for example, by treatment with a combined acid. Examples of pharmaceutically acceptable acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, phosphate, and the like; organic acid addition salts such as oxalate, maleate, tartrate, methanesulfonate and so on.

Since the above-mentioned reaction of the present invention proceeds without racemization, the compound (I) can be obtained in an optical form by using the optically active compound (II).

As mentioned above, the 1,5-benzothiazepine derivative (I) according to the invention can be obtained in a high yield by one method.

Thus, preferred examples of the 1,5-diazepine derivatives obtained in the present invention include compounds of formula (I) wherein R 1 is an alkyl or alkoxy group having 1 to 6 carbon atoms; R 2 is a hydrogen atom or an alkanoyl group having 2 to 6 carbon atoms; each of R 3 and R 4 is an alkyl group having 1 to 6 carbon atoms; and one of R5 and R6 is a halogen atom or an alkyl group having 1 to 6 carbon atoms, and the other is a hydrogen atom.

More preferred examples of compounds of formula (I) are those in which R 1 is an alkyl or alkoxy group having 1 to 4 carbon atoms; R 2 is a hydrogen atom or an alkanoyl group having 2 to 4 carbon atoms; each of R 3 and R 4 is an alkyl group having 1 to 4 carbon atoms; and one of R5 and R6 is a chlorine atom or an alkyl group having 1 to 4 carbon atoms, and the other is a hydrogen atom.

Since the compound (I) may exist in the form of a cis or trans isomer or an optical isomer (e.g. (+) - cis, (-) - cis, (+) - trans and (-) - trans), due to the two of the asymmetric carbon atom, all these isomers and mixtures thereof are within the scope of the invention. Among these isomers, the cis isomer of compound (I) is preferred for pharmacological use.

7 92393

The starting material (II) of the present invention is prepared, for example, (A) by administering a compound of the following formula: 5 Ϊ * -r w 1 li / * 0H (III)

COOH

B

wherein X is a hydrogen atom or a conventional protecting group, R 1, R 5 and R 6 are as defined above, react with a di (lower alkyl) aminoethyl halide, (B) optionally reacting the product with alenun alkanic acid or a reactive derivative thereof, and (C) when X is a conventional protecting group, further removing it from the obtained product.

Example 1 (1) 10.49 g of (+) - threo-3- (4-methoxyphenyl) -3- (2-amino-5-chlorophenyl) thio-2-hydroxypropionic acid are dissolved in an aqueous solution containing 1.2 g sodium hydroxide, and ether is added thereto. A diethyl ether solution containing 9.21 g of benzyloxycarbonyl chloride and an aqueous solution containing 2.16 g of sodium hydroxide are added dropwise simultaneously at 4-10 ° C, and the mixture is stirred at the same temperature for 3.5 hours. The reaction mixture is poured into hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. The residue is crystallized from isopropanol to give 12.0 g of (+) - threo-3- (4-methoxyphenyl) -3-Q2- (benzyloxycarbonyl) amino-5-chlorophenyl] thio-2-hydroxypropionic acid, m.p. 159-162 ° C.

(2) 0.76 g of potassium hydroxide is added to a solution of dimethyl sulfoxide β 92393 containing 1.9 g of the product obtained above, and a further 0.67 g of 2- (dimethylamino) ethyl chloride hydrochloride is added thereto. After stirring overnight, the reaction mixture is poured into ice water and acidified with hydrochloric acid. The mixture is washed with ether and the pH is adjusted to 4-5. The mixture is then extracted with chloroform, and the extract is washed with water, dried and evaporated to remove the solvent to give 1.81 g of (+) - threo-3- (4-methoxyphenyl) -3- [2-N-benzyloxycarbonyl-N - 2- (dimethylamino) ethylamino (-5-chloro-phenyl) -thio-2-hydroxypropionic acid.

Nujol IRV (cm-1): 3400, 2700-2400, 1700, 1610 Max (3) A mixture of 6.90 g of the product obtained above, 5 ml of acetic anhydride and 15 ml of pyridine is stirred at room temperature for 2 hours. The reaction mixture is poured into ice water and extracted with chloroform. The extract is washed with water, dried and evaporated to remove the solvent. Diethyl ether was added to the portion and the crystalline precipitates were collected by filtration to give 7.01 g of (+) - threo-3- (4-methoxyphenyl) -3 - '[(2- {N-benzyloxycarbonyl-N-] 2- ( dimethylamino) ethyl] amino--5-chlorophenyl-thio-2-acetoxypropionic acid.

Nujol, IRV (cm): 3420, 2720-2400, 1740 (weak), 1710, 1610 Max (4) 2.10 g of the product obtained above are dissolved in 10 ml of acetic acid. 15 ml of 25% hydrobromic acid-acetic acid solution and 0.2 ml of anisole are added thereto under cooling. After stirring at room temperature for 2.5 hours, the mixture is condensed under reduced pressure and the fraction is added to the portion. The pH of the mixture is adjusted to 4-5 with aqueous sodium bicarbonate solution, and then extracted with methylene chloride. The extract is washed with saturated aqueous sodium chloride solution, dried and evaporated to remove the solvent. A portion of the mixture is recrystallized from a mixture of isopropyl alcohol and diethyl ether to give 1.591 g of (+) - threo-3- (4-methoxyphenyl) -3- {2- [2- (dimethylamino) ethyl] amino] -5-chlorophenyl. · Thio-2-acetoxypropionic acid acetate. Sp. 150-153 ° C (dec.).

Hydrochloride: chci 3, IRV J (cm -1): 3370, 2700-2460, 1740, 1600, 1580 max (5) The product obtained above (hydrochloride) is converted into the free base form in the usual manner, and 2.0 g of the compound thus obtained Dissolve in 70 ml of xylene and reflux for 20 hours, condense under reduced pressure, convert the residue (oil) to the maleate in the usual manner and recrystallize from ethanol to give 2.1 g of (+) - cis-2- (4-methoxyphenyl). ) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one maleate Yield: 86.8%, m.p. 158-160 ° C.

Example 2 (1) 1.01 g of (+) - threo-3- (4-methoxyphenyl) -3- [2- [N-benzyloxycarbonyl-N- [2- (dimethylamino) ethyl] amino] -5-chlorophenyl Thio-2-hydroxypropionic acid is added to 8 ml of a 25% hydrochloric acid-methanol solution, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is condensed under reduced pressure to give methyl - (+) - threo-3- (4-methoxyphenyl) -3- [2- (1-benzyloxycarbonyl) -N- {2- (dimethylamino) ethyl] amino] -5-chlorophenyl] thio-2 -hydroxypropionate hydrochloride in quantitative yield.

CHCl 3 1 IRV fem): 3520, 1740, 1700 Max (2) The product obtained above is treated in the same manner as described in Example 1- (3) to give 980 mg of methyl-11- (+) - threo-3- (4 -methoxyphenyl) -3- [2- [N-benzyl] oxycarbonyl-N- [2- (dimethylamino) ethyl] [amino] -5-chlorophenyl] thio-2-acetoxypropionate.

10 g o z g 7

7 c. o ./ O

liquid IRV (cm -1): 1750, 1730, 1700 Max

Oxalate * 1/2 hydrate:

Nujol, IRV (cm): 3370, 2700-2400, 1750 max MS (m / e): 4 8 0 (M +) (4) The product obtained above is treated in the same manner as described in Example 1- (5) to give ( +) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one.

The maleate of this product has the same physicochemical properties as the product obtained in Example 1- (5).

Example 3 6.0 g of Ν, Ν'-dicyclohexylcarbodiimide are added to a mixture of 5.0 g of (+) - threo-3- (4-methoxyphenyl) -3- [2- [2- (dimethylamino) ethyl] amino-5-chlorophenyl-thio-2-acetoxypropionic acid hydrochloride, 200 mg of N-hydroxybenzotriazole, 100 mg of methylene chloride and 500 ml of dimethylformamide, with cooling. After stirring at room temperature for 17 hours, water is added. The mixture is then stirred for a further 1 hour and 5% aqueous sodium bicarbonate solution and ethyl acetate are added. The insolubles are filtered off and the filtrate is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. The residue is converted into maleate in a conventional manner and recrystallized from ethanol to give 4.48 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2, 3-dihydro-l, 5-benzothiazepin-4 (5H) -onimaleaattia. Yield: 79.8%.

11 92393

The product thus obtained has the same physicochemical properties as the product obtained in Example 1— (5).

Example 4 7.55 g of (+) - threo-3- (4-methoxyphenyl) -3- [2- [2- (dimethylamino) ethyl] amino-5-chlorophenyl] thio-2-acetoxypropionic acid hydrochloride are dissolved in 100 ml of methylene chloride. 8 ml of pyridine are then added at a temperature not exceeding 10 ° C, and then 3.56 g of benzyloxycarbonyl chloride are added. After stirring for 2 hours, the reaction mixture is poured into 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. After toluene is added to the solution, the pyridine is removed as a toluene azeotrope. The residue is converted into the maleate in the usual manner and recrystallized from ethanol to give 6.12 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8- chloro-2,3-di-hydro-1,5-benzothiazepin-4 (5H) -onimaleaattia. Yield: 72.2%.

The product thus obtained has the same physicochemical properties as the product obtained in Example 1— (5).

Example 5 1/0 g of (+) - threo-3- (4-methoxyphenyl) -3- [2- [2- (dimethylamino) ethyl] amino-5-chlorophenyl] thio-2-acetoxypropionic acid hydrochloride is dissolved in 5 ml of: methylene chloride and 2 ml of thionyl chloride are added. After stirring for 2 hours, the reaction mixture is condensed under reduced pressure and the portion is dissolved in 50 ml of methylene chloride. Said solution is added to a mixture of 1 ml of pyridine and 20 ml of methylene chloride, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate and basified with 5% aqueous sodium bicarbonate solution. The mixture is then washed, dried and evaporated to remove the solvent. The residue is converted to the maleate in a conventional manner and recrystallized from ethanol to give 970 mg of (+) - cis-2- (4-methoxy-12,9393 phenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro -2,3-dihydro-1,5-benzothiazepin-4 (5H) one maleate.

The product thus obtained has the same physicochemical properties as the product obtained from Example 1— (5) -

Examples 6-12

The corresponding starting materials are treated in the same manner as described in any of Examples 1-5 to give the following compounds.

[6] (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine 4 (5H) -one

Sp. 122-124 ° C (dec.)

[V] (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -9-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one perchlorate · l / 4hydrate M.p. 190-192 ° C

N- (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -9-chloro-2,3-dihydro-1,5-benzothiazepine; 5H) -onihydrokloridihydraatti

Sp. 140-143 ° C

(±) -cis-2- (4-methylphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one

Sp. 142-143 ° C (recrystallized from ethyl acetate) [1] (}] (±) -cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl- 2,3-dihydro-l, 5-benzothiazepin-4 (5H) -one hydrochloride

Sp. 184-186 ° C (recrystallized from a mixture of isopropyl alcohol and ether)

Sp. 190-192 ° C (recrystallized from a mixture of acetone and isopropyl ether) 13 92393

fumarate:

Sp. 196.5-198.5 ° C (dec., Recrystallized from isopropyl alcohol)

The maleate;

Sp. 173.5-175.5 ° C (dec., Recrystallized from ethanol)

Sp. 172.5-174 ° C (recrystallized from methanol)

Sp. 191.5 ° C (recrystallized from water)

methanesulfonate:

Sp. 124-128 ° C (recrystallized from isopropyl alcohol) [11] (+) - cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3 dihydro-l, 5-benzothiazepin-4 (5H) -onimaleaatti

Sp. 194-197 ° C (dec., Recrystallized from ethanol) [α] D + 83.7 ° (c = 0.362, methanol)

oxalate:

Sp. 179-180 ° C (recrystallized from ethanol) r i10 C *] d + 88.2 ° (c = 0.288, methanol) • 12-12 (-) - cis-2- (4-methylphenyl) -3-acetoxy-5 - E 2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one oxalate

Sp. 179.5-181 ° C (dec., Recrystallized from ethanol) Γ [α] 25 D -83.8 ° (c = 0.333, methanol)

maleate:

Sp. 195-197.5 ° C (dec., Recrystallized from ethanol) {mp 83.6 ° (c = 0.50, methanol)

Claims (7)

14 '.y Z 5 y 3 Fumarate: Sp. 210.5-212.5 ° C (dec., Recrystallized from ethanol) W 2 O D -91.3 ° (c = 0.323, methanol) »L - (+) - tartrate: m.p. 140-143 ° C (recrystallized from a mixture of ethanol and ether) A process for the preparation of a 1,5-benzothiazepine derivative represented by the following formula: wherein R 1 is a lower alkyl group, or lower alkoxy group; r2 is a hydrogen atom or a lower alkanoyl group; each of R 1 and R 4 is a lower alkyl group; and one of R 5 and R 6 is a halogen atom or a lower alkyl group and the other is a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof, characterized in that it is carried out on a propionic acid derivative of the following formula: R 6 y = Vpi COOH. the same as defined above, or for its reactive derivative, intramolecular cyclization, and if necessary, converting the product into a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that the reactive derivative of the compound (II) is chosen from a lower alkyl ester, an active ester, a mixed anhydride and an acid halide. Process according to Claim 2, characterized in that the propionic acid compound (II) or a lower alkyl ester thereof is subjected to an intramolecular cyclization at a temperature of 100 to 180 ° C. Process according to Claim 2, characterized in that the propionic acid compound (II) is subjected to intramolecular cyclization in the presence of a condensing agent at a temperature between cooling and 150 ° C. Process according to Claim 2, characterized in that the active ester, mixed anhydride or acid halide of the compound (11) is subjected to intramolecular cyclization in the presence or absence of the acid acceptor at a temperature of -50 to 60 ° C. Process according to one of Claims 1 to 5, characterized in that the 1,5-benzothiazepine derivative is 2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3 dihydro-l, 5-benzothiazepin-4 (5H) -one. Process according to one of Claims 1 to 5, characterized in that the 1,5-benzothiazepine derivative is 2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2, 3-dihydro-l, 5-benzothiazepin-4 (5H) -one. 16 92393