FI61894B - SOM MELLANPRODUKTER ANVAENDBARA 1-SUBSTITUERADE ELLER 1-OSUBSTITUERADE 5-, 6-, 7- ELLER 8- (2,3-SUBSTITUERADE) -PROPOXI-3,4-DIHYDROXIKARBOSTYRILDERIVAT - Google Patents

Description

I- - “Π Γβ1 / 44. PUBLICATION

^ jlgA 1 * 1 (11) UTLÄGGNINGSSKRIFT 6 * 894 5¾¾ (45) c Patent granted 11 10 1932 'Zgg', 5 ,, K & J £ S.'ä, '- dde1tf7 D * 05/12, 215/58 FINLAND - FINLAND (21) P * t «nttJhik« mu »- pKwitaraBknlng 770713 (22) HikemtapWv * - Antfknlnpdag 07.03.77 ^ (23) Alkupllvi — GMtlghttidag 31.01.73 (41) Tullut | ulklMlul - Bllvlt offuntltg 07.03.7

Patent and Registry Office / 44) Date of issue of the publication

Patent- och registrertenels Ameban utlagd «dl utlakriftun pubUccrad 30,06,82 (32) (33) (31)« tuolkuu »—Bugtrd priorttvt 13.OL.72 13.0¾.72, lU.09.72, 1U .09.72, iU. 09.72, 02.12.72, lU.12.72, 21.12.72 Japan-Japan (JP) 37181/72, 37182/72, 92557/72, 92558/72, 92560/72, 120953/72, 125858/72, 128972/72 (71) Otsuka Pharmaceutical Co., Ltd., No 209, Kandatsukasa-Cho, Chiyoda-Ku,

Tokyo, Japan-Japan (JP) (72) Kazuyuki Nakagawa, Tokushima, Nanami Murakami, Tokushima, Shiro Yoshi-Zaki, Tokushima, Hideo Mori, Tokushima, Michiaki Tominaga, Tokushima, Yasumitsu Tamura, Hyogo, Japan-Japan (JP) ( 7U) Oy Borenius & Co Ab (5U) 1-Substituted or 1-unsubstituted 5-, 6-, 7- or 8- (2,3-substituted) -propoxy-3, U-dihydrocarbostyril derivatives useful as intermediates - Som mellanprodukter användbara 1-substituents or 1-substituents 5 ~, 6-, 7 ~ or 8- (2,3-substituents) -propoxy-3, U-dioxycarbostyrilderivat (62) Separated from application 279/73 (patent 53703) - Avdelad frän ansökan 279/73 (patent 53703)

The invention relates to novel 1-substituted or 1-unsubstituted 5-, 6-, 7- or 8-C2,3-substituted) -propoxy-3,4-dihydrocarbostyril derivatives of the formula och2z (II) »R1 in the formula R represents a hydrogen atom, a lower alkyl group, a benzyl group or an allyl group and Z represents a group of the formula

-CH-CH 2 or -CH-CH 2 Y

\ / r 2

0 OH

2,61894 wherein Y represents a halogen atom.

These novel 3,4-dihydrocarbostyril derivatives are intermediates in the preparation of β-receptor blocking 5-, 6-, 7- or 8- [3- (substituted or unsubstituted amino) -2-substituted-7-propoxy-1-substituted or unsubstituted-3,4-dihydrocarbostyril derivatives in the manufacture of which are disclosed in Finnish patent publication 53,703. The formula of these pharmacologically valuable compounds is

0, CHO-chchonC

R1 • 1. 2 in which R represents the same as above, R represents a hydrogen atom or an aryl group of formula COR in which R represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a 3,4,5-trimethoxyphenyl group, and RT and R "may be the same or different groups and represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl group, or a cycloalkane group having 4 to 6 carbon atoms, or R 'and R "together with the nitrogen atom to which they are attached may form a piperidino, piperazino or morpholino group which may be substituted by a lower alkyl group.

The novel compounds of the invention have proved to be very valuable intermediates in the preparation of the above-mentioned pharmacologically valuable compounds, since the compounds according to the invention have a high reactivity and give the final product in high yield under favorable conditions.

The use of an intermediate to prepare a valuable end product is exemplified in FI Patent Publication No. 53,703, which also describes the β-receptor blocking properties of pharmacologically valuable end products.

3 ö 1 öy4

The compounds of the invention can be prepared according to the following reaction formula:

0 OH

(VIII) ΛΛ -V (VI) R1 \ R1 (IX) CH2CHCH2-Y1 / XCH9CH-CH2 (VII) I ^ I ^ X / OH OH \ ^ $

Z-OCH

(ID

R1

The alkyl group represented by the substituent R may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. The unsubstituted phenylalkyl group may be, for example, a benzyl group. The alkenyl group may be a straight-chain or branched alkenyl group having 2 to 4 carbon atoms, for example, an allyl group.

The novel intermediates of formula (II) can be readily prepared by administering the corresponding 5- (or 6-, 7- or 8-) hydroxy-3,4-dihydrocarbostyril derivative of formula OH 2 R 4 wherein R is as defined above. , reacting the formula XCH-CH - OHo, Tr__s 2 v ^ 2 Uii

CT

with an epihalohydrin according to claim 1, wherein X is the same as eael. Usually 1 to 10 moles of epihalohydrin, preferably 1 to 3 moles, are used per mole of compound (VI). The starting compounds of formula (VI) are known and are described in Japanese Patent Nos. 6,189,939 and 38789/1971, which are described in Chemistry and Industry, p. 1435 (1970). Reference may also be made to the article: Fritz Mayer, Berichte 60, 858-862 for the preparation of 6-, 7- and 8-hydroxy compounds of formula (VI).

5-Hydroxy-3,4-dihydrocarbostyril derivatives which are representative of the compounds represented by formula (VI) can be prepared from 3,4,5,6,7,8-hexahydrocarbostyril-5-one by reacting it with a brominating agent to give the corresponding 8 (or 6) -bromo-3,4,5,6,7,8-hexahydrocarbostyril-5-one, which is then heated during the following reaction:

0 0 OH

bromination

| * I 1 * I

0 1 1 »R1 R 'R1

Examples of suitable epihalohydrins are epibromohydrin, epichlorohydrin and epiodihydrin. Suitable basic compounds include alkali metals, alkali hydroxides, alkali carbonates and organic bases. Examples of preferred basic compounds are sodium metals, potassium metal, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, piperidine, piperazine, pyridine, lower alkylamines such as diethylamine, triethylamine, methylamine and the like. The reaction between compounds (VI) and (VII) can be carried out without solvents, but is preferably carried out in the presence of an ineffective solvent, for example, lower alkanols, water, lower alkyl acetate and ketones. Examples of suitable lower alkanols include methanol, ethanol, isopropanol, n-propanol, n-butanol and the like. Examples of suitable lower alkyl acetates include ethyl acetate, methyl acetate and propyl acetate and the like. Examples of suitable ketones are acetone and methyl ethyl ketone. Although various combinations of solvent and basic compound may be used, it is preferable to select the solvent depending on the basic compound used. In preferred applications, lower alkanols are used with alkali metals and water with alkali hydroxides. The basic compounds of X are organic bases, the reaction can be carried out without using any solvent or using a lower alkanol, lower alkyl acetate or ketone.

The reaction temperature may range from 0 ° to the boiling point of the solvent used, preferably from 50 ° to ... the boiling point of the solvent, for 4 to 6 hours, preferably 4 to 5 hours when an alkali metal or alkali hydroxides are used as the basic substance. , and the reaction temperature may range from 0 to 120 ° C, preferably from 80 to 120 ° C for 4 to 6 hours, preferably for 5 to 6 hours when organic bases are used as the basic substance. The reaction is usually carried out at atmospheric pressure. Both 5 (or 6, 7 or 8) - (2,3-epoxy) propoxy-3,4-dihydrocarbostyril derivatives and 5 (or 6, 7 or 8) - (2-hydroxy-3-halo) propoxy are obtained as reaction products in this reaction. -3,4-dihydrocarbostyril derivatives (compounds of formula (II) wherein Y is -CH-CEL and -CH-CH9Y, respectively). Between products (I) and (II)

O OH

the ratios vary depending on the type of basic compounds used. The preparation of the former compound (I) is foreground when the reaction is carried out in the presence of strongly basic compounds such as the alkali metals and alkali hydroxides listed above, and the preparation of the latter compound is predominant when the reaction is carried out in the presence of a weakly basic compound, especially piperidine and epihalohydrin is used in excess.

These compounds can be separated from one another using conventional methods, for example by fractional crystallization, but are preferably separated by column chromatography using a column packed with active alumina, silica gel or the like.

An intermediate represented by formula (II) wherein Z represents a group -CH-CHgY (Y represents the same as above) can also be prepared by OH

UCX

A 5-hydroxy-3,4-dihydrocarbostyril derivative of formula r1 (Vili), wherein R1 is as defined above, to react a compound of formula 6 61894

CH2 - CH - CH2Y OH OH

with 3-halo-1,2-propanediol, wherein Y in the formula has the same meaning as above. It is preferable to react 1 to 5 moles of the compound (IX), preferably 1 to 3 moles, to react with one mole of the compound (VIII). This reaction is carried out at atmospheric pressure for 3 to 6 hours, preferably 4 to 5 hours, in the presence of a chrominating agent, e.g. pyridine bromide, perbromide or bromine, in an ineffective solvent which does not participate in the reaction, such as carbon tetrachloride at room temperature to the boiling point, preferably at or near the boiling point of the solvent used. Suitable solvents include halogenated hydrocarbons and mixtures of halogenated hydrocarbons and lower alkanols, for example, chloroform, carbon tetrachloride, dichloroethane, a mixture of methanol and chloroform, and a mixture of ethanol and carbon tetrachloride and the like. The most preferred solvents are chloroform and carbon tetrachloride. The compounds of formula (VIII) are known per se and are mentioned in the article: K.R.W.

Böhme, Z. Valenta, Tetrahedron letters, 1965, 2441. It is preferred to use 1 to 1.5 moles of brominating agent per one mole of compound (VIII).

The present invention will now be described by way of some examples. Example 1 5- (2-Hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril 1.53 g of 5-hydroxy-3,4-dihydrocarbostyril and 3.5 g of epichlorohydrin were added to 30 ml of a methanol solution containing 0.216 g. sodium metal, and the resulting solution was stirred at 55-60 ° C for 4 hours. after cooling the solution, the precipitated sodium chloride was filtered off, and the filtrate was concentrated to dryness under reduced pressure. Acetone was added to the resulting residue to crystallize the product. Crystallization from ethanol gave 0.8 g of 5- (2,3-epoxy) -propoxy-3,4-dihydrocarbostyril, m.p. 172-173 ° C, as a colorless amorphous solid. The acetone solution of the filtrate was concentrated to dryness, and the resulting residue was crystallized from ethyl acetate to give 0.05 g of 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 157-158. 0.

61 894 7

Example 2 5- (2,3-Epoxy) propoxy-3,4-dihydrocarbostyril

To a solution of 0.6 g of sodium hydroxide dissolved in 40 ml of water were added 2.5 g of 5-hydroxy-3,4-dihydrocarbostyril and 3.0 g of epibromohydrin, and the resulting solution was stirred for 4 hours at 60-65 ° C. After allowing the solution to cool, the precipitated crystals were separated by filtration and crystallized from ethanol to give 1.9 g of 5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril, m.p. 172-173 ° C.

Example 3 1-Benzyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril 4.7 g of epichlorohydrin and 3 drops of piperidine were added to 5.1 g of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and the resulting mixture was stirred for 5 hours at 95-100 ° C. The reaction mixture was then concentrated to dryness, and the residue was dissolved in 60 ml of chloroform. The solution thus obtained was washed successively with 5% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The dried solution was then passed through a chromatography column packed with active alumina, and the column was developed with chloroform. The first eluate containing 1-benzyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril was concentrated to dryness and the residue was crystallized from ethanol to give 0.5 g of the above product, m.p. 122 ° C, as colorless amorphous crystals. The next eluate containing 1-benzyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril was concentrated to dryness, and the residue was crystallized from carbon tetrachloride to give 3.2 g of the above product as colorless amorphous crystals having a melting point. was 103-107 ° C.

Example 4 1-Ethyl-5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril> 3.8 g of epichlorohydrin and 3 drops of piperidine were added to 3.0 g of 1-ethyl-5-hydroxy-3,4-dihydrocarbostyril. , and the mixture was stirred for 5 hours at 95-100 ° C. The reaction mixture was then concentrated to dryness and the residue was dissolved in 10 ml of acetone. After adding 10 ml of ether and 20 ml of benzene, the solution was poured onto a chromatography column packed with silica gel, and the column was developed with a solvent containing acetone: ether: benzene (1: 1: 2). The first eluate was concentrated to dryness, and the residue was crystallized from n-hexane to give 0.3 g of 1-ethyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril as colorless, amorphous crystals having a melting point of 011 50. .52.5 ° C. The next eluate containing 1-ethyl-5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril was concentrated to dryness, and the residue was crystallized from carbon tetrachloride to give the above product as colorless amorphous crystals, melting at 115 ° C. .17.5 ° C.

Example 5 1-Allyl-5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril 4.2 g of epibromohydrin and 3 drops of piperidine were added to 2.5 g of 1-allyl-5-hydroxy-3,4- dihydrocarbostyril. After the reaction, the reaction mixture was treated as in Example 4 and chromatographed using the same chromatography column as in Example 4. The first eluate from the column was concentrated to give 1-allyl-5- (2,3-epoxy) propoxy-3,4-crude as a crude product. dihydrokarbo-styriiliä. Recrystallization from carbon tetrachloride gave 0.4 g of the same product, m.p. 73.5-75.8 ° C, as colorless amorphous crystals. The next eluate was concentrated to give crude 1-allyl-5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril. Recrystallization from carbon tetrachloride gave 1.7 g of the same product, m.p. 82-84 ° C, as colorless amorphous crystals.

Example 6 5- (2-Hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril 5.5 g of 3-chloro-1,2-propanediol were added to a solution containing 3.3 g of 3,4,5,6,7, 8-Hexahydrocarbostyril-5-one in 80 ml of chloroform, followed by the addition of 8.9 g of N-bromo-succinimide. The mixture was then heated to reflux for 2 hours in a water bath. After cooling, 50 ml of water was added to the mixture, and the precipitated crystals were separated by filtration, and the chloroform layer was separated. The chloroform layer was washed successively with 5% aqueous sodium hydroxide solution 9 61 894 and anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and ether was added to the residue to crystallize the product. When the product was crystallized from ethyl acetate, 2.8 g of 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril having a melting point of 157-158 ° C were obtained as colorless amorphous crystals.

Example 7 5- (2-Hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril

A solution of 3.6 g of bromine in 50 ml of carbon tetrachloride was added with stirring and ice-cooling to a solution of 4.0 g of 3,4,5,6,7,8-hexahydrocarbostyril-5-one in 50 ml of carbon tetrachloride. . After standing for one minute, the precipitate formed was removed by decantation. The carbon tetrachloride layer was distilled at room temperature to remove the solvent (CCl 4), and the resulting crystals were combined with the above precipitate, followed by washing with acetone to give a quantitative amount of 8- (or 6-) bromo-3,4,5,6,7,8- hexahydro-carbostyril-5-one with a melting point of 126-127 ° C as yellow crystals. The crystals thus obtained were dissolved in 80 ml of carbon tetrachloride, and 3.0 g of 3-chloro-1,2-propanediol and 1.5 g of 2,4,6-tribromophenol were added to the solution. The mixture was heated at reflux for 2 hours and then treated in the same manner as in Example 6 to give 2.1 g of 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril, m.p. 157. .158 ° C, as colorless crystals.

Example 8 5- (2-Hydroxy-3-bromo) propoxy-1-methyl-3,4-dihydrocarbostyril

To a solution of 40 g of 1-methyl-3,4,5,6,7,8-hexahydrocarbostyril-5-one dissolved in 50 ml of chloroform was added 6.6 g of 3-bromo-1,2-propanediol. , then 40 g of N-bromomeric succinimide were added, and the resulting mixture was heated under reflux for 2 hours. After allowing the mixture to cool, it was washed successively with 5% aqueous sodium hydroxide solution and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and carbon tetrachloride was added to the resulting residue to crystallize the product. Recrystallization from carbon tetrachloride gave 2.7 g of 5- (2-hydroxy-3-bromo) propoxy-1-methyl-3,4-dihydrocarbostyril as colorless amorphous crystals with a melting point of 155-157 ° C.

1 o 61894

Example 9 1-Benzyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril

To a solution of 5.0 g of 1-benzyl-3,4-5-6-7-8-hexahydrocarbostyril-5-one dissolved in 60 ml of chloroform was added 2.9 g of 8-chloro-1.2 -propanediol and 3.5 g of N-bromosuccinimide.

The resulting solution was heated under reflux for 2 hours in a water bath and then treated in the same manner as in Example 8 to crystallize the crude product. Recrystallization of the product from carbon tetrachloride gave 3.7 g of 1-benzyl-5- (2-hydroxy-3-chloro) -propoxy-3,4-dihydrocarbostyril, m.p. 105-107 ° C, colorless. as amorphous crystals.

Example 10 Preparation of 1-allyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 1-allyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril 4.0 g of epichlorohydrin and 3 drops of piperidine were added to 3 g of 1-allyl-5-hydroxy-3,4-dihydrocarbostyril and the mixture was stirred for 5 hours at a temperature of 95-100 ° C. The reaction mixture was then concentrated to dryness and the residue was dissolved in 10 ml of acetone. 10 ml of ether and 20 ml of benzene were added and the solution was poured onto a chromatography column packed with silica gel, which was developed with a solvent system consisting of acetone: ether: benzene (1: 1: 2). The first eluate was concentrated to dryness and the residue was crystallized from carbon tetrachloride to give 0.4 g of 1-allyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril, m.p. 73.5-75.0 ° C. as colorless amorphous crystals. The next eluate was concentrated to dryness and the residue was recrystallized from carbon tetrachloride to give 2.0 g of 1-allyl-5- (2-hydroxy-3-chloro) -propoxy-3,4-dihydrocarbostyril, m.p. 65-67 ° C. as colorless amorphous crystals.

Example 11 Preparation of 1-ethyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 1-ethyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril 4.0 g of epichlorohydrin and 3 drops of piperidine were added to 3 g of 61894 11 1-ethyl-5-hydroxy-3,4-dihydrocarbostyril and the mixture was stirred for 5 hours at a temperature of 95-100 ° C. The reaction mixture was then concentrated to dryness and the residue was dissolved in 10 ml of acetone. 10 ml of ether and 20 ml of benzene were added and the solution was poured onto a chromatography column packed with silica gel, which was developed with a solvent system consisting of acetone: ether: benzene (1: 1: 2). The first eluate was concentrated to dryness and the residue was crystallized from n-hexane to give 0.3 g of 1-ethyl-5- (2,3-epoxy) -propoxy-3,4-dihydrocarbostyril, m.p. 50-52.5 ° C as colorless amorphous crystals. The eluate was concentrated to dryness, and the residue was recrystallized from carbon tetrachloride to give 2.0 g of 1-ethyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril, m.p. 117-119 ° C, as colorless amorphous crystals.

Example 12 Preparation of 1-methyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 1-methyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril 4.0 g epichlorohydrin and 3 drops of piperidine were added to 3 g of 1-methyl-5-hydroxy-3,4-dihydrocarbostyril and the mixture was stirred for 5 hours at 95-100 ° C. The reaction mixture was then concentrated to dryness and the residue was dissolved in 10 ml of acetone. 10 ml of ether and 20 ml of benzene were added and the solution was poured onto a chromatography column packed with silica gel, which was developed with a solvent system consisting of acetone: ether: benzene (1: 1: 2). The first eluate was concentrated to dryness and the residue was crystallized from carbon tetrachloride to give 0.4 g of 1-methyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril, m.p. 76-78 ° C, as colorless amorphous crystals. The eluate was concentrated to dryness and the residue was recrystallized from carbon tetrachloride to give 0.2 g of 1-methyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril, m.p. 137-139 ° C, as colorless amorphous crystals.

Example 13 Preparation of 1-methyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 1-methyl-5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril 61 8 9 Λ 1 2 3.8 g of epibromohydrin and 3 drops of piperidine were added to 3.0 g of i-methyl-5-hydroxy-3,4-dihydrocarbostyril and the mixture was stirred for 5 hours at 95-100 ° C. The reaction mixture was then concentrated to dryness and the residue was dissolved in 10 ml of acetone. 10 ml of ether and 20 ml of benzene were added and the solution was poured onto a chromatography column packed with silica gel, which was developed with a solvent system consisting of acetone: ether: benzene (1: 1: 2). The first eluate was concentrated to dryness and the residue was crystallized from carbon tetrachloride-n-hexane to give 0.3 g of 1-methyl-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril, m.p. 71-78 ° C. as colorless amorphous crystals. The eluate was concentrated to dryness and the residue was recrystallized from carbon tetrachloride to give 2.0 g of 1-methyl-5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril, m.p. 155-157 ° C, as colorless amorphous crystals.

Example 1 Preparation of M-5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril 3.8 g of epibromohydrin and 3 drops of piperidine were added. To 3.0 g of 5-hydroxy-3,4-dihydrocarbostyril and the mixture was stirred for 5 hours at a temperature of 95-100 ° C. The reaction mixture was then concentrated to dryness and the residue was dissolved in 10 ml of acetone. 10 ml of ether and 20 ml of benzene were added and the solution was poured onto a chromatography column packed with silica gel, which was developed with a solvent system consisting of acetone: ether: benzene (1: 1: 2). The first eluate was concentrated to dryness and the residue was crystallized from ethanol to give 0.4 g of 5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril, m.p. 172-173 ° C, as colorless amorphous crystals. The eluate was concentrated to dryness, and the residue was recrystallized from ethyl ether to give 1.3 g of 5- (2-hydroxy-3-bromo) propoxy) -3,4-dihydrocarbostyril, m.p. 133-135 ° C, as colorless amorphous crystals.

Example 15 Preparation of 5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril

To a solution of 38 g of 3,4,5,5,7,8-hexahydrocarbostyril-5-one dissolved in 50 ml of chloroform was added 6.6 g of 3-bromo-1,2-61,894 13 propanediol, followed by 40 g of N-bromosuccinimide, and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool and washed alternately with 5% aqueous sodium hydroxide solution and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and carbon tetrachloride was added to crystallize the product. Recrystallization from ether gave 2.5 g of 5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril, m.p. 133-135 ° C, as colorless amorphous crystals.

Example 16 Preparation of 5- (2-hydroxy-3-chloro) propoxy-1-methyl-3,4-dihydrocarbostyril

To a solution of 40 g of 1-methyl-3,4,5,6,7,8-hexahydrocarbostyril-5-one dissolved in 50 ml of chloroform was added 6.6 g of 3-chloro-1,2-propanediol, followed by 40 g of g of N-bromosuccinimide, and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool and washed alternately with 5% aqueous sodium hydroxide solution and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and carbon tetrachloride was added to crystallize the product from carbon tetrachloride to give 3.0 g of 5- (2-hydroxy-3-chloro) propoxy-1-methyl-3,4-dihydrocarbostyril, m.p. 137-139 ° C. as colorless amorphous crystals.

Example 17 Preparation of 5- (2-hydroxy-3-chloro) propoxy-1-ethyl-3,4-dihydrocarbostyril

To a solution of 40 g of 1-ethyl-3,4,5,6,7,8-hexahydrocarbostyril-5-one dissolved in 50 ml of chloroform was added 6.6 g of 3-chloro-1,2-propanediol, followed by 40 g of g of N-bromosuccinimide, and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool and washed alternately with 5% aqueous sodium hydroxide solution and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and carbon tetrachloride was added to crystallize the product. Recrystallization from carbon tetrachloride gave 3.0 g of 5- (2-hydroxy-3-chloro) propoxy-1-ethyl-61,894,144-dihydrocarbostyril, m.p. 117-119 ° C, as colorless amorphous crystals.

Example 18 Preparation of 5- (2-hydroxy-3-bromo) propoxy-1-ethyl-3,4-dihydrocarbostyril

To a solution of 40 g of 1-ethyl-3,4,5,6,7-hexahydrocarbostyril-5-one dissolved in 50 ml of chloroform was added 6.6 g of 3-bromo-1,2-propanediol, followed by 40 g of g of N-bromosuccinimide, and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool and washed alternately with 5% aqueous sodium hydroxide solution and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and carbon tetrachloride was added to crystallize the product. Recrystallization from carbon tetrachloride gave 2.9 g of 5- (2-hydroxy-3-bromo) propoxy-1-ethyl-3,4-dihydrocarbostyril, m.p. 115-117.5 ° C, as colorless amorphous crystals.

Example 19 Preparation of 5- (2-hydroxy-3-chloro) propoxy-1-allyl-3,4-dihydrocarbostyril

To a solution of 40 g of 1-allyl-3,4,5,6,7,8-hexahydrocarbostyril-5-one dissolved in 50 ml of chloroform was added 7.0 g of 3-chloro-1,2-propanediol and then 40 g of N-bromosuccinimide and the mixture were heated under reflux for 2 hours. The mixture was allowed to cool and washed alternately with 5% aqueous sodium hydroxide solution and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and carbon tetrachloride was added to crystallize the product. Recrystallization from carbon tetrachloride gave 3.0 g of 5- (2-hydroxy-3-chloro) propoxy-1-allyl-3,4-dihydrocarbostyril, m.p. 65-67 ° C, as colorless amorphous crystals.

Example 20 Preparation of 5- (2-hydroxy-3-bromo) propoxy-1-allyl-3,4-dihydrocarbostyridine 61,894 15

To a solution of 40 g of 1-allyl-3,4,5,6,7-hexahydrocarbostyril-5-one dissolved in 50 ml of chloroform was added 6.6 g of 3-bromo-1,2-propanediol, followed by 40 g of g of N-bromosuccinimide, and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool and washed alternately with 5% aqueous sodium hydroxide solution and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The dried chloroform solution was concentrated under reduced pressure, and carbon tetrachloride was added to crystallize the product. Recrystallization from carbon tetrachloride gave 2.8 g of 5- (2-hydroxy-3-bromo) propoxy-1-allyl-3,4-dihydrocarbostyril, m.p. 82-84 ° C, as colorless amorphous crystals.

Example 21 Preparation of 6- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 6- (3-chloro-2-hydroxy) propoxy-3,4-dihydrocarbostyril in 30 ml of methanol dissolved in 0.25 ml g of sodium (metal), 1.6 g of 6-hydroxy-3,4-dihydrocarbostyril and 3.5 g of epi-chlorohydrin were added and the mixture was stirred for 4 hours at a temperature of 50 to 60 ° C. The mixture was allowed to cool and the precipitated sodium chloride was removed by filtration, after which the filtrate was concentrated to dryness. The residue was applied to a chromatography column packed with silica gel (Wako gel C-200) and developed with acetone. The first eluate was concentrated to dryness and recrystallized from ethanol to give 0.9 g of 6- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril, m.p. 138-140 ° C, as colorless, amorphous crystals. The next eluate was evaporated to dryness and recrystallized from acetone to give 0.3 g of 6- (3-chloro-2-hydroxy) propoxy-3,4-dihydrocarbostyril, m.p. 167-170 ° C, as colorless amorphous crystals.

Example 22 Preparation of 8- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 8- (3-chloro-2-hydroxy) propoxy-3,4-dihydrocarbostyril to 3.1 g of 8-hydroxy -3,4-Dihydrocarbostyril was added 2.8 g of epi-chlorohydrin and 3 drops of piperidine, and the mixture was stirred for 5 hours at 95-100 ° C, after which the mixture was concentrated to dryness. The residue was dissolved in 50 ml of chloroform, and the solution was washed alternately with 5% aqueous sodium hydroxide solution and water, and then dried over sodium sulfate. The residue was applied to a chromatography column packed with silica gel (Wako gel C-200) and developed with acetone. The first eluate was concentrated to dryness and recrystallized from ethyl acetate to give 0.3 g of 8- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril, m.p. 124-126 ° C. Recrystallization of the next eluate from acetone gave 1.5 g of 8- (3-chloro-2-hydroxy) propoxy-3,4-dihydrocarbostyril, m.p. 179.5-180.5 ° C.

Example 23 Preparation of 7- (3-chloro-2-hydroxy) propoxy-3,4-dihydrocarbostyril To 3.1 g of 7-hydroxy-3,4-dihydrocarbostyril was added 2.8 g of epichlorohydrin and 3 drops of piperidine. and the mixture was stirred for 5 hours at 95-100 ° C, then concentrated to dryness, the residue was dissolved in 50 ml of chloroform, and the solution was washed alternately with 5% aqueous sodium hydroxide solution and water, and then dried over sodium sulfate. The residue was applied to a chromatography column packed with silica gel (Wako gel C-200) and developed with acetone. The first eluate was concentrated to dryness and recrystallized from acetone to give 1.4 g of 7- (C3-chloro-2-hydroxy) propoxy-3,4-dihydrocarbostyril, m.p. 138-140 ° C.

Example 24 5- (2,3-Epoxy) propoxy-3,4-dihydrocarbostyril 1.53 g of 5-hydroxy-3,4-dihydrocarbostyril and 3.5 g of epichlorohydrin were added to 30 ml of a methanol solution containing 0.216 g. sodium metal, and the resulting solution was stirred at 55-60 ° C for 4 hours. After allowing the solution to cool, the precipitated sodium chloride was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue thus obtained was then extracted while warm with ethyl acetate, which was then distilled off. The resulting residue was crystallized from acetone-ethyl ether to give 1.0 g of 5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid, m.p. 172-173 ° C. The characteristic points of the infrared spectrum of 61894 17 -1 -1 were 3020 cm, 1665 cm and 1590 cm

Analysis calculated for C 65.74; H 5.98; N 6.39 Found: C 65.35; H 5.84; N 6.47

Example 25 5- (2,3-Epoxy) propoxy-3,4-dihydrocarbostyril

A mixture of 1.63 g of 5-hydroxy-3,4-dihydrocarbostyril, 2.5 g of epibromohydrin and 2 drops of piperidine was heated at 95-100 ° C for 4 hours with stirring. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was crystallized from acetone to give 1.2 g of 5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril as a colorless powder, m.p. 172-173 ° C.

Example 26 5- (2,3-Epoxy) propoxy-3,4-dihydrocarbostyril

To a solution of 0.6 g of sodium hydroxide dissolved in 40 ml of water were added 2.45 g of 5-hydroxy-3,4-dihydrocarbostyril and 3.5 g of epichlorohydrin, and the resulting solution was stirred for 4 hours at 30 to 40 ° C. ° C. After cooling, the precipitated crystals were separated by filtration and recrystallized from acetone to give 1.75 g of 5- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 172. .1 73 ° C.

Claims (1)

A novel 1-substituted or 1-unsubstituted 5-, 6-, 7- or 8- (2,3-substituted) -propoxy-3,4-dihydrocarbostyril compound useful as an intermediate having the general formula och2z γΊι ^ <n> A> t R1 1 ... in which R is a hydrogen atom, a lower alkyl group, a benzyl group or an allyl group, and Z is a group of the formula -CH - CH2 or -CH - CHOY \ ' V OH wherein Y is halogen, which compound is suitable for use as an intermediate in the preparation of pharmacologically valuable 5-, 6-, 7- or 8- [3- (substituted or unsubstituted amino) -2-substituted- and -7-propoxy-1-substituted or unsubstituted-3,4-dihydrocarbostyril compounds. In this case, the by-product is 1-substituted or 1-substituted 5-, 6-, 7- or 8- (2,3-substituted) -propoxy-3,3 * 4-dihydrocarbostyril in the form of OCH „ZI v an R1 is R is a hydrogen atom, an alkyl group, a benzyl group or an allyl group ooh Z is a group of formula