FI76341C - PROCEDURE FOR FRAMSTAELLNING AV 5,6-DIHYDROIMIDAZO / 4,5,1-J-K // 1 / BENZAZEPIN-2,7 (1H, 4H) -DION. - Google Patents

Description

7 6 3 41

Process for the preparation of 5,6-dihydroimidazoZT4,5,1-j-k7ZT7benzazepine-2,7 (1H, 4H) dione

Separated by division of patent application 833697 5

The invention relates to a process for the preparation of a compound of formula (II)

B

And used as an intermediate in the preparation of therapeutically useful 6-amino-7-hydroxy-4,5,6,7-tetrahydroimidazo [4,5,1-j-? 7] benzazepin-2 (1H) one derivatives of the formula (I)

H R

20 HO \

Js. OF

uc>

25 I

B

wherein R is a hydrogen atom, a straight-chain or branched alkyl radical having 1 to 8 carbon atoms which may be substituted by a hydroxyl radical, a phenyl radical or a phenoxy radical, or a cycloalkyl radical having 3 to 7 carbon atoms which may further contain a nitrogen atom and be substituted by an alkyl radical of 1 to 4 carbon atoms, and the wavy lines mean that the hydroxyl radical in position 7 and the 35 amino radicals in position 6 have a trans configuration relative to each other, the compounds of formula (I) can be prepared by reacting a compound of formula (II) ) 2 76341 Ί> Ν \ 5 i li, = 0 (II)

'·> \ N H

is reacted with an alkyl nitrite, preferably in the presence of an acid to give a compound of formula (III):

HO

nn o ,, Λ \ I / (III) 15,> VN \ L I / = 0

V KK

B

which is reduced to give a compound of formula (I);

A

20

H \ H

H0; J ^ 25 I> = 0 - n /

B

wherein the wavy lines have the same meaning as above, and that the compound (IA) is then separated and, if desired, salified, or alkylated after first protecting the -NH 2 - group with a benzyl derivative to give a deprotected compound of formula (Ιβ) : 3 76341

H .R

- - N

5 H0Y ^ (IB> I 11> = °

B

10 wherein the wavy lines have the same meaning as above and R has the same meaning as above, except that it cannot be a hydrogen atom, after which the compound is separated and, if desired, converted into a salt, or the compound (1) is reacted with a carbonyl derivative of formula ( IV): 15

R 0 = C (IV) ^ R 2 wherein and R 2 are such that -CHCl 2 "means R 2 is the same as R above, except that it cannot be a hydrogen atom or a methyl radical, in the presence of a tertiary amine and then with a reducing agent, to give the compound .25 of formula (I ^,):

B

HO ,, ^ R, 30 ^ (lc)

B

35 with wavy lines 5 4 76341 ^ "R1

-CH

have the same meaning as above, and that the compound obtained is isolated.

The compound (II) prepared according to the present invention is useful as an intermediate in the process described above.

The present invention is characterized in that the compound of formula (V)

B

15 NX

il 0 (V)

H 2 Cl 2 CH 3 O 20 is reacted with an alkyl 4-halobutyrate of formula (VI)

Hai- (CH2) 3-COOalc (VI) 25 wherein Hai is a chlorine, bromine or iodine atom and ale is an alkyl group having 1 to 4 carbon atoms, followed by a compound of formula (VII) / H, C ..

30 ^ alcO-C | 2 ^ CH „|| = 0 (VII) 35 I H2c N: h3 76341 5 is hydrolyzed under acidic conditions to give a compound of formula (VIII) / HCO.

, / 2 -CH

5 alcO-C; 2 • CH2 «VIII)! I N> = o

io S

B

and the ester group of which is saponified to give an acid of formula (IX) 15 / H2C "C [h / XH0 H2" C | 2 I il> = ° (IX) 20 j

B

and whose side chain is cyclized to give a compound of formula (II).

According to a preferred embodiment of the process according to the invention: the alkyl halobutyrate is preferably methyl or ethyl bromobutyrate and the condensation is carried out in the presence of a base such as an alkali metal hydride; The hydrolysis of a compound of formula (VII) is carried out in the presence of an acid such as sulfuric acid using an alcohol such as ethanol as a solvent in the reaction; - saponification of a compound of formula (VIII) is carried out with a base such as sodium hydroxide or potassium hydroxide in an alcohol such as methanol or ethanol; - the side chain cyclization of a compound of formula (IX) is carried out either by preparing the acid chloride, for example by reaction with 7 6 3 41 6 thionyl chloride, which is then treated with a Lewis acid, for example aluminum chloride in an organic solvent such as methylene chloride or dichloroethane, or with a dehydrating agent such as polyphosphorus.

The starting compound of formula V is known and described, for example, in J. Chem. Soc. Perkin I (1982) - 261.

The following examples illustrate the invention.

Example 1 10 (6RS, trans) -6-amino-7-hydroxy-4,5,6,7-tetrahydroimidazo-4,5,1-j-k7Z.1 / benzazepine-2- (1H) -one hydrochloride

Step A: 1,3-Dihydro-2-oxo-3-phenylmethyl-1H-benzimidazole-1-butanol ethyl ester

29.6 g of 1,3-dihydro-1-phenylmethyl-2H-benzimidazol-2-one (described in Helv. (44) 1961 3 p. 1278) were mixed with 296 cm of dimethylformamide, 7.6 g were added over 30 minutes. g of sodium hydride as a 50% oil mixture, stirred for a further 30 minutes, the reaction mixture was cooled to + 5 ° C, 33.9 g of ethyl 4-bromobutyrate were added dropwise over 15 minutes and stirring was continued for a further 3 hours at room temperature. The solution was poured into 900 cm 2 of ice water, extracted with ether, the extracts washed with water, dried, evaporated to dryness and the oil 3 thus obtained dissolved in 50 cm of isopropyl ether, left to crystallize for 16 hours, separated by centrifugation to give 22.6 g of the title compound ( mp 50 ° C), (mp 52 ° C recrystallized from cyclohexane).

Analysis for C 20 H 22 N 2 O 3 = ^ 38.39

Calculated: C% 70.98, H% 6.55, N% 8.28 Found: 70.8 6.6 8.2

Step B: 1,3-Dihydro-2-oxo-3-phenylmethyl-1H-benzimidazole-35-butyric acid

A mixture of 40.6 g of the product obtained above 3 7 76341 and 400 cm of 1N methanolic sodium hydroxide solution was refluxed for 3 hours under nitrogen, the mixture was concentrated to half its volume, poured into 1 liter of ice water, concentrated hydrochloric acid was added until the pH of the mixture was 2. separated by centrifugation, washed, dried to give 35.2 g of the desired product, mp 166 ° C (168 ° C recrystallized from ethyl acetate).

Analysis: ^ ^ 8 ^ 28 ^^ 2 ^ 3 = ^ 10.33 Calculated: C% 69.66, H% 5.84, N% 9.02 Found: 69.4 5.9 8.9 10 Step C : 5,6-Dihydro-1-phenylmethylimidazo [1,5,1-b] [1 H] -benzazepine-2,7- (1H, 4H) -dione

21.5 g of the compound obtained above were suspended in 3,430 cm of chloroform, 21.5 g of thionyl chloride were added, the reaction mixture was refluxed for 1 hour and 15 minutes and then evaporated to dryness under reduced pressure.

3 The product thus obtained was dissolved in 860 cm 2 of dichloroethane under an inert atmosphere, cooled to + 15 ° C, 18.67 g of aluminum chloride were added, stirred for 4 hours at 20 ° C, the reaction mixture was poured into 1 liter of ice water, 3 cm of concentrated hydrochloric acid, stirred for 10 minutes and filtered. The organic phase was separated by decantation, the aqueous phase was extracted with methylene chloride, the organic phases were combined, washed with 10% aqueous potassium carbonate solution until pH 6 of the washing water, dried, evaporated to dryness under reduced pressure, crystallized from ethyl acetate to give = 135 ° C).

Analysis: (recrystallized from isopropanol) C18H16N2 ° 2 = 292'32

Calculated: C% 73.95, H% 5.51, N% 9.58 Found: 73.9 5.5 9.4

Step D: 35,6,6-Dihydro-imidazo-ε 4,5,1-β-1H-benzazepine-2,7- (1H, 4H) -dione

A mixture of 8 76341 containing 29.2 g of the compound obtained above, 292 g of o-phosphoric acid and 14.1 g of phenol was heated in an inert atmosphere to 150 ° C and after 2 hours the mixture was cooled to about +35 ° C. poured with stirring into 3,200 cm of ice water, 2 liters of methylene chloride were added, the mixture was basified with sodium hydroxide, the insoluble matter was filtered off and washed with methylene chloride. The organic phase was washed, dried and evaporated to dryness under reduced pressure. 9.7 g of the desired compound (m.p. = 235 [deg.] C.) were obtained by recrystallizing the residue obtained above and then purifying it by chromatography under pressure (eluent: ethyl acetate-methanol-triethylamine 90-2-2).

Analysis: Chio N 2 O 2 ~ 202.20 Calculated: C% 65.33, H% 4.98, N% 13.85 Found: 65.0 4.9 13.7 Step E: 4,5-Dihydroimidazo - £ 3,5,1-j-k7 '/ T7-benzazepine-2,6,7- (1H) -trione oxime

15.5 g were suspended in an inert atmosphere above 3

to 620 cm-tetrahydrofuran, the mixture was cooled to + 5 ° C, 42.5 cm-1N hydrochloric acid was added.

3 ethanol solution and 10.5 cm of tert-butyl nitrite, stirred for 3 hours at + 5 ° C, the product was separated by centrifugation, washed with tetrahydrofuran and then with a mixture of chloroform and methanol (1: 1) to give 16.5 g of the desired product. 25 (mp> 280 ° C).

Step F: (6RS-trans) -6-Amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo-74,5,1-j-k7-Z-17-benzazepine-2 (1H) -one hydrochloride 30 4 g of the compound obtained above and 2 g ... 3 of palladium in 10% methanol were suspended in 150 cm of methanol, stirred in the presence of hydrogen gas for 2 hours and 30 minutes, filtered, the filtrate cooled in an ice bath and added slowly with gentle stirring. 66 g of 35 sodium borohydride were stirred for a further 1 hour and 30 minutes at + 5 ° C and the mixture was evaporated to dryness under reduced pressure at + 30 ° C. The residue obtained was dissolved in 15 cm -1 of 9 7 6 3 41 methanol, ethyl acetate containing hydrogen chloride was added until the pH of the mixture was 1-2, the product was separated by centrifugation to give 3.6 g of the desired hydrochloride. (Mp> 260 ° C). The compound was recrystallized from methanol followed by ethanol (mp> 260 ° C).

Analysis: C 11 H 14 N 3 Cl 2 = 255.7

Calculated: C% 51.66, H% 5.51, N% 16.43, Cl% 13.86 Found: 51.5 5.6 16.7 14.2

Example 2 4,5-Dihydroimidazo [4,5,1-b] z7-benzazepine-2,7- (1H, 6H) -dione Step A: 2,3-Dihydro-3- (1-methyleneethenyl) - 2-Oxo-1H-benzimidazole-1-butyric acid ethyl ester 5.75 g of sodium hydride were mixed as a 50% mixture of 3 oils in 10 cm of dimethylformamide, added over 45 minutes while maintaining the temperature at 20 ° C to 2 ° C for 19 g 1, 3-Dihydro-1- (1-methylethenyl) -2H-benzimidazol-2-one (described in J. Chem. Soc.perkin (1982) 261) in 150 cm-dimethylformamide and stirring was continued for another half hour. 23.4 g of ethyl 4-bromobutyrate were added over 15 minutes and stirred for 4 hours at room temperature. The reaction mixture was poured into 800 cm of ice water, extracted with ether, washed with water, dried and evaporated to dryness. 33 g of the desired compound were obtained.

Step B; 2,3-Dihydro-2-oxo-1H-benzimidazole-1-butyric acid ethyl ester 3 3

15.5 cm of sulfuric acid were mixed with 155 cm of ethanol, the mixture was cooled to 0 to + 5 ° C, 31.4 g of the compound obtained above were added and stirred for 5 hours at 0 to + 5 ° C. The reaction mixture was neutralized with sodium hydroxide solution and poured into 1.5 liters of ice water and stirred for 5 minutes. The precipitate formed was separated by centrifugation, washed with water to give 22 g of the desired compound. Mp = 88 ° C.

Step C: 2,3-Dihydro-2-oxo-1H-benzimidazole-1-butyric acid 76341 ίο

22 g of the compound obtained in step B 3 were dissolved in 22 cm of sodium hydroxide solution and 200 cm of methanol.

The mixture was refluxed for 1 hour, the methanol was evaporated off and the residue was taken up in 1.5 liters of ice water. The reaction mixture was acidified by adding concentrated hydrochloric acid, the formed precipitate was separated by centrifugation, washed with water to give 18.1 g of product. Mp = 180 ° C. The product was recrystallized from isopropanol to give 15.2 g of the title compound. Mp = 185 ° C.

Step D: 4,5-Dihydro-imidazo [4,5,1-j] -7-benzazepine-2,7- (1H, 6H) -dione

A mixture of 300 cm 3 of chloroform, 15.2 cm 3 of thionyl chloride and 15.2 g of the acid obtained in the previous step was refluxed for 1.5 hours. The reaction mixture was cooled to + 15 ° C and 18.4 g of aluminum chloride was added in one portion. After stirring for 4 hours at room temperature, the reaction mixture was poured into 600 cm @ 4 of ice water 3 containing 15 cm of concentrated hydrochloric acid, stirred for 5 minutes and the precipitate formed was separated by centrifugation to give 9.9 g of the desired compound as a crude product. An additional 2.5 g was recovered from the mother liquor. The resulting product batches were combined and recrystallized from isopropanol. 8.5 g of the desired compound were obtained. Mp = 238 ° C.

Claims (5)

76341 A process for the preparation of 5,6-dihydroimidazo [4,5,1-j-k] ZT, benzazepine-2,7 (1H, 4H) dione of formula (II) 5 f) rYN \ | / = 0 (II) 10 I H characterized in that the compound of formula (V) H i CI./ “! H2C ch3 is reacted with an alkyl 4-halobutyrate of the formula (VI) Hal- (CH2) 3-C00alc (VI) 25 wherein Hal is a chlorine, bromine or iodine atom and ale is an alkyl group having 1 to 4 carbon atoms, followed by the compound of formula (VII) thus obtained (X) "XCH" alcO "Cl 2 Z ^ CH \ (VII) il / = 0 V" ^ N 7 35 L of H27 ^ TH 76341 are hydrolyzed under acidic conditions to give a compound of formula (VIII) / H "C \ / 2 ^ CH" alcO "C | z 5. CH_ / ^ (VIII) UL> - 10 H and whose ester group is saponified to give an acid of formula (IX) / H2C-CH2 15 H02C f * 2 | (IX) H 2 O and the side chain of which is cyclized to give a compound of formula (II). Process according to Claim 1, characterized in that the alkyl 4-halobutyrate is methyl or ethyl 4-butyrate and the condensation is carried out in the presence of a base such as an alkali metal hydride; - the compound of formula (VII) is hydrolysed in the presence of an acid such as sulfuric acid in an alcohol such as ethanol; 30. saponifying the compound of formula (VIII) with a base such as sodium or potassium hydroxide in an alcohol such as methanol or ethanol; the cyclization of a compound of formula (IX) is carried out either by preparing an acid chloride which is treated with a Lewis acid 35 such as aluminum chloride in an organic solvent such as methylene chloride or dichloroethane or by the action of a dehydrating agent such as polyphosphoric acid. 5 13 7 6 3 41