FI71931C - Lower alkyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrochlorides for use as intermediates in the preparation of therapeutically valuable 6,7-dichloro-1,5-dihydroimidazo / 2, 1-b / quinazolin-2 (3H) -one and process for their preparation - Google Patents

Description

1 71931

In the preparation of the therapeutically valuable 6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one, lower alkyl-5,5-dichloro-3,4-dihydro-2 (1H) - iminoquinazoline-3-acetate hydro-5 halides and a process for their preparation

Divided by application 791125 (patent 66616)

The invention relates to a novel lower alkyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrohalide of formula III for use as an intermediate,

B

15 "x ^ NH-HX

N III

Cl \? .

CH ^ COR

Cl 2 wherein R 1 is a lower alkyl group and X is chlorine, bromine or iodine. Preferably X is bromine and an ethyl group.

The compounds of the formula III are used as intermediates in the preparation of the known antiplatelet agent of the formula I, 6,7-dichloro-1,5-dihydroimidazo [2,1-b] -quinazolin-2 (3H) -one,

B

/ x N - 1

30 Cl J

Cl wherein first lower alkyl-N- (6-amino-2,3-dichlorobenzyl) glycine of formula II, 35 τ ~ 2 71931 ΝΗ2 C /% A 2 χ (II)

C1 and CH2NHCH2COR

Cl where R 1 is a lower alkyl group is reacted with a capped compound of formula CNX wherein X is chlorine, bromine or iodine in an aprotic organic solvent which does not participate in the reaction to give an intermediate of formula (III) followed by The compound of formula (I) is reacted with approximately equal molar amounts of organic base to give the final product of formula (I).

U.S. Patent No. 3,932,407 (corresponding to FI Monthly Publication No. 56,012) deals with the following types of compounds

B

R --- | J

-Hn 20 Rf Li

R

1. 2 3 wherein R is H, phenyl or alkyl, R and R are the same when H, chlorine, bromine, fluorine, alkyl, hydroxy or alkoxy, and different when H, chlorine, bromine, fluorine, SO 2 H, 25 CF -, hydroxy, nitro, amino or phenyl, alkyl or alkoxy, 7 2.3 or, R and R together form a methylenedioxy group or a phenyl group, and n is an integer of 1 or 2, and pharmaceutically acceptable acid addition salts thereof. These compounds, which lower blood pressure, inhibit platelet aggregation or dilate the bronchi, are prepared e.g. by a multi-step process culminating in a reaction in which CNBr reacts with an ethanolic solution of the following compound in NH-

35 R2_T V

I o CH-NH (CH_) -COR4 R3 .i 2 n

R

3,71931 12 3 4 wherein R, R, R and n are the same as above and R is alkyl.

Although the above-mentioned patent generally describes the preparation of a compound of formula (I) by the above-mentioned method, only the chlorination of 5 compounds of the following type is exemplified in particular: 10 Cl

When a compound of formula (II) is reacted with CNBr in an alcoholic solution in a generally known manner, a compound of formula (I) is obtained directly. Contrary to expectations, it has been found that the yield of the product of formula (I) is much better when compound II is reacted with CNBr, CNCl or CNI in an inert, aprotic organic solution and the novel intermediate of formula (III) is isolated. Intermediate III is then treated with a base to give a compound of formula (I). SURPRISINGLY, the yield of product I obtained by this two-step process is generally about four times higher than that obtained by the one-step process.

The invention also relates to a process for the preparation of an intermediate of formula (III), wherein a compound of formula (II) is reacted with a compound of the form CNX, wherein X

2 is the same as above, in an aprotic organic solvent which does not participate in the reaction, at a temperature not exceeding about 200 ° C. The temperature is preferably maintained between 80 ° C and 150 ° C and the best result is obtained when the temperature is between about 80 ° C and 120 ° C. The reaction mixture preferably contains at least one mole of 3 0 CNX per mole of compound II, and the best result is obtained when the moles are present in equal molar amounts.

Conventional aprotic, unreacted organic solvents can be used in the reaction. Such are e.g.

benzene, toluene, xylene, hexane, heptane, octane, nonane, 2,2,4-trimethylpentane, cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, dioxane, chloroform, carbon tetrachloride, di-n-propyl ether and di-n-n-butyl ether . The most preferred solvent used is toluene.

4,71931 The preparation of intermediate II is disclosed in FI patent 66,616.

The compounds of formula III may also exist in tautomeric form IIIa:

^ \ / Ν ^ ΝΗ2 · HX

5 0 1113 C1 Ct ^ COR1

Cl 10 of each tautomeric form, i.e. forms III and lila, gives the desired end product of formula I by base treatment. Thus, structural formula III used in this presentation and claims also comprises the purple form of the tautomeric form.

The term used in the text, a lower alkyl group, means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. All temperatures mentioned are in degrees Celsius.

The following are examples of these 20 inventions.

Example 1

Ethyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminokinatso-morpholine-3-asetaattivetybromidi

A mixture of cyanogen bromide (0.53 g, 5 mmol) and toluene (10 mL) was added to a solution of N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester (1.39 g, 5 mmol) and toluene (10 mL). and the mixture was stirred at room temperature. Crystallization occurred almost immediately. Stirring was continued for half an hour, after which the reaction mixture was heated to reflux for 18 hours. After cooling, the solid was filtered, washed with toluene and dried to give 1.81 g (94.5%) of the desired product. A portion of the product was recrystallized from ethanol, washed with ethanol and ether and dried in vacuo at 73 ° C to give an analytical sample as golden yellow crystals.

5,71931

Calculated values for HBr: C 37.62, H 3.68, N 10.97 Observed values: C 37.59, H 3.57, N 10.30 Example 2 Ethyl-5,6-dichloro-3 , 4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrobromide

A mixture of cyanogen bromide (89.6 g, 0.35 mol) and toluene (1.6 liters) was poured into N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester (231 g, 0.834 mol) and toluene. (1.6 liters) to the mixture. The temperature rose rapidly from 18 ° C to 31 ° C. The mixture was slowly heated (one hour) to reflux and refluxed for 12 hours. The mixture was cooled to room temperature and filtered, the mixture was washed with toluene both on a decanter and a filter. The residue was washed with ether and dried with a vacuum pump (0.5-1 mm Hg) over P 2 O 5. There was thus obtained 290 g (92%) of the desired product as a brown powder. Upon heating, the powder decomposed over a wide temperature range: 200-300 ° C.

The infrared and nmr spectra of the obtained product corresponded to those of the desired product. Infrared peaks at 3140 (broad), 1745 (-C = 0), 1661 (-ON), 1636, 1550, 1371, and 1215 cm Nmr peaks (TMS as standard) were at & 8.24 (broad s) 7.25 (AB, q, 2H), 4.69 (s, 2H), 4.55 (s, 2H), 4.27 (q, 2H) and 1.32 (t, 3H).

Example 3 6,7-Dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one

Ethyl 5,6-dichloro-3,4-dihydro-2- (1H) -iminoquinazoline-3-acetate hydrobromide (289.6 g, 0.756 mol), anhydrous ethanol (4.5 liters) and triethylamine (106 ml, 0.758 mol) the mixture was refluxed for four hours. The mixture was cooled and as much ethanol as possible was decanted off. The solid was slurried in 35 in fresh anhydrous ethanol, which is filtered off after June 71 931 half an hour of mixing. The solid was then slurried in a mixture of anhydrous ethanol (600 mL) and 95% ethanol (2.4 liters) and refluxed for four hours. The mixture was filtered while warm. The solid was dried with a vacuum pump (0.5-1 mm Hg) P2O5 ·. with.

There was thus obtained 179 g (92%) of the desired product as a cream solid.

The infrared peaks at 1702 (weak), 1638, 1554, 1468 and 1440 cm Nmr peaks (TFA) at 10 were έ> 7.33 (AB, q, 2H), 4.97 (s, 2H) and 4.59 (s, 2 H).

Example 4 6,7-Dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one monohydrochloride monohydrate 6,7-Dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one ( 94.0 g, 0.367 mol) was added to 2.82 liters of boiling methanol. To the slurry was added 77 mL (0.92 moles) of concentrated hydrochloric acid. The result was an almost pure solution. Darco G-60 was added, the mixture was boiled for about three minutes, after which it was filtered. The filtrate was reheated to the boiling point, after which it was slowly cooled and 1.9 liters of ether were carefully added. The mixture was stirred at room temperature for 2 hours and the solid was filtered. (Yield A).

Some of the material tended to crystallize in the funnel during the charcoal-25 treatment; therefore, charcoal and solid were slurried in hot methanol and filtered. This filtrate was combined with the filtrate from Step A and the mixture was concentrated in vacuo to about 1.3 liters and heated to boiling point to allow complete Liu-30 lubrication. After the mixture was filtered and cooled slightly, 800 ml of ether was added thereto, and it was stirred at room temperature for 1 hour. The precipitate formed was filtered (yield B). Liquid chromatography showed both catches to be very pure. They were combined and dried in vacuo (about 1 mm Hg) overnight. The total amount of product 7,71931 was 88.1 g. By Karl Fischer analysis, it was found to contain 2.27% water. The product was placed in a desiccator containing saturated Ca (NO 3) 2 (about 50% relative humidity) and its water content was analyzed daily. After four days, the water content was 5.64% (theoretical value for the monohydrate is 5.80%). The product weighed 91.9 g (80.6% of theory).

Example 5

The process is otherwise the same as in Example 1, except that an equal molar amount of cyanogen chloride is used instead of the cyanogen bromide used, so that the final product obtained is 5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazolin-3-one. asetaattivetykloridi.

Example 6 The process is otherwise the same as described in Example 1, except that an equal molar amount of cyanogen iodide is used instead of the cyanogen bromide used, so that the final product obtained is 5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline. 3-asetaattivetyjodidi.

20 Example 7

The process is otherwise the same as described in Example 1, except that the N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester used therein is replaced by an equal molar amount of N- (6-amino-2,3-dichlorobenzyl) glycine-25. methyl ester, N- (6-amino-2,3-dichlorobenzyl) glycine n-propyl ester, N- (6-amino-2,3-dichlorobenzyl) glycine isopropyl ester and N- (6-amino-2,3 -dichlorobenzyl) glycine-n-butyl ester to give methyl 5,6-dichloro-3,4-dihydro-30 (1H) -iminoquinazoline-3-acetate hydrobromide, n-propyl-5,6-dichloro, respectively. -3,4-Dihydro-2 (1H) -iminoquinazoline-3-acetate hydrobromide, isopropyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrobromide and n-butyl -5,6-Dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-35 acetate hydrobromide.

8 71931

Example 3

The procedure is otherwise the same as in Example 5, except that an equal amount of N- (6-amino-2,3-dichlorobenzyl) is used in place of the N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester used therein. glycine methyl ester, N- (6-amino-2,3-dichlorobenzyl) glycine-n-propyl ester, N- (6-amino-2,3-dichlorobenzyl) glycine isopropyl ester and N- (6-amino-2 (3-dichlorobenzyl) -glycine-n-butyl ester to give methyl 5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrochloride, n-propyl-5 , 6-Dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrochloride, isopropyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrochloride and n-butyl-5,6-dichloro-3,4-di-15-hydro-2 (1H) -iminoquinazoline-3-acetate hydrochloride.

Example 9

The process is otherwise the same as in Example 6, except that the N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester used therein is replaced by an equal molar amount of N- (6-amino-2,3-dichlorobenzyl). glycine methyl ester, N- (6-amino-2,3-dichlorobenzyl) glycine n-propyl ester. N- (6-amino-2,3-dichlorobenzyl) glycine isopropyl ester and N- (6-amino-2,3-dichlorobenzyl) glycine n-butyl ester, and the final product is methyl 5,6- dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydroiodide, n-propyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydroiodide; dia, isopropyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydroiodide and n-butyl-5,6-dichloro-3,4-dihydro-2 (1H) -iminokinatsoliini-3-asetaattivetyjodidia.

Claims (7)

9,71931 A lower alkyl-5,6-dichloro-3,4-dihydro-intermediate used as an intermediate in the preparation of therapeutically valuable 6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one 2 (1H) -Aminoquinazoline-3-acetate hydrohalide, characterized in that it has the formula H .N. NH. HX r V 10. im) ClA / V / Nx O I CH2C-OR Cl where R · * "is lower alkyl and X is chlorine, bromine or 3 ° di. Ethyl 5,6-dichloro-3,4-dihydro-2 (1H) -iminoquinazoline-3-acetate hydrobromide according to Claim 1, characterized in that it has the formula 20. NH ‘HBr dj ch2coc2h5 ci 25 A process for the preparation of a compound of claim 1 of formula H VNH 1 HX I 1 - (III) Avd / K ° 1 Cl T CH 2 -C OR Cl 35 10 71 931 wherein R 1 is lower alkyl and X is chlorine, bromine or iodine, characterized in that the compound of the formula II is NH_ 5. I 2 n II Cl I Cl ^ NHCl ^ COR1 Cl wherein R · * · is the same as above is reacted with a compound of formula CNX wherein X is the same as above in an aprotic reaction inert organic solvent. 11 71931