HU213619B - Process for producing quinolinyl acetic acid esters - Google Patents

Abstract

Quinazoline acetic acid esters of formula (I) are prepd. in presence of a catalyst from a di amino ester of formula (II) and a cyano-imide deriv. (III) R1, R2 = 1-4C alkyl opt. substd. by phenyl. - Cpds. (I) are intermediates in prepn. of anagrelids (sic), blood platelet aggregation inhibitors.

Description

The present invention relates to a novel process for the preparation of quinazolinyl acetic acid esters of formula I wherein R ¹ is C 1-4 alkyl optionally substituted with phenyl.

The invention encompasses the preparation of all tautomeric forms of the compounds of formula (I).

The compounds of formula (I) are valuable intermediates for the preparation of the known platelet aggregation inhibiting anagrelide.

The preparation of compounds of formula I is described in Hungarian Patent Application No. 208,681. In one embodiment, a diamino ester of formula (II) wherein R ¹ is C 1-7 alkyl optionally substituted by a phenyl substituent is reacted with a cyano imido derivative of formula (III) wherein R ² is 1-7 C 1-7 -alkyl or optionally substituted C 1-7 -alkyl, and yields only about 37% yield.

The reason for the poor production is that one of the alkylthio leaving groups of the dialkyl (N-cyanimidodithiocarbonates) is highly reactive and is easily cleaved. However, in the resulting S-alkylisothiourea derivative, the other S-alkyl group is already very unreactive, and consequently the completion of the reaction requires a higher temperature and longer reaction time, as known in the literature [Org. Prep. Proc. Int., 20, 465 (1988)], instead of the S-alkyl leaving group, the cleavage of the cyano imino leaving group is preferred, leading to the formation of the undesired compounds of formula IV wherein R ¹ and R ² are as defined above.

According to a further process known from Hungarian Patent Application No. 208,681, the diamino ester of formula II is reacted with diphenyl N-cyanimidocarbonate and in some cases is obtained in more than 80% yield of the compound of formula I.

This known process is uneconomical despite the favorable production achievable, since the starting diphenyl N-cyanimidocarbonate is a readily available, moisture sensitive compound which can only be obtained from diphenyl carbonate by the complete exclusion of moisture through the corresponding diphenyl dichloromethane derivative. , using absolute cyanamide. The industrial scale implementation of this reaction under absolute conditions is extremely disadvantageous.

Considering that dialkyl (N-cyanoimidodithiocarbonate) compounds of formula (III) are readily available, see, for example, Chem. Abstr., 1986, Publication No. 1051,171868e. It is an object of the present invention to provide an economical process for the preparation of quinazolinyl acetic acid esters of formula (I) using these starting materials.

It has now been found that the above object is achieved by reacting a diamino ester of Formula II with a cyano-imido derivative of Formula III in the presence of a catalyst of 1-3 molar equivalent of heavy metal oxide or heavy metal salt per compound of Formula II. applied.

The heavy metal salt may be an inorganic or organic salt of a heavy metal. The preferred heavy metal oxide is mercury (II) oxide, the preferred heavy metal oxide is mercury (II) chloride, mercury (II) acetate or lead (II) acetate.

Surprisingly, the process of the present invention achieves a yield above 80%, since it was not at all expected that the heavy metal compounds added to the reaction mixture would increase the reactivity of the second alkylthio group to completely suppress the reaction of the competing cyanimino leaving group. no undesired compounds of formula (IV) are formed, leading to a large increase in yield.

Furthermore, it was not at all expected that the heavy metal compounds added to the reaction mixture would be easily and quantitatively removed from the product, which is extremely important for the purity of the compounds of formula (I) and the anagrelide product prepared therefrom.

The amount of heavy metal oxide or heavy metal salt is chosen such that 13 molar equivalents, preferably 1 molar equivalent, of the heavy metal oxide or heavy metal salt is obtained per 1 mole of the diamino ester (II).

The reaction is conveniently carried out in a polar protic or aprotic organic solvent, preferably methanol, ethanol, ethylene glycol, acetonitrile, butyl acetate, Ν, Ν-dimethylformamide or dimethylsulfoxide.

The reaction temperature is generally from 20 to 120 ° C, preferably from 50 to 70 ° C.

The reaction produces a heavy metal mercaptide from the catalyst which remains in the mother liquor and can be removed by simple filtration. The product may be isolated in a manner known per se, for example by filtration, after evaporation of the solution the product usually crystallizes out or crystallizes after addition of water to the reaction mixture.

The process of the present invention is extremely simple and economically feasible and provides compounds of Formula I from readily available starting materials in over 80% yield.

The invention is illustrated in detail by the following examples.

Example 1

Ethyl (3,4-dihydro-5,6-dichloro-2 (l //) - cyanimino-quinazolin-3-yl) acetate

To a solution of 14.6 g (0.1 M) dimethyl (N-cyanoimidodithiocarbonate) in 100 ml dimethylformamide at 5 ° C

21.7 g (0.1 M) of mercury (II) oxide and 27.7 g (0.1 M) of ethyl N- (6-amino-2,3-dichlorobenzyl) glycine are added.

The resulting suspension was heated to 70 ° C with stirring and stirred at this temperature for an additional three hours.

After cooling, 30 ml of water are added to the reaction mixture, the precipitated crystals are collected and washed with a little acetonitrile. About 30 g of crude product (95% purity by HPLC) was stirred in 150 ml of 18% (0.75 M) hydrochloric acid for 2 hours and then filtered, washed with 30 ml of 18% hydrochloric acid and 40 ml of water. .

26.7 g (81.5%) of the title compound are obtained, m.p. 274-277 ° C. The purity was determined to be 99.4% by HPLC.

Example 2

Ethyl (3,4-dihydro-5,6-dichloro-2 (l //) - cyanimino-quinazolin-3-yl) acetate

In each case, the procedure of Example 1 was followed except that 100 ml of dimethyl sulfoxide was used instead of 100 ml of dimethylformamide.

25.0 g (78.0%) of the title compound are obtained, m.p. 274-278 DEG C. The purity is determined to be 99.1% by HPLC.

Example 3

Ethyl (3,4-dihydro-5,6-dichloro-2 (l //) - cyanimino-quinazolin-3-yl) acetate

In each case, the procedure of Example 1 was followed, except that 100 ml of ethylene glycol was used instead of 100 ml of dimethylformamide.

20.0 g (61.2%) of the title compound are obtained, m.p. 274-277 ° C. The purity was determined to be 99.1% by HPLC.

Example 4

Ethyl 1- (3,4-dihydro-5,6-dichloro-2 (177) -cyano-iminoquinazolin-3-yl) -acetate

In each case, the procedure of Example 1 was followed except that 19.8 g (0.1 M) of dibenzyl- (N-cyanimidoyl) were replaced by 14.8 g (0.1 M) of dimethyl (N-cyanimidodithiocarbonate). dithiocarbonate).

26.4 g (80.8%) of the title compound are obtained, m.p. 274-277 ° C. The purity was determined to be 99.0% by HPLC.

Example 5

Ethyl (3,4-dihydro-5,6-dichloro-2 (l //) - cyanimino-quinazolin-3-yl) acetate

In each case, the procedure of Example 2 was followed except that instead of 14.6 g (0.1 M) of dimethyl (N-cyanoimidodithiocarbonate) 19.8 g (0.1 M) of dibenzyl- ( N-cyanoimidodithiocarbonate) is used.

26.0 g (79.5%) of the title compound are obtained, m.p. 274-278 ° C. The purity was determined to be 99.0% by HPLC.

Example 6

Ethyl 1- (3,4-dihydro-5,6-dichloro-2 (17 H) -cyanoimino-quinazolin-3-yl) -acetate

In each case, the procedure of Example 3 was followed, except that 14.8 g (0.1 M) of dimethyl (N-cyanimidodithiocarbonate) was replaced by 19.8 g (0.1 M) of dibenzyl (N-). cyanimidodithiocarbonate).

21.5 g (65.8%) of the title compound are obtained, m.p. 274278 ° C. The purity was determined to be 99.2% by HPLC.

Example 7

Benzyl- (3,4-dihydro-5,6-dichloro-2 (l / 7) -ciánimino-quinazolin-3-yl) acetate

In each case, the procedure of Example 1 was followed except that 33.9 g (0.1 M) of N- (6-amino-) - instead of N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester were used. 2,3-Dichlorobenzyl) glycine benzyl ester is used.

31.2 g (80.3%) of the title compound are obtained, m.p. 285-288 ° C. The purity was determined to be 99.2% by HPLC.

Example 8

Benzyl- (3,4-dihydro-5,6-dichloro-2 (177) -ciánimino-quinazolin-3-yl) acetate

In all of Example 2, except that instead of N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester, 33.9 g (0.1 M) of N- (6-amino-2, 3-Dichlorobenzyl) glycine benzyl ester is used.

30.4 g (78.2%) of the title compound are obtained, m.p. 285-288 ° C. The purity was determined to be 99.0% by HPLC.

Example 9

Benzyl (3,4-dihydro-5,6-dichloro-2 (1 H) -cyanoimino-quinazolin-3-yl) -acetate

In each case, the procedure of Example 3 was followed, except that 33.9 g (0.1 M) of N- (6-amino-2) was replaced by N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester. Benzyl ester of 3-dichlorobenzyl) glycine is used.

25.0 g (64.3%) of the title compound are obtained, m.p. 285-288 ° C. Purity by high performance liquid chromatography (HPLC): 98.5%.

Example 10

Benzyl (3,4-dihydro-5,6-dichloro-2 (1 H) -cyanimino-quinazolin-3-yl) -acetate

In all cases, the procedure of Example 4 was followed except that 33.9 g (0.1 M) of N- (6-amino) was replaced with N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester. -2,3-dichlorobenzyl) glycine benzyl ester is used.

31.1 g (80.0%) of the title compound are obtained, m.p. 285-288 ° C. The purity was determined to be 99.1% by HPLC.

Example 11

Benzyl (3,4-dihydro-5,6-dichloro-2 (177) -cyano-iminoquinazolin-3-yl) -acetate

In all cases, the procedure of Example 5 was followed, except that 33.9 g (0.1 M) of N- (6-amino) was replaced with N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester. -2,3-dichlorobenzyl) glycine benzyl ester is used.

31.7 g (81.6%) of the title compound are obtained, m.p. 285-288 ° C. Purity by HPLC was 99.0%.

Example 12

Benzyl (3,4-dihydro-5,6-dichloro-2 (1/7) -cyanoimino-quinazolin-3-yl) -acetate

In each case, the procedure of Example 6 was followed, except that 33.9 g (0.1 M) of N- (6-amino) was replaced by N- (6-amino-2,3-dichlorobenzyl) glycine ethyl ester. -2,3-dichlorobenzyl) glycine benzyl ester is used.

HU213 619 Β

23.9 g (61.4%) of the title compound are obtained, m.p. 285-288 ° C. The purity was determined to be 99.0% by HPLC.

Example 13

Ethyl (3,4-dihydro-5,6-dichloro-2 (177) -cyano-iminoquinazolin-3-yl) -acetate

In each case, the procedure of Example 1 was followed except that 150 ml of butyl acetate instead of dimethylformamide and 65.1 g (0.3 M) of mercury (II) instead of 21.7 g (0.1 M) of mercury (II) N-oxide was used and the reaction was carried out at a reflux temperature of 70 ° C and the reaction was worked up using 300 ml of 18% hydrochloric acid instead of 150 ml of 18% hydrochloric acid.

20.2 g (61.9%) of the title compound are obtained, m.p. 274-278 ° C. The purity was 97.7% by HPLC.

Example 14

Ethyl (3,4-dihydro-5,6-dichloro-2 (177) -ciánimino-quinazolin-3-yl) acetate

In each case, the procedure of Example 1 was followed except that 27.2 g (0.1 M) of mercury (II) chloride was used instead of mercury (II) oxide.

27.7 g (84.9%) of the title compound are obtained, m.p. 274-278 ° C. The purity was determined to be 99.2% by HPLC.

Example 75

Ethyl (3,4-dihydro-5,6-dichloro-2 (1/7) -cyanoimino-quinazolin-3-yl) -acetate

In each case, the procedure of Example 2 was followed except that 31.9 g (0.1 M) of mercury (II) acetate was used in place of mercury (II) oxide and the reaction was carried out at 40 ° C for 5 hours. .

27.1 g (83.0%) of the title compound are obtained, m.p. 274-278 ° C. The purity was determined to be 99.2% by HPLC.

Example 76

Ethyl (3,4-dihydro-5,6-dichloro-2 (177) -ciánimino-quinazolin-3-yl) acetate

In each case, the procedure of Example 3 was followed, except that instead of 14.6 g (0.1 M) dimethyl (N-cyanimidodithiocarbonate), 19.8 g (0.1 M) dibenzyl- ( N-cyanoimidodithiocarbonate) is used.

21.5 g (65.8%) of the title compound are obtained, m.p. 274-278 ° C. The purity was determined to be 99.2% by HPLC.

Example 7

Ethyl (3,4-dihydro-5,6-dichloro-2 (177) -ciánimino-quinazolin-3-yl) acetate

All were obtained according to Example 1 except that 32.5 g (0.1 M) of lead (II) acetate was used instead of mercury (II) oxide.

22.7 g (69.4%) of the title compound are obtained, m.p. 274-278 ° C. The purity was determined to be 98.1% by HPLC.

Claims (2)

PATENT CLAIMS A process for the preparation of quinazolinylacetic acid esters of formula (I) wherein R ¹ is C 1-4 alkyl optionally substituted by phenyl, a process for preparing diaminoestems of formula (II) wherein R ¹ is as defined above. with a cyano-imido derivative of the Formula III wherein R ² is a C 1-4 alkyl group optionally substituted with a phenyl group, wherein the reaction is carried out with 1 to 3 molar equivalents of a heavy metal relative to the compound of Formula Π oxide or heavy metal salt. Process according to claim 1, characterized in that the heavy metal oxide is selected from the group consisting of mercury (II) oxide, the heavy metal salt being lead (II) acetate, mercury (II) acetate and mercury (II) chloride.