FI59800B - PROCEDURE FOR FRAMSTATING AV 6,7-DIMETOXY-4-AMINO-2- (4- (FURO-2-YL) -PIPERAZIN-1-YL) -QUINAZOLINE - Google Patents

Description

@ SUOM I — FI N LAN D patent publication patent crypt 5 9 8 0 0 _ 3 3 c 07 D 239/95 * 4-05 / 12 ^ ® Kv.ikr / Int.ci. // c 07 D 403/04 φ Patent application - Patentansökning 790066 ® Application date - Ansökningsdag 10.01.79 © Start date - Giltlghetsdag 10.01.79 @ Published public - Blivlt offentlig 11.07 * 00 © Date of publication and publication publication—

Ansökan utlagd och utl.skriften publicerad 30.06.8l

National Board of Patents and Registration © Patent granted - Patent meddelat 12.10.8l

Patents and registries

Privilege claimed - Begärd prloritet (73) Orion Group Oy Fermion, PO Box 19, FI-00101 Helsinki 10, Finland-Finland (Fl) (72) Heinrich Thaler, Espoo, Finland-Finland (FI) (51 *) Method 6,7- for the preparation of dimethoxy-1 + -amino-2- [U- (furo-2-yl) -piperazin-1-yl] -quinazoline - Preparation for the preparation of 6,7-dimethoxy-U-amino-2- / 1 + - (furo-2-yl) -piperazin-1-yl] -quinazoline (6l) Addition to patent 57751 - Tillägg till patent 57751

The invention relates to a process further developed from the process of patent 57751 for the preparation of 6,7-dimethoxy-4-amino-2- [4- (furo-2-yl) -piperazin-1-yl] -quinazoline of the formula

Ch3 ° JL3X ^ N N- / L_J I.

nh2 This substance has an antihypertensive effect.

The present invention provides a compound of formula I by carrying out 4- (furo-2-yl) -piperazine-1- [N-cyano-N'- (3,4-dimethoxy-phenyl)] - carboximidamide of the formula CH3O S ^ cJH ^ 11 -

III

OF

thermal ring closure reaction either without solvent or in the presence of a suitable solvent.

Finnish Patent No. 57751 discloses a process for the preparation of 6,7-dimethoxy and 6,7, Θ-trimethoxy-4-amino-2- (4-substituted-piperazin-1-yl) -quinazolines from piperazine-1 Ring closure of - (N-aryl-1'-cyano) -carboximidamides by reaction in the presence of a Friede-Crafts catalyst. The preparation of neutral 4-aminoquinazolines by an intramolecular ring closure reaction in the presence of a Friede-Crafts catalyst is also known from Zeitschrift fiir Chemie 17, (1977) p. 223-224.

In contrast, it was found that the ring closure reaction of the starting material of formula II is also possible without a Friedel-Crafts catalyst. The preparation of the starting material of formula II is described in more detail in Finnish Patent No. 56-36. This piperazine-1- (N-aryl-N'-cyano) -carboximide diamide 1a prepared as a ring for the swell reaction does not have a clear melting point. From a temperature of about 12 ° C, it slowly begins to decompose. However, this decomposition does not occur in a narrowly defined temperature range, but during a temperature rise of 50-100 ° C. When looking at the melting event under a Kofler-Fleiz microscope, it can be seen that new crystals form in the partially molten material, which in turn decomposes when heating is continued. This phenomenon can also be studied chromatographically. A small amount of 4- (furo-2-yl) piperazine-1- [N-cyano-N '- (3,4-dimethoxyphenyl)] carboximidamide is slowly heated to 25 DEG C. under a nitrogen atmosphere.

3 59800

At 10 ° C, the mixture is sampled and subjected to thin layer chromatography on a Merck Kieselgel 60 F2cj4 plate and methanol as eluent. In this case, it can be stated that heating the mixture to 140 ° C, among other products, also gives 6,7-dimethoxy-4-amino-2- [4- (furo-2-yl) -piperazin-1-yl] -quinazoline, which on further heating to 220 ° C begins to decompose.

The method according to the invention provides a considerable advantage over the methods used in the prior art. When Friede1-Crafts catalysts are not added to the reaction mixture, these difficult-to-remove inorganic salts also do not need to be removed from the reaction mixture. This results in a cleaner product without cumbersome separation methods and purification steps.

The novel process of the invention uses this thermal ring closure reaction to prepare 6,7-dimethoxy-4-amino-2- [4- (furo-2-yl) -piperazin-1-yl] quinazoline. N-cyano-N '- (3,4-dimethoxyphenyl) -S-methylisothiourea or by a method known per se (W. Will, Chem. Ber. 14, 14-5 (1881), AF Ferris, BA Schutz, J. Org Chem. _28, 71 (1963), CG McCarthy, JE Parkinson, □ M. Wieland, 3. Grg. Chem. 35, 2067 (1970), MT Wu, 3. Heterocyclic Chem. N-cyano-N '- (3,4-dimethoxyphenyl) carbodiimide is reacted with 1- (furo-2-yl) piperazine to form 4 - (- fluoro-2-yl) pipeline. Razine-1- [1'-cyano-N '- (3,4-dimethoxyphenyl)] -carboximid diamide cyclizes under the reaction conditions to 6,7-dimethoxy-4-amino-2- [4-furo- 2-yl) -piperazin-1-yl] -quinazoline as shown in the reaction scheme.

4,5800

ToJ 2

CH3G

CH 3 S

= N - C S N

'(CH 3 S / [oj S 3

: h3d- ^ i ^ c m N

-CHpSH

Ψ 3 CH30 ^^ - n = c = N - C s N ch3o hO- * -ύ CHo0 / \ «[o]? v7 c ~ f 1 CH30 ^ k ^ C ^ NH - -

HI

OF

T ° y o

ToTotW lj nh2 5 59800 Heating 3,4-dimethoxyaniline and S, S'-dimethyl-N-cyanodithioimidocarbonate in suitable solvents such as methanol, ethanol or isopropanol gives the very pure N-cyano-N '- (3.4 -dimethoxyphenyl) -S-methylisothiourea B5-90% yield. 3,4-Dimethoxyaniline can be prepared in quantitative yield from cheap 1,2-dimethoxybenzene, first by nitration with dilute nitric acid (D. Cardwell, R. Robinson Soc. 107, 256 (1915)) and then by reduction of the nitro group (KC Frisch, MT Bogert, 3 Org. Chem. J9, 331 (1 943)). S, S'-Dimethyl iN-cyanodithioimidocarbonate, on the other hand, can be prepared from cyanamide, carbon disulfide and dimethyl sulfate in the presence of NaOH in 90% yield (A. Hantsch, Π. Wolvekamp, Ann.33J. '265 Π904), HG Guy, HF Dietz, US 2430332 (1 947), T. Suyama, K. Odo, 3rd Syn. Org. Chem. (Japan) 2j3, 65 (1 971)).

The N-cyano-N '- (3,4-dimethoxyphenyl) -5-methylisothiourea and 1- (furo-2-yl) piperazine thus obtained (T. H. Althuis et al. J. Ned. Chem.

20, 14B (1977)) is heated to a suitable temperature of 150-220 ° C, most preferably 160-190 ° C in a suitable inert, high boiling solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, in hexamethylphosphoric acid triamide, dimethyl sulfoxide, sulfolane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether or nitrobenzene, dichlorobenzene, tetrahydronaphthalene and diphenyl ether.

The reaction time varies from 15 minutes to 4 hours depending on the temperature and the solvent. The reaction mixture is cooled to room temperature and diluted with a suitable solvent such as lower aliphatic alcohol, methylene chloride, chloroform and acetone. 6,7-Dimethoxy-4-amino-2- [4-furo-2-yl) -piperazin-1-yl] quinazoline is accompanying as the hydrochloride by the addition of hydrochloric acid.

In a variant of this process, N-cyano-N '- (3,4-dimethoxyphenyl-S-methylisothiourea in a suitable solvent such as dimethylformamide N-cyano-N' - (3,4-dimethoxyphenyl) carbodi is first prepared in a manner known per se. 1- (furo-2-yl) -piperazine is then added and the mixture is heated to 160-190 [deg.] C. The preparation of carbodiimide can also take place in the presence of 1- (furo-2-yl) -piperazines, directly forming (4-furo-2-yl) -piperazine-B 59800 1- (JM-cyano-N '- (3,4-dimethylphenyl) -carboximidamide which, on heating The mixture can then be further treated as described above.

The preparation can also be carried out without solvents. N-Cyano-N '- (3,4-dimethoxyphenyl) -S-methylisothiourea and 1- (furo-2-yl-piperazine, most preferably used in excess, are ground together and the mixture is heated to 160-190 ° C: After the reaction has cooled, the solidified melt is dissolved in a suitable solvent such as methylene chloride or chloroform and mixed with 6,7-dimethoxy-4-amino-2- [4-trifluoro-2-yl) -piperazin-1-yl [] quinazoline as the hydrochloride. hydrochloric acid.

The method described above is particularly well suited for 6,7-dimethoxy-4-amino-2 - [] 4- (furo-2-yl) -piperazin-1-yl] due to its low labor cost, cheap, easily available raw materials and simple work steps. for the preparation of quinazoline.

The following examples illustrate the method of the invention in more detail.

Example 1 24 g of S, S'-dimethyl-N-cyanodithioimidocarbonate and 20 g of 3,4-dimethoxyaniline are heated in 200 ml of isopropanol under reflux for 8 hours. The mixture is cooled to room temperature and the precipitate is collected by filtration and washed with isopropanol. The N-cyano-N '- (3,4-dimethoxyphenyl) -5-methylisothiourea thus obtained is dried under vacuum at 50 ° C. Yield: 29.1 g (88.6% of theory). Melting point: 190 ° C. IR: (KBr tablet) N-H 3220 cm-1, CH (OCH 2) 2980 cm-1,

- 1 -9 J

-C = N 2170 cm, -ON- 1530 cm (very wide), -GCH ^ 1240 and 1265 cm * 1.

Example 2 25.1 g of N-cyano-N * - (3,4-dimethoxyphenyl) -5-methylisothiourea and 23.5 g of 1- (furo-2-yl) piperazine are added to 50 ml of diethylene glycol diethyl ether and the mixture heated at 180 ° C for 2 hours. Cool and dilute with 100 ml of methylene chloride. The solution 7 59800 is cooled in an ice bath and hydrochloric acid is added until the pH of the aqueous phase is 3. After stirring for 2 hours at 0-5 ° C, the mixture is filtered and the precipitate is washed first with water and then with cold acetone. 23.6 g of 6,7-dimethoxy-4-amino-2 - [[4- (furo-2-yl) -piperazin-1-yl] -quinazoline hydrochloride (56.2% of theory) are obtained. Melting point: 266-270 ° C. □ flash chromatography: EtOAc-MeGH (2: 1),

Rf 0.50 (literature 0.48), EtOAc-HeOH-Et2NH (70: 20: 5), Rf 0.70 (literature 0.70).

Example 3 250 ml of [1'-cyano-N '- (3,4-dimethoxyphenyl) carbodiimide prepared from 25.1 g of N-cyano-N' - (3,4-dimethoxyphenyl) -5-methylisothiourea: in dry dimethylformamide and 27.2 g of 1- (furo-2-yl) -piperazine are heated for two hours at 50 ° C under a nitrogen atmosphere. The temperature is then raised and 150 ml of dimethylformamide are removed by distillation over a period of two hours. The brown solution thus obtained is cooled to room temperature, and 6,7-dimethoxy-4-amino-2- [4- (furo-2-yl) -piperazin-1-yl] quinazoline is mixed as the hydrochloride by adding alcoholic hydrochloric acid. Stir for 5 hours under cooling, filter and wash with cold dimethylformamide. Yield: 28.9 g (68.7% of theory). The product is the same as the product obtained in Example 2.

Example 4 25.1 g of N-Cyano-N '- (3,4-dimethoxyphenyl) -Ξ-methylisothiourea and 27.2 g of 1- (furo-2-yl) -piperazine are ground together and the mixture thus obtained is transferred to a flask and heated under a nitrogen atmosphere. min at 185 ° C. After cooling, the solidified melt is dissolved by heating in chloroform. The solution is cooled in an ice bath and hydrochloric acid is added with stirring until the pH of the aqueous phase is 3. After stirring for 2 hours at 0-5 ° C, the mixture is filtered and the precipitate is washed first with water and then with cold acetone. Yield: 17.7 g (42.3% of theory). The product is the same as the product obtained in Example 2.

I - '

Claims (4)

0 59800 A modification of the process according to Patent No. 5775 1 for the preparation of 6,7-dimethoxy-4-amino-2- [4- (furo-2-yl) -piperazin-1-yl] quinazoline according to the formula .G. 3 jo] Oi— N n - co-tj ^>) V— / '-> I, NH2 characterized in that 4- (furo-2 ~ yy li) - pi stern ts ii ni - 1 - [l \ | -cyano-N '- (3,4-dimethoxyphenyl]] - carbaximidamide of the formula CH3 ° ToY0 O - co-f0j | CH3Q'V ^' c ^ NH 1- II, III N is subjected to thermal ring closure either without solvent or in the presence of a suitable solvent at a temperature of 150 to 220 ° C for a reaction time ranging from 15 minutes to 4 hours and that the product obtained or its salt is separated from the solution by treatment with acid. Process according to Claim 1, characterized in that the thermal ring closure is carried out without solvent. Process according to Claim 1, characterized in that the thermal sealing of the ring is carried out in the presence of a suitable solvent. Method according to Claims 1 to 3, characterized in that the thermal sealing of the ring is not carried out at a temperature of 16 ° to 190 ° C.