NL7902400A - PROCESS FOR PREPARING CHINAZOLINES. - Google Patents

Description

79 vA / mm s; '* ΐ>

Applicant: Fermion Oy, P.0. Box 28, SF-02101 Espoo 10, Finland.

Inventor: Heinrich Thaler, Niittykummuntie 6 E 38, SF-022TO Espoo 20, Finland.

Title: "Approval for the preparation of quinazolines".

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The invention relates to a process for preparing quinazolines of the general formula 1 of the formula sheet, wherein R is hydrogen or methoxy and R is an alkenyl group with 3-5 carbon atoms, a benzoyl, furoyl- , thienylcarbonyl, cyclopentylcarbonyl or alkoxycarbonyl group of 2-5 carbon atoms, an alkenyloxycarbonyl group of 4-5 carbon atoms, a (2-hydroxyalkoxy) carbonyl group of 4-5 carbon atoms, or a group of the formula 3 of

O

10 the formula sheet, wherein RJ is an alkyl group with 1-6 carbon atoms or a benzyl group. In this application, 12-R is hydrogen and R is furo-2-yl. These substances have one. action against increased blood pressure.

According to the invention compounds of the general formula 1 of the formula sheet are prepared by thermal ring closure, either in the presence of a suitable solvent or without a solvent, of a piperazine-1- (N-aryl-N * -cyano) - carboximidamide of the general formula 2 of the formula sheet, wherein R 2 and R mean the same as indicated above.

The preparation of the materials of the general formula II of the formula sheet used as starting materials is described in patent application NL 78 NL4ΐ35 · These piperazine-1- (N-aryl-N * -cyano) -carboximidamides, which are prepared for the cyclization, have no clear melting point. When the temperature exceeds 120 ° C or above, they slowly begin to decompose. This decomposition does not occur within a narrow temperature range, but 7 90 24 00. '2 ί *> continues when the temperature rises to 50-100 ° C.

When the melting process is observed under a Kofler-Heiz microscope, the formation of new crystals can be observed in the partially molten substance, which crystals melt again as heating is continued. This phenomenon can also be observed chromatographically. A small amount of 4- (furo-2-yl) -piperazin-1-N-cyano-N '- (3,4-dimethoxyphenyl-27-carboximid-amide) is slowly heated at 250 ° C in a nitrogen atmosphere. this mixture is taken at 10 ° C intervals and examined by thin layer chromatography, using Merck Kieselgel 6θ P254 plates and methanol as the solvent system, 6,7-dimethoxy-4-amino-2- / 4 is found - (furo-2-yl) -piperazin-1-yl} 7-15 quinazoline is formed, together with other compounds, when the mixture is heated to 140 ° C, and begins to decompose when the temperature rises to 220 ° C.

According to the method of the invention, this thermal cyclization reaction is used in the preparation of 6,7-dimethoxy-4-amino-2- / 5- (furo-2-yl) -piperazin-1-yl7 "quinazolines. N-cyano-N '- (3> 4-dimethoxyphenyl) -S-methylisothiourea, or N-cyano-N' - (3,4-dimethoxyphenyl) -carbodiimide prepared from the former by a known method ( W. (Will, Chem. Ber. 1-4, 1485 (1881); AP Eerris, 25, BA Schütz, J. Org. Chem. 28, 7 (1963) 1 CG McCarthy,.

J.E. Parkinson, D.M. Wieland, J. Org. Chem. 35 »2067 (197 ^)» M.T. Wu, J. Heterocyclic Chem. 14, 443 (1977)) are reacted with 1- (furo-2-yl) -piperazine. Under suitable reaction conditions, the 4- (furo-2-yl) -piperazin-30 l -N-cyano-N '- (3> 4-dimethoxyphenyl} 7 "car: boxlinldamide is cycled to 6.7 dimethoxy-4-amino-2-74- (furo-2-yl) -pipe-razin-1-yl7-quinazoline according to the reaction scheme A of the formula sheet.

By heating 3'-4-dimethoxyaniline and S, S'-35 dimethyl-N-cyano-dithioimidocarbonate in suitable solvents, such as methanol, ethanol, or isopropanol, 7902400-1.

3 Λ the required starting material, H-cyano-H1- (3,4-dimethoxy-phenyl) -S-methyl-isothiourea, obtained in high purity in a yield of 85-90%. 3,4-dimethoxyaniline can be prepared in a quantitative yield from inexpensive starting material, 1,2-dimethoxybenzenes, by nitration with dilute nitric acid (D. Cardwell, R. Robinson, Soc.

107, 256 (1915)) »after which the nitro group is reduced (KC Frisch, MT Bogert, J. Org. Chem. _8, 331 (19 ^ -3 The S, S * -dimethyl-H-cyano-dithioimido carbonate can be reduced to 10 themselves are obtained from cyanamide, carbon disulfide, or dimethyl sulfate in the presence of RaOH, in a yield of $ 90 (A. Hantsch, M. ¥ olvekamp, Ann. 331, 265 (1904) j HG ·. g-uy, Η.Ρ Dietz, U.S. Patent 2430332 (1947)} Suyama, K. Odo, J. Syn.Org. Chem. (Japan) 15, 29, 65 (1971)).

A mixture of the N-cyano-K '- (3,4-dimethoxyphenyl) -S-methylisothiourea and 1- (furo-2-yl) -piperazine thus obtained (ΐ.Η. Althuis et al., Je Med Chem. 20, 148 (1977)) is heated to a suitable temperature between 150 ° C and 220 ° C, preferably 160-190 ° C in a suitable inert solvent with a high boiling point, for example dimethylformamide, dimethyl acetamide, R- methyl pyrrolidine, hexamethylphosphoric acid triamide, dimethyl sulfoxide, sulfolane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether or nitrobenzene, dichlorobenzene, tetrahydronaphthalene, or diphenyl ether.

The reaction time varies from 15 minutes to 4 hours, depending on the temperature and the solvent used.

The reaction mixture is cooled to room temperature and diluted with a suitable solvent, for example a lower aliphatic alcohol, methylene chloride, chloroform, or acetone. The 6,7-dimethoxy-4-amino-2- / 5- (furo-2-yl) piperazin-1-yl7-quinazoline is precipitated as hydrochloride by addition of hydrochloric acid.

In a modification of this method, F-cyano-R '- (3 »4-dimethoxyphenyl) - 790 24 0 0 1 # f' 4 carbodiimide is first prepared according to a known method from N-cyano-N1 - (3> 4-dimethoxyphenyl) -S-methyl-isothiourea in a suitable solvent such as dimethylformamide.

1- (furo-2-yl) -piperazine is then added, and the mixture is heated to 160-190 ° C. Carbodiimide can also be prepared in the presence of 1- (furo-2-yl) -piperazines, in which case (4-furo-2-yl) -piperazine-1 - / N-cyano-N '* ( 3,4-dimethoxyphenyl27 'carboxylic damide is directly formed and, when heated, cyclizes The mixture 10 can then be treated as described above.

The preparation can also be carried out without solvents. N-cyano-W1 - (3 »4-dimethoxyphenyl) -S-methyl-isothiourea is ground together with Ί- (furo-2-yl) -piperazine, the the last compound is preferably used in excess. The mixture is heated to 160-190 ° C in a nitrogen atmosphere. When the reaction has taken place, the product is cooled, and the solidified molten product is dissolved in a suitable solvent, for example methylene chloride or chloroform, and the 6,7-dimethoxy-4-amino-2- ^ 5- (furo-2-yl) -piperazin-1-yl7-quinazoline is precipitated as hydrochloride by addition of hydrochloric acid

The above-described process, with its low labor costs, readily available and inexpensive starting materials, and simple production steps, is particularly suitable for the preparation of 6,7-dimethoxy-4-amino-2- ^ 5- (furo-2 -yl) -piperazin-1-yl7-ehinazoline.

In the following examples the method according to the invention is described in more detail.

EXAMPLE I

24 g of S, S'-dimethyl-N-cyano-dithioimidocarbonate 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, the precipitate filtered off and washed with isopropanol. The N-cyano-N '- (3,4-dimethoxyphenyl) -S-methyl-isothiourea thus obtained is dried in vacuum at 50 ° C in 7 9 0 2 4 0 <3 -5. Yield: 29.1 g ($ 88.6 of the tbeoretic yield). Melting point: 190 ° C. IR: (KBr tablet) NH 3220 cm "1, CH (0CH) 2980 cm" 1, -C = N 2170 cm "1, - • 2 -C = N- 1530 cm (extra wide), -0CH" 124ο and 1265 - -1 J 5 cm

EXAMPLE II

25.1 g of N-cyano-R '- (3,4-dimethoxyphenyl) -S-methyl-isotbiourea and 23-5 ff l- (furo-2-yl) -piperazine are added to 50 ml of diethylene glycol diethyl ether, the mixture is added for 2 hours heated to 180 ° C, cooled and diluted with 100 ml of methylene chloride. The solution is cooled in an ice bath, and hydrochloric acid is added until the pH of the aqueous phase is 3

Mixing for 2 hours at 0-5 ° C, the precipitate is filtered off and washed, first with water and then with

cold acetone. 23.6 g of 6,7-dimethoxy-4-amino-2- / 5- (furo-2-yl.) Piperazin-1-yl7-quinazoline hydrochloride (56.2% of theory) are obtained. Melting point: .266-270 ° (hr Thin layer chrome ogr af ie: EtOAc-MeOH 20 (2: 1), Rf 0.50 (in literature: 0.48), EtOAc-MeOH-Et ^ NH

(70: 20: 5), Rf 0.70 (literature, 0.70).

EXAMPLE -III

iT-cyano-M '- (3,4-dimethoxyphenyl) -carbodiimide, prepared from 25.1 g of N-cyano-N, - (3,4-dimethoxyphenyl) -S-methyl-25 isothiourea in 250 ml of dry methyl formamide and 27.2 g of 1- (furo-2-yl) -piperazine, is heated at 50 ° C for 2 hours in a nitrogen atmosphere. The temperature is then raised and, for 2 hours, 150 ml of dimethylformamide are removed by distillation. The brown solution thus obtained is cooled to room temperature and the 6,7-dimethoxy-4-amino-2- / 4- (furo-2-yl) -piperazin-1-yl / -quinazoline is precipitated as hydrochloride addition of alcoholic hydrochloric acid. The solution is cooled with stirring for 5 hours, and the precipitate is filtered off and washed with cold dimethylformamide. Yield: 28.9 ff (68.7 $ from the theoretical).

790 24 0 0

Claims (5)

1. Process for the preparation of quinazolines of the general formula I of the formula sheet, wherein R 2 is hydrogen or methoxy and R is an alkenyl group with 3-5 carbon atoms, a benzoyl, furoyl, thienylcarbonyl, cyclopentylcarbonyl, alkoxycarbonyl group with 2-5 carbon atoms, an alkenyl oxycarb ony l * group with 4 or 5 carbon atoms, a (2-hydroxyalkoxy) carbonyl group with 4 or 5 carbon atoms, or a group of the general formula 3 is 3 of the formula sheet, wherein R is an alkyl or benzyl group of 1-6 carbon atoms, characterized by thermal ring closure, either without a solvent or in the presence of a suitable solvent, at a temperature of 150-220 ° C and during a reaction time of from 15 minutes to 4 hours, of a piperazine-1- (N-aryl-N * -cyano) -carboximidamide of the general formula 2, wherein 12 R and R are the same as above, and by separating the product or a salt thereof from the solution with 35 using an acid. 2. Process according to claim 1 for the preparation 790 24 0 0 7 5.> Of a compound of the general formula 1 of the 1 formula sheet, wherein R is hydrogen and R is furo-2-yl, characterized by gland ring closure, or without a solvent or in the presence of a suitable solvent, at a temperature of 150-220 ° C and for a reaction time in the range of 15 minutes to 4 hours, of a compound of the general formula 2 1 2 of the formula sheet, wherein R and R are the same as described above, and by separating the product 10 or a salt thereof from the solution using an acid. Method according to claims 1 and 2, characterized in that the thermal ring closure is carried out without a solvent. Method according to claims 1-2, characterized in that the cyclization takes place in the presence of a suitable solvent. Method according to claims 1-4, characterized in that the thermal ring closure is carried out at a temperature of 160-190 ° C. 7902 400 r song. Os A. no * 7902400 Fermion Oy R1 CHv 0. N \ kt ^ u n.2 WnT \ / # Mftmc / 7e / 77 <7 A ch3o- ^ yn --— Λ »2 CH30 - ^^ HHo Tor Formula t C «, SN; c = N-CsjV C% SX CHjO A / Hs. ^ SC« 3. ToJ 11 CHjO '^ Ν'0ξΝ f! CW3 ° XcTVO- * 2 "-c« 3s «. CH3orr cyW III Cft; Ck / - \. W = C = A / -C = / Y Τ3Γ Formula 2 3 t— ^ ft n 0 CH - / 1 ^ —1 * - 3 "/0.¾ Cy" • Λ S — jf Y "C— in H II NN — A / VT ° Formula 3, _>. TcXorw 'c_f 7 c% o" ^ Y'v - nh2 790 2 4 0 0