DD293816A5 - PROCESS FOR THE PREPARATION OF 3- (ALKYLTHIOALKYL) -2,4-DIOXO-1,2,3,4-TETRAHYDRO-CHINAZOLINES - Google Patents

Abstract

The invention relates to a process for the preparation of * the general formula I, wherein {biologically active substances; immunomodulating compounds; Starting products for active ingredients; Intermediates for the chemical and pharmaceutical industries; potential immunomodulators; thioether; * *}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of 3- (alkylthioalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of the general formula I. Such compounds can be obtained as biologically active compounds of meaning as pharmaceuticals or to the Production can be used.

Characteristic of the known state of the art

Compounds of the general formula I have not been listed either in the patent or in the specialist literature.

Object of the invention

The aim of the invention is to produce 3- (alkylthioalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines in a simple manner in high yield.

Explanation of the essence of the invention

The object of the invention is to find technically applicable synthetic routes for the preparation of 3- (alkylthioalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of general formula I.

The object of the preparation of compounds of general formula I, wherein R ¹ = H, 6-CH ₃ , 6-CI, 6-Br, 6,7- (OCH ₃ ) ₂ ;

R ² = H, CHj;

R ³ = alkyl, C ₁ -C ₁₂ , unsubstituted or substituted benzyl or phenacyl, allyl, hydroxyalkyl, cyanomethyl and η = 1 or 2,

is solved by

that according to a first embodiment of the invention

a) 3- (co-mercaptoalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of general formula II, wherein R ¹ , R ² and η have the meanings given above, with alkyl halides of the general Formula R ³ shark, where R ^{3 has} the abovementioned meanings and Hai Broder Cl is reacted in aqueous-alkanolic, C | -C ₃ , solution in the presence of alkali metal hydroxide solution and / or alkanolic solution in the presence of alkali alkanolates,

that according to a second embodiment of the invention

b) 3- (u-chloro or 8romalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of general formula III, wherein R ^{4 is} Br or Cl and R ¹ , R ² and η have the abovementioned meanings, with alkyl mercaptans of the general formula R ³ SH, where R ³ corresponds to the above-mentioned meaning, in aqueous-alkanolic, Ct-C ₃ , solution in the presence of alkali metal hydroxide and / or alkanolic solution in the presence of Alkalialkanolaten be implemented, that according to a third embodiment of the invention

c) 2,3-dihydro-5-oxo-oxazolo / 2,3-b / or 3,4-dihydro-6-oxo-2H- / 1,3 / -oxazino / 2,3-b / quinazolines the general formula IV, wherein R 'and η have the meanings given above, with alkyl mercaptans of the general formula R ³ SH, wherein R ^{3 has} the abovementioned meanings, in aqueous-alkanolic, C ₁ -C ₃ , solution in the presence of alkali metal hydroxide and / or alkanolic solution in the presence of alkali alkanolates at room temperature or under refluxing heating.

The preparation of the starting compounds of the general formulas II, III and IV is carried out, if not known from the literature, based on known methods of preparation of analogous compounds.

embodiments

The invention will be explained in more detail below with reference to 4 exemplary embodiments.

example 1

/ 2- (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl / - (3-chlorobenzyl) -sulfane; I; R ¹ , R ² = H, R ³ = 3-CI-C ₆ H ₄ CH ₂ , η = 1 8,8 g 3 (2-mercaptoethyl) -2,4-dioxo-1,2,3,4-tetrahydro quinazoline (II; R ', R ² = H, η = 1; Schmb .: 194-196 ⁰ C [n-propanol]) are suspended in 30 ml methanol, by adding 22 ml NaOH (2 mol / l) with gentle Heating dissolved and filtered after cooling a little undissolved. The filtrate is added slowly with stirring to 6.2 ml of 3-chlorobenzyl chloride and the reaction mixture after four hours of stirring for 3 days stored in a sealed vessel at room temperature. The precipitate formed, as well as the acidification with dilute HCl obtained precipitate is filtered off with suction, washed with water and recrystallized from n-propanol

 Melting point: 157-161 ° C, yield: 91%

Example 2

/1-(2,4-Dioxo-1,2,3,4-tetrahydro-chK.wZolin-3yl)-prop-2-yl/-(4-cyanbenzyl)-sulfan; I; R ¹ = H, R ² - ^ CH ₃ , R ³ = 4-CN-C ₆ H ₄ CH ₂ , η = 1 1.18 g of 3- (2-mercaptopropyl) -2,4-dioxo-1,2, 3,4-tetrahydro-quinazoline (II, R ¹ = H, R ² = CH ₃ , η = 1, mp: 195 ⁰ C [ethanol]) are dissolved in 30 ml of abs. Ethanol, dissolved by addition of 0.12 g of sodium with gentle heating and filtered from a little undissolved. The filtrate is abs in 20ml. Ethanol dissolved 1.0g 4-Cyanbenzylbromid and stored for one day at room temperature in a sealed vessel. The resulting precipitate is filtered off, washed with water and recrystallized from 50% ethanol

 Melting point: 196-197 ° C, yield: 76%

Example 3

/ 2- (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl / - (2-hydroxyethyl) -su: fan; I; R ¹ , R ² = H, R ³ = HIGH ₂ CH ₂ , η = 1, 0.4 g 3 - (2-chloroethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (III; R ¹ , R ² = H, η = 1, mp: 194-196 ⁰ C [methanol]) are in 15 ml abs. Dissolved ethanol and with a from 0.48 ml of mercaptoethanol, 0.092 mg of sodium and 4 ml of abs. Ethanol thiolate solution added with stirring and heated 5h reflux. Subsequently, after cooling, the reaction time is acidified with dilute HCl and the resulting precipitate is filtered off with suction, washed with water and recrystallized from water. Melting point: 143-144 ° C, yield: 52%

Example 4

/ 2- (2,4-dioxo-1,2,3,4-tetrahydrorhinazolin-3-yl) ethyl / -benzylsulfan; I; R ¹ , R ² = H, R ³ = C ₆ H ₅ CH ₂ , η = 1 0.3 g, 2,3-dihydro-5-oxo-oxazolo / 2,3-b / quinazoline (IV, R '= H, n = 1, mp: 166-168 ° C. Ethanol]) are dissolved in 12mlabs.Ethanol and with aor from 0.2g Benzylmercaptan, 0.035g sodium and 2ml abs. Ethanol prepared thiolate solution added with stirring. The reaction mixture is heated for 30 minutes on a boiling water bath. After cooling, it is acidified with dilute HCl and the precipitate formed is filtered off, washed with water and recrystallized from 50% ethanol. MP: 148-152 ⁰ C, Yield: 85%

In addition, the following 3- (alkylthioalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines represented by the general formula I:

η R ¹ R ¹ R ³ analogous Schmb. Yield (%) 1 -H -H -CH ₃ example (Umkrist.aus) 76 1. 1 -H -H -C ₄ Hg 1 A 196-198 ° C (EtOH / H ₂ O) Ό \ 72 Second 1 163-164 ⁰ C (EtOH) 52 1 -CH ₃ -H -C ₂ H ₄ OH 4 66 Third 2 -H -H -C ₂ H ₄ OH 1 187-189 ⁰ C (H ₂ O) 74 4th 1 -H -H -C ₃ H ₆ OH 1 145-147 ⁰ C (H ₂ O) 40 5th 1 -H -CH ₃ -C ₃ H ₆ OH 2 128-130 ° C (EtOH / H ₂ O) 35 6th 1 -H -H -CH ₂ CHOHCH ₂ OH 2 117-119 ° C (EtOH / H ₂ O) 47 7th 1 -H -H -CH ₂ CN 4 139-140 ⁰ C (H ₂ O) 40 8th. 1 -H -H -CH ₂ COC ₆ H ₆ 2 159-160 ° C (toluene) 59 9th 1 -H -H -CH ₂ C ₆ H ₄ ^ -F 1 181-183 ⁰ C (EtOH) 76 10th 2 188-189 ° C (EtOH / H ₂ O)

(CM ₂ J _n CH SR ^

Claims (1)

A process for the preparation of 3- (alkylthioalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of general formula I ₁ wherein R ¹ = H, 6-CH _3, 6-Cl, 6-Br, 6,7- (OCH _{3) 2;} R ² = H, CH ₃ ; R ³ = alkyl, C ₁ -C ₁₂ , unsubstituted or substituted benzyl or phenacyl, allyl, hydroxyalkyl, Cyanomethyl and
η = 1 or 2, characterized in that S-lco-MercaptoaikyO ^ Adioxo-i, 2,3,4-tetrahydro-quinazolines of the general formula II wherein R ¹ , R ² and η have the meanings given above, with alkyl halides Allgomeinen the formula R ³ shark in which R ^{3 has} the abovementioned meanings and Hal is Br or Cl, are reacted in aqueous-alkanolic, C ₁ -C ₃ , solution in the presence of alkali metal hydroxide and / or alkanolic solution in the presence of alkali alkoxides or in that 3- ()) Chloro or bromoalkyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolines of the general formula III, wherein R ^{4 is} Br or Cl and R ¹ , R ² and η have the abovementioned meanings, with alkylmercaptans the general formula R ³ SH, wherein R ³ corresponds to the meanings mentioned above, are reacted in aqueous-alkanolic, C ₁ -C ₃ , solution in the presence of alkali metal hydroxide and / or alkanolic solution in the presence of Alkalialkanolaten or 2,3-dihydro 5-oxo-oxazolo / 2,3-b / or 3,4-dihydro-6-o xo-2H- / 1,3 / -oxazino / 2,3-b / quinazolines of general formula IV, wherein R ¹ and η have the meanings given above, with Alk \ Imercaptanen of the general formula R ³ SH, wherein R ^{3 is} the Having the abovementioned meanings, in aqueous alkanolic, C ₁ -C ₃ , solution in the presence of alkali metal hydroxide and / or alkanolic solution in the presence of Alkalialkanolaten at room temperature or under refluxing heating are reacted.