DD293817A5 - PROCESS FOR THE PREPARATION OF (2,4-DIOXO-1,2,3,4-TETRAHYDRO-CHINAZOLIN-3-YL) ALKYLTHIOALKANSAURES AND THEIR ALKYL ESTERS - Google Patents

Abstract

The invention relates to a process for the preparation of * and their alkyl esters of general formula I, whereinY is CH or CH 2 CH; {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 (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) -alkylthioalkansäuren and their alkyl esters of the general formula I. Such compounds may be used as biologically active compounds meaning Pharmaceuticals obtain or used for their preparation.

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 (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) -alkylthioalkansäuren or their alkyl esters in high yield.

Explanation of the essence of the invention

The object of the invention is technically applicable synthetic routes for the preparation of (2,4-oioxo-1,2,3,4-tetrahydroquinazolin-3-yl7-alkylthioalkansäuren or their alkyl esters of general formula I, wherein Y = -CH- or -CH ₂ IpH-;

R ⁴ R ⁴

R '= H, 6-CH ₃ , 6-CI, 6-Br, 6,7- (OCH ₃ ) ₂ ; R ² = H, CH ₃ ; R ³ = H, alkyl, C ₁ -C ₃ ; R ⁴ = H, alkyl, C ₁ -C ₆ , and η = 1 or 2 corresponds to find.

According to the invention, this object is achieved in a first embodiment in that 3- (mercaptoalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of the general formula II, wherein R ¹ , R ² and η are the above having meanings mentioned, haloalkanoic acids or their alkyl esters of the general formula HaIYCOOR ¹ , wherein Y and R ^{3 have} the meanings mentioned above besitzei and Hal is Br or Cl, are reacted.

In a second embodiment of the invention 3- (chloro or bromoalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of general formula III, wherein R ^{5 is} Br or Cl and R ¹ , R ² and η have the abovementioned meanings, with mercaptoalkanoic acids or their alkyl esters of the general formula HSYCOOR ³ , wherein Y and R ³ corresponds to the meanings listed above, reacted.

In a third embodiment of the invention 2,3-dihydro-5-oxo-oxazolo [2,3-b] - or 3,4-DihyJro-6-oxo-2H [1,3] oxazino [2,3- b] quinazolines of the general formula IV, wherein R ¹ and η have the meaning given above, reacted with mercaptoalkanoic acids or their alkyl esters of the general formula HSYCOOR ³ , where Y and R ^{3 have} the meanings given above.

The reactions according to the first, second and third embodiments of the invention are carried out in aqueous-alkanolic, C) -C ₃ , solution in the presence of alkali metal hydroxide and / or alkanolic solution in the presence of alkali alkanolates at room temperature or optionally under refluxing heating.

In a fourth embodiment of the invention, (2 _, 4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) -alkylthioalkansäurealkylester of general formula I, wherein Y, R ¹ , R ² , R ⁴ and η possess dio Bedoutungen above R ³ is alkyl, C ₁ -C ₃ means by heating in alkanolilscher, C ₁ -C _3, or alkanolisch-aqueous alkali metal hydroxide, preferably sodium hydroxide, in the (2,4-dioxo-1,2 , 3,4-tetrahydro-quinazolin-3-yl) -alkanoic acids of general formula I, wherein Y, R ¹ , R ² , R ⁴ and η have the abovementioned meanings and R ³ corresponds to a Η-atom, converted.

The e'netzten starting compounds of the general formulas II, IM 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 on 5 exemplary embodiments.

example 1

r; I; Y = CH ₂ CH ₂ , R ¹ = H, R ² = CH ₃ , R ³ = C ₂ H ₅ , η = 1

0.55 g 3 - (2-mercaptopropyl) 2,4-dioxo-1,2,3,4-tetrahydroquinazoline (II; R ¹ = H, R ² = CH ₃ , η = 1, mp: 195 ° C [Ethanol]) are in 1OmI abs. Ethanol suspended, dissolved by the addition of 0.06 g of sodium and filtered after cooling a little undissolved. The filtrate is treated with 0.5 g of 3-Brompropionsäureethylester and stored for two days at room temperature in a sealed vessel. The precipitate formed is filtered off, washed with water and recrystallized from 50% ethanol

MP: 158-160 ⁰ C, yield: 95%

Example 2

aia-ta ^ -Dloxo-iaSAtetrahydro-quinazolin-S-yDpropylthloJproplonsäure; I; Y = CH (CH ₃ ); R ¹ , R ² , R ³ = H, η = 2 0.47 g S-β-mercaptopropyD ^ adioxo-I ^ .S ^ -tetrahydro-quinazoline (II; R ¹ , R ² = H, η = 2, Schmb .: 165-167 ° C [n-propanol]) are suspended in 4 ml of water and dissolved by addition of 1 ml of NaOH (3mol / l) and filtered from a little undissolved. The filtrate is dissolved with 0.41 g of α-bromopropionic acid in 5 ml of ethanol, added and buffered with 1.5 ml of NaOH (1 mol / l). After 20h storage at room temperature, the reaction mixture is acidified with dilute HCl, the resulting precipitate is filtered off with suction, washed with water and stirred for 2 h at room temperature in 5% NaHCO ₃ solution. It is then filtered and the filtrate is acidified with dilute HCl. The resulting precipitate is recrystallized from water.

MP: 141-143T, yield: 70%

Example 3

3- (2,4-dioxo-1,2,3,4-tetrahydro-ehinazolin-3-yl) -propylthloessigsäure; IY = CH ₂ , R '= R ² = R ³ = H, η = 2 0.48 g of SO-chloropropyldi adioxo-i ^^ -tetrahydroquinazoline (III; R ¹ , R ² = H, R ⁵ = Cl , η = 2, mp: 174-176 ⁰ C [n-propanol]) are in 30ml abs. Dissolved ethanol, treated with 0.5 g of sodium and 1.85 g of thioglycolic acid. The reaction mixture is stored for 7 days at room temperature in a sealed vessel and then acidified with dilute HCl, the precipitate formed is filtered off with suction, washed with water and stirred for 2 h at room temperature in 5% NaHCO ₃ solution.

After filtration, the filtrate is acidified with dilute HCl and the resulting precipitate is filtered off and recrystallized from methanol.

M.p .: 151-153 ⁰ C, yield: 48%

Example 4

2- (2,4-dioxo-1,2,3,4-tetrahydro-inches china-3-vl) ethylthioessi98äuremethylester; I; Y = CH ₂ , R ¹ , R ² = H, R ³ = CH ₃ , η = 1 0.28 g of 2,3-dihydro-5-oxo-oxazolo [2,3-b] quinazoline (IV; R ' = H, η = 1, mp: 166-168 ⁰ C [ethanol]) are in 10ml abs. Dissolved methanol and with a from 0.18g Thioglycolsä'uremethylester, 0.035y sodium and 2 ml abs. Methanol prepared thiolate solution added with stirring. The reaction mixture is heated for 6 h on boiling water, acidified after cooling with dilute HCl and the precipitate formed is filtered off with suction, washed with water and recrystallized from 50% methanol.

Schmb .: 122-124 ⁰ C, yield: 40%

example

[2- (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) propylthio] propionic acid; I; Y = C ₂ H ₄ , R '= H, R ² = CH ₃ , R ³ = H, η = 1 0.55 g of [2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline 3-yl) propylthio) propionic acid ethyl ester (I; Y = C ₂ H ₄ , R ¹ = H, R ² = CH ₃ , R ³ = C ₂ H ₅ , η = 1, mp: 158-16O ⁰ C ( 50% ethanol]), 4.5 ml of NaOH (1 mol / l) and 4.5 ml of water are heated under reflux for 3 h, acidified with dilute HCl after cooling and 30 ml of water are added to the resulting precipitate is filtered off with suction and washed thoroughly with water For purification, the precipitate is stirred for 2 h at room temperature in 5% NaHCO ₃ solution, filtered and the filtrate acidified with dilute HCl The precipitate is recrystallized from water.

Shear: 194-196 ⁰ C, Yield: 70%

In addition, the following (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) -alkylthioalkanoic acids and their alkyl esters of general formula I were also shown:

η Y R ¹ R ' ^RJ analogous Schmb. ⁰ C (umkrist. off) Yield (%) example 1. 1 -CH ₂ -H -H -H 5 188-189 (EtOH / HzO) 75 Second 1 -CH ₂ -H -H -C ₂ H ₆ 1 108-110 (Toluene) 68 Third 1 -CH ₂ -H -CH ₃ -H 5 204 (Methylene glycol / HzO) 70 4th 1 -CH ₂ -H -CH ₃ -C ₂ H ₆ 1 136 (Toluene / petrol) 35 5th 1 - (CH (CH ₃ ) -H -H -H 5 156-159 (Toluene) 80 6th 1 -CH (CH ₃ ) -H -H -C ₂ H ₆ 1 121-123 (Toluene / petrol) 65 7th 1 -CH (C ₂ H ₅ ) -H -H -H 2 147 (H ₂ O) 49 8th. 1 -CH (C ₄ H ₉ ) -H -H -H 2 143-145 (EtOH / H ₂ O) 37 9th 1 -C ₂ H ₄ -H -H -H 2 151-152 (EtOH) 78 10th 2 -CH ₂ -H -H -C ₂ H ₆ 1 124-126 (MetOH) 78

Claims (2)

1. A process for the preparation of (2,4-dioxo-1,2,3,4-tetrahydiu-quinazolin-3-yl) -alkylthioalkansäuren and their alkyl esters of the general formula I, wherein Y = -CH- or -CH ₂ CH-; R ⁴ R ⁴ R ¹ = H, 6-CH ₃ , 6-CI, 6-Br, 6,7- (OCH ₃ I ₂ ;
R ² = H, CH ₃ ; R ³ = H, alkyl, C ₁ -C ₃ ;
R ⁴ = H, alkyl, C ₁ -C ₆ , and
η = 1 or 2,
characterized in that a) according to a first embodiment of the invention 3- (mercaptoalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of general formula II, wherein R ¹ , R ² and η have the meanings mentioned above, with haloalkanoic acids or their alkyl esters of the general formula HalCOOR ³ , where Y and R ^{3 have} the meanings given above and Hal is Br or Cl, are reacted; b) according to a second embodiment of the invention 3- (chloro or bromoalkyl) -2,4-dioxo-1,2,3,4-tetrahydro-quinazolines of general formula III, wherein R ^{5 is} Br or Cl and R ¹ , R ² and η have the abovementioned meanings, with mercaptoalkanoic acids or their alkyl esters of the general formula HSYCOOR ³ , wherein Y and R ^{3 are} as defined above, are reacted; c) according to a third embodiment of the invention 2,3-dihydro-5-oxo-oxazolo [2,3-b] - or 3,4-dihydro-6-oxo-2H [1,3joxazino (2,3-b ] quinazolines of the general formula IV, wherein R ¹ and η have the meanings given above, are reacted with mercaptoalkanoic acids or their alkyl esters of the general formula HSYCOOR ³ , where Y and R ^{3 have} the meanings given above; d) according to a fourth embodiment of the invention (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) -alkylthio-alkansäurealkylester of general formula I, wherein Y, R ¹ , R ² , R ⁴ and η have the abovementioned meanings and R ^{3 is} alkyl, C ₁ -C ₃ , by heating in alkano-crescent, C ₁ -C ₃ , or alkanolic-aqueous alkali lye, preferably sodium hydroxide solution, into the (2,4-dioxo) 1,2,3,4-tetrahydro-quinazolin-3-yl) -alkanoic acids of the general formula I, wherein Y, R ¹ , R ² , R ⁴ and η have the abovementioned meanings and R ³ corresponds to a Η-atom, converted become. 2. The method according to claim 1, characterized in that the reactions according to the first, second and third embodiments of the invention in aqueous-alkanolic, C ₁ -C ₃ , solution in the presence of alkali and / or alkanoüscher solution in the presence of Alkalialkanolaten at room temperature or optionally by heating under refluxing reaction conditions.