DD273441A1 - PROCESS FOR THE PREPARATION OF 2-ALKOXY-5-AMINO-4-PHENYL-THIENO [2,3-D] PYRIMIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of 2-alkoxy-5-amino-4-phenyl-thieno & 2,3-d! Pyrimidines. The title compounds, which can be used as intermediates, are made accessible by an optional one- or two-stage process by reacting 3-chloro-2-cyano-quinonitrile in an alcohol first with potassium thiocyanate and then with the addition of a base with acceptor-substituted halomethanes.

Description

273 44 t

Ancestors for the preparation of 2-alkoxy-5-amino-4-phenylthieno [2,3-d] pyrimidines

Field of application of the invention

The invention relates to a process for the preparation of 2-alkoxy- ^t 3-amino-4-phenyl-thieno [2,3-d] pyrimidines, which can find use αία intermediates.

Characteristic of the known technical solutions

E3 is known to be able to prepare related 5 ~ amino thieno [2,3-d! Pyrimidines with the aid of a Thorpe cyclization as last step of the synthesis. Thus, in J. Heterocycl. Chem. 8 (1971), 445 the 4-chloro-2-methylthio-pyrimidine-5-carbonitrile 'reacted with substituted methanethiols * By methods described in Jap. Pat. 75 140 487 (1975), Chem.Abstr. 85 (1976) 21, 428 are substituted 4-mercapto and DDR-Bat. 136,500 (1979), Chera. Ab. 92 (1980) 58807 reacted 2,6-diaryl-4-mercapto-pyrimidine-5-carbonitriles with acceptor-substituted halomethanes. The required, substituted pyrimidine-5-carbonitriles must first in all procedures in z. Part elaborate multi-stage actions are produced. 2 ~ alkoxy-5-amino-thieno [2,3-d] pyrimidines can not be prepared with the aid of these syntheses and have not been described in the literature so far.

Object of the invention

The aim of the invention is to produce new, previously unknown 2-alkoxy-5-amino-4-phenylthieno [2,3-d] pyrimidines.

Explanation of the essence of the invention

The object of the invention is to prepare 2-alkoxy-5-amino-thieno [2,3-cl] -pyrimidines by a simple process. According to the invention, the object is achieved by reacting 2-alkoxy-3-amino-4-methylpyrimidines -phenyl-thieno [2,3-d] pyrimidines of the formula I,

ir

R ¹ -O ^- ""

1 2

wherein R is an alkyl radical and R is an acyl, alkoxycarbonyl,

Garbamoyl or cyano group, prepared by reacting 3-chloro-2-cyan-cinnamonitril II

G AL · GN op /

^) = G II

Gl " ^X GN

first with potassium thiocyanate (KSGlI) in boiling alcohol of formula III

R ¹ -OH III

and then with the addition of a base with substituted halomethanes of the formula IV

Hal-GH ₂ -R ² IV

implemented in one stage · in formulas III and IV

In this case, R 2 and R 2 have the values entered above for the formula I.

Meaning, shark represents a chlorine or bromine atom # Optionally, the thieno [2,3-d] pyrimidines I can also be prepared in 2 stages, by adding first of 3-chloro-2-cyano-cinnamonitrile II, potassium thiocyanate (KSGN) v, uu Alcohol III arising

27344 f

2-alkoxy-6-phenyl-4-thioxo-3> 4-dihydropyridine ~ 5-carbonyl trile of the formula V ₁

in which R is an alkyl group, isolated as an intermediate and these are reacted separately in a solvent, preferably alcohol, ruit substituted halomethanes of the formula II in the presence of a base. As the base, which functions as both an alkylation auxiliary and a cyclization agent, potassium carbonate is preferably used. The reaction temperatures are between 40 and 100 ⁰ G. The advantage of the method is that new, previously unknown compounds are made access lent by a simple synthesis method, are combined by the 4 reaction steps in one stage or in each case 2 reaction steps in 2 steps. Also advantageous is the use of potassium carbonate. The 3-chloro-2-cya: i-cinnamoronitrile required as the starting material can, according to J.prakt. Chem. 325 (1983) 876 in a simple manner.

Exemplary embodiments

example 1

5-amino-2-ethoxy-4-phenyl-thieii: [2,3-d] pyrimidine-6-carboxylic acid ethyl ester

a) 10 mmol of 3-chloro-2-cyan-cinnamonitril be with 12 mmol of potassium thiocyanate in 20 ml of abs. Ethanol stirred for 1 h under reflux. Thereafter, 40 mmol of potassium carbonate are added and the mixture is heated for 15 minutes. Thereafter, 10 mmol of ethyl chloroacetate are stirred into the cooled or still moderately warm solution. The mixture is then kept at room temperature for 30 minutes and in the boiling water bath for 30 minutes. As it cools, it is stirred into 100 ml of water and filtered with suction. Mp. 164-166 ⁰ C, recrystallized from Bropanol y. 47 %

2 73 4 4

b) A mixture of 25 mmol 3-chloro-2-cyan-cinnamonitrile, 27 mmol Kallumrhodanid and 50-60 ml aba. Ethanol is refluxed for 1 h, stirred after cooling in 200 ml of water v.nd daa resulting 2-ethoxy-6-phenyl-4-thioxo ~ 3,4-di.hydropyridin-5 ~ carbonitrile filtered off with suction. Mp 197-200 ⁰ G (from ethanol), Yield V / abs [S'.i \ j, 10 mmol of this product ground together with 40 mmol potassium carbonate in 30 ml. Ethanol heated for 10 min. Then, at 20-50 ⁰ G 10 mmol Chloressigsäureethy! Eye dropwise ester and 30 min refluxed liach cooling, it is stirred into 100 ml of water and suction filtered. Sc.bmp. 164-166 ⁰ G (au3 ethanol), Ausb. 58 <; j.

3eiapiel 2

5-amino-2-ethoxy-4-phenyl ~ thieno [2,3-d] pyrimidine-6--phenylketon y!

According to the procedure given for example 1, variant a, with 10 mmol phenacyl bromide instead of glacracetic acid ester dissolved in 5 ml ethanol, R1 ^c , j yellow-colored crystals of mp 182-183 G (from propanol) are obtained.

Example 3 5-Amino-2-ethoxy-4-phenylthieno [2,3- (i] pyrimidine-6-carbonitrile

According to the procedure given for example 1, variant a, instead of chloroacetic acid ester, 10 mmol of chloroacetonitrile are reacted. Thus 44 ^ι ) Ό yellowish colored crystals of mp, 214-216 ⁰ G (from propanol) are obtained.

Example 4

R-amino-2-methoxy-4 ~ phenyl-thieno [2,3-dJpyriroidin-6-carbonaäuremethyleater

a) 10 mmol of 3-chloro-2-cyan ~ cinnamonitril and 12 mmol of potassium thiocyanate are stirred in 20 ml of methanol for 1.5 h under reflux. After addition of 40 nunol of potassium carbonate is heated for a further 15 min. The slightly cooled mixture is added slowly while stirring with 10 mmol Ghloiessigsäuremethy! And held for 30 min in the boiling heat. After cooling, it is diluted with 100 ml of water and filtered with suction. M.p. 181-183 ⁰ G (from ethanol), Yield 5I %,

b) Following the procedure given for Example 1, variant b, with methanol 59 ', * 2-l.ethoxy-6-phenyl-4-thioxo «'3> 4 ~ dihydropyridine-6-carbonitrile Schmp, 106-186 ⁰ C. (from ethanol) · Chloressigsäuremethylester is used for the further reaction described. M.p. 181-183 ⁰ C, yield 76 \ '; _t

Example 5

5 "~ amino-2-methoxy-4-phenylthieno [2,3-d] pyrimidine-6-carboxamide

According to the procedure given for example 4, variant a, 10 mmol of chloroacetamide are reacted instead of chloroacetic ester. Here, v / ground 4I ^c io product of mp. 211-213 (from llitromethan) was obtained.

Example 6

5-Amino-2-propoxy-4-phenyl ~ thieno [2,3-d] pyrimidine-6-carbonsüureethy! Ester

Ϊ According to the procedure specified for example 1, variant a, alcohol is used instead of ethanol n-propyl alcohol in the reaction. The product from Schmp, 160-162 ⁰ C (from propanol) is with 45proz. Yield obtained.

Example 7 ⁽ 5-Amino-2-propoxy-4-phenylthieno [2,3-d] pyrimidine-6-carbonitrile

Example 1, variant a, are obtained with 20 ml of n-propyl alcohol in place of ethanol and with 10 mmol of chloroacetonitrile instead of chloroacetic ester 42 % of yellowish crystals of mp 201-203 ⁰ C (from ethanol),

Example 8

3-Amino-2-propoxy-4 ~ phenyl-thieno [2,3-d] pyrimid "6-yl-methyl-ketone

According to the procedure given for example 1, variant b, 55 % of 2-propoxy-6-phenyl-4-thioxo-3,4-dihydropyridine-5-carbonitrile of the mp 213 are first of all replaced with n-propyl alcohol instead of ethanol. 215 ⁰ C (from propanol). For the reaction described further 10 mmol of chloroacetone are used instead of chloroacetic ester. Mp. 160-162 ⁰ C (from ethanol), yield 51%.

Claims (3)

claims 1 2 in which R represents an alkyl radical and R represents an acyl, alkoxycarbonyl, garbamoyl or cyano group, characterized in that in one step 3-chloro-2-cyano-cinnamonitrile of the formula II (VH _r CN ^X G = C II Gl ^ CN first in a boiling alcohol of the formula III, R ¹ -OH III • I Y / orin R is an alkyl radical, with potassium thiocyanate (KSGN) and then, with the addition of a base as Alkylierungshilfs- and cyclization with halomethanes of the formula IV Hal-CH ₂ -R ² IV in which shark represents a chlorine or bromine atom and R has the meaning given above, be reacted at 40-100 ⁰ C » 1. A process for the preparation of 2-alkoxy-5-amino-4-phenylthieno [2,3-d] pyrimidlonone of the general formula I, ^G 6 ^H 5 -R ² 2. The method according to item 1, characterized in that the first off 3-chloro-2-cyano-cinnamonitrile II and potassium thiocyanate (KSClI) in an alcohol III resulting 2-alkoxy-6 "phenyl-4-thioxo-3,4-dihydropyridine-5-carbonitriles of the formula V, I ⁵ IT 2734 • ι wherein R is an alkyl group, isolated as intermediates and these are reacted in a second stage, after addition of a Baae, with substituted Ilalogenmethanen IV, in a solvent, preferably alcohol, at 40-100 ⁰ G. Process according to items 1 and 2, characterized in that potassium carbonate is preferably used as the base.