Process for preparing 5-(fluoro-4-imino-3-methyl)-1-tosyl-3,4 dihydropyrimidine-(1H)-one and derivatives of the compound

Patent metadata

Field	Value
Publication number	US-12466796-B2
Application number	US-202017762557-A
Country	US
Kind code	B2
Filing date	Sep 23, 2020
Priority date	Sep 23, 2019
Publication date	Nov 11, 2025
Grant date	Nov 11, 2025

Abstract

The present invention provides a process for preparing a compound having the formula (I):whereinR is alkyl or alkylaryl;each of X1, X2, X3, X4 and X5 is, independently, H, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, —SH, —OH, —NH2, —NO2, —CN or CF3;Y is O or S; andand Z is a halogen.

First claim

What is claimed is:

1 . A process for preparing a compound having the formula (I):

wherein
R is alkyl or alkylaryl;
each of X 1 , X 2 , X 3 , X 4 and X 5 is, independently, H, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, a halogen, —SH, —OH, —NH 2 , —NO 2 , —CN or CF 3 ;
Y is O or S;
and Z is a halogen,
comprising reacting an alkyl-urea or thiourea of the formula RNH(C═Y) NH 2 with a trialkyl orthoformate in the presence of a cyanoacyl derivative having the formula R′C(O)CH 2 CN, wherein R′ is OH, O—R″ or S—R″, wherein R″ is alkyl, or with a cyanoacetaldehyde dialkyl acetal, under conditions sufficient to obtain the compound of formula (III),

2 . The process of claim 1 , wherein the compound of formula (III) is prepared by reacting the compound of formula (II),

with a halogenating agent under conditions sufficient to obtain the compound of formula (III) having the structure

and/or
wherein the compound of formula (III) is reacted with a compound having the following structure:

wherein Y 1 is halogen, imidazole, or

 under conditions sufficient to obtain the compound of formula (I).

3 . The process of claim 1 , wherein the process comprises the steps of:
(i) reacting an alkyl-urea of the formula RNH(C═Y)NH 2 with a trialkyl orthoformate in the presence of cyanoacetic acid; and (ii) adding a base to the reaction mixture under conditions sufficient to obtain the compound of formula (II),

wherein at least one of steps (i) and (ii) is carried out in the presence of at least one suitable solvent.

4 . The process of claim 3 , comprising the following steps:
(i) reacting an alkyl-urea of the formula RNH(C═Y)NH 2 with a trialkyl orthoformate in the presence of cyanoacetic acid to form the compound of formula (V),

(iia) adding a base to the reaction mixture of step (i) under conditions sufficient to obtain the compound of formula (IV),

(iib) heating the product obtained in step (iia) under conditions sufficient to obtain the compound of formula (II),

 and
(iii) reacting the compound of formula (II) with a halogenating agent under conditions sufficient to obtain the compound of formula (III),

wherein at least one of steps (i), (iia) and (iib) is carried out in the presence of at least one suitable solvent,
or comprising the following steps:
(ia) reacting an alkyl-urea of the formula RNH(C═Y)NH 2 with a trialkyl orthoformate in the presence of cyanoacetic acid to form the compound of formula (V),

(ib) heating the product obtained in step (ia) under conditions sufficient to obtain the compound of formula (VI),

(ii) adding a base to the reaction mixture of step (ib) under conditions sufficient to obtain the compound of formula (II),

 and
(iii) reacting the compound of formula (II) with a halogenating agent under conditions sufficient to obtain the compound of formula (III),

wherein at least one of steps (ia), (ib), (ic) and (ii) is carried out in the presence of at least one suitable solvent.

5 . The process of claim 1 for preparing a compound having the formula (I) comprising the steps of:
(i) reacting an alkyl-urea of the formula RNH(C═Y)NH 2 with a trialkyl orthoformate in the presence of a cyanoacetaldehyde dialkyl acetal; and
(ii) adding a base to the reaction mixture under conditions sufficient to obtain the compound of formula (II),

wherein at least one of steps (i) and (ii) is carried out in the presence of at least one suitable solvent.

6 . The process of claim 1 for preparing a compound having the formula (I) comprising reacting the compound of formula (VIII) with

with a base under conditions sufficient to obtain the compound of formula (III),

7 . The process of claim 1 , wherein the compound of formula (I) produced has the structure:

8 . A process for preparing a compound having the structure (I) according to claim 1 :

wherein
R is alkyl or alkylaryl;
each of X 1 , X 2 , X 3 , X 4 and X 5 is, independently, H, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, —SH, —OH, —NH 2 , —NO 2 , —CN or CF 3 ;
Y is O or S;
and Z is a halogen,
comprising reacting the compound of formula (III) having the structure:

with a compound having the following structure in the presence of a base,

wherein Y 1 is halogen, imidazole, or under conditions sufficient to obtain the compound of formula (I).

9 . A method for isolating (I) as defined according to claim 1 after conversion of the compound of formula (III) to the compound of formula (I), wherein the method comprises separation of residual salts and the compound of formula (I) in the reaction mixture.

10 . A process for isolating compound (I) as defined according to claim 1 comprising contacting compound (I) with a polar solvent or a mixture of polar solvents.

11 . The process of claim 1 , wherein the alkyl-urea has the formu

Assignees

• Adama Makhteshim Ltd

Inventors

• Suez Gal
• Alasibi Samaa
• Mines Yaakov

Classifications

• C07C273/1863

  from urea · CPC title

• A01N43/54

  1,3-Diazines; Hydrogenated 1,3-diazines · CPC title

• C07C273/1854

  by reactions not involving the formation of the N-C(O)-N- moiety · CPC title

• C07D239/47 Primary

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title