Process for preparing chiral 2,3-dihydrothiazolo[3,2-A] pyrimidin-4-ium compounds

Patent metadata

Field	Value
Publication number	US-11034703-B2
Application number	US-201816610186-A
Country	US
Kind code	B2
Filing date	May 2, 2018
Priority date	May 3, 2017
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

The present invention relates to a process for preparing optically active compounds of formula X and intermediates thereof,

wherein the variables of compound of formula X are as defined in the claims and the description.

First claim

The invention claimed is:

1. A process for preparing S-containing pyrimidinium compound of formula X

wherein
C* is an asymmetric carbon atom of S or R-configuration;
R 1 is C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 4 -alkenyl, or —CH 2 -phenyl, which groups are unsubstituted or substituted with halogen or C 1 -C 4 -alkyl;
R 2 is a 5- or 6-membered saturated, partially unsaturated or aromatic carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with R 2a ;
Het is selected from D-1, D-2, and D-3:

wherein
R a is each independently R a is halogen, C 1 -C 4 -haloalkyl, C 1 C 4 -alkoxy, C 1 -C 4 -alkylthio, or phenyl;
n is 0, 1 or 2; and
# denotes the bond in formula X;

R 2a is halogen, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, OR c , C(═O)OR c , C(═O)NR b R c , phenyl, or pyridyl, which is unsubstituted or substituted with halogen, C 1 -C 6 -haloalkyl or C 1 -C 6 -haloalkoxy;
R b is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, or C 1 -C 6 -haloalkoxy; and
R c is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, or C 1 -C 6 cycloalkyl;
wherein two geminally bound groups R c R b together with the atom to which they are bound, may form a 3- to 7-membered saturated, partially unsaturated or aromatic heterocyclic ring;
comprising at least the step of,
(E) reacting the compound of formula VII,

wherein
C* is an asymmetric carbon atom of S or R-configuration;
Het is as defined in compound of formula X;

with R 1 NCS, wherein R 1 is C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 4 -alkenyl or —CH 2 -phenyl, which groups unsubstituted or substituted by halogen or C 1 -C 4 -alkyl;
in the presence of a base,
to obtain a compound of formula VIII,

wherein
C* and Het are as defined in the compound of formula VII;
R 1 is as defined herein;

and further reacting the compound of formula VIII to obtain the compound of formula X.

2. The process according to claim 1 , further comprising at least the steps of,
(A) reacting a compound of formula III,

wherein
W is halogen, O-p-toluenesulfonyl, O-methanesulfonyl, or O-trifluoromethanesulfonyl;
Het is as defined in compound of formula X in claim 1 ;

with M 2 OR AC wherein M 2 is selected from lithium, sodium, potassium, aluminium, barium, caesium, calcium, and magnesium; R AC is C(═O)—C 1 -C 4 -alkyl;
to obtain the compound of formula IV,

wherein Het and R A c are as defined herein;

(B) hydrolyzing the compound of formula IV as defined herein in the presence of an acid or a base to obtain a compound of formula V,

wherein Het is as defined in compound of formula IV;

(C) reacting the compound of formula V with X 2 SO 2 NH 2 wherein X 2 is halogen, to obtain the compound of formula VI

wherein Het is as defined in compound of formula V;

(D) hydrogenation of the compound of formula VI,
in the presence of a hydrogenation catalyst MXLn(η-arene) m wherein
η-arene is selected from benzene, p-cymene, mesitylene, 1,3,5-triethylbenzene, hexamethylbenzene, anisole, 1,5-cyclooctadiene, cyclopentadienyl (Cp), norbornadiene, pentamethylcyclopentadienyl (Cp*), and an aryl ring which is unsubstituted or substituted with C 1 -C 4 -alkyl;
M is a transition metal from group VIII to group XII of the periodic table;
X is an anion;
m is 0 or 1;
Ln is Ln1 or Ln2,
wherein
Ln1 is a chiral ligand of the formula Ln1,

wherein
C* is an asymmetric carbon atom of S or R-configuration;
R 10 is OH or NH—SO 2 —R 1 ;
R 11 is aryl unsubstituted or substituted independently of each other with halogen, C 1 -C 10 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, SO 3 H, or SO 3 Na;
or
R 1 is C 1 -C 10 -perfluoroalkyl, or R 13 R 14 N wherein R 13 and R 14 independently represent C 1 -C 10 -alkyl unsubstituted or substituted with C 6 -C 10 -aryl, or R 13 and R 14 each independently represent a C 6 -C 10 -cycloalkyl;
R 12 independently represents aryl ring or C 6 -C 10 -cycloalkyl ring, wherein the ring is unsubstituted or substituted independently of each other with halogen, C 1 -C 10 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, SO 3 H, or SO 3 Na, or both R 12 are linked together to form a 3- to 6-membered carbocyclic ring or a 5- to 10-membered partially unsaturated carbocyclic ring;

Ln2 is a chiral phosphorous ligand;

and a hydrogen source selected from a) hydrogen, b) mixture of N(R) 3 wherein R is H or C 1 -C 6 -alkyl, and HCOOH, c) HCOONa or HCOOK, d) mixture of C 1 -C 8 -alcohol and t-BuOK, t-BuONa, or t-BuOLi, and e) combination of two or more from a) to d);
to obtain a compound of formula VII,

wherein
C* is an asymmetric carbon atom of S or R-configuration;
Het is as defined in compound of formula VI.

3. The process according to claim 1 , wherein further reacting the compound of formula VIII comprises the step (F) of reacting the compound of formula VIII with a compound of formula IX,

wherein,
LG is a leaving group selected from halogen, OR u , and SR u ; wherein
R u is C 1 -C 6 -alkyl or aryl, which is unsubstituted or substituted with halogen;

R 2 is a 5- or 6-membered saturated, partially unsaturated or aromatic carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with R 2a ;
to obtain the compound of formula X.

4. The process according to claim 2 , wherein η-arene is an aryl ring which is unsubstituted or substituted with C 1 -C 4 -alkyl.

5. The process according to claim 2 , wherein η-arene is selected from benzene, p-cymene, mesitylene, 1,3,5-triethylbenzene, hexamethylbenzene, anisole, 1,5-cyclooctadiene, cyclopentadienyl (Cp), norbornadiene, and pentamethylcyclopentadienyl (Cp*).

6. The process according to claim 2 , wherein MXLn(η-arene) m in step (D) is MXLn1(η-arene) m and wherein R 10 is NH—SO 2 —R 11 ; and R 12 and R 11 independently are phenyl which are unsubstituted or substituted with 1 or 2 substituents selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, SO 3 H, and SO 3 Na.

Assignees

• Basf Se

Inventors

• Shinde Harish
• Koradin Christopher
• Dickhaut Joachim
• Goetz Roland
• Klauber Eric George
• Narayanan Sukunath
• Raut Dhanyakumar

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07C403/04

  having side-chains substituted by halogen atoms · CPC title

• C07D277/32

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title