Process for preparing optically active 2,3-dihydrothiazolo[3,2-A]pyrimidin-4-ium compounds
11124528 · 2021-09-21
Assignee
Inventors
- Harish Shinde (Navi Mumbai, IN)
- Christopher Koradin (Ludwigshafen, DE)
- Joachim Dickhaut (Ludwigshafen, DE)
- Roland Goetz (Ludwigshafen, DE)
- Michael Rack (Ludwigshafen, DE)
- Eric George Klauber (Huntsville, AL)
- Sukunath Narayanan (Ludwigshafen, DE)
- Dhanyakumar Raut (Navi Mumbai, IN)
Cpc classification
C07D277/32
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
International classification
C07D417/04
CHEMISTRY; METALLURGY
Abstract
The present invention relates to a process for preparing optically active compounds of formula X and intermediates thereof, ##STR00001##
wherein the variables of compound of formula X are as defined in the claims or the description.
Claims
1. A process for preparing a compound of formula VI ##STR00066## wherein C* is an asymmetric carbon atom of S or R-configuration; Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00067## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula X; R.sup.A is S(═O).sub.oR.sup.x, P(═O)(R.sup.x).sub.2, C.sub.1-C.sub.4-alkoxy, or —CH.sub.2-phenyl, wherein phenyl is unsubstituted or substituted with halogen, methoxy, or nitro; wherein R.sup.x is C.sub.1-C.sub.6 alkyl or aryl which is unsubstituted or substituted with halogen; and o is 1 or 2; and W is halogen, hydroxy, O-p-toluenesulphonyl, O-methanesulphonyl, or O-trifluoromethanesulphonyl; comprising the step of: (A) hydrogenation of a compound of formula V, ##STR00068## in the presence of a hydrogenation catalyst MXLn(η-arene).sub.m, wherein 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 ##STR00069## wherein C* is an asymmetric carbon atom of S or R-configuration; R.sup.10 is OH or NH—SO.sub.2—R.sup.11; wherein R.sup.11 is aryl unsubstituted or substituted independently of each other with halogen, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, SO.sub.3H, or SO.sub.3Na or R.sup.11 is C.sub.1-C.sub.10-perfluoroalkyl, or R.sup.13R.sup.14N wherein R.sup.13 and R.sup.14 independently represent C.sub.1-C.sub.10-alkyl unsubstituted or substituted with C.sub.6-C.sub.10-aryl, or R.sup.13 and R.sup.14 each independently represents a C.sub.6-C.sub.10-cycloalkyl; R.sup.12 independently represents C.sub.6-C.sub.10-aryl ring or C.sub.6—C.sub.10-cycloalkyl ring, wherein the ring is aryl unsubstituted or substituted independently of each other with halogen, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, SO.sub.3H, or SO.sub.3Na, or both R.sup.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 the group consisting of a) hydrogen, b) mixture of N(R).sub.3 wherein R is H or C.sub.1-C.sub.6-alkyl, and HCOOH, c) HCOONa or HCOOK, d) mixture of C.sub.1-C.sub.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 VI, ##STR00070## wherein C* is an asymmetric carbon atom of S or R-configuration.
2. A process for preparing a compound of formula VII, ##STR00071## wherein C* is an asymmetric carbon atom of S or R-configuration; Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00072## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula X; and W is halogen, hydroxy, O-p-toluenesulphonyl, O-methanesulphonyl, or O-trifluoromethanesulphonyl; comprising the step of hydrolyzing the compound of the formula VI, ##STR00073## wherein R.sup.A is S(═O).sub.oR.sup.x, P(═O)(R.sup.x).sub.2, C.sub.1-C.sub.4-alkoxy, or —CH.sub.2-phenyl, wherein phenyl is unsubstituted or substituted with halogen, methoxy, or nitro; wherein R.sup.x is C.sub.1-C.sub.6 alkyl or aryl which is unsubstituted or substituted with halogen; and o is 1 or 2; in the presence of an acid or a base, to obtain a compound of formula VII, ##STR00074##
3. A process of preparing an optically active pyrimidinium compound of formula X, ##STR00075## wherein C* is an asymmetric carbon atom of S or R-configuration; R.sup.1 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.2-C.sub.4-alkenyl or —CH.sub.2-phenyl, which groups are unsubstituted or substituted with halogen or C.sub.1-C.sub.4-alkyl; R.sup.2 is a 5- or 6-membered saturated, partially unsaturated or aromatic carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with Rea; Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00076## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula X; R.sup.2a is halogen, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, OW, C(═O)OR.sup.c, C(═O)NR.sup.bR.sup.c, phenyl, or pyridyl, which groups are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-haloalkyl or C.sub.1-C.sub.6-haloalkoxy; R.sup.b is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, or C.sub.1-C.sub.6-haloalkoxy; R.sup.c is hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, or C.sub.1-C.sub.6-cycloalkyl; wherein two geminally bound groups R.sup.cR.sup.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 the steps of reacting the compound of formula VII ##STR00077## wherein W is halogen, hydroxy, O-p-toluenesulphonyl, O-methanesulphonyl, or O-trifluoromethanesulphonyl; with R.sup.1NCS, wherein R.sup.1 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.2-C.sub.4-alkenyl or —CH.sub.2-phenyl, which groups are unsubstituted or substituted with halogen or C.sub.1-C.sub.4-alkyl; in the presence of a base to obtain a compound of formula VIII, ##STR00078## and reacting the compound of formula VIII with a compound of formula IX ##STR00079## wherein, LG is a leaving group selected from the group consisting of halogen, OR.sup.u and SR.sup.u; wherein R.sup.u is C.sub.1-C.sub.6-alkyl or aryl, which is unsubstituted or substituted with halogen; to obtain the compound of formula X.
4. The process of claim 1, wherein in step (A) the chiral phosphorous ligand Ln2 is selected from the ligands listed in Table-A below or selected from their corresponding enantiomers, TABLE-US-00003 TABLE-A Sr. No. Structure Name 1.
5. The process of claim 1, wherein η-arene is selected from the group consisting of benzene, p-cymene, mesitylene, 1,3,5-triethylbenzene, hexamethylbenzene, anisole, 1,5-cyclooctadiene, cyclopentadienyl (Cp), norbornadiene, and pentamethylcyclopentadienyl (Cp*).
6. The process of claim 1, wherein MXLn(η-arene), is MXLn1(η-arene), and wherein R.sup.10 is NH—SO.sub.2—R.sup.11; and R.sup.12 and R.sup.11 independently are phenyl which are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, SO.sub.3H, and SO.sub.3Na.
7. The process of claim 1, wherein MXLn(η-arene), is MXLn1(η-arene), and wherein X is halide; R.sup.12 independently is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl or 4-methoxyphenyl; R.sup.10 is NH—SO.sub.2—R.sup.11 and —SO.sub.2—R.sup.11 is p-toluenesulphonyl, methanesulphonyl, 4-benzenesulfonyl, or pentafluorophenyl-sulfonyl.
8. The process of claim 1, wherein m is 1 and MXLn(η-arene), is of the formula MXLnCp*, wherein M is rhodium, ruthenium, iridium, palladium, iron, platinum, or nickel. ##STR00110##
9. The process of claim 1, wherein M is rhodium, ruthenium, or iridium.
10. The process of claim 2, wherein the acid in step (B) is selected from the group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, polyphosphoric acid, hydroiodic acid, C.sub.1-C.sub.8-alkyl-(COOH).sub.y, C.sub.1-C.sub.8-haloalkyl-(COOH)y, CH.sub.3SO.sub.3H, citric acid, oxalic acid, p-toluenesulphonic acid, and mixtures of two or more thereof; wherein y is 1 or 2.
11. The process of claim 1, wherein R.sup.1 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, or C.sub.2-C.sub.4-alkenyl, which is unsubstituted, or substituted with halogen.
12. The process of claim 1, wherein R.sup.2 is phenyl, pyridinyl or thiophenyl, which is unsubstituted or substituted with R.sup.2a.
13. The process of claim 1, wherein Het is D-2 wherein n is 0 and R.sup.a is halogen.
14. A compound of formula V, ##STR00111## wherein R.sup.A is S(═O).sub.oR.sup.x, P(═O)(R.sup.x).sub.2, C.sub.1-C.sub.4-alkoxy, or —CH.sub.2-phenyl, wherein phenyl is unsubstituted or substituted with halogen, methoxy, or nitro; W is halogen, hydroxy, O-p-toluenesulphonyl, O-methanesulphonyl, or O-trifluoromethanesulphonyl; and Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00112## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula V.
15. An optically active compound of formula VI ##STR00113## wherein C* is an asymmetric carbon atom of S or R-configuration; R.sup.A is S(═O).sub.oR.sup.x, P(═O)(R.sup.x).sub.2, C.sub.1-C.sub.4-alkoxy, or —CH.sub.2-phenyl, wherein phenyl is unsubstituted or substituted with halogen, methoxy, or nitro; W is halogen, hydroxy, O-p-toluenesulphonyl, O-methanesulphonyl, or O-trifluoromethanesulphonyl; and Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00114## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula VI.
16. An optically active compound of formula VII ##STR00115## wherein C* is an asymmetric carbon atom of S or R-configuration; W is halogen, hydroxy, O-p-toluenesulphonyl, O-methanesulphonyl, or O-trifluoromethanesulphonyl; and Het is D-2 or D-3: ##STR00116## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula VII.
17. An optically active compound of formula VIII ##STR00117## wherein C* is an asymmetric carbon atom of S or R-configuration; Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00118## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula VIII; and R.sup.1 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.2-C.sub.4-alkenyl or —CH.sub.2-phenyl, which groups are unsubstituted or substituted with halogen or C.sub.1-C.sub.4-alkyl.
18. An optically active compound of formula VIII ##STR00119## wherein C* is an asymmetric carbon atom of S or R-configuration; Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00120## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula VIII; and R.sup.1 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, or C.sub.2-C.sub.4-alkenyl, which is unsubstituted, or substituted with halogen.
19. A process for preparing an optically active pyrimidinium compound of formula X ##STR00121## wherein C* is an asymmetric carbon atom of S or R-configuration; R.sup.1 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.2-C.sub.4-alkenyl or —CH.sub.2-phenyl, which groups are unsubstituted or substituted with halogen or C.sub.1-C.sub.4-alkyl; R.sup.2 is a 5- or 6-membered saturated, partially unsaturated or aromatic carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with Rea; Het is selected from the group consisting of D-1, D-2, and D-3: ##STR00122## wherein R.sup.a is each independently halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, or phenyl; n is 0, 1 or 2, and # denotes the bond in formula X; R.sup.2a is halogen, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, OR.sup.c, C(═O)OR.sup.c, C(═O)NR.sup.bR.sup.c, phenyl, or pyridyl, which groups are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-haloalkyl or C.sub.1-C.sub.6-haloalkoxy; R.sup.b is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, or C.sub.1-C.sub.6-haloalkoxy; R.sup.c is hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, or 01-O.sub.6-cycloalkyl; wherein two geminally bound groups R.sub.cR.sup.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 the steps of: (A) hydrogenation of a compound of formula V, ##STR00123## wherein R.sup.A is S(═O).sub.oR.sup.x, P(═O)(R.sup.x).sub.2, C.sub.1-C.sub.4-alkoxy, or —CH.sub.2-phenyl, wherein phenyl is unsubstituted or substituted with halogen, methoxy, or nitro; and R.sup.x is C.sub.1-C.sub.6 alkyl or aryl which is unsubstituted or substituted with halogen; and o is 1 or 2; W is halogen, hydroxy, O-p-toluenesulphonyl, O-methanesulphonyl, or O-trifluoromethanesulphonyl; in the presence of a hydrogenation catalyst MXLn(η-arene).sub.m, wherein 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 ##STR00124## wherein C* is an asymmetric carbon atom of S or R-configuration; R.sup.10 is OH or NH—SO.sub.2—R.sup.11; wherein R.sup.11 is aryl unsubstituted or substituted independently of each other with halogen, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.4-alkoxy, O.sub.3-O.sub.6-cycloalkyl, SO.sub.3H, or SO.sub.3Na or R.sup.11 is C.sub.1-C.sub.10-perfluoroalkyl, or R.sup.13R.sup.14N wherein R.sup.13 and R.sup.14 independently represent C.sub.1-C.sub.10-alkyl unsubstituted or substituted with C.sub.6-C.sub.10-aryl, or R.sup.13 and R.sup.14 each independently represents a C.sub.6-C.sub.10-cycloalkyl; R.sup.12 independently represents C.sub.6-C.sub.10-aryl ring or C.sub.6-C.sub.10-cycloalkyl ring, wherein the ring is aryl unsubstituted or substituted independently of each other with halogen, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, SO.sub.3H, or SO.sub.3Na, or both R.sup.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 the group consisting of a) hydrogen, b) mixture of N(R).sub.3 wherein R is H or 01-O.sub.6-alkyl, and HCOOH, c) HCOONa or HCOOK, d) mixture of C.sub.1-C.sub.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 VI, ##STR00125## wherein C* is an asymmetric carbon atom of S or R-configuration; (B) hydrolyzing the compound of the formula VI in the presence of an acid or a base, to obtain a compound of formula VII, ##STR00126## (C) reacting the compound of formula VII with R.sup.1NCS, wherein R.sup.1 is C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.2-C.sub.4-alkenyl or —CH.sub.2-phenyl, which groups are unsubstituted or substituted with halogen or C.sub.1-C.sub.4-alkyl; in the presence of a base to obtain a compound of formula VIII, ##STR00127## and (D) reacting the compound of formula VIII with a compound of formula IX ##STR00128## wherein, LG is a leaving group selected from the group consisting of halogen, OR.sup.u and SR.sup.u; wherein R.sup.u is C.sub.1-C.sub.6-alkyl or aryl, which is unsubstituted or substituted with halogen; to obtain the compound of formula X.
Description
EXAMPLES
(1) The characterization can be done by coupled High Performance Liquid Chromatography/mass spectrometry (HPLC/MS), Gas chromatography (GC), by NMR or by their melting points.
(2) HPLC method 1: Agilent Eclipse Plus C18, 150 mm×4.6 mm ID×5 um
(3) Gradient A=0.1% TFA in Water, B=0.1% TFA in Acetonitrile.
(4) Flow=1.4 ml/min., column oven temperature=30 C
(5) Gradient program=10% B-100% B—5 min, hold for 2 min, 3 min—10% B.
(6) Run Time=10 min
(7) LCMS method 1: C18 Column (50 mm×3.0 mm×3μ)
(8) Gradient A=10 Mm Ammonium formate in water, B=0.1% Formic acid in acetonitrile
(9) Flow=1.2 ml/min., column oven temperature=40° C.
(10) Gradient program=10% B to 100% B in 1.5 min., hold for 1 min 100% B, 1 min—10% B
(11) Run time: 3.75 min
(12) Chiral HPLC method 1: ChiralPak IA column, 150 mm×4.6 mm×5μ
(13) Mobile phase A=heptane, B=isopropanol,
(14) Flow=1.0 ml/min, column oven temperature=40° C.
(15) Gradient program=5% B Isocratic; run time: 20 min
(16) Chiral HPLC method 2: ChiralPak IC column, 150 mm×4.6 mm×5μ
(17) Mobile phase A=0.1% diethylamine in heptane, B=0.1% diethylamine in isopropanol,
(18) Flow=1.0 ml/min, column oven temperature=40° C.
(19) Gradient program=15% B Isocratic; run time: 20 min
(20) Chiral HPLC method 3: ChiralPak IA column, 150 mm×4.6 mm×5μ
(21) Mobile phase A=heptane, B=isopropanol,
(22) Flow=1.0 ml/min, column oven temperature=40° C.
(23) Gradient program=40% B Isocratic; run time: 20 min
(24) .sup.1H-NMR: The signals are characterized by chemical shift (ppm) vs. tetramethylsilane, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m=multiplet, q=quartet, t=triplet, d=doublet and s=singlet.
(25) Abbreviations used are: h for hour(s), min for minute(s), rt for retention time, ee for enantiomeric excess, and ambient temperature for 22-27° C.
(26) The present invention is now illustrated in further details by the following examples, without imposing any limitation thereto.
(27) With appropriate modification of the starting materials, the procedures as described in the examples below can be used to obtain further compounds of formula VI, VII, VIII, or X.
Example-1: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
Step-1: Preparation of 2-chloro-N-methoxy-N-methyl-acetamide
(28) A 3 L four necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with N-methoxymethanamine hydrochloride (345 g), water (1.6 L) and the resulting reaction mixture was cooled to 0 to −5° C. Then potassium carbonate (1466 g) was added in lots to above reaction mixture followed by the addition of methyl tert-butyl ether (1.4 L). The chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 L) and added drop wise in to the above kept reaction mixture at −5° C. to 0° C. and the reaction mixture was stirred for 2 h at 0° C. The reaction mixture was allowed to come to ambient temperature and two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated to provide 2-chloro-N-methoxy-N-methyl-acetamide as white solid (440 g, 90% yield and 98.0% area purity by HPLC).
Step-2: Preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethenone
(29) A 5 L, four necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with 2-chlorothiazole (250 g), THF (0.75 L) and the resulting reaction mixture was cooled to 0 to −5° C. Then isopropylmagnesium chloride lithium chloride (1.929 L, 1.3 M solution in THF) was added over 0.5 h into the above kept reaction mixture at 0 to −5° C. The reaction mixture was then heated to 40° C. and the reaction was continued at 40° C. for 2 h. The formation of chloro-(2-chlorothiazol-5-yl)magnesium species was confirmed by quenching the small aliquot of the reaction mixture with Iodine and monitoring the formation of 2-chloro-5-iodo-thiazole by GC analysis (96% conversion was observed by GC analysis). The reaction mixture was cooled to 0 to −5° C. and the solution of 2-chloro-N-methoxy-N-methyl-acetamide (343 g) in THF (0.25 L) was added dropwise. The reaction was continued at −5 to 0° C. for 1 h and the reaction progress was monitored by HPLC. The reaction mixture was quenched with 1.5 N aq. HCl solution (1 L) at −5 to 0° C. and then warm to ambient temperature. The two phases were separated and the aqueous phase extracted with methyl tert-butyl ether (2×300 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to obtain crude residue. The crude product was dissolved in methyl tert-butyl ether (0.7 L) at ambient temperature and activated charcoal (4 g) and silica (80 g, 60-120 mesh) were added. The slurry was stirred for 0.5 h, filtered through Buchner funnel and washed with methyl tert-butyl ether (0.3 L). The filtrate was evaporated to obtain 2-chloro-1-(2-chlorothiazol-5-yl)ethanone as pale brown colored oil (409 g, 46% area purity by HPLC)
Step-3: Preparation of N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide
(30) A 5 L four necked flask equipped with teflon-blade stirrer, reflux condenser and thermo-pocket was charged with 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (409 g, 46 area % purity by HPLC), THF (1.2 L), 2-methylpropane-2-sulfinamide (252.4 g) and Titanium(IV)ethoxide (485 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was heated to 50° C. and stirred for 2 h. The reaction progress was monitored by HPLC (>95% conversion by HPLC). The reaction was charged with methyl tert-butyl ether (2.4 L), cooled to 0 to 10° C., quenched slowly with 1 N aq. HCl solution (3.6 L) and stirred for 10 min. The two phases were separated and the organic phase was washed with water (2×800 mL). The organic phase was dried over sodium sulphate, filtered and evaporated to obtain crude residue. The crude product was dissolved in methyl tert-butyl ether (1 L) at ambient temperature and activated charcoal (5.5 g) and silica (100 g, 60-120 mesh) were added. The slurry was stirred for 0.5 h, filtered through Buchner funnel and washed with methyl tert-butyl ether (0.3 L). The filtrate was evaporated to obtain N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide as pale brown colored oil (510 g, 68% area purity by HPLC).
Step-4: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
a) Preparation of Rhodium Catalyst—RhCl[(R,R)-TsDPEN]Cp*
(31) A 250 mL, three necked flask equipped with Teflon-blade stirrer, nitrogen inlet and thermo-pocket was charged with [RhCl.sub.2Cp*].sub.2 (2.0 g), (1R,2R)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine (2.38 g), dichloromethane (68 mL) and TEA (1.72 ml) under nitrogen atmosphere. The resulting slurry was stirred for 0.5 h at 22-27° C. and distilled water was added (40 mL). The two phases were separated and the organic phase was washed with water (40 mL). The organic phase was dried over sodium sulphate, filtered and evaporated to get brown coloured solid residue. The brown residue was triturated with n-heptane (20 mL), filtered and dried under nitrogen atmosphere to get obtain RhCl [(R,R)-TsDPEN]Cp* as red coloured solid (3.4 g).
b) Preparation of HCOOH-NEt.SUB.3 .Mixture
(32) In a 2 L, 3 neck round bottom flask Formic acid (275 mL, >=99% w/w) was added and cooled to 0° C. To this, triethylamine 250 mL, >=99% w/w) was added slowly at 0° C. and used immediately in reaction.
c) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
(33) A 5 L four necked flask equipped with magnetic stirrer, nitrogen inlet and thermo-pocket was charged with dimethylformamide (2.9 L) and degassed with nitrogen for 10 min. Then RhCl[(R,R)-TsDPEN]Cp* (3.63 g) was added under nitrogen atmosphere at 22 to 27° C. To above kept solution, N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide (170 g) dissolved in dimethylformamide (0.51 L), and HCOOH-NEt.sub.3 (425 mL, in a ratio of 1.1:1) solutions were added simultaneously at 22 to 27° C. over a period of 0.5 h and resulting mixture was stirred at 22-27° C. for 2 h. The HPLC showed >97% conversion. The reaction mixture was quenched with water (3.4 L) and extracted with methyl tert-butyl ether (3×1500 mL). The combined organic phase was evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide (180 g, 80% HPLC purity (rt=4.48 & 4.52 min.))
Step-5: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine
(34) A 1 L three necked flask equipped with magnetic stirrer, nitrogen inlet and thermo-pocket was charged with N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide (180 g) and 1 N HCl in MeOH (540 mL) at ambient temperature and the reaction mixture was stirred at 22-27° C. for 14 h. The reaction progress was monitored by HPLC. The organic volatiles were removed under vacuum and the residue was triturated with methyl tert-butyl ether (3×300 mL) and organic phase containing methyl tert-butyl ether was separated from pale yellow colored oily residue. The pale yellow colored residue containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine; hydrochloride was neutralized with 1 N aq. NaOH and extracted with MTBE (3×300 ml). The organic phases were dried over sodium sulphate, filtered and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine as brown colored residue (51 g; 93 area % HPLC purity (rt=2.646 min.) and 72% ee by chiral HPLC method 1).
Step-6: Preparation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine
(35) A 500 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine (51 g, 72% ee), ethanol (200 ml), methyl isothiocyanate (28.53 g) and triethylamine (70 ml). The resulting mixture was stirred for 14 h at 22-27° C. The HPLC analysis showed >99% conversion with formation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine. Then organic volatiles were removed under vacuum and sodium hydroxide (26 g) and water (200 mL) were added into the reaction flask. The reaction mixture was heated to 100° C. and stirred for 2 h. The reaction was diluted with water (200 mL) and extracted with methyl tert-butyl ether (2×500 mL). The organic phases were dried over sodium sulfate and evaporated under vacuum to provide (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine as brown oil [53 g, 98 area % HPLC purity (rt=2.506 min.), m/z=234 amu (M+H.sup.+)].
Step-7: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
(36) A 500 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (53 g, 98% HPLC purity), Toluene (160 mL) and heated to 110° C. under nitrogen atmosphere. Then bis(4-chlorophenyl) 2-phenylpropanedioate (109 g) was added in three portions into the reaction mass kept at 110° C. After stirring at 110° C. for 2 h, HPLC showed >99% conversion. The reaction was cooled between 45 to 50° C. and the precipitated pale yellow colored solid was filtered through sintered funnel, washed with methyl tert-butyl ether (480 mL) and dried under vacuum to provide (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate [54 g, 98.8 area % HPLC purity (rt=3.86 min.), m/z=378 amu (M+H.sup.+) & 99% enantiomeric excess by chiral HPLC method 3).
(37) .sup.1H NMR (300 MHz, DMSO-d6): 3.42 (s, 3H), 3.94 (d, J=12 Hz, 1H), 4.25-4.32 (m, 1H), 6.48 (d, J=8.1 Hz, 1H), 7.06-7.11 (m, 1H), 7.21-7.26 (m, 2H), 7.6 (d, J=7.5 Hz, 1H), 7.96 (s, 1H)
Example-2: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
Step-1: Preparation of N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide
(38) A 0.5 L, three necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (60 g, 97 area % purity by HPLC), THF (180 ml), 2-methylpropane-2-sulfinamide (44 g) and Titanium(IV)ethoxide (77 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was heated to 50° C. and stirred for 2 h. The reaction progress was monitored by HPLC (>95% conversion by HPLC). The reaction was charged with methyl tert-butyl ether (360 ml), cooled to 0 to 10° C., quenched slowly with 1 N aq. HCl solution (540 ml) and stirred for 10 min. The two phases were separated and the organic phase was washed with water (2×300 mL). The organic phase was dried over sodium sulphate, filtered and evaporated to obtain crude residue. The crude product was dissolved in methyl tert-butyl ether (100 ml) at ambient temperature and activated charcoal (1.8 g) and silica (5 g, 60-120 mesh) were added. The slurry was stirred for 0.5 h, filtered through Buchner funnel and washed with methyl tert-butyl ether (0.3 L). The filtrate was evaporated to obtain N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide as pale brown colored oil (88 g, 84% area purity by HPLC method 1).
Step-2: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
a) Preparation of Rhodium Catalyst—RhCl[(R,R)-TsDPEN]Cp*
(39) The catalyst was prepared as mentioned in step-4 of example 1.
b) Preparation of HCOOH-NEt.SUB.3 .Mixture
(40) prepared as described in step-4 of example 1.
c) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
(41) A 3 L four necked flask equipped with magnetic stirrer, nitrogen inlet and thermo-pocket was charged with dimethylformamide (1.5 L) and degassed with nitrogen for 10 min. Then RhCl[(R,R)-TsDPEN]Cp* (1.87 g) was added under nitrogen atmosphere at 22 to 27° C. To above kept solution, N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide (88 g) dissolved in dimethylformamide (260 ml), and HCOOH-NEt.sub.3 (220 mL, in a ratio of 1.1:1) solutions were added simultaneously at 22 to 27° C. over a period of 0.5 h and resulting mixture was stirred at 22-27° C. for 2 h. The HPLC showed >97% conversion. The reaction mixture was quenched with water (1700 ml) and extracted with methyl tert-butyl ether (3×1000 mL). The combined organic phase was evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide (95 g)
Step-3: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine
(42) A 1 L three necked flask equipped with magnetic stirrer, nitrogen inlet and thermo-pocket was charged with N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide (95 g) and 1 N HCl in MeOH (285 mL) at ambient temperature and the reaction mixture was stirred at 22-27° C. for 14 h. The reaction progress was monitored by HPLC. The organic volatiles were removed under vacuum and the residue was triturated with methyl tert-butyl ether (3×150 mL) and organic phase containing methyl tert-butyl ether was separated from pale yellow colored oily residue. The pale yellow coloured residue containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine; hydrochloride was neutralized with 1 N aq. NaOH and extracted with MTBE (3×150 ml). The organic phases were dried over sodium sulphate, filtered and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine as brown coloured residue (35 g; 99.5 area % HPLC purity (rt=2.64 min.), m/z=198 amu (M+H.sup.+) & 96.2% ee by chiral HPLC method 1).
Step-4: Preparation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine
(43) A 250 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine (35 g, 96.2% ee), ethanol (140 ml), methyl isothiocyanate (19.58 g) and triethylamine (48 ml). The resulting mixture was stirred for 14 h at 22-27° C. The HPLC analysis showed >99% conversion with formation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine Then organic volatiles were removed under vacuum and sodium hydroxide (17.15 g) and water (140 mL) were added into the reaction flask. The reaction mixture was heated to 100° C. and stirred for 2 h. The reaction was diluted with water (140 mL) and extracted with methyl tert-butyl ether (3×200 mL). The organic phases were dried over sodium sulphate and evaporated under vacuum to provide (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine as brown oil [41 g, 96 area % HPLC purity (rt=2.506 min.), m/z=234 amu (M+H.sup.+)].
Step-5: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
(44) A 500 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (41 g, 96% HPLC purity), Toluene (125 mL) and heated to 110° C. under nitrogen atmosphere. Then bis(4-chlorophenyl) 2-phenylpropanedioate (85 g) was added in three portions into the reaction mass kept at 110° C. After stirring at 110° C. for 2 h, HPLC showed >99% conversion. The reaction was cooled between 45 to 50° C. and the precipitated pale yellow colored solid was filtered through sintered funnel, washed with methyl tert-butyl ether (480 mL) and dried under vacuum to provide (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate (38 g, 99.3 area % HPLC purity, m/z=378 amu (M+H.sup.+) & 99% ee by chiral HPLC method 3).
Example-3: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
Step-1: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
a) Preparation of Rhodium Catalyst—RhCl[(R,R)-TsDPEN]Cp*
(45) The catalyst was prepared as mentioned in step-4 of example 1.
b) Preparation of HCOOH-NEt.SUB.3 .Mixture
(46) prepared as described in step-4 of example 1.
c) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
(47) A 20 L reactor, was charged with N-[2-chloro-1-(2-chlorothiazol-5-yl) ethylidene]-2-methyl-propane-2-sulfinamide (1275 g, 2.2 mol, 68% purity by HPLC), dimethyl formamide (2550 ml) & toluene (2550 ml) and degassed with nitrogen for 10 min. Then RhCl[(R,R)-TsDPEN]Cp* (7.0 g, 0.01 mol) was added under nitrogen atmosphere. The resulting mixture was cooled to 0 to 5° C. and the freshly prepared HCOOH-NEt.sub.3 (375 mL, in a ratio of 1.1:1) solution was added drop wise over a period of 30 min and stirred between 0° C. to 5° C. for 3 h. The reaction was monitored by HPLC and quenched with water (2550 mL) and extracted with Toluene (2550 mL). The combined organic phase was washed with water (3×3750 ml) and evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide brown colored residue (1150 g, 68% purity by HPLC (rt=4.70 & 4.82 min)).
Step-2: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine
(48) A 5 L four necked flask equipped with magnetic stirrer, nitrogen inlet and thermo-pocket was charged with N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide (1150 g) was diluted in MTBE (3210 ml) and HCl gas was purged for 1 h at 25° C. to 30° C. The reaction progress was monitored by HPLC. The precipitated yellow colored hydrochloride salt was filtered, and the residue was washed with MTBE (2×2000 ml) to obtain pale yellow colored solid (500 g). The pale yellow colored solid containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine; hydrochloride was adjusted to pH 8.5 to 9 with 2 N aq. NaOH and extracted with toluene (3×1000 ml). The combined organic phases were washed with water (1 L) and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine as brown colored residue (370 g; 98% HPLC purity (rt=2.64 min.), m/z=198 amu (M+H.sup.+) & 93% ee by chiral HPLC method 1).
Step-3: Preparation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine
(49) A 2 L three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine (165 g, 0.83 mol, with 93% ee), Methanol (400 ml), Methyl isothiocyanate (91.86 g, 1.25 mol) and triethylamine (225 ml, 1.67 mol) at ambient temperature. The resulting mixture was stirred for 14 h at 22-27° C. The HPLC analysis showed >99% conversion with formation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine. Then sodium hydroxide (67 g, 1.67 mol) and water (660 mL) were added into the reaction flask. The reaction mixture was heated to 65° C. and stirred for 2 h. The reaction mixture was extracted with Toluene (3×660 mL). The combined organic phases were dried over sodium sulfate and evaporated under vacuum to provide (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine as brown oil (198 g, 94 area % HPLC purity), m/z=234 amu (M+H+)).
Step-4: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
(50) A 20 L reactor, was charged with (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (2070 g, 98% HPLC purity), toluene (4140 mL) and heated to 80° C. under nitrogen atmosphere. Then bis(4-chlorophenyl) 2-phenylpropanedioate (3553 g, 8.8 mol) was dissolved in toluene (4140 ml) at 45° C. and added drop wise into the reaction mass kept at 80° C. After stirring at 100° C. for 1 h, HPLC showed >99% conversion. The reaction was cooled below 40° C. and the precipitated pale yellow colored solid was filtered & washed with Toluene (3×2070 ml) to provide (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate as 1st lot (1660 g, 99 area % HPLC purity & 100% enantiomeric excess) The combined mother liquor was transferred to 20 L reactor, acetone (6210 ml) was added and stirred at 22-27° C. for 1 h. The precipitated pale yellow colored solid was filtered and washed with toluene (2070 ml×3) to obtain (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate as 2.sup.nd lot (718 g, 99 area % HPLC purity & 100% enantiomeric excess by chiral HPLC method 3).
Example-4: Preparation of Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine
Step-1: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
a) Preparation of HCOOH-NEt.SUB.3 .Mixture
(51) prepared as described in step-4 of example 1.
b) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide
(52) A 1 L 3 neck round bottom flask, was charged with N-[2-chloro-1-(2-chlorothiazol-5-yl) ethylidene]-2-methyl-propane-2-sulfinamide (50 g, 85% HPLC purity), dimethylformamide (100 ml), toluene (100 ml) and degassed with nitrogen for 10 min. Then pentamethylcyclopentadienyl rhodium chloride dimer (150 mg) & (1R,2R)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine (170 mg) were added under nitrogen atmosphere at ambient temperature. The resulting mixture was cooled to 0 to 5° C. & freshly prepared HCOOH-NEt.sub.3 (15 mL, in a ratio of 1.1:1) was added & stirred for 2 h. The reaction was monitored by HPLC and quenched with water (100 mL) and extracted with Toluene (200 mL). The combined organic phase was washed with water (3×20 ml) and evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide brown colored residue (49 g, 88% purity by HPLC).
Step-2: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine
(53) A 5 L four necked flask equipped with magnetic stirrer, nitrogen inlet and thermo-pocket was charged with N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfinamide (49 g) was diluted in MTBE (147 ml) and HCl gas was purged for 15 min at 25° C. to 30° C. The reaction progress was monitored by HPLC. The precipitated yellow colored hydrochloride salt was filtered, and the residue was washed with MTBE (2×100 ml) to obtain pale yellow colored solid (35 g). The pale yellow colored solid containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine; hydrochloride was adjusted to pH 8.5 with 2 N aq. NaOH and extracted with Toluene (3×80 ml). The combined organic phases were washed with water (100 ml) and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethanamine as brown colored residue (30 g; m/z=198 amu (M+H.sup.+), 98.5% HPLC purity & 99% ee by chiral HPLC method 1).
Example-5: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-6-(3,5-dichlorophenyl)-8-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
(54) A process analogous to the process described in step-4 of example 3 was followed. The reaction was conducted using (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (1 g, 96% HPLC purity), toluene (3 mL) and bis(4-chlorophenyl) 2-(3,5-dichlorophenyl)propanedioate (2.8 g) to obtain (3R)-3-(2-chlorothiazol-5-yl)-6-(3,5-dichlorophenyl)-8-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate (1.1 g & 94% enantiomeric excess by chiral HPLC method 3 (rt=5.01 min), m/z=448 amu (M+H+)).
Example-6: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-6-(4-methoxyphenyl)-8-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
(55) A process analogous to the process described in step-4 of example 3 was followed. The reaction was conducted using (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (1 g, 96% HPLC purity), toluene (3 mL) and bis(4-chlorophenyl) 2-(4-methoxyphenyl)propanedioate (2.6 g) to obtain (3R)-3-(2-chlorothiazol-5-yl)-6-(4-methoxyphenyl)-8-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate (1.1 g & 95% enantiomeric excess by chiral HPLC method 3 (rt=3.85 min), m/z=408 amu (M+H+)).
Example-7: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-[3-(trifluoromethyl)phenyl]-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate
(56) A process analogous to the process described in step-4 of example 3 was followed. The reaction was conducted using (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (1 g, 96% HPLC purity), toluene (3 mL) and bis(4-chlorophenyl) 2-(3-(trifluoromethyl)phenyl)propanedioate (2.7 g) to obtain (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-[3-(trifluoromethyl)phenyl]-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate (1.05 g & 97% enantiomeric excess by chiral HPLC method 3 (rt=4.66 min), m/z=446 amu (M+H+)).