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

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 and the description.

Claims

1. A process for preparing S-containing pyrimidinium compound of formula X ##STR00070## 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 R.sup.2a; Het is selected from D-1, D-2, and D-3: ##STR00071## wherein R.sup.a is each independently R.sup.a is halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1C.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 is 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; and 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 at least the step of, (E) reacting the compound of formula VII, ##STR00072## wherein C* is an asymmetric carbon atom of S or R-configuration; Het is as defined in compound of formula X; 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 unsubstituted or substituted by halogen or C.sub.1-C.sub.4-alkyl; in the presence of a base, to obtain a compound of formula VIII, ##STR00073## wherein C* and Het are as defined in the compound of formula VII; R.sup.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, ##STR00074## 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.sup.2OR.sup.AC wherein M.sup.2 is selected from lithium, sodium, potassium, aluminium, barium, caesium, calcium, and magnesium; R.sup.AC is C(═O)—C.sub.1-C.sub.4-alkyl; to obtain the compound of formula IV, ##STR00075## wherein Het and R.sup.Ac 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, ##STR00076## wherein Het is as defined in compound of formula IV; (C) reacting the compound of formula V with X.sup.2SO.sub.2NH.sub.2 wherein X.sup.2 is halogen, to obtain the compound of formula VI ##STR00077## 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).sub.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.sub.1-C.sub.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, ##STR00078## wherein C* is an asymmetric carbon atom of S or R-configuration; R.sup.10 is OH or NH—SO.sub.2—R.sup.1; 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.1 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 represent a C.sub.6-C.sub.10-cycloalkyl; R.sup.12 independently represents aryl ring or C.sub.6-C.sub.10-cycloalkyl ring, wherein the ring is 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 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 VII, ##STR00079## 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, ##STR00080## wherein, LG is a leaving group selected from 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; 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 R.sup.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.sub.1-C.sub.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).sub.m in step (D) is MXLn1(η-arene).sub.m 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 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 according to claim 2, wherein MXLn(η-arene).sub.m in step (D) is MXLn1(η-arene).sub.m 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-toluenesulfonyl, 4-benzenesulfonyl, or pentafluorophenyl-sulfonyl.

8. The process according to claim 2, wherein m is 1 and MXLn(η-arene).sub.m in step (D) is of the formula MXLnCp*, wherein M is rhodium, ruthenium, iridium, palladium, iron, platinum, or nickel, ##STR00081##

9. The process according to claim 2, wherein M in step (D) is rhodium, ruthenium, or iridium.

10. The process according to claim 1, wherein the base in step (E) is selected from triethylamine, diisopropylethyl amine, tri-nbutylamine, sodium hydroxide, and potassium hydroxide.

11. The process according to 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 according to claim 1, wherein R.sup.2 is phenyl, pyridinyl, or thiophenyl, which is unsubstituted or substituted by R.sup.2a.

13. The process according to claim 1, wherein R.sup.a is halogen or C.sub.1-C.sub.4-haloalkyl.

14. The process according to claim 1, wherein Het is D-2 wherein n is 0 and R.sup.a is halogen.

15. An optically active compound of formula VII ##STR00082## wherein C* is an asymmetric carbon atom of S or R-configuration; and Het is selected from D-2 or D-3: ##STR00083## wherein R.sup.a is each independently R.sup.a is halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1C.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.

16. A process for preparing a compound of formula VIII ##STR00084## 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; and Het is selected from D-1, D-2, and D-3: ##STR00085## wherein R.sup.a is each independently R.sup.a is halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1C.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; comprising at least the step of, (E) reacting the compound of formula VII, ##STR00086## wherein C* is an asymmetric carbon atom of S or R-configuration; Het is as defined in compound of formula VIII; 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 unsubstituted or substituted by halogen or C.sub.1-C.sub.4-alkyl; in the presence of a base, to obtain the compound of formula VIII.

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: 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=10% B Isocratic; run time: 20 min

(16) Chiral HPLC method 3: ChiralPak IA column, 150 mm×4.6 mm×5μ

(17) Mobile phase A=heptane, B=isopropanol,

(18) Flow=1.0 ml/min, column oven temperature=40° C.

(19) Gradient program=40% B Isocratic; run time: 20 min

(20) .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.

(21) Abbreviations used are: h for hour(s), min for minute(s), rt for retention time and ambient temperature for 20-25° C.

(22) The present invention is now illustrated in further details by the following examples, without imposing any limitation thereto.

(23) With appropriate modification of the starting materials, the procedures as described in the examples below can be used to obtain further compounds of formula V, 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

(24) 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 litre) and the resulting reaction mixture was cooled to 0 to −5° C. Then potassium carbonate (1466 g) was added in lots to the above reaction mixture followed by the addition of methyl tert-butyl ether (1.4 litre). The chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 litre) and added dropwise 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 sulfate, 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

(25) A 5 L, four necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with 2-chlorothiazole (250 g), TH F (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-iodothiazole 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 THE (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 warmed 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 sulfate, 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 [2-(2-chlorothiazol-5-yl)-2-oxo-ethyl] acetate

(26) A 0.25 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 (15 g, 46 area % HPLC purity) and dimethylformamide (45 mL) at ambient temperature. Then sodium acetate (12.55 g) was added in portions and reaction was continued at ambient temperature for 4 h. The reaction progress was monitored by HPLC (>95% conversion by HPLC). The reaction was quenched with water (50 mL) and extracted with methyl tert-butyl ether (3×100 mL). The two phases were separated and the combined organic phases were dried over sodium sulfate, filtered and evaporated to obtain crude residue (17 g). The crude product was purified by silica gel column chromatography to obtain [2-(2-chlorothiazol-5-yl)-2-oxo-ethyl] acetate as yellow colored solid (7.5 g).

Step-4: Preparation of 1-(2-chlorothiazol-5-yl)-2-hydroxy-ethanone

(27) A 250 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with [2-(2-chlorothiazol-5-yl)-2-oxo-ethyl] acetate (7.5 g) and 1 N HCl in MeOH (50 mL). The resulting solution was stirred for 5 h and reaction progress was monitored by TLC. The methanol from reaction mixture was distilled under vacuum and crude residue obtained was purified by column chromatography to obtain 1-(2-chlorothiazol-5-yl)-2-hydroxy-ethanone as pale yellow solid (2.8 g, 84% area purity by HPLC).

Step-5: Preparation of 4-(2-chlorothiazol-5-yl)-5H-oxathiazole 2,2-dioxide

(28) A 100 mL, three neck flasks equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with 1-(2-chlorothiazol-5-yl)-2-hydroxy-ethanone (1 g), toluene (20 mL), chlorosulfonamide (0.975 g) and p-toluenesulfonic acid (0.214 g). The resulting solution was heated to 100° C. and stirred for 1 h. The reaction progress was monitored by HPLC (>95% conversion). The reaction mixture was quenched with water and extracted with MTBE (15 mL×2). The two phases were separated, organic phase was evaporated and purified by column chromatography 4-(2-chlorothiazol-5-yl)-5H-oxathiazole 2,2-dioxide (0.42 g).

Step-6: Preparation of (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide

(29) a) Preparation of Rhodium Catalyst—RhCl[(R,R)-TsDPEN]Cp*:

(30) 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 triethylamine (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 sulfate, 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).

(31) b) Preparation of HCOOH-NEt.sub.3 Mixture:

(32) In a 2 liter, 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.

(33) c) Preparation of (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide:

(34) A 100 ml, two necked flask equipped with magnetic stirrer, condenser and thermo-pocket was charged with 4-(2-chlorothiazol-5-yl)-5H-oxathiazole 2,2-dioxide (0.5 g) and dimethylformamide (15 mL, 30V) was degassed with nitrogen for 10 min. Then RhCl[(R,R)-TsDPEN]Cp* (27 mg) was added followed by dropwise addition of HCOOH-NEt.sub.3 (2.5 mL, in a ratio of 5:2). The resulting mixture was stirred for 2 h. The HPLC showed >97% conversion. The reaction mixture was quenched with water (15 ml) and extracted with methyl tert-butyl ether (3×50 mL). The combined organic phase was evaporated to obtain (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide (500 mg; 90 area % HPLC purity (rt=3.645 min.), >99% ee by chiral HPLC method 1).

Step-7: Preparation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine

(35) A 100 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide (0.5 g, with 99% ee), ethanol (2 ml), methyl isothiocyanate (0.228 g) and triethylamine (0.56 ml) at ambient temperature. The resulting mixture was stirred for 14 h at 22-27° C. Then organic volatiles were removed under vacuum and sodium hydroxide (0.2 g) and water (2 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 (2 mL) and extracted with methyl tert-butyl ether (2×50 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 [0.34 g, m/z=234 amu (M+H.sup.+)].

Step-8: 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 50 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (E,4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (0.34 g), toluene (2 mL) and heated to 110° C. under nitrogen atmosphere. Then bis(2,4,6-trichlorophenyl) 2-phenylpropanedioate (0.857 g) was added in lots into the reaction mass kept at 110° C. After stirring at 110° C. for 2 h, H PLC showed >99% conversion. The reaction was cooled below 50° C. and the precipitated pale yellow colored solid was filtered through sintered funnel and then solid residue was washed with methyl tert-butyl ether (4 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 (110 mg, m/z=378 amu (M+H+) & 95.2% enantiomeric excess by chiral HPLC method 3). .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 (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide

(37) a) Preparation of HCOOH-NEt.sub.3 mixture: prepared as described in step-4 of example 1.

(38) b) Preparation of Preparation of (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide:

(39) A 1 L 3 neck round bottom flask, was charged with 4-(2-chlorothiazol-5-yl)-5H-oxathiazole 2,2-dioxide (50 g), dimethylformamide (100 ml), toluene (100 ml) and degassed with nitrogen for 10 min. Then pentamethylcyclopentadienyl rhodium chloride dimer (120 mg) & (1R,2R)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine (136 mg) were added under nitrogen atmosphere at ambient temperature. The resulting mixture was cooled to 0 to 5° C. & freshly prepared HCOOHNEt.sub.3 (12 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 (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide (49 g, 98% ee by chiral HPLC method 1).

Step-2: Preparation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine

(40) A 1 L, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (4R)-4-(2-chlorothiazol-5-yl)oxathiazolidine 2,2-dioxide (49 g, with 98% ee), ethanol (196 ml), methyl isothiocyanate (22.5 g) and triethylamine (56 ml) at ambient temperature. The resulting mixture was stirred for 14 h at 22-27° C. Then organic volatiles were removed under vacuum and sodium hydroxide (0.2 g) and water (2 mL) were added into the reaction flask. The reaction mixture was heated to 70° C. and stirred for 2 h. The reaction was diluted with water (2 mL) and extracted with toluene (2×500 mL). The organic phases were dried over sodium sulfate and evaporated under vacuum to provide (4R)-4-(2-chlorothiazol-5-yl)-N-methylthiazolidin-2-imine as brown oil [44.7 g, m/z=234 amu (M+H+)].

Step-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

(41) A 500 mL, three necked flask equipped with magnetic stirrer, reflux condenser and thermo-pocket was charged with (E,4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidin-2-imine (35 g), toluene (70 mL) and heated to 80° C. under nitrogen atmosphere. Then bis(4-chlorophenyl) 2-phenylpropanedioate (60 g) was dissolved in toluene (70 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 50° C. and the precipitated pale yellow coloured solid was filtered, washed with toluene (3×70 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 as 1 st lot (29 g, m/z=378 amu (M+H+) & 99% enantiomeric excess by chiral HPLC method 3); The combined mother liquor was transferred to reactor, acetone (105 ml) was added and stirred at 22-27° C. for 1 h. The precipitated pale yellow colored solid was filtered and washed with toluene (70 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 (13 g, 99 area % HPLC purity & 98.7% enantiomeric excess by chiral HPLC method 3).