Method of synthesizing prothioconazole and optically active isomers thereof and intermediates

Abstract

Disclosed are a method of synthesizing prothioconazole and optically active isomers thereof and intermediates. The method includes reacting hydrazine with glyoxylic acid to produce a hydrazono acetic acid as an intermediate, and then reacting the intermediate with thiocyanate to produce the target product prothioconazole. The present method is very specific in terms of regioselectivity, resulting in minimum byproducts and a high product yield. The present method does not require special equipment, nor anhydrous or oxygen-free manipulations. The process is simple and generates minimum wastes, suitable for industrial production.

Claims

1. A method of synthesizing prothioconazole or optically active isomers thereof, comprising: step 1: reacting compound 22 or compound 22 with compound 23 or compound 23 to produce compound 24 or compound 24, as shown in the following reaction scheme: ##STR00017## wherein: R is selected from ##STR00018## R.sup.1 and R.sup.2 are independently hydrogen or a C.sub.1-C.sub.6 alkyl group; or R.sup.1, R.sup.2 taking together to form a ring selected from dimethylene, trimethylene, tetramethylene, or pentamethylene group; n is 0.5, 1 or 2; HX is selected from a haloid acid, a sulfuric acid or a phosphoric acid; M is selected from hydrogen, an alkali metal or a NR.sup.3R.sup.4R.sup.5R.sup.6 group where R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, a C.sub.1-C.sub.18 alkyl group or a C.sub.6-C.sub.18 aryl group; and m is 0 or 1; and step 2: reacting compound 24 or compound 24 with thiocyanate (MSCN) to produce the prothioconazole compound 1 or optically active isomers thereof, as shown in the following reaction scheme: ##STR00019## wherein: R is selected from ##STR00020## M is selected from hydrogen, an alkali metal or a NR.sup.3R.sup.4R.sup.5R.sup.6 group where R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, a C.sub.1-C.sub.18 alkyl group or a C.sub.6-C.sub.18 aryl group; M is selected from an alkali metal or a NR.sup.3R.sup.4R.sup.5R.sup.6 group where R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, a C.sub.1-C.sub.18 alkyl group or C.sub.6-C.sub.18 aryl group; m is 0 or 1; and HX is selected from a haloid acid, a sulfuric acid or a phosphoric acid.

2. The method of claim 1, wherein step 1 is carried out in the presence or absence of a solvent; a molar ratio of compound 22 or compound 22 to compound 23 or compound 23 is 1:1-10; and a reaction temperature in step 1 is 0-40 C.

3. The method of claim 2, wherein the solvent is selected from water, acetonitrile, tert-butanol, dichloromethane, DMF, DMSO and methylbenzene or mixture thereof.

4. The method of claim 1, wherein steps 1 and 2 are carried out in a stepwise or a one-spot manner.

5. A method of synthesizing prothioconazole or optically active isomers thereof, comprising: reacting compound 24 or compound 24 with thiocyanate (MSCN) to produce the prothioconazole compound 1 or optically active isomers thereof, as shown in the following reaction scheme: ##STR00021## wherein: R is selected from ##STR00022## M is selected from hydrogen, an alkali metal or a NR.sup.3R.sup.4R.sup.5R.sup.6 group where R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, a C.sub.1-C.sub.18 alkyl group or a C.sub.6-C.sub.18 aryl group; M is selected from an alkali metal or a NR.sup.3R.sup.4R.sup.5R.sup.6 group where R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, a C.sub.1-C.sub.18 alkyl group or a C.sub.6-C.sub.18 aryl group; m is 0 or 1; and HX is selected from a haloid acid, a sulfuric acid or a phosphoric acid.

6. The method of claim 1, wherein compound 24 or compound 24 is reacted with MSCN in the presence of an acid; a molar ratio of compound 24 or compound 24 to MSCN is 1:1-5; and a reaction temperature is 50-80 C.

7. The method of claim 5, wherein compound 24 or compound 24 is reacted with MSCN in the presence of an acid; a molar ratio of compound 24 or compound 24 to MSCN is 1:1-5; and a reaction temperature is 50-80 C.

8. The method of claim 6, wherein the acid is an organic acid; and a molar ratio of the acid to compound 24 or compound 24 is 0.01-100:1.

9. The method of claim 7, wherein the acid is an organic acid; and a molar ratio of the acid to compound 24 or compound 24 is 0.01-100:1.

10. The method of claim 8, wherein the organic acid is selected from a formic acid, an acetic acid, a trifluoroacetic acid, a methanesulfonic acid and a p-toluenesulfonic acid or mixture thereof.

11. The method of claim 9, wherein the organic acid is selected from a formic acid, an acetic acid, a trifluoroacetic acid, a methanesulfonic acid and a p-toluenesulfonic acid or mixture thereof.

12. A compound 24 shown as the following formula: ##STR00023## wherein: R is selected from ##STR00024## and M is selected from hydrogen, an alkali metal or a NR.sup.3R.sup.4R.sup.5R.sup.6 group where R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, a C.sub.1-C.sub.18 alkyl group or a C.sub.6-C.sub.18 aryl group.

13. A compound 24 shown as the following formula: ##STR00025## wherein: R is selected from ##STR00026## m is 0 or 1; and HX is selected from a haloid acid, a sulfuric acid or a phosphoric acid.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) The following embodiments are intended to illustrate the features of the present invention. The scope of the application is not limited to these embodiments.

Example 1: synthesis of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid

(2) To a 250 mL reaction flask were added 15.5 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol hydrochloride, 120 mL of water and 15 mL of acetonitrile. Then 7.5 g of 50% glyoxylic acid solution was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was filtered, washed with water and dried to give 16.4 g of product as a solid (99% yield).

(3) .sup.1H NMR (, CDCl.sub.3): 7.456-7.437 (m, 1H), 7.405-7.386 (m, 1H), 7.271-7.252 (m, 1H), 7.245-7.223 (m, 1H), 6.971-6.899 (t, 1H), 6.781 (s, 1H), 3.906-3.898, 3.878-3.869 (dd, 1H), 3.547-3.519 (d, 1H), 3.519-3.508, 3.491-3.480 (dd, 1H), 3.211-3.183 (d, 1H), 2.506 (s, 2H), 1.175-1.134 (m, 1H), 0.964-0.852 (m, 3H); MS: m/z=330.9 ([M+1].sup.+).

Example 2: synthesis of (2R)-2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid

(4) To a 250 mL reaction flask were added 13.7 g of (2R)-2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol, 100 mL of water and 20 mL of acetonitrile. Then 7.5 g of 50% glyoxylic acid solution was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was filtered, washed with water and dried to give 15.2 g of product as a solid (92% yield).

Example 3: synthesis of (2S)-2-{2-[2-(1-chlorocyclpropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid

(5) To a 250 mL reaction flask were added 13.7 g of (2S)-2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol, 100 mL of water and 20 mL of acetonitrile. Then 7.5 g of 50% glyoxylic acid solution was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was filtered, washed with water and dried to give 15.0 g of product as a solid (91% yield).

Example 4: synthesis of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid

(6) To a 250 mL reaction flask was added 15.5 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol hydrochloride. 7.5 g of 50% glyoxylic acid solution was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was filtered, washed with water and dried to give 16.0 g of product as a solid (97% yield).

Example 5: synthesis of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid

(7) To a 250 mL reaction flask were added 15.5 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol hydrochloride and 100 mL of water. 10 g of 50% glyoxylic acid solution was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was filtered, washed with water and dried to give 15.7 g of product as a solid (95% yield).

Example 6: synthesis of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid

(8) To a 250 mL reaction flask were added 13.7 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol and 150 mL of dichloromethane. 9.6 g of 50% glyoxylic acid solution was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the solvent was removed to give 15.4 g of product as a solid (93% yield).

Example 7: synthesis of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid

(9) To a 250 mL reaction flask were added 13.7 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol and 100 mL of water. 4.7 g of glyoxylic acid monohydrate was added in portions. The reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was filtered, washed with water and dried to give 14.5 g of product as a solid (88% yield).

Example 8: synthesis of sodium 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetate

(10) To a 250 mL reaction flask were added 13.7 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol and 150 mL of dichloromethane. 12.5 g of 50% sodium glyoxylate solution was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the solvent was removed. 14.9 g of a solid product was obtained by lyophilization (90% yield).

Example 9: synthesis of sodium 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetate

(11) To a 250 mL reaction flask were added 16.5 g of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid and 150 mL of ethanol. 4 g of 50% sodium hydroxide aqueous solution was added dropwise. The reaction was stirred at room temperature. After the reaction was complete, the solvent was removed. 17.4 g of a solid product was obtained by lyophilization (99% yield).

Example 10: synthesis of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid hemisulfate

(12) To a 25 mL reaction flask were added 1.37 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol and 15 mL of acetonitrile. 0.96 g of 50% glyoxylic acid solution and 0.25 g of concentrated sulfuric acid were added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the solvent was removed. 1.89 g of a solid product was obtained by lyophilization (99% yield).

Example 11: synthesis of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid hemisulphate

(13) To a 250 mL reaction flask were added 3.3 g of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid and 10 mL of acetonitrile. 0.5 g of concentrated sulfuric acid was added dropwise. The reaction mixture was stirred at room temperature. After the reaction was complete, the solvent was removed. 3.8 g of a solid product was obtained by lyophilization (99% yield).

Example 12: synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazo-3-thione

(14) To a 250 mL reaction flask were added 16.5 g of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid, 6.1 g of sodium thiocyanate and 80 mL of acetic acid. The reaction was heated to 80 C. After the reaction was complete, the reaction mixture was concentrated. 16.3 g of a solid product was obtained by adding with toluene, washing with water and distillation (95% yield).

(15) .sup.1H NMR (, CDCl.sub.3): 12.300 (s, 1H), 7.856 (s, 1H), 7.549-7.544, 7.534-7.530 (dd, 1H), 7.377-7.374, 7.362-7.358 (dd, 1H), 7.242-7.183 (m, 2H), 4.802-4.773 (d, 1H), 4.510-4.481 (d, 1H), 4.212 (s, 1H), 3.621-3.594 (d, 1H), 3.193-3.166 (d, 1H), 0.943-0.922 (m, 1H), 0.885-0.767 (m, 3H); MS: m/z=343.9 ([M+1].sup.+).

Example 13: synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazo-3-thione

(16) To a 25 mL reaction flask were added 1.89 g of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid hemisulphate, 0.62 g of sodium thiocyanate and 10 mL of acetic acid. The reaction was heated to 50 C. After the reaction was complete, the reaction mixture was concentrated. 1.43 g of a solid product was obtained by adding with toluene, washing with water and distillation (83% yield).

Example 14: synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazo-3-thione

(17) To a 250 mL reaction flask were added 17.6 g of sodium 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetate, 6.1 g of sodium thiocyanate and 25 mL of acetic acid. The reaction was heated to 80 C. After the reaction was complete, the reaction mixture was concentrated. 14.6 g of a solid product was obtained by adding with toluene, washing with water and distillation (85% yield).

Example 15: synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazo-3-thione

(18) To a 250 mL reaction flask were added 16.5 g of 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid, 3.8 g of ammonium thiocyanate and 25 mL of formic acid. The reaction was heated to 50 C. After the reaction was complete, the reaction mixture was concentrated. 13.8 g of a solid product was obtained by adding with toluene, washing with water and distillation (80% yield).

Example 16: synthesis of (R)-2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazo-3-thione

(19) To a 250 mL reaction flask were added 16.5 g of (2R)-2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid, 24.3 g of potassium thiocyanate and 25 mL of trifluoroacetic acid. The reaction was heated to 80 C. After the reaction was complete, the reaction mixture was concentrated. 15.5 g of a solid product was obtained by adding with toluene, washing with water and distillation (90% yield).

Example 17: synthesis of (S)-2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazo-3-thione

(20) To a 250 mL reaction flask were added 16.5 g of (2S)-2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid, 24.3 g of potassium thiocyanate and 25 mL of trifluoroacetic acid. The reaction was heated to 80 C. After the reaction was complete, the reaction mixture was concentrated. 15.2 g of a solid product was obtained by adding with toluene, washing with water and distillation (88% yield).

Example 18: synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazo-3-thione

(21) To a 100 mL reaction flask were added 0.93 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol hydrochloride, 15 mL of acetonitrile, 0.55 g of a 50% glyoxylic acid solution and 0.24 g of sodium thiocyanate. The reaction was heated to 60 C. After the reaction was complete, 10 mL of water was added, the pH of the reaction mixture was adjusted to 2. The phases were separated, the aqueous phase was extracted using toluene, the organic phases were combined and concentrated to give 0.92 g of product as a solid (89% yield).