Synthesis method of 4-piperidine sulfamide

Abstract

The invention provides a synthetic method of 4-piperidine sulfamide. The synthesis method of 4-piperidine sulfamide comprises the following step: in a solvent, in the presence of an iron source, a sulfur source and alkali, 4-piperidine sulfamide 2 is subjected to a reaction to obtain 4-piperidine sulfamide 1. The method has the advantages of easily available and stable raw materials, simple preparation method, easily realized reaction conditions, low cost, safety, environmental protection, high atom economy, few side reactions and high target product yield.

Description

TECHNICAL FIELD

[0001] The present application relates to a synthesis method of 4-piperidine thioamide, and belongs to the technical field of drug synthesis. BACKGROUND

[0002] Oxathiapiprolin is a new fungicide developed by DuPont, which is the first piperidyl thiazole isoxazoline fungicide. As an inhibitor of oxidized sterol binding protein (OSBP), it can cause the death of pathogenic fungi by hindering the synthesis of intracellular lipids, sterol transport and signal transduction, and show excellent control effect on oomycete diseases such as late blight, downy mildew, root rot, stem rot and blight. Oxathiapiprolin has excellent fungicidal activity against oomycete diseases on specialty crops such as potatoes, grapes and vegetables, and stable efficacy, which can show good control effect at very low dosage, not only reducing the cost of agricultural production, but also reducing pesticide residues and improving the quality and safety of agricultural products. Oxathiapiprolin is lowly toxic to mammals, non-irritating to skin and eyes, and non-carcinogenic, non-mutagenic and non-neurotoxic. The synthesis process of piperidine sulfamide, a key intermediate, is an important link in the synthesis of oxathiapiprolin. Through the research on the synthesis process of piperidine sulfamide, a more efficient and economical synthesis route can be explored, which can not only reduce the consumption of raw materials and energy consumption in the production process, but also reduce the production cost and improve the production efficiency. Optimizing the synthesis process conditions can improve the yield and purity of piperidine sulfamide, and high-purity intermediates are an important guarantee for the synthesis of high-quality oxathiapiprolin, which is of great significance to improve the market competitiveness of the final product. Efficient synthesis process of piperidine sulfamide is the key to the industrial production of oxathiapiprolin; through process optimization, the supply of piperidine sulfamide can be stable and reliable in industrial production, so as to meet the demand of large-scale production of oxathiapiprolin. Cost is one of the important factors that restrict the market competitiveness of products. By optimizing the synthesis process of piperidine sulfamide, the production cost can be reduced, so that oxathiapiprolin has a price advantage in the market, thereby expanding its market share. The synthesis of oxathiapiprolin usually involves multiple complex reaction steps, and piperidine sulfamide as a key intermediate, its synthesis process has important influence on the yield and quality of the whole product. At present, foreign countries are relatively mature in the synthesis of oxathiapiprolin and its key intermediates. DuPont (now Corteva) as the original research unit of the fungicide has mastered the synthesis process (US2010240619, WO02010123791, WO02011146182) and realized industrial production. At present, foreign research mainly focuses on optimizing the synthesis route, improving the yield and purity, reducing the cost and other aspects. In addition, foreign research also involves the study of the mechanism of action, biological activity, environmental behavior and other aspects of oxathiapiprolin, which provides a scientific basis for its wide application in agricultural production. At present, there are relatively few studies on the synthesis of oxathiapiprolin and its key intermediate piperidine sulfamide in China, and there is no mature industrial production report. Although there are some explorations of laboratory synthesis routes, these routes are not suitable for industrial production due to the unavailability of raw materials, long reaction route and harsh reaction conditions.Therefore, there is still a great research space and development potential in the synthesis of flutianil and its key intermediates in China. In the synthesis routes of flutianil reported in the literature, many routes involve the synthesis of piperidine thioamide or its analogues.

[0003] The original route of DuPont (US2010240619) takes 2-substituted thiazole aldehyde as the starting material, and the target product is obtained through four steps of oximation, oxazole ring closure, deprotection, and finally condensation with 3-trifluoromethyl-5-methyl-1-pyrazole acetic acid amide. The thioamide intermediate involved is obtained by Boc protection of 4-amido piperidine and thioamidation. The use of Lawesson's reagent involves high cost, poor atom economy, and the phosphorus-containing waste liquid of the by-product causes great environmental problems, greatly increasing the cost of post-treatment. This route cannot meet the needs of industrial production.

[0004] DuPont developed a route from thiazole ring cleavage based on the original route (WO2010123791), and supplemented the synthesis of thioamide intermediates after thiazole ring cleavage in the patent WO2011146182. The patent route takes 4-cyanopiperidine as the starting material, and the target intermediate is obtained through several steps of acetyl protection, alpha-methyl halogenation, and addition of hydrogen sulfide and cyano. The process route is relatively complex, and requires the use of hydrogen sulfide gas, which has high requirements for the production site.

[0005] Alternatively, 4-piperidine nitrile is used as the starting material, and acylamide reaction with chloroacetyl chloride gives compound 1-(2-chloroacetyl)-4-piperidine nitrile. Subsequently, substitution reaction with 3-methyl-5-trifluoromethylpyrazole gives 1-{2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-piperidine nitrile, and finally, under the action of diethylamine, hydrogen sulfide is reacted by thio reaction to prepare intermediate A: 1-{2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-piperidine thioamide. The process route is complex, and also requires the use of hydrogen sulfide gas, which has high requirements for the production site, and the atom utilization rate is low, and the cost is high.

[0006] In summary, the preparation of the sulfamide skeleton is involved in multiple routes in the industrial production of flutianil, and the selection and optimization of the synthetic route are crucial. The existing synthesis methods of sulfamide face challenges such as high cost, poor atom economy, high equipment production requirement, and large environmental impact, which are difficult to meet the demand of large-scale industrial production. Therefore, developing a new process for synthesizing sulfamide with low cost, high atom economy, easy implementation, high efficiency and environmental friendliness is of great significance to improve the production efficiency of flutianil, reduce the production cost and alleviate the environmental burden, which not only relates to the industrialization process of flutianil, but also is an important practice to promote green chemistry and sustainable development. SUMMARY

[0007] In view of the deficiencies of the prior art, the present application provides a synthesis method of 4-piperidine sulfamide. The raw materials of the method are easy to obtain and stable, the preparation method is simple and the reaction conditions are easy to realize, the cost is low, it is safe and environmentally friendly, the atom economy is high, the side reactions are few and the yield of the target product is high.

[0008] The technical scheme of the present application is as follows: A synthesis method of 4-piperidine sulfamide, comprising the steps of: In a solvent, 4-piperidine amide 2 is reacted in the presence of an iron source, a sulfur source and a base to obtain 4-piperidine sulfamide 1. .

[0009] According to the present application, the solvent is one or a combination of two or more of toluene, acetonitrile or chlorobenzene, preferably toluene; the molar ratio of 4-piperidine amide 2 to the volume of the solvent is 0.1-1 mmol / mL.

[0010] According to the present application, the iron source is one or both of FeCl2, FeCl3 or Fe powder, preferably FeCl2; the molar ratio of the iron source to 4-piperidine amide 2 is 0.01-0.5:1; preferably 0.03-0.15:1, further preferably 0.1:1.

[0011] According to the present application, the sulfur source is elemental sulfur (S8); the molar ratio of the sulfur source to 4-piperidine amide 2 is 0.5-1:1; preferably 0.5-0.8:1, further preferably 0.5:1.

[0012] According to the present application, the base is one or both of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium tert-butoxide or potassium tert-butoxide, preferably potassium carbonate; the molar ratio of the base to 4-piperidine amide 2 is 1-2:1; preferably 1-1.3:1, further preferably 1.1:1.

[0013] According to the present application, the reaction temperature is preferably 25-80℃, more preferably 55-65℃, and further more preferably 60℃.

[0014] According to the present application, the reaction time is preferably 1-5h, and more preferably 1h.

[0015] According to the present application, the reaction atmosphere is preferably one or a mixture of two or more of air, oxygen, nitrogen or argon.

[0016] According to the present application, the post-treatment method of the reaction solution obtained by reacting 4-piperidinecarboxamide 2 is as follows: the reaction solution is subjected to reduced pressure to remove the solvent, the residue is dissolved in ethyl acetate, and washed with saturated K2CO3 aqueous solution; the organic layer is dried with anhydrous Na2SO4, filtered and concentrated to dryness to obtain 4-piperidinethiocarboxamide 1.

[0017] The synthetic route of the present application is as follows: The technical features and beneficial effects of the present application are as follows: 1. In the present application, elemental sulfur undergoes disproportionation reaction (self-oxidation and reduction) under the action of alkali to generate a series of intermediate products such as polysulfides (S n 2- ) and thiosulfate (S2O3 2- ). The intermediate products are further oxidized in the solution to ultimately generate stable sulfate (SO4 2- ). Under the catalysis of iron source, S n 2- attacks the carbonyl group of 4-piperidinecarboxamide 2 to realize the transfer of sulfur, thereby synthesizing 4-piperidinethiocarboxamide, which provides a new idea for the synthesis of 4-piperidinethiocarboxamide 1. The present application has high atom economy, less waste, and a more green and environmentally friendly route compared with the traditional synthetic route.

[0018] 2. The raw materials of the method of the present application are easy to obtain and stable, the preparation method is simple and easy to operate, the reaction conditions are easy to realize, safe and environmentally friendly, 4-piperidinethiocarboxamide is constructed in one step, the cost is low, the side reactions are few, the yield of the target product is high, and the yield can reach 95%, which provides a new idea for the synthesis of the key intermediate of fluazinam.

[0019] 3. The iron source, sulfur source, alkali and their amounts, the type of reaction solvent and reaction temperature and other conditions have a great influence on the reaction of the present application. The amounts of different iron salts and sulfur sources and the solvent have a great influence on the selectivity of the reaction and the yield. As a whole, the preparation method of the present application, each step and each condition jointly act to realize the excellent effect of the present application. DETAILED DESCRIPTION

[0020] The present application will be further described below in conjunction with specific examples. However, it is not limited thereto.

[0021] The experimental methods described in the following examples are conventional methods unless otherwise specified. The reagents and materials described are commercially available unless otherwise specified.

[0022] In the examples, 4-piperidinecarboxamide 2 was prepared from 4-piperidinecarboxamide 3. 4-piperidinecarboxamide 3 was stirred with di-tert-butyl dicarbonate in triethylamine, DCM at room temperature until the reaction was complete. After removing the solvent, it was recrystallized to obtain. Reference: “ Bioorg. Med. Chem. Lett. 2020, 30 , 126855”.

[0023] Example 1 A method for synthesizing 4-piperidinecarboxamide, comprising the steps of: Into a 25 mL reaction tube was added 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.15 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, and dispersed thoroughly. The reaction was stirred at 60°C in air for 1 h. The obtained reaction solution was removed under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated K2CO3 aqueous solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-piperidinecarboxamide 1 (yield 95%) was obtained as a white solid.

[0024] Characterization data of piperidinecarboxamide 1: 4-piperidinecarboxamide 1, white solid.

[0025] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.39 (br. s., 1H), 9.09 (br. s., 1H), 4.00 (d, J = 12.6 Hz, 2H), 2.77-2.61 (m, 3H), 1.71-1.51 (m, 4H), 1.39 (br. s., 9H). C 11 H 20 HRMS for N2O2S [M+H] + : 245.1324; Found: 245.1329. Example 2 A method for synthesizing 4-piperidinecarboxamide, comprising the steps of: A 25 mL reaction tube was charged with 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.3 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, and the mixture was stirred at 60 °C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous K2CO3solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 was obtained as a white solid (yield 90%).

[0026] Example 3 A method of synthesizing 4-piperidinethiocarboxamide, comprising the steps of: A 25 mL reaction tube was charged with 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.3 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, and the mixture was stirred at 60 °C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous K2CO3solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 was obtained as a white solid (yield 90%).

[0027] Example 4 A method of synthesizing 4-piperidinethiocarboxamide, comprising the steps of: A 25 mL reaction tube was charged with 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.3 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, and the mixture was stirred at 60 °C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous K2CO3solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 was obtained as a white solid (yield 90%).

[0028] Example 5 A method of synthesizing 4-piperidinethiocarboxamide, comprising the steps of: A 25 mL reaction tube was charged with 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.15 mmol), K2CO3(0.33 mmol), chlorobenzene (2 mL), and stirred at 60 °C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous K2CO3solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 was obtained as a white solid (yield 79%).

[0029] Example 6 A method of synthesizing 4-piperidinethiocarboxamide, comprising the steps of: A 25 mL reaction tube was charged with 4-piperidinecarboxamide 2 (0.3 mmol), Fe (0.03 mmol), elemental sulfur (S8) (0.15 mmol), K2CO3(0.33 mmol), toluene (2 mL), and stirred at 60 °C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous K2CO3solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 was obtained as a white solid (yield 80%).

[0030] Example 7 A method of synthesizing 4-piperidinethiocarboxamide, comprising the steps of: A 25 mL reaction tube was charged with 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.15 mmol), potassium hydroxide (0.33 mmol), toluene (2 mL), and stirred at 60 °C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous K2CO3solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 was obtained as a white solid (yield 86%).

[0031] Example 8 A method of synthesizing 4-piperidinethiocarboxamide, comprising the steps of: Into a 25 mL reaction tube was added 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.15 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, dispersed well, and stirred at room temperature 25 °C for 1 h in air. The resulting reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate and washed with saturated K2CO3aqueous solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 (yield 12%) was obtained as a white solid.

[0032] Example 9 A method for synthesizing 4-piperidinethiocarboxamide, comprising the steps of: Into a 25 mL reaction tube was added 4-piperidinecarboxamide 2 (0.3 mmol), FeCl3(0.03 mmol), elemental sulfur (S8) (0.15 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, dispersed well, and stirred at 60 °C for 1 h in air. The resulting reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate and washed with saturated K2CO3aqueous solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 (yield 84%) was obtained as a white solid.

[0033] Example 10 A method for synthesizing 4-piperidinethiocarboxamide, comprising the steps of: Into a 25 mL reaction tube was added 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.15 mmol), potassium tert-butoxide (0.33 mmol), toluene (2 mL) was added, dispersed well, and stirred at 60 °C for 1 h in air. The resulting reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate and washed with saturated K2CO3aqueous solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 (yield 66%) was obtained as a white solid.

[0034] Example 11 A method for synthesizing 4-piperidinethiocarboxamide, comprising the steps of: Into a 25 mL reaction tube was added 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.15 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, dispersed well, and stirred at 80°C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated K2CO3aqueous solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 (yield 73%) was obtained as a white solid.

[0035] Example 12 A method for synthesizing 4-piperidinethiocarboxamide, comprising the steps of: Into a 25 mL reaction tube was added 4-piperidinecarboxamide 2 (0.3 mmol), FeCl2(0.03 mmol), elemental sulfur (S8) (0.15 mmol), K2CO3(0.33 mmol), toluene (2 mL) was added, dispersed well, and stirred at 40°C for 1 h under air. The resulting reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated K2CO3aqueous solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. 4-Piperidinethiocarboxamide 1 (yield 25%) was obtained as a white solid.

[0036] Comparative Example 1 A method for synthesizing 4-piperidinethiocarboxamide, as described in Example 1, except that K2CO3was not added, and the other steps and conditions were the same as in Example 1.

[0037] The yield of 4-piperidinethiocarboxamide 1 was 0%, and 4-piperidinethiocarboxamide 1 was not obtained.

[0038] Comparative Example 2 A method for synthesizing 4-piperidinethiocarboxamide, as described in Example 1, except that FeCl2was not added, and the other steps and conditions were the same as in Example 1.

[0039] The yield of 4-piperidinethiocarboxamide 1 was 0%, and 4-piperidinethiocarboxamide 1 was not obtained.

Claims

1. A method for synthesizing 4-piperidinethioamide, comprising the steps of: In a solvent, in the presence of an iron source, a sulfur source, and a base, 4-piperidineamide 2 reacts to give 4-piperidinethioamide 1; 。 2. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The solvent is one or a combination of two or more of toluene, acetonitrile, or chlorobenzene, preferably toluene; the molar amount of 4-piperidineamide 2 and the volume ratio of the solvent are 0.1-1 mmol / mL.

3. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The iron source is one or two of FeCl2, FeCl3, or Fe powder, preferably FeCl2; the molar ratio of the iron source to 4-piperidineamide 2 is 0.01-0.5:1; preferably 0.03-0.15:1, and more preferably 0.1:

1.

4. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The sulfur source is elemental sulfur (S8); the molar ratio of the sulfur source to 4-piperidine amide 2 is 0.5-1:1; preferably 0.5-0.8:1, and more preferably 0.5:

1.

5. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The alkali is one or two of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, or potassium tert-butoxide, preferably potassium carbonate; the molar ratio of the alkali to 4-piperidineamide 2 is 1-2:1; preferably 1-1.3:1, and more preferably 1.1:

1.

6. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The reaction temperature is 25-80℃, preferably 55-65℃, and more preferably 60℃.

7. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The reaction time is 1-5 hours, preferably 1 hour.

8. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The reaction atmosphere is one or a mixture of two or more of the following: air, oxygen, nitrogen, or argon.

9. The method for synthesizing 4-piperidinethioamide according to claim 1, characterized in that, The post-treatment method of the reaction solution obtained from the reaction of 4-piperidine amide 2 is as follows: the solvent is removed from the reaction solution under reduced pressure, the residue is dissolved in ethyl acetate and washed with saturated K2CO3 aqueous solution; the organic layer is taken, dried with anhydrous Na2SO4, filtered and concentrated to dryness to obtain 4-piperidine thioamide 1.

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