Preparation method of fluopyram intermediate

Abstract

The invention relates to a preparation method of a fluopyram intermediate, which is characterized in that carbamate is used as a raw material, the fluopyram intermediate is synthesized through a multi-step simple reaction, the reaction operation is simple, a dangerous hydrogenation process and an expensive catalyst do not need to be used, a product is separated out in a salt form, the operation is simple, and a reaction reagent can be recycled and reused; meanwhile, the yield of the product can reach 65% or above, the purity of the product is 98% or above, and the method has a good industrial prospect.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis of pesticides, and particularly relates to a method for preparing a fluopyram intermediate. Background Art

[0002] Fluopyram is the first nematicide that targets mitochondrial complex II. It represents a class of nematicides with a new mechanism of action, with advantages such as unique mechanism of action, broad control spectrum, diverse modes of action, high nematicidal activity, and low toxicity. 3-Chloro-5-(trifluoromethyl)-2-ethylaminopyridine is the core intermediate for the synthesis of fluopyram.

[0003] The main synthetic methods reported so far are as follows: Patent WO2004016088A3 discloses that 2,3-dichloro-5-trifluoromethylpyridine is used as a raw material, condensed with ethyl cyanoacetate, and hydrolyzed to obtain 2-cyanomethyl-3-chloro-5-trifluoromethylpyridine, which is then catalyzed by palladium carbon for hydrogenation reduction, while protecting the amine group, and then reacting under acidic conditions, and deprotecting to obtain 3-chloro-5-(trifluoromethyl)-2-ethylaminopyridine hydrochloride. This route has relatively long steps, the condensation and hydrolysis steps are not completely reacted, the by-product content is high, the cyanide hydrogenation reduction step requires the use of precious metal catalysts, the equipment investment is large, the cost is relatively high, and the overall yield is low. Furthermore, in order to protect the amine group, it is necessary to add and remove the protecting group, which makes the operation more cumbersome and not conducive to industrialization.

[0004]

[0005] In addition, the document Revue Roumaine de Chimie, 2010, 55(9): 559-564 adopts the following technical route to synthesize fluopyram intermediates. 2,3-dichloro-5-trifluoromethylpyridine is used as a raw material, and a primary amine intermediate is generated through nucleophilic substitution, hydrolysis decarboxylation, hydrazinolysis and other reactions. The chlorinated product in this route needs to be synthesized separately, which is costly, and there are many by-products in the hydrazinolysis process, and the target product is not easy to purify.

[0006]

[0007] In summary, the synthesis route of fluopyram intermediates in the prior art is long, the cost is high, and the yield is low, and a new method for preparing fluopyram intermediates is urgently needed. Summary of the invention

[0008] In order to solve the problems of long synthesis route, high cost and low yield of fluopyram intermediate in the prior art, the present invention provides a method for preparing fluopyram intermediate with high safety, green environmental protection, high yield and suitable for industrial production, comprising the following steps:

[0009]

[0010] (1) The acyloxymethylcarbamate intermediate (III) is condensed with 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (IV) in an alkaline environment to generate a malonate diester compound (II), wherein:

[0011] R 1 Selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 6 -C 10 Aryl, C 3 -C 6 Heterocyclic group,

[0012] and may be substituted or polysubstituted by one or more identical or different substituents selected from the group consisting of halogen, hydroxyl, nitro, amino, carboxyl, sulfonic acid, phosphoric acid, C 1 -C 6 Alkoxy, C 1 -C 6 Acyl, C 1 -C 6 Amide, C 1 -C 6 Acyloxy, C 1 -C 6 Amine, C 6 -C 10 aryloxy;

[0013] R 2 Selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 6 -C 10 Aryl, C 3 -C 6 Heterocyclic group,

[0014] and may be substituted or polysubstituted by one or more identical or different substituents selected from the group consisting of halogen, hydroxyl, nitro, amino, carboxyl, sulfonic acid, phosphoric acid, sulfate, phosphate, C 1 -C 6 Alkoxy, C 1 -C 6 Sulfanyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Acyl, C 1 -C 6 Amide, C 1 -C6 Acyloxy, C 1 -C 6 Amine, C 6 -C 10 aryloxy;

[0015] R 3 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Cycloalkyl, C 6 -C 10 Aryl;

[0016] (2) Malonic acid diester compound (II) is hydrolyzed in an acidic environment to form salt compound (I) of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine.

[0017] The molar ratio of the acyloxymethylcarbamate intermediate (III) to 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (IV) in step (1) is 1:1 to 3:1, preferably 1.1 to 1.3:1.

[0018] Wherein, the base used in the reaction in step (1) is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0019] Wherein, the acid used in the reaction in step (2) is selected from any one of sulfuric acid, phosphoric acid, acetic acid, hydrochloric acid and hydrobromic acid.

[0020] Wherein, the reaction solvent in step (1) is selected from any one of acetone, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide.

[0021] Wherein, the reaction solvent in step (2) is selected from any one of water and acetic acid.

[0022] Wherein, in step (1), the reaction temperature is 25-150° C., and the reaction time is 3-24 h; in step (2), the reaction temperature is 60-150° C., and the reaction time is 3-48 h.

[0023] Furthermore, the acyloxymethylcarbamate intermediate (III) can be obtained by reacting a carbamate compound (V), polyformaldehyde and anhydride, preferably by a one-pot synthesis.

[0024]

[0025] The molar ratio of the carbamate compound (V) to polyformaldehyde in the reaction is 1:1 to 1:3; the molar ratio of the carbamate compound (V) to the acid anhydride is 1:2 to 1:50; acetic acid is used as the reaction solvent; and the reaction temperature is 50 to 120°C.

[0026] The acid anhydride is selected from carboxylic anhydride, such as acetic anhydride, benzoic anhydride, etc., and can be substituted or polysubstituted by one or more identical or different substituents, and the substituents are selected from any one of halogen, alkyl, cycloalkyl, aryl, and heterocyclic groups.

[0027] In another aspect, the present invention provides a malonic acid diester compound, the compound structure of which is shown in general formula II:

[0028]

[0029] in,

[0030] R 1 Selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 6 -C 10 Aryl, C 3 -C 6 Heterocyclic group,

[0031] and may be substituted or polysubstituted by one or more identical or different substituents selected from the group consisting of halogen, hydroxyl, nitro, amino, carboxyl, sulfonic acid, phosphoric acid, C 1 -C 6 Alkoxy, C 1 -C 6 Acyl, C 1 -C 6 Amide, C 1 -C 6 Acyloxy, C 1 -C 6 Amine, C 6 -C 10 aryloxy;

[0032] R 3 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Cycloalkyl, C 6 -C 10 Aryl.

[0033] Furthermore, the present invention provides an application of a malonic acid diester compound, specifically an application of a malonic acid diester compound represented by general formula II in the preparation of a fluopyram intermediate;

[0034] The structure of the fluopyram intermediate is:

[0035]

[0036] Further, the salt compound (I) of 3-chloro-5-(trifluoromethyl)-2-ethylaminopyridine undergoes an acylation reaction with o-trifluoromethylbenzoyl chloride under alkaline conditions to generate fluopyram.

[0037]

[0038] The base used in the reaction is selected from any one of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, preferably triethylamine and pyridine; the reaction solvent is selected from any one of dichloromethane, chloroform and toluene, preferably dichloromethane; the reaction temperature is 0 to 60°C, preferably 0 to 30°C.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] 1. The present invention uses carbamate as a raw material and synthesizes a fluopyram intermediate through multiple simple reactions. No explosive, highly toxic or difficult-to-store reagents are used in each reaction step, thereby avoiding harm to the environment and operators. At the same time, the yield of the product can reach more than 65%, and the purity is more than 98%.

[0041] 2. The reaction operation of the present invention is simple, and the equipment required for separation and purification of the intermediates are all commonly used industrial equipment, which avoids cyanide reduction, does not require the use of dangerous hydrogenation processes and expensive catalysts, and the product is precipitated in the form of salt. The operation is simple, the reaction reagents can be recycled, and the three wastes of the reaction are small. It has good industrial prospects and provides a new idea suitable for the industrial large-scale production of fluopyram. DETAILED DESCRIPTION

[0042] Example 1

[0043] Step (1): Add 10.0 g (29.4 mmol, 1.0 eq) of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetonitrile (30 mL) and 12.2 g (88.3 mmol) of potassium carbonate into a 500 mL round-bottom flask, then dropwise add 7.2 g (38.1 mmol, 1.3 eq) of acetonitrile (20 mL) of methyl ((tert-butoxycarbonyl)amino)acetate (III), and then react the reaction solution at 65-110° C. for 5 h until the reaction is completed; after post-treatment, 11.9 g of a white solid product (II-1) (yield 87%) is obtained, and the next step is carried out.

[0044] Step (2): 2.5 g (5.3 mmol) of diethyl 2-(((tert-butoxycarbonyl)amino)methyl)-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (II-1) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added. The reaction solution was heated to 110° C. and refluxed, and the reaction was kept warm for 6 to 24 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 1, and ethyl acetate was added for extraction (3 x 150 mL), and dried to obtain 1.0 g of white solid 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride (yield 75%), which can be directly used to prepare fluopyram.

[0045] Example 2

[0046] Step (1): Add 10 g (29.4 mmol, 1.0 eq) of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetonitrile (30 mL) and 12.2 g (88.3 mmol) of potassium carbonate into a 500 mL round-bottom flask, then dropwise add 7.9 g (35.4 mmol, 1.2 eq) of acetonitrile (20 mL) of methyl (((benzyloxy)carbonyl)amino)acetate (III), then heat the reaction solution to 65-110° C. and keep warm for 5 h until the reaction is completed; after post-treatment, 12.4 g of a transparent colloidal product (II-2) (yield 84%) is obtained, and the next step is carried out.

[0047] Step (2): 2.5 g (5 mmol) of diethyl 2-((((benzyloxy)carbonyl)amino)methyl)-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (II-2) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added, and then the reaction solution was heated to 110° C. and refluxed, and the reaction was kept warm for 24 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 1, and ethyl acetate was added for extraction (3×150 mL), dried, and the solvent was removed to recover the solvent, and 0.93 g of white solid 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride was obtained (yield 72%).

[0048] Example 3

[0049] Step (1): Add 10 g (29.4 mmol, 1.0 eq) of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetonitrile (30 mL) and 12.2 g (88.3 mmol) of potassium carbonate into a 500 mL round-bottom flask, then dropwise add 5.7 g (35.4 mmol, 1.2 eq) of acetonitrile (20 mL) of methyl ((ethoxycarbonyl)amino)acetate (III), then heat the reaction solution to 50-60° C. and keep warm for 10 h until the reaction is completed; after post-treatment, 10.9 g of white solid product (II-3) (yield 84%) is obtained, and the next step is carried out.

[0050] Step (2): 2.5 g (5.6 mmol) of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-(((ethoxycarbonyl)amino)methyl)malonate (II-3) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added, and then the reaction solution was heated to 110° C. and refluxed, and the reaction was kept warm for 24 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 1, and ethyl acetate was added for extraction (3×150 mL), dried, and the solvent was removed to recover the solvent to obtain 1.1 g of white solid 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride (yield 73%).

[0051] Example 4

[0052] Step (1): 10 g (29.4 mmol, 1.0 eq) of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetone (30 mL) and 12.2 g (88.3 mmol) of potassium carbonate were added to a 500 mL round-bottom flask, and then 7.1 g (35.4 mmol, 1.2 eq) of methyl (((cyclopentyloxy)carbonyl)amino)acetate (III) in acetone (20 mL) was added dropwise, and the reaction solution was heated to 60-80° C. and refluxed for 18 h until the reaction was completed; after post-treatment, 12.5 g of a white solid product (II-4) (yield 88%) was obtained, and the next step reaction was carried out.

[0053] Step (2): 2.5 g (5.2 mmol) of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((((cyclopentyloxy)carbonyl)amino)methyl)malonate (II-4) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added. The reaction solution was then heated to 110° C. and refluxed for 24 h. After the reaction was completed, the pH of the reaction solution was adjusted to 1, and ethyl acetate was added for extraction (3×150 mL), dried, and the solvent was removed to recover the solvent to obtain 0.95 g of white solid 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride (yield 70%).

[0054] Example 5

[0055] Step (1): Add 10 g (32.1 mmol, 1.0 eq) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetonitrile (30 mL) and 13.3 g (96.3 mmol) of potassium carbonate into a 500 mL round-bottom flask, then dropwise add 10.4 g (38.5 mmol) of methyl ((phenoxycarbonyl)amino)benzoate (III) in acetonitrile (20 mL), then heat the reaction solution to 65-110° C. and keep warm for 5 h until the reaction is completed; after post-treatment, 12.8 g of white solid product (II-5) (yield 87%) is obtained, and the next step is carried out.

[0056] Step (2): 2.5 g (5.4 mmol) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-(((phenoxycarbonyl)amino)methyl)malonate (II-5) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added, and then the reaction solution was heated to 110° C. and refluxed, and the reaction was kept warm for 24 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 1, and ethyl acetate was added for extraction (3×150 mL), dried, and the solvent was removed to recover the solvent, and 1.01 g of white solid 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride was obtained (yield 71%).

[0057] Example 6

[0058] Step (1): Add 10 g (32.1 mmol, 1.0 eq) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetonitrile (30 mL) and 13.3 g (96.3 mmol) of potassium carbonate into a 500 mL round-bottom flask, then dropwise add 10.5 g (38.5 mmol, 1.2 eq) of (((pyridin-3-yloxy)carbonyl)amino)methyl benzoate (III) in acetonitrile (20 mL), then heat the reaction solution to 65-110° C. and keep warm for 5 h until the reaction is completed; after post-treatment, 12.7 g of white solid product (II-6) (yield 86%) is obtained, and the next step is carried out.

[0059] Step (2): 2.5 g (5.4 mmol) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((((pyridin-3-yloxy)carbonyl)amino)methyl)malonate (II-6) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added. The reaction solution was then heated to 110° C. and refluxed, and the reaction was kept warm for 24 h. After the reaction was completed, the pH of the reaction solution was adjusted to 1, and ethyl acetate was added for extraction (3×150 mL), dried, and the solvent was removed to recover the solvent to obtain 1.02 g of white solid 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride (yield 72%).

[0060] Example 7

[0061] Step (1): Add 10 g (32.1 mmol, 1.0 eq) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetonitrile (30 mL) and 13.3 g (96.3 mmol) of potassium carbonate into a 500 mL round-bottom flask, then dropwise add 10.4 g (38.5 mmol) of methyl (((phenoxycarbonyl)amino)benzoate (III) in acetonitrile (20 mL), then heat the reaction solution to 65-110° C. and keep warm for 5 h until the reaction is completed; after post-treatment, 12.8 g of white solid product (II-5) (yield 87%) is obtained, and the next step is carried out.

[0062] Step (2): 2.5 g (5.6 mmol) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-(((phenoxycarbonyl)amino)methyl)malonate (II-5) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added, and then the reaction solution was heated to 130° C. and refluxed, and the reaction was kept warm for 24 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 1, and ethyl acetate was added for extraction (3×150 mL), dried, and the solvent was removed to recover the solvent, and 1.01 g of white solid 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride was obtained (yield 71%).

[0063] Example 8

[0064] Step (1): Add 10 g (32.1 mmol, 1.0 eq) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate in acetonitrile (30 mL) and 13.3 g (96.3 mmol) of potassium carbonate into a 500 mL round-bottom flask, then dropwise add 10.5 g (38.5 mmol, 1.2 eq) of (((pyridin-3-yloxy)carbonyl)amino)methyl benzoate (III) in acetonitrile (20 mL), then heat the reaction solution to 65-110° C. and keep warm for 5 h until the reaction is completed; after post-treatment, 12.7 g of white solid product (II-6) (yield 86%) is obtained, and the next step is carried out.

[0065] Step (2): 2.5 g (5.4 mmol) of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((((pyridin-3-yloxy)carbonyl)amino)methyl)malonate (II-6) was added to a 250 mL round-bottom flask, and 50 mL of concentrated hydrochloric acid solution was added. The reaction solution was then heated to 110° C. and refluxed for 24 h. After the reaction was completed, the pH of the reaction solution was adjusted to 2-4, and ethyl acetate was added for extraction (3×150 mL), dried, and the solvent was removed to recover the solvent to obtain 1.06 g of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine hydrochloride as a white solid (yield 74%).

[0066] Example 9 Preparation of Intermediate III-1:

[0067] 5.0 g (42.7 mmol, 1.0 eq) of tert-butyl carbamate (V-1) and 1.4 g (46.9 mmol, 1.1 eq) of paraformaldehyde were suspended in a mixture of 30 mL of acetic acid and 115 mL (1216 mmol) of acetic anhydride. The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 6.95 g of a colorless transparent liquid (yield 86%).

[0068] Example 10 Preparation of intermediate III-2:

[0069] Benzyl carbamate (V-2) 5.0 g (33.1 mmol, 1.0 eq) and paraformaldehyde 1.1 g (36.6 mmol, 1.1 eq) were suspended in a mixture of 30 mL of acetic acid and 89 mL of acetic anhydride (944 mmol). The reaction was stirred at 60 ° C for 48 h. After the reaction was completed, the solvent was removed under vacuum at 70 ° C, and the crude product was recrystallized to obtain 7.24 g of colorless transparent liquid (yield 98%).

[0070] Example 11 Preparation of intermediate III-3:

[0071] 5.0 g (42.7 mmol, 1.0 eq) of tert-butyl carbamate (V-1) and 1.4 g (46.9 mmol, 1.1 eq) of paraformaldehyde were suspended in a mixture of 30 mL of acetic acid and 115 mL (1216 mmol) of acetic anhydride. The reaction was stirred at 80°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 6.7 g of a colorless transparent liquid (yield 83%).

[0072] Example 12 Preparation of intermediate III-4:

[0073] 5.0 g (42.7 mmol, 1.0 eq) of tert-butyl carbamate (V-1) and 1.4 g (46.9 mmol, 1.1 eq) of paraformaldehyde were suspended in a mixture of 30 mL of acetic acid and 115 mL (1216 mmol) of acetic anhydride. The reaction was stirred at 120°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 6.5 g of a colorless transparent liquid (yield 80%).

[0074] Example 13 Preparation of Intermediate III-5:

[0075] 5.0 g (42.7 mmol, 1.0 eq) of tert-butyl carbamate (V-1) and 1.4 g (46.9 mmol, 1.1 eq) of paraformaldehyde were suspended in a mixture of 30 mL of acetic acid and 107 mL (1139 mmol) of acetic anhydride. The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 6.6 g of a colorless transparent liquid (yield 82%).

[0076] Example 14 Preparation of Intermediate III-6:

[0077] 5.0 g (42.7 mmol, 1.0 eq) of tert-butyl carbamate (V-1) and 1.4 g (46.9 mmol, 1.1 eq) of paraformaldehyde were suspended in a mixture of 30 mL of acetic acid and 97 mL (1032 mmol) of acetic anhydride. The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 6.5 g of a colorless transparent liquid (yield 80%).

[0078] Example 15 Preparation of intermediate III-7:

[0079] 5.0 g (56.1 mmol, 1.0 eq) of ethyl carbamate (V-3) and 1.85 g (46.9 mmol, 1.1 eq) of paraformaldehyde were suspended in a mixture of 30 mL of acetic acid and 150 mL (1599 mmol) of acetic anhydride. The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 7.6 g of a colorless transparent liquid (yield 84%).

[0080] Example 16 Preparation of Intermediate III-8:

[0081] Cyclopentyl carbamate (V-4) 5.0 g (38.7 mmol, 1.0 eq) and paraformaldehyde 1.28 g (42.6 mmol, 1.1 eq) were suspended in a mixture of 30 mL of acetic acid and 104 mL (1104 mmol) of acetic anhydride. The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 160°C to obtain 6.5 g of a colorless transparent liquid (yield 83%).

[0082] Example 17 Preparation of Intermediate III-9:

[0083] Phenyl carbamate (V-5) 5.0 g (36 mmol, 1.0 eq) and paraformaldehyde 1.2 g (40 mmol, 1.1 eq) were suspended in a mixture of 30 mL of acetic acid and 98 mL of acetic anhydride (1039 mmol). The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 8.2 g of a colorless transparent liquid (yield 83%).

[0084] Example 18 Preparation of intermediate III-10:

[0085] Pyridin-3-ylcarbamate (V-6) 5.0 g (36.2 mmol, 1.0 eq) and paraformaldehyde 1.2 g (39.8 mmol, 1.1 eq) were suspended in a mixture of 30 mL of acetic acid and 97 mL of acetic anhydride (1032 mmol). The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 6.1 g of a colorless transparent liquid (yield 80%).

[0086] Example 19 Preparation of intermediate III-11:

[0087] 5.0 g (36 mmol, 1.0 eq) of phenyl carbamate (V-5) and 1.2 g (40 mmol, 1.1 eq) of paraformaldehyde were suspended in a mixture of 30 mL of acetic acid and 216 mL (1039 mmol) of benzoic anhydride. The reaction was stirred at 60°C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70°C, and the crude product was purified by reduced pressure distillation at 150°C to obtain 8.0 g of a colorless transparent liquid (yield 81%).

[0088] Example 20 Preparation of intermediate III-12:

[0089] Pyridin-3-ylcarbamate (V-6) 5.0 g (36.2 mmol, 1.0 eq) and paraformaldehyde 1.2 g (39.8 mmol, 1.1 eq) were suspended in a mixture of acetic acid 30 mL and benzoic anhydride 195 mL (1032 mmol). The reaction was stirred at 60 ° C for 10 to 48 h. After the reaction was completed, the solvent was removed under vacuum at 70 ° C, and the crude product was purified by reduced pressure distillation at 150 ° C to obtain 8.2 g of colorless transparent liquid (yield 83%).

[0090] As shown in Examples 1-8, the present invention can prepare a fluopyram intermediate by using acyloxymethylcarbamate intermediates of various structures as raw materials and reacting them with 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate. The product yield of the reaction is high and the operation is simple.

[0091] Further, the inventors have found through research that when preparing compound II, the choice of organic solvent in the reaction has a great influence on the reaction. Further, see Examples 1-3, by adjusting the reaction temperature, the reaction will be affected. When the solvent is acetonitrile, the reaction temperature is high and the reaction rate is fast. See Example 4. When the solvent is acetone, the reaction temperature needs to be lowered, and the time required for the reaction to complete is more than 10 hours. Further, as the amount of feed increases, when the reaction temperature increases, preferably at 110°C, the reaction yield is the highest.

[0092] When preparing compound I, the reaction temperature, hydrochloric acid concentration, and pH value of the system during post-treatment all have a great influence on the reaction, see Examples 7 and 8. The product yield increases with the increase of temperature, and when it increases to 120°C, the reaction is more intense; the product yield increases with the increase of hydrochloric acid concentration, that is, the product yield increases with the decrease of the pH of the reaction solution, and the product yield is the highest when the pH is about 1.

[0093] When preparing compound III, the amount of acetic anhydride added and the reaction temperature in the reaction have a great influence on the reaction. See Examples 9, 13, and 14. The product yield increases with the increase in the amount of acetic anhydride added. When the amount added is about 30 times the molar equivalent, the product yield is the highest; see Examples 9 and 11. When the reaction temperature is 60 to 80°C, the product yield is high. However, as the temperature increases, see Example 12, the by-products generated by the reaction increase, resulting in a decrease in the product yield.

[0094] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a fluopyram intermediate, characterized in that: The following steps are involved: (1) The acyloxymethylcarbamate intermediate (III) is condensed with 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (IV) in an alkaline environment to generate a malonate diester compound (II), wherein: R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C6 heterocyclic group, and may be substituted or polysubstituted by one or more identical or different substituents, wherein the substituents are selected from the group consisting of halogen, hydroxyl, nitro, amino, carboxyl, sulfonic acid, phosphate, C1-C6 alkoxy, C1-C6 acyl, C1-C6 amide, C1-C6 acyloxy, C1-C6 amine, C6-C 10 aryloxy; R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C6 heterocyclic group, and may be substituted or polysubstituted by one or more identical or different substituents, wherein the substituents are selected from the group consisting of halogen, hydroxyl, nitro, amino, carboxyl, sulfonic acid, phosphate, sulfate, phosphate, C1-C6 alkoxy, C1-C6 sulfanyl, C1-C6 haloalkyl, C1-C6 acyl, C1-C6 amide, C1-C6 acyloxy, C1-C6 amine, C6-C 10 aryloxy; R 3 Selected from C1-C6 alkyl, C1-C6 cycloalkyl, C6-C 10 Aryl; (2) The diethyl malonate compound (II) is hydrolyzed in an acidic environment to form the salt compound (I) of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethane-1-amine.

2. The method for preparing a fluopyram intermediate according to claim 1, wherein: In the step (1), the molar ratio of the carbamate intermediate (III) to 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (IV) is 1:1 to 3:

1.

3. The method for preparing a fluopyram intermediate according to claim 1, wherein: The base used in the reaction in step (1) is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; the acid used in the reaction in step (2) is selected from any one of sulfuric acid, phosphoric acid, acetic acid, hydrochloric acid, and hydrobromic acid.

4. The method for preparing a fluopyram intermediate according to claim 1, wherein: In the step (1), the reaction solvent is selected from any one of acetone, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; and in the step (2), the reaction solvent is selected from any one of water and acetic acid.

5. The method for preparing a fluopyram intermediate according to claim 1, wherein: The reaction temperature in step (1) is 25 to 150° C.; the reaction temperature in step (2) is 60 to 150° C.

6. The method for preparing a fluopyram intermediate according to claim 1, wherein: The acyloxymethylcarbamate intermediate (III) is obtained by reacting a carbamate compound (V), polyformaldehyde and anhydride.

7. The method for preparing a fluopyram intermediate according to claim 6, wherein: In the reaction, the molar ratio of the carbamate compound (V) to polyformaldehyde is 1:1-1:3; the molar ratio of the carbamate compound (V) to the acid anhydride is 1:2-1:50; acetic acid is used as the reaction solvent; and the reaction temperature is 50-120°C.

8. A malonic acid diester compound, characterized in that: The compound structure is shown in general formula II: in, R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C6 heterocyclic group, and may be substituted or polysubstituted by one or more identical or different substituents, wherein the substituents are selected from the group consisting of halogen, hydroxyl, nitro, amino, carboxyl, sulfonic acid, phosphate, C1-C6 alkoxy, C1-C6 acyl, C1-C6 amide, C1-C6 acyloxy, C1-C6 amine, C6-C 10 aryloxy; R 3 Selected from C1-C6 alkyl, C1-C6 cycloalkyl, C6-C 10 Aryl.

9. An application of the malonic acid diester compound according to claim 8, characterized in that: Application of the malonate diester compound represented by the general formula II in the preparation of fluopyram intermediates; The structure of the fluopyram intermediate is:

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