MXPA97003603A - A method for preparing crotonatos 3-amino substitui - Google Patents

Abstract

The present invention relates to methods for preparing 3-amino-4,4,4-trihalocrotonates and their derivatives from a 4,4,4-trihaloacetoacetate derivative and an amine or ammonium salt.

Description

A METHOD FOR PREPARING CROTONAT.OS 3-AMINO SUBSTITUTE The present invention relates to a method for preparing 3-amino-4, 4, 4-trihalocrotonates and their derivatives from a 4, 4, 4-trihaloacetoacetate or its analogs. 3-substituted crotonates are valuable intermediates in the synthesis of agrochemicals, pharmaceuticals and other industrial chemicals. The 4, 4, 4-trihalocrotonates 3-amino substituted are particularly useful in the preparation of heterocyclic compounds substituted with trihalomethyl. The description of the Japanese patent no. 06-321877 discloses a method for preparing 3-substituted amino-4,4,4-trifluorocrotonates, in which a mixture of an alkyl 4,4,4-trifluoroacetoacetate and a primary amine in a solvent is dehydrated in the presence of a fatty acid. The method requires two steps: (1) the formation of an intermediate amine salt of trifluoroacetoacetate, and (2) the dehydration of the salt. Using this method, the total yield is at an index of 60 to 65%. The present invention is a high performance method, which avoids the need to form an intermediate amine salt of a trihaloacetoacetate to prepare a 3-amino-4, 4, 4-trihalocrotonate. Specifically, this invention provides a method for the preparation of a 3-amino-4, 4-trihalocrotonate compound of the formula I: wherein X is fluorine or chlorine; A is O, S or NR3 B is R6, OR6, SR6 or NR3R4; R, R1, R2, R3, R4, R5 and R6 are each, separately, H, (C? -C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, phenyl or phenalkyl (C? -C6); or (C? -C6) alkyl (C2-C6) alkenyl, (C2-C6) alkynyl, phenyl or (C? -C6) substituted phenyl (C? -C6) with one or more groups independently selected from the halo, CN, N02, alkyl (C) C6), alkenyl (C2-C6), alkynyl (C2-C6), phenyl, phenalkyl (C6-6), alkoxy (C6-6), alkenyloxy (C2-C6) and phenoxy; or R1 and R2, and R3 and R4 can each, separately, be taken together with the nitrogen, to which they are attached, to form a five, six or seven membered heterocyclic ring; or, when A is NR5 and B is OR6 or SR6, R5 and R6 can be taken together with the group A = C-B, to which they are attached, to form a five, six or seven membered heterocyclic ring; or, when A is NR5 and B is NR3R4, R3 or R4 and R5 can be taken together with the group A = C-B, to which they are attached, to form a five, six or seven membered heterocyclic ring; comprising the following steps: (i) forming a mixture comprising a 4,, 4-trihaloacetoacetate derivative of the formula II p where X, R, A and B are the same as defined for the formula and an amine or ammonium salt of a weak acid of the formula RXR2NH2 + Y ~ wherein R1 and R2 are the same as defined for formula I, and Y "is the weak acid anion, and ii) heat the mixture .

The terms "alkyl" and "alkenyl" include straight chain, branched chain and alkenyl groups and cyclic alkyl groups. The term "alkynyl" includes straight chain and branched chain alkynyl groups. The term "alkoxy" includes, as the alkyl portion, straight chain, branched chain and cyclic alkyl groups. The term "alkenyloxy" includes, as the alkenyl portion, straight chain, branched chain and cyclic alkenyl groups. The term "halo" means F, Cl, Br and I. Due to their commercial utility, the preferred 3-amino-4, 4, 4-trihalocrotonate derivatives are those wherein X is F; A is O or S; B is OR6 or SR6, wherein R6 is alkyl (C? -C6); R1 and R2 are each, separately, H or alkyl (C? ~ C6); and R is H or alkyl (C? -C6). Further preferred are the derivatives wherein A is O, B is OR6, R6 is methyl or ethyl, R1 and R2 are each, separately, H or methyl, and R is H. The preferred amine or ammonium salts are the salts of organic acids, such as formic, acetic, propionic and butyric acid. Even more amine or ammonium salts of acetic acid are preferred due to their availability. The method is conducted with or without present solvent. The choice of solvent is not critical if it is used. Nevertheless, must be inert to the reactants and to the reaction conditions. Preferred solvents include aromatic and non-aromatic hydrocarbons such as cyclohexane, benzene, toluene and xylanes, ethers and polyethers such as diethyl ether and diglyme, esters such as ethyl acetate, and alcohols such as ethyl and propyl alcohol. Solvents such as alcohols, cyclohexane and benzene are preferred because they have favorable boiling points and are easy to remove when the reaction is complete. When a hydrocarbon solvent such as cyclohexane or benzene is used, the reaction can be carried out by re-flowing the reaction mixture with the azeotropic removal of the water, although the removal of the same is not required. When a polar solvent such as an alcohol is used, the reaction mixture simply re-flows during the reaction period. In either case, no acid catalyst is needed. Ethanol is a preferred solvent since it is soluble in water. and it has a convenient boiling point. The temperature chosen to heat the mixture depends on the desired conversion rate. Temperatures of about 20 ° C to 180 ° C are preferred because the reaction proceeds at a reasonable rate without unwanted side reactions. Temperatures of 60 ° C to 120 ° C are preferred even more since the reaction proceeds at a reasonable rate. If a solvent is used, it is convenient to choose one that has a boiling point close to the desired reaction temperature. In those cases the reaction can be conducted in reflux solvent. Depending on the solvent and the amine or ammonium salt of the chosen weak acid and the chosen reaction temperature, the reaction is typically completed from 1 to 24 hours.

The 3-amino-4,4,4-trihalocrotonate can be separated from the reaction mixture using common separation techniques such as by distillation, solvent / solvent extraction and solvent / water extraction. The preferred method is to remove the 3-amino-4,4,4-trihalocrotonate from the reaction mixture by means of a solvent / water extraction, since the crotonate is usually insoluble in water, and the products of Remaining unwanted reaction and the components of the mixture are soluble in water. When conducting the reaction either by not using solvent or by using a water-soluble solvent, it is convenient to empty the mixture directly into the water when the reaction is complete, and then extract the product with a non-miscible solvent in water. The amount of amine or ammonium salt used in the weak acid is not at all critical. However, when less than one equivalent is used, based on the amount of the 4, 4, 4-trihaloacetoacetate derivative, the reaction will not be completed. A slight excess of the amine or ammonium salt is preferred, ie from about 1.1 to about 4.0 equivalents. Even more than 1.1 to 2.0 equivalents of salt are preferred. Whether or not a solvent is employed in the process, the amine or ammonium salt of the weak acid can be formed either prior to its reaction with the 4,4,4-trihaloacetoacetate derivative, using methods known to those skilled in the art. , or in situ from the ammonia or the amine of the formula RaR2NH in the presence of a weak acid. The amount of the weak acid is approximately 0.01 equivalents to the desired equivalents relative to the ammonia or amine employed, to effect the reaction at a convenient rate. The following examples are provided only as exemplification, but are not intended to limit the scope of the invention as defined by the claims.

Example 1: Preparation of ethyl 3-amino-4,4,4-trifluorocrotonate in ethanol. 30.8 gr. (0.4mol) of ammonium acetate to a stirred solution of 18.4 gr. (0.1 mol) of ethyl 4,4,4-trifluoroacetoacetate in ethanol, and the mixture was returned to flow for 10 hours. After cooling to room temperature, the solution was poured into water and extracted with CH2C12. The organic extract was washed with aqueous NaHCO 3 solution, followed by water and then dried (MgSO 4). The solvent was removed by evaporation to give a liquid residue which was distilled to provide the product as a colorless liquid; bp (atmospheric) 145-160 ° C (65-67 ° C / 20 torr); 16.1 gr. (88%); IR (clean) 3380, 3560, 1690, 1660 cm- x. XH NMR (200MHz, CDC13) d 1.3 (t, 3H); 4.18 (q, 2H); 5.15 (S, 1H); 6.2 (br 2 H); 19 F NMR (90 MHz, Acetone-d 6 / Freon) 70.9 ppm.

Example 2: Preparation of ethyl 3-amino-4,4,4-trifluorocrotonate in cyclohexane. 18.4 gr. (0.1 mol) of a mixture of ethyl 4,4,4-trifluoroacetoacetate, 15.4 gr. (0.2 mol) of ammonium acetate in 160 ml. of dry cliclohexane, with the azeotropic removal of water, using a Dean-Stark trap. After six hours, the reaction mixture was cooled to room temperature and washed with water. The aqueous wash was extracted with methylene chloride. The methylene chloride extract was combined with the cyclohexane solution and then the mixture was dried (MgSO) and concentrated to a liquid residue by means of rotary evaporation. The liquid residue was distilled under reduced pressure to give the product as a colorless liquid; bp 65-67 ° C / 20 torr; 15.1 gr. (83%); IR (pure) 3380, 3560, 1690, 1660 cm "1. XH NMR (200 MHz, CDC13) d 1.3 (t, 3H); 4.18 (q, 2H); 5.15 (s, 1H); 6.2 (br 2 H); 19 F NMR (90 MHz, Acetone-d 6 / Freon) 70.9 ppm.

Example 3_ Preparation of ethyl 3- (N-methylamino) -4,4,4-trifluorocrotonate in ethanol. 200 ml were added. from 95% ethanol to 25.6 gr. (0.14 mol) of ethyl 4,4,4-trifluoroacetoacetate followed by 38 gr. (0.42 mol) of methylammonium acetate. The mixture was refluxed for 1.5 hours. When the reaction was completed based on gas chromatography (GC), the solvent was removed in vacuo. The residue was divided by 100 ml. of 2% aqueous sodium hydroxide and 100 ml. of dichloromethane. The layers were separated and the aqueous layer was extracted once more with 100 ml. of dichloromethane. The dichloromethane layers were combined, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give 20 g. (101 mmol, 73%) of product in the form of a pale yellow oil. The distillate (20 mm., 100 ° C) gave 17.5 gr. (88.8 mmol, 63%) of clear liquid. XH NMR (400 MHz, CDC13) d 1.2 (t, 3H), 3.0 (d, 3H), 4.1 (q, 2H), 5.1 (s, 1H), 8.2 (br.S, 1H).

Example 4: Preparation and isolation of methylammonium acetate. Methylammonium acetate was formed in two ways. The first included introducing methylamine gas into a 50 ml solution. of acetic acid in 150 ml. of diethyl ether at 0 ° C. When the precipitation of the product was completed, the solvent was removed in vacuo and the residue was used without further purification. In an alternative method, a commercial solution of 2M methylamine in tetrahydrofuran was used. 6 gr. (100 mmol) of acetic acid at 50 ml. (100 mmol) of said solution, at 0 ° C. After stirring for an additional hour, the solvent was removed in vacuo and the solid methylammonium acetate was used without further purification.

Example 5 Preparation of ethyl 3-amino-2-methyl-4,4,4-trifluorocrotonate in ethanol. 10.2 gr. (51 mmol) of ethyl 2-methyl-4,4-trifluoroacetoacetate, 11.9 g. (150 mmoles) of ammonium acetate, 20 gr. of ethanol and 1 gr. of water in a 10 ml round bottom flask. The mixture was heated for 6 hours at 70 ° C. Then, the mixture was cooled to room temperature and emptied into 50 ml. of water. The aqueous mixture was extracted with approximately 40 ml. of ethyl acetate and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated to give an 88% yield of 3-amino-2-methyl-4,4,4-trifluorocrotonate.

Example 6_ Preparation of ethyl 3- (N-methylamino) -4,4,4-tri-luorocrotonate. Boiling 31.06 gr. (1.0 mol) of methylamine gas in a stirred solution of 57.6 gr. (0.96 mol) of acetic acid in 250 ml. of anhydrous ether, while maintaining the reaction temperature at 0 ° C. After adding the amine, the mixture was stirred for four hours to complete the precipitation of the salt. The mixture was concentrated to complete the drying, and then 87.8 g. (0.48 mol) of ethyl trifluoroacetoacetate were mixed with the salt residue and heated with vigorous stirring at 85 ° C for five hours. After this period, the GC analysis of the reaction mixture showed that the production of ethyl 3- (N-methylamino) -4,4,4-trifluorocrotonate was greater than 90%.

Example 7: Preparation of ethyl 3-amino-,, -tri luorocrotonate. 74.0 gr were added in portions. (0.96 mol) of ammonium acetate at 87.8 gr. (0.48 mol) of ethyl trifluoroacetoacetate stirred at 85 ° C, for one hour, in such a way that an efficient agitation of the mixture was maintained. The mixture was heated at 85 ° C for four additional hours. After this period, GC analysis of the reaction mixture showed that all the ethyl trifluoroacetoacetate had been consumed, and the production of ethyl 3-amino-4,4,4-trifluorocrotonate was greater than 98%.

Example 8 Preparation of ethyl 3- (N-methylamino) -4,4,4-trifluorocrotonate. In a stirred mixture of 58.5 gr. (0.318 mol) of ethyl trifluoroacetoacetate and 19.1 gr. (0.318 mol) of acetic acid, at 85 ° C, 19.8 gr. (0.636 mol) of methylamine gas for a period of 1.5 to 2 hours, while the reaction temperature was maintained at 85 ° C. The mixture was maintained at 85 ° C for two additional hours. The GC analysis of the mixture showed that all of the ethyl trifluoroacetate had been used and the production of ethyl 3- (N-methylamino) -4,4,4-trifluorocrotonate was greater than 95%.

Example 9: Preparation of ethyl 3-amino-4,4,4-trifluorocrotonate. 10.83 gr. (0.636 mol) of ammonia gas in a stirred mixture of 58.5 gr. (0.318 mol) of ethyl trifluoroacetoacetate and 19.1 gr. (0.318 mol) of acetic acid, at 85 ° C, for a period of 1.5 to 2 hours, while maintaining the reaction temperature at 85 ° C. The mixture was maintained at 85 ° C for two additional hours. Analysis of the mixture showed that all ethyl trifluoroacetate had been used and the production of ethyl 3-amino-4,4,4-trifluorocrotonate was greater than 98%. It is to be understood that the foregoing description and examples are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention, as defined by the following claims.

Claims (13)

1. Claims 1. A method for preparing a 3-amino-4,4,4-trihalocrotonate compound of the formula I wherein X is fluorine or chlorine; A is O, S or NRS; B is R6, OR6, SR6 or NR3R4; R, R1, R2, R3, R4, R5 and R6 are each, separately, H, (C? -C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, phenyl or phenalkyl (C? -C6); or alkyl (C? -C6), alkenyl (C2-C6), alkynyl (C2-C6), phenyl or phenalkyl (d-C6) substituted with one or more groups selected, separately, from halo, CN, N02, alkyl (Cx-C6), alkenyl (C2-C6), alkynyl (C2-C6), phenyl, phenalkyl (C? -C6), alkoxy (C? -C6), alkenyloxy (C2-C6) and phenoxy; or R1 and R2, and R3 and R4 can each, separately, be taken together with the nitrogen, to which they are adhered, to form a five, six or seven membered heterocyclic ring; or when A is NR5 and B is OR6 or SR6, R5 and R6 can be combined together with the group A = C-B, to which they are attached, to form a five, six or seven membered heterocyclic ring; or when A is NR5 and B is NR3R4, R3 or R4 and R5 can be taken together with the group A = C-B, to which they are attached, to form a five, six or seven membered heterocyclic ring; said method comprises the following steps: i) forming a mixture comprising a 4,4,4-trihaloacetoacetate derivative of the formula II
2. H, L5 wherein X, R, A and B are the same as defined for formula I, and an amine or ammonium salt of a weak acid of formula 0 R1R2NH + Y " wherein R1 and R2 are as defined for formula I and Y is the anion of a weak acid; and ii) heating the mixture. 2. The method according to claim 1, wherein X is F; A is 0 or S; B is OR6 or SR6, wherein R6 is alkyl (C6C6); R1 and R2 are each, separately, H or alkyl (C? -C6); and R is H or alkyl (C? -C6).
3. 3. The method according to claim 2, wherein A is 0, B is OR6, R6 is methyl or ethyl, R1 and R2 are each, separately, H or methyl, and R is H.
4. 4. The method according to claim 1, wherein the formula R1R2NH2 + Y "is an ammonium or amine salt of an organic acid
5. 5. The method according to claim 4, wherein the organic acid is selected from formic, acetic acid. , propionic and butyric
6. 6. The method according to claim 5, wherein the acid is acetic acid
7. 7. The method according to claim 1, wherein the process is carried out without a solvent being present.
8. 8. The method according to claim 1, wherein the process is carried out in the presence of a solvent.
9. 9. The method according to claim 8, wherein the solvent is an aromatic or non-aromatic hydriocarbon, an ether or a polyether, an ester or an alcohol.
10. 10. The method according to claim 9, wherein the solvent is an alcohol, a cyclohexane or a benzene.
11. 11. The method according to claim 10, wherein the solvent is ethanol. The method according to claim 1, wherein the preparation is conducted at a temperature of about 20 ° C to 180 ° C. The method according to claim 1, wherein the ammonium or amine salt of the weak acid is formed in situ from the ammonia or the amine of the formula RXR2NH, in the presence of the weak acid.