Process for preparing aminofuranes

Abstract

The present invention relates to a novel method for preparing 4-aminofurans of the general formula (I) and salts thereof.

Claims

1. A method for preparing a compound of formula (I) and/or salt thereof, ##STR00008## in which R.sup.1 is CF.sub.3, CF.sub.2H, CCl.sub.3, COOCH.sub.3, COOC.sub.2H.sub.5, and R.sup.2 is H, COCF.sub.3, COCH.sub.3, COCCl.sub.3, phenyl-CH.sub.2, (diphenyl)CH, CH.sub.3OCO, (CH.sub.3).sub.3COCO, comprising converting a compound of formula (II) ##STR00009## in which R.sup.3 and R.sup.4 are each independently H and or CH.sub.3, and R.sup.1 has the definitions specified above, with aid of an amine of formula R.sup.5NH.sub.2 (V) to a compound of formula (III) ##STR00010## in which R.sup.5 is H, and then reacting said compound of formula III in presence of a dehydrating reagent to give a compound of formula (I).

2. The method according to claim 1, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is CF.sub.3, COOCH.sub.3, or COOC.sub.2H.sub.5, R.sup.2 is H, COCF.sub.3, or (CH.sub.3).sub.3COCO, and R.sup.3 and R.sup.4 are each CH.sub.3.

3. The method according to claim 2, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is COOCH.sub.3 or COOC.sub.2H.sub.5, and R.sup.2 is H.

4. The method according to claim 3, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is COOCH.sub.3.

5. The method according to claim 1, wherein the reaction of the compound of formula III is carried out at approximately room temperature.

6. The method according to claim 1, wherein the reaction of the compound of formula III is further in the presence of at least one solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, and chlorobenzene.

7. The method according to claim 1, wherein the dehydrating reagent comprises at least one compound selected from the group consisting of SOCl.sub.2, POCl.sub.3, PCl.sub.3, phosgene, diphosgene, triphosgene, ClCOCOCl, (CF.sub.3CO).sub.2, P.sub.4O.sub.10, SO.sub.2F.sub.2, and HCL, or comprises a mixture of trimethyl orthoformate and triethyl orthoformate.

8. The method according to claim 7, wherein the dehydrating reagent comprises at least one compound selected from the group consisting of SOCl.sub.2, POCl.sub.3, PCl.sub.3, phosgene, diphosgene, triphosgene, and ClCOCOCl.

9. The method according to claim 8, wherein the dehydrating reagent comprises at least one compound selected from the group consisting of OCl.sub.2, POCl.sub.3, ClCOCOCl, and phosgene.

10. A method for preparing a compound of formula (I) and/or salt thereof, ##STR00011## in which R.sup.1 is CF.sub.3, CF.sub.2H, C.sub.2F.sub.5, CF.sub.2Cl, CCl.sub.3, COO(C.sub.1-C.sub.4)alkyl, or COOH, R.sup.2 is H, CH.sub.3CO, CCl.sub.3CO, CF.sub.3CO, phenyl-CO, CH.sub.3OCO, (CH.sub.3).sub.3COCO, phenyl, phenyl-CH.sub.2, or (diphenyl)CH, comprising converting a compound of formula (II) ##STR00012## in which R.sup.3 and R.sup.4 are each independently H or C.sub.1-C.sub.4-alkyl, and R.sup.1 has the definitions specified above, with aid of an amine of formula R.sup.5NH.sub.2 (V) to a compound of formula (III) ##STR00013## in which R.sup.5 is H, phenyl, phenyl-CH.sub.2, or (diphenyl)CH, and then reacting said compound of formula III in presence of a dehydrating reagent to give a compound of formula (I), wherein the dehydrating reagent comprises at least one compound selected from the group consisting of SOCl.sub.2, POCl.sub.3, PCl.sub.3, phosgene, diphosgene, triphosgene, ClCOCOCl, (CF.sub.3CO).sub.2, P.sub.4O.sub.10, SO.sub.2F.sub.2, and HCL, or comprises a mixture of trimethyl orthoformate and triethyl orthoformate.

11. The method according to claim 10, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is CF.sub.3, CF.sub.2H, CF.sub.2Cl, C.sub.2F.sub.5, CCl.sub.3, COOCH.sub.3, or COOC.sub.2H.sub.5, R.sup.2 is H, CF.sub.3CO, CH.sub.3CO, CCl.sub.3CO, phenyl, phenyl-CH.sub.2, (diphenyl)CH, CH.sub.3OCO, or (CH.sub.3).sub.3COCO, R.sup.3 and R.sup.4 are each independently H or CH.sub.3, and R.sup.5 is H, phenyl, phenyl-CH.sub.2, or (diphenyl)CH.

12. The method according to claim 11, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is CF.sub.3, CF.sub.2H, CCl.sub.3, COOCH.sub.3, or COOC.sub.2H.sub.5, R.sup.2 is H, COCF.sub.3, COCH.sub.3, COCCl.sub.3, phenyl-CH.sub.2, (diphenyl)CH, CHOCO, or (CH.sub.3).sub.3COCO, R.sup.3 and R.sup.4 are each independently H or CH.sub.3, and R.sup.5 is H.

13. The method according to claim 12, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is CF.sub.3, COOCH.sub.3, or COOC.sub.2H.sub.5, R.sup.2 is H, COCF.sub.3, or (CH.sub.3).sub.3COCO, and R.sup.3 and R.sup.4 are each CH.sub.3.

14. The method according to claim 13, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is COOCH.sub.3 or COOC.sub.2H.sub.5, and R.sup.2 is H.

15. The method according to claim 14, wherein definitions of radicals of compounds of formulae (I), (II), (III), and (V) are as follows: R.sup.1 is COOCH.sub.3.

16. The method according to claim 10, wherein the reaction is carried out at approximately room temperature.

17. The method according to claim 10, wherein the reaction of the compound of formula III is further in the presence of at least one solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, and chlorobenzene.

18. The method according to claim 10, wherein the dehydrating reagent comprises at least one compound selected from the group consisting of SOCl.sub.2, POCl.sub.3, PCl.sub.3, phosgene, diphosgene, triphosgene, and ClCOCOCl.

19. The method according to claim 18, wherein the dehydrating reagent comprises at least one compound selected from the group consisting of SOCl.sub.2, POCl.sub.3, ClCOCOCl, and phosgene.

Description

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

(1) Preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows: is CF.sub.3, CF.sub.2H, CF.sub.2Cl, C.sub.2F.sub.5, CCl.sub.3, COOCH.sub.3, COOC.sub.2H.sub.5, R.sup.2 is H, CF.sub.3CO, CH.sub.3CO, CCl.sub.3CO, phenyl, phenyl-CH.sub.2, (diphenyl)CH, CH.sub.3OCO, (CH.sub.3).sub.3COCO, R.sup.3 and R.sup.4 are each independently H or CH.sub.3, R.sup.5 is H, phenyl, phenyl-CH.sub.2, (diphenyl)CH.

(2) Particularly preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows: R.sup.1 is CF.sub.3, CF.sub.2H, CCl.sub.3, COOCH.sub.3, COOC.sub.2H.sub.5, R.sup.2 is H, COCF.sub.3, COCH.sub.3, COCCl.sub.3, Ph-CH.sub.2, (diphenyl)CH, CH.sub.3OCO, (CH.sub.3).sub.3COCO, R.sup.3 and R.sup.4 are each independently H or CH.sub.3, R.sup.5 is H.

(3) Especially preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows: R.sup.1 is CF.sub.3, COOCH.sub.3, COOC.sub.2H.sub.5, R.sup.2 is H, COCF.sub.3, (CH.sub.3).sub.3COCO, R.sup.3 and R.sup.4 are CH.sub.3, R.sup.5 is H.

(4) Further especially preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows: R.sup.1 is COOCH.sub.3, COOC.sub.2H.sub.5, R.sup.2 is H, R.sup.3 and R.sup.4 are CH.sub.3, R.sup.5 is H.

(5) Further especially preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows: R.sup.1 is COOCH.sub.3, R.sup.2 is H, R.sup.3 and R.sup.4 are CH.sub.3, R.sup.5 is H.

(6) The reaction sequence for preparing compounds of the formula (I) is shown in Scheme 2:

Scheme 2

(7) ##STR00005##

(8) The compounds of the formula (II) react in the first reaction step with ammonia or amines (compounds of the general formula (V)) to form compounds of the general formula (III), which are then converted in the second reaction step to compounds of the general formula (I). Several compounds of the general formula (II) and (III), in which R.sup.1, R.sup.3, R.sup.4 and R.sup.5 have the definitions specified above, are known. These compounds can be prepared by the method known from WO 2011/073100, WO 2011/073101 and European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861.

(9) By way of example, the following compounds of the formula (II) may be mentioned:

(10) ##STR00006## 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-1,1,1-trifluoropropan-2-one 3-(1,3-dioxolan-4-ylidene)-1,1,1-trifluoropropan-2-one methyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate

(11) By way of example, the following compounds of the formula (III) may be mentioned:

(12) ##STR00007## 4-amino-1,1,1-trifluoro-5-hydroxypent-3-en-2-one 4-amino-1,1-difluoro-5-hydroxypent-3-en-2-one 4-amino-1,1,1-trichloro-5-hydroxypent-3-en-2-one methyl 4-amino-5-hydroxy-2-oxopent-3-enoate ethyl 4-amino-5-hydroxy-2-oxopent-3-enoate methyl 4-benzylamino-5-hydroxy-2-oxopent-3-enoate.

(13) In the second reaction step, the compounds of the formula (III) are cyclized. The ring closure takes place in the presence of a dehydrating reagent such as SOCl.sub.2, POCl.sub.3, PCl.sub.3, phosgene, diphosgene, triphosgene, ClCOCOCl, (CF.sub.3CO).sub.2, P.sub.4O.sub.10, SO.sub.2F.sub.2, trimethyl orthoformate and triethyl orthoformate and HCl. Preferred dehydrating reagents are SOCl.sub.2, POCl.sub.3, PCl.sub.3, phosgene, diphosgene, triphosgene and ClCOCOCl. Especially preferred dehydrating reagents are SOCl.sub.2, POCl.sub.3, ClCOCOCl and phosgene.

(14) Using reagents such as SOCl.sub.2, POCl.sub.3, PCl.sub.3, phosgene, diphosgene, triphosgene and ClCOCOCl, compounds of the formula (I) where R.sup.2=H, CH.sub.3, phenyl, phenyl-CH.sub.2 and (diphenyl)CH are obtained. Said compounds are formed in the form of HCl salts thereof.

(15) If the compounds of the general formula (I) are obtained in the form of salts thereof, for example as a hydrochloride, the salt-free forms can be obtained by treating the salt with a base, for example triethylamine (see Example 2).

(16) Using reagents such as (CF.sub.3CO).sub.2O, compounds of the formula (I) where R.sup.2=CF.sub.3CO are obtained.

(17) The molar ratio of the compound of the formula (III) to the cyclization reagents is in the range of about 1:0.1 to 1:5, preferably from 1:0.5 to 1:3.

(18) Reaction step 2 is usually carried out in a temperature range of 0 C. to 40 C. and optionally in the presence of a solvent or diluent. The reaction is preferably carried out in a solvent at approximately room temperature (RT).

(19) Preferred solvents are methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, chlorobenzene.

Description of the Methods and Intermediates

EXAMPLES

(20) The present invention is elucidated in more detail by the examples which follow, without restricting the invention to these examples.

(21) Method of Measurement

(22) The products were characterized by .sup.1H NMR spectroscopy and/or LC-MS (Liquid Chromatography Mass Spectrometry).

(23) The NMR spectra were determined using a Bruker Avance 400 fitted with a flow probe head (volume 60 l). In individual cases, the NMR spectra were measured with a Bruker Avance II 600.

Example 1

Methyl 4-aminofuran-2-carboxylate hydrochloride (salt of the formula (I)

(24) 15.9 g (0.1 mol) of methyl 4-amino-5-hydroxy-2-oxopent-3-enoate were suspended in 50 ml of methanol and the mixture was cooled to 0 C. 17.7 g (0.15 mol) of SOCl.sub.2 were added thereto at 0 C. over 2 hours. The mixture was stirred at 10 C. for a further 5 hours and the precipitate was filtered off, washed with 5 ml of methanol and dried. This gave 16.8 g, 95% of pale beige crystals.

(25) .sup.1H-NMR (400 MHz, CDCl.sub.3): 10.07 (3H, s, br.); 8.10 (1H, d); 7.32 (1H, d); 3.83 (3H, s) ppm.

(26) .sup.13C-NMR 158.0 (s); 143.6 (s); 140.2 (d); 121.8 (s); 114.5 (d); 52.3 (q) ppm.

Example 2

Conversion of methyl 4-aminofuran-2-carboxylate hydrochloride (salt of the formula (I)) to methyl 4-aminofuran-2-carboxylate (salt-free product of the formula (I))

(27) 9.2 g of methyl 4-aminofuran-2-carboxylate hydrochloride were suspended in 50 ml of ethyl acetate and 15.7 g of Et.sub.3N were added. The mixture was stirred at RT for 3 hours, the precipitate was filtered off and ethyl acetate fully concentrated under vacuum. This gave 6.96 g, 95% of beige crystals, with m.p. 79-81 C.

(28) .sup.1H-NMR (400 MHz, CDCl.sub.3): : 7.24 (1H, d); 6.8 (1H, d); 4.3 (2H, s) 3.75 (3H, s) ppm.

Example 3

Methyl 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate

(29) 1.59 g (0.01 mol) of methyl 4-amino-5-hydroxy-2-oxopent-3-enoate were suspended in 50 ml of dichloromethane and the mixture was cooled to 0 C. 2 ml of (CF.sub.3CO).sub.2O were added thereto at 0 C. over 2 hours. The mixture was stirred at 10 C. for a further 5 hours and 20 ml of water were added. The mixture was stirred for 5 h at room temperature (RT) and then the phases were separated. The organic phase was concentrated. The precipitate was stirred with 5 ml of diisopropyl ether and filtered off. This gave 1 mg of the product as a beige solid.

(30) .sup.1H-NMR (400 MHz, CDCl.sub.3): 11.76 (1H, s, br.); 8.26 (1H, d); 7.24 (1H, d); 3.76 (3H, s) ppm.

(31) .sup.13C-NMR 158.2 (s); 154.1 (s, q); 142.5 (s); 137.4 (d); 124.7 (s); 115.8 (s); 112.1 (d); 52.3 (q) ppm.