Method for preparing aminofuran

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to a novel method for preparing 4-aminofuran of general formula (I) and its salts. [Background technology]

[0002] General formula (I) (especially R 1 4-aminofuran (COOMe) is an important precursor of pesticide active ingredients (see International Publication No. 2018 / 228985) and pharmacoactive ingredients (e.g., DNA binding agents: Woods, Craig R. et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002).

[0003] 4-aminofurans of general formula (I) serve as starting materials for the preparation of tetrahydrofurancarboxylic acids, dihydrofurancarboxylic acids, and esters. To date, these compounds of formula (I) have been prepared by multi-step synthesis involving bromination, dehalogenation, coupling reactions, and deprotection. (See F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012). Scheme 1: [ka] a) BR2, AlCl3; b) Zn, NH4Cl; c) CuI / (CH3NHCH2)2, Boc-NH2, K2CO3; d) Removal of Boc protecting group

[0004] The above synthesis has numerous drawbacks, including low atomic economy (bromination and dehalogenation), the use of heavy metals such as zinc, and the use of protecting groups such as Boc-amines. The method described in Bioorganic & Medicinal Chemistry, 20(6), 2019-2024;2012 further requires the use of a metal-containing catalyst (e.g., copper(I) iodide).

[0005] Due to these drawbacks, the method for preparing the compound of general formula (I) is uneconomical and thus very expensive.

[0006] F. Wolter et al. (Organic Letters, 11(13), 2804 - 2807; 2009) describe another method for preparing aminofurans of general formula (I), especially by the Curtius rearrangement of dimethyl 2,4 - furandicarboxylate using (PhO3)2P(O)N3. This method is not suitable for industrial applications due to the high explosiveness of organic azides.

[0007] Some compounds of general formula (I), for example where R 1 = CF3 and R 2 = NH aryl, are described in European Journal of Organic Chemistry 2018, 3853 - 3861. However, this compound was detected in a mixture of several components.

Prior Art Documents

Patent Documents

Summary of the Invention

Problems to be Solved by the Invention

[0010] In light of the above prior art, an object of the present invention is to find a method for preparing a specified compound that is cost - effective and can be used on an industrial scale. It is also desirable to obtain these compounds in high yields and high purity, so that these compounds do not need to be subjected to further complicated purification.

Means for Solving the Problems

[0011] The above object of being simple, cost - effective, and mass - producible is a method for preparing a compound of general formula (I) and its salts,

Chemical Formula

Chemical Formula

Chemical Formula

[0012] The preferred definitions of the groups in compounds of general formulas (I), (II), (III), (IV), and (V) are as follows: R 1 These are CF3, CF2H, CF2Cl, C2F5, CCl3, COOCH3, and COOC2H5. R 2 These are H, CF3CO, CH3CO, CCl3CO, phenyl, phenyl-CH2, (diphenyl)CH, CH3OCO, (CH3)3COCO, R 3 and R 4 Each of these is independently either H or CH3. R 5 These are H, phenyl, phenyl-CH2, and (diphenyl)CH.

[0013] Particularly preferred definitions of the groups in compounds of general formulas (I), (II), (III), (IV), and (V) are as follows: R 1 These are CF3, CF2H, CCl3, COOCH3, and COOC2H5. R 2 These are H, COCF3, COCH3, COCCl3, Ph-CH2, (diphenyl)CH, CH3OCO, (CH3)3COCO, R 3 and R 4 Each of these is independently either H or CH3. R 5 H is H.

[0014] Particularly preferred definitions of the groups in compounds of general formulas (I), (II), (III), (IV), and (V) are as follows: R 1 These are CF3, COOCH3, and COOC2H5. R 2 It is H, COCF3, (CH3)3COCO, R 3 and R 4 It is CH3, R 5 H is H.

[0015] A more particularly preferred definition of the groups of compounds of general formulas (I), (II), (III), (IV), and (V) is as follows: R 1 These are COOCH3 and COOC2H5. R 2 H is, R 3 and R 4 It is CH3, R 5 H is H.

[0016] A more particularly preferred definition of the groups of compounds of general formulas (I), (II), (III), (IV), and (V) is as follows: R 1 COOCH3 is, R 2 H is, R 3 and R 4 It is CH3, R 5 H is H. The reaction sequence for preparing the compound of formula (I) is shown in Scheme 2. Scheme 2 [ka]

[0017] The compound of formula (II) reacts with ammonia or an amine (a compound of general formula (V)) in the first reaction step to form the compound of general formula (III), and then converts this compound to the compound of general formula (I) in the second reaction step. 1 , R 3 , R 4 , and R 5 Several compounds of general formulas (II) and (III) having the above definitions are known. These compounds can be prepared by methods known from International Publication Brochure 2011 / 073100, International Publication Brochure 2011 / 073101, and European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861.

[0018] As an example, we can consider the compound represented by the following formula (II). [ka] 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 3-(2,2-dimethyl-1,3-dioxolane-4-ylidene)-2-methyl oxopropanoate 3-(2,2-dimethyl-1,3-dioxolane-4-ylidene)-2-oxopropanoate ethyl

[0019] As an example, we can consider the compound represented by the following formula (III). [ka] 4-amino-1,1,1-trifluoro-5-hydroxypenta-3-en-2-one 4-amino-1,1-difluoro-5-hydroxypenta-3-en-2-one 4-amino-1,1,1-trichloro-5-hydroxypenta-3-en-2-one 4-amino-5-hydroxy-2-oxopenta-3-methyl enoate 4-amino-5-hydroxy-2-oxopenta-3-ethyl amino-5-hydroxy-2-oxopenta-3-enoate 4-Benzylamino-5-hydroxy-2-oxopenta-3-methyl enoate

[0020] In the second reaction step, the compound of formula (III) is cyclized. Ring closure is performed on SOCl2, POCl3, PCl3, phosgene, diphosgene, triphosgene, ClCOCOCl, (CF3CO)2, P4O 10 The process is carried out in the presence of a dehydrating agent such as SO2F2, trimethyl orthoformate, triethyl orthoformate, and HCl. Preferred dehydrating agents are SOCl2, POCl3, PCl3, phosgene, diphosgene, triphosgene, and ClCOCOCl. Particularly preferred dehydrating agents are SOCl2, POCl3, ClCOCOCl, and phosgene.

[0021] Using reagents such as SOCl2, POCl3, PCl3, phosgene, diphosgene, triphosgene, and ClCOCOCl, R 2 A compound of formula (I) is obtained, consisting of H, CH3, phenyl, phenyl-CH2, and (diphenyl)CH. The compound is formed in the form of its HCl salt.

[0022] If a compound of general formula (I) is obtained in the form of a salt, for example as a hydrochloride salt, the salt-free form can be obtained by treating the salt with a base, such as triethylamine (see Example 2).

[0023] Using reagents such as (CF3CO)2O, R 2 The compound of formula (I), which is equal to CF3CO, is obtained.

[0024] The molar ratio of the compound of formula (III) to the cyclizing agent is approximately 1:0.1 to 1:5, preferably in the range of 1:0.5 to 1:3.

[0025] Reaction step 2 is typically carried out at a temperature range of 0°C to 40°C, sometimes in the presence of a solvent or diluent. The reaction is preferably carried out in a solvent at approximately room temperature (RT).

[0026] Preferred solvents are methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, and chlorobenzene. Description of method and intermediates Examples

[0027] The present invention will be described in more detail by the following embodiments, but the present invention is not limited to these embodiments. Measurement method The product, 1 The samples were characterized by 1H NMR spectroscopy and / or LC-MS (liquid chromatography-mass spectrometry). NMR spectra were measured using a Bruker Avance 400 equipped with a flow probe head (60 μl capacity). In individual cases, NMR spectra were measured using a Bruker Avance II 600.

[0028] Example 1 4-aminofuran-2-carboxylate methyl hydrochloride (salt of formula (I)) 15.9 g (0.1 mol) of methyl 4-amino-5-hydroxy-2-oxopenta-3-enoate was suspended in 50 ml of methanol, and the mixture was cooled to 0°C. 17.7 g (0.15 mol) of SOCl2 was added over 2 hours at 0°C. The mixture was stirred for a further 5 hours at 10°C, the precipitate was filtered off, washed with 5 ml of methanol, and dried. This yielded 16.8 g of pale beige crystals with a concentration of 95%. 1 H-NMR (400MHz, CDCl3): δ10.07(3H, s,br.);8.10(1H,d);7.32(1H,d);3.83(3H, s) ppm. 13C-NMR 158.0(s);143.6(s);140.2(d);121.8(s);114.5(d);52.3(q) ppm.

[0029] Example 2 Conversion of 4-aminofuran-2-carboxylate methyl hydrochloride (salt of formula (I)) to 4-aminofuran-2-carboxylate methyl (salt-free product of formula (I)) 9.2 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 50 ml of ethyl acetate, and 15.7 g of Et3N was added. The mixture was stirred at RT for 3 hours, the precipitate was filtered off, and the ethyl acetate was completely concentrated under vacuum. This yielded 6.96 g of 95% beige crystals with a melting point of 79-81°C. 1 H-NMR (400 MHz, CDCl3): δ:7.24(1H,d);6.8(1H,d);4.3(2H,s)3.75(3H,s) ppm.

[0030] Example 3 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate methyl 1.59 g (0.01 mol) of methyl 4-amino-5-hydroxy-2-oxopenta-3-enoate was suspended in 50 ml of dichloromethane, and the mixture was cooled to 0°C. 2 ml of (CF3CO)2O was added over 2 hours at 0°C. The mixture was stirred at 10°C for a further 5 hours, and 20 ml of water was added. The mixture was stirred at room temperature (RT) for 5 hours, 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 yielded 1 mg of the product as a beige solid. 1 H-NMR (400 MHz, CDCl3): δ11.76(1H,s,br.);8.26(1H,d);7.24(1H,d);3.76(3H,s) ppm. 13 C-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.

Claims

1. A method for preparing a compound of general formula (I) and its salt, 【Chemistry 1】 During the ceremony, R 1 is CF 3 , CF 2 H, C 2 F 5 , CF 2 Cl, CCl 3 , COO(C 1 ~C 4 ) alkyl, COOH, and R 2 H, CH 3 CO, CCl 3 CO, CF 3 CO, phenyl-CO, CH 3 OCO, (CH 3 ) 3 COCO, phenyl, phenyl-CH 2 , (diphenyl)CH, In the first step, General formula (II) 【Chemistry 2】 (In the formula, R 3 and R 4 These are H and C, respectively, independently. 1 ~C 4 -It is alkyl, R 1 Compounds having the above definition (of the general formula R 5 -NH 2 Using the amine (V), general formula (III) 【Transformation 3】 (In the formula, R 5 H, phenyl, phenyl-CH 2 It is converted into a compound of (diphenyl)CH, The method is characterized by subsequently reacting these in the presence of a dehydrating agent in a second reaction step to obtain a compound of general formula (I).

2. The method according to claim 1, characterized in that the definitions of the groups of compounds of general formulas (I), (II), (III), and (V) are as follows: R 1 , CF 3 , CF 2 H, CF 2 Cl, C 2 F 5 , CCl 3 COOCH 3 COOC 2 H 5 And, R 2 H, CF 3 CO, CH 3 CO, CCl 3 CO, phenyl, phenyl-CH 2 (Diphenyl)CH,CH 3 OCO, (CH 3 ) 3 COCO, R 3 and R 4 These are, independently, H or CH 3 And, R 5 H, phenyl, phenyl-CH 2 , (diphenyl)CH.

3. The method according to claim 1, characterized in that the definitions of the groups of compounds of general formulas (I), (II), (III), and (V) are as follows: R 1 , CF 3 , CF 2 H, CCl 3 COOCH 3 COOC 2 H 5 And, R 2 H, COCF 3 COCH 3 COCCl 3 , phenyl-CH 2 (Diphenyl)CH,CH 3 OCO, (CH 3 ) 3 COCO, R 3 and R 4 These are, independently, H or CH 3 And, R 5 H is H.

4. The method according to claim 1, characterized in that the definitions of the groups of compounds of general formulas (I), (II), (III), and (V) are as follows: R 1 , CF 3 COOCH 3 COOC 2 H 5 And, R 2 H, COCF 3 , (CH 3 ) 3 COCO, R 3 and R 4 CH 3 And, R 5 H is H.

5. The method according to claim 1, characterized in that the definitions of the groups of compounds of general formulas (I), (II), (III), and (V) are as follows: R 1 COOCH 3 COOC 2 H 5 And, R 2 H is, R 3 and R 4 CH 3 And, R 5 is H.

6. The method according to claim 1, characterized in that the definitions of the groups of compounds of general formulas (I), (II), (III), and (V) are as follows: R 1 COOCH 3 And, R 2 H is, R 3 and R 4 CH 3 And, R 5 is H.

7. The method according to any one of claims 1 to 6, characterized in that the reaction is carried out in a temperature range of 0°C to 40°C.

8. The method according to any one of claims 1 to 7, characterized in that the solvent is methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, or chlorobenzene.

9. The dehydrating reagent is SOCl 2 , POCl 3 , PCl 3 Phosgene, diphosgene, triphosgene, ClCOCOCl, (CF 3 CO) 2 , P 4 O 10 , SO 2 F 2 The method according to any one of claims 1 to 8, characterized in that the orthoformate is trimethyl orthoformate, triethyl orthoformate, or HCl.

10. The dehydrating reagent is SOCl 2 , POCl 3 , PCl 3 The method according to any one of claims 1 to 8, characterized in that the material is phosgene, diphosgene, triphosgene, or ClCOCOCl.

11. The dehydrating reagent is SOCl 2 , POCl 3 The method according to any one of claims 1 to 8, characterized in that the material is ClCOCOCl or phosgene.

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