Method for producing carbonylaminofuran

Abstract

The present invention relates to a novel process for preparing carbonylaminofurans of general formula (I). JPEG2023545715000015.jpg55170

Description

[Technical Field]

[0001] The present invention relates to a novel process for preparing carbonylaminofurans of general formula (I). [Background technology]

[0002] General formula (I) (particularly R 1 =COOmethyl, R 2 4-Acylaminofurans and alkoxycarbonylaminofurans (=OtButyl) are important precursors of pesticide active ingredients (see WO 2018 / 228985) and pharmaceutical active ingredients (e.g., DNA binders: Woods, Craig R. et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002).

[0003] 4-Acylaminofurans of general formula (I) serve as starting materials for the preparation of tetrahydrofuran and dihydrofuran carboxylic acids and esters. Previously, these compounds of formula (I) have been prepared by multi-step synthesis involving bromination, dehalogenation, and coupling reactions (see F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012).

[0004] Scheme 1: [ka] a) Br2, AlCl3;b) Zn, NH4Cl;c) CuI / (CH3NHCH2)2, Boc-NH2, K2CO3 The above synthesis has many drawbacks, including poor atom economy (bromination and debromination), the use of heavy metals such as zinc, and the use of expensive reagents such as Boc-amine. The method described in Bioorganic & Medicinal Chemistry, 20(6), 2019-2024;2012 further requires the use of a metal-containing (e.g., copper(I) iodide) catalyst.

[0005] These drawbacks make the process for preparing the compounds of general formula (I) uneconomical and therefore very expensive.

[0006] F. Wolter et al. (Organic Letters, 11(13), 2804-2807; 2009) describe another method for preparing aminofurans of general formula (I), in particular by the Curtius rearrangement of 2-methylfuran-2,4-dicarboxylate using (PhO3)2P(O)N3. This method is not suitable for industrial use due to the highly explosive nature of the organic azide.

[0007] Some compounds of general formula (I), such as R 1 = CF3 and R 2 The compound =NHaryl is described in EOC 2018, 3853-3861. However, this compound was detected in a mixture of several components. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2018 / 228985 [Non-patent literature]

[0009] [Non-Patent Document 1] Woods, Craig R. et al., Bioorganic&Medicinal Chemistry Letters, 12(18), 2647-2650;2002 [Non-patent document 2] F. Brucoli et al., Bioorganic&Medicinal Chemistry, 20(6), 2019-2024;2012 [Non-patent document 3] F. Wolter et al. (Organic Letters, 11(13), 2804-2807; 2009) [Non-patent document 4] EOC 2018, 3853-3861 Summary of the Invention [Problem to be solved by the invention]

[0010] In light of the above prior art, the object of the present invention is to find a method for preparing compounds of general formula (I) that is cost-effective and can be used on an industrial scale. It is also desirable to obtain these compounds in high yield and high purity, so that they do not need to be subjected to further complex purification. [Means for solving the problem]

[0011] The above objective of simple and cost-effective industrial preparation is achieved by the preparation of compounds of general formula (I) [ka] (In the formula, R 1 is CF3, CF2H, C2F5, CF2Cl, -COO-(C1-C6)-alkyl, COOH, R 2 is H, (C1-C6)-alkyl, Cl, F, CF3, CF2Cl, CCl3, -O-(C1-C6)-alkyl, -O-(C1-C6)-alkylaryl, -COO-(C1-C6)-alkyl) A method for preparing a compound of the formula In the first step, a compound of general formula (II) [ka] (In the formula, R 3 and R 4 are each independently H and (C1-C6)-alkyl; R 1 has the definition above) with ammonia to form a compound of general formula (III) [ka] (In the formula, R 1 has the definition above) is converted into the compound In a second reaction step, they are reacted in the presence of a dehydrating reagent to give a compound of general formula (IV): [ka] (In the formula, R 1 has the definition above) to obtain a compound of Then, in a third reaction step, they are reacted with a compound of formula (V) R 2 COX (V) (In the formula, R 2 is as defined above, X is F, Cl, Br, H3CSO2O, p-TolSO2O, -OCOR 2 is) to obtain a compound of general formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0012] definition Alkyl means a saturated, linear or branched hydrocarbyl radical having the number of carbon atoms specified in each case, for example (C1-C6)-alkyl, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl.

[0013] Aryl refers to a monocyclic, bicyclic, or tricyclic aromatic or partially aromatic group having 6 to 14 carbon atoms, such as (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl. Attachment to the parent general structure can be through any desired suitable ring member of the aryl radical. Aryl is preferably selected from phenyl, 1-naphthyl, and 2-naphthyl. Phenyl is particularly preferred.

[0014] The compounds according to the present invention are generally defined by formula (I): Preferred substituents or ranges for the radicals described in the above and following formulae are set out below. Preferred definitions of the radicals of general formulae (I), (II), (III), (IV) and (V) are as follows: R 1 are CF3, CF2H, CF2Cl, C2F5, COOCH3, COOC2H5, R 2is H, -(C1-C4)-alkyl, Cl, CF3, CF2Cl, CCl3, -O-(C1-C4)-alkyl, -O-CH2-phenyl, COOCH3, COOC2H5, R 3 and R 4 are each independently H or CH3; X is F, Cl, -OCOR 2 , H3CSO2O, p-TolSO2O.

[0015] Particularly preferred definitions of the radicals of general formulae (I), (II), (III), (IV) and (V) are as follows: R 1 are COOCH3 and COOC2H5, R 2 are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, CF3, -O-methyl, -O-ethyl, -O-propyl, -O-1-methylethyl, -O-butyl, -O-1-methylpropyl, -O-2-methylpropyl, -O-1,1-dimethylethyl, -O-pentyl, -O-1-methylbutyl, -O-2-methylbutyl, -O-3-methylbutyl, -O-2,2-dimethylpropyl, -O-1-ethylpropyl, COOCH3, R 3 and R 4 are each independently H or CH3; X is Cl, -OCOR 2 , H3CSO2O.

[0016] Particularly preferred definitions of the radicals of general formulae (I), (II), (III), (IV) and (V) are as follows: R 1 are COOCH3 and COOC2H5, R 2are H, CH3, CF3, -OCH3, -OC2H5, (CH3)3CO-, CCl3, COOCH3, -O-CH2-phenyl; R 3 and R 4 is CH3, X is Cl, -OCOR 2 is.

[0017] The most preferred definitions of the radicals of general formulae (I), (II), (III), (IV), and (V) are as follows: R 1 are COOCH3 and COOC2H5, R 2 are CF3, -OCH3, -OC2H5, (CH3)3CO-, CCl3, COOCH3, -O-CH2-phenyl, R 3 and R 4 is CH3, X is Cl. The reaction sequence for preparing compounds of formula (I) is shown in Scheme 2.

[0018] Scheme 2 [ka] The compound of formula (II) is reacted with ammonia to form a compound of general formula (III), which is then converted in a second reaction step by removal of water to a compound of general formula (IV), which is then reacted with an acylating reagent of general formula (V) to give a compound of general formula (I).

[0019] Step 1 The compound of formula (II) reacts with ammonia to form a compound of general formula (III).

[0020] R 1 , R 3 , and R 4The synthesis of compounds of the general formulae (II) and (III) having the above definitions is known. These compounds can be prepared by methods known from WO 2011 / 073100, WO 2011 / 073101, and European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861.

[0021] By way of example, the following compounds of formula (II) may be mentioned: [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 Methyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate Ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate By way of example, the following compounds of formula (III) may be mentioned: [ka] 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 4-Amino-5-hydroxy-2-oxopent-3-enoic acid methyl ester 4-amino-5-hydroxy-2-oxopent-3-enoic acid ethyl ester

[0022] Step 2 In the second reaction step, the compound of formula (III) is cyclized. The ring closure can be carried out with SOCl, POCl, PCl, phosgene, diphosgene, triphosgene, ClCOCOCl, (CFCO), PO 10 The reaction is carried out in the presence of dehydrating reagents such as SO2F2, trimethyl orthoformate and triethyl orthoformate, and HCl. Preferred reagents are SOCl2, POCl3, oxalyl chloride, phosgene, and HCl.

[0023] The molar ratio of the compound of formula (III) to the cyclization reagent is in the range of about 1:0.1 to 1:5, preferably 1:0.5 to 1:2.

[0024] Reaction step 2 is typically carried out in the temperature range of 0° C. to 40° C., optionally in the presence of a solvent or diluent. The reaction is preferably carried out in a solvent at about room temperature (RT).

[0025] Preferred solvents are methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, chlorobenzene, ethyl acetate, and isopropyl acetate.

[0026] In reactions with SOCl2, POCl3, PCl3, phosgene, diphosgene, triphosgene, ClCOCOCl, the compounds of general formula (IV) are obtained in the form of their HCl salts.

[0027] The salt-free form can be obtained by treating the salt with a base, for example triethylamine in ethyl acetate (see Example 2).

[0028] Mention may be made, by way of example, of the following compounds of formula (IV): [ka] Methyl 4-aminofuran-2-carboxylate hydrochloride / Methyl 4-aminofuran-2-carboxylate Ethyl 4-aminofuran-2-carboxylate hydrochloride / Ethyl 4-aminofuran-2-carboxylate 4-Amino-2-trifluoromethylfuran hydrochloride

[0029] Step 3 In the third reaction step, the compound of formula (III) is acylated. The acylation is carried out using a reagent of formula (V). The following compounds of formula (V) may be mentioned as examples: acetyl chloride, trichloroacetyl chloride, trifluoroacetyl chloride or trifluoroacetyl anhydride, methyloxalyl chloride, methyl chloroformate, tert-butyl chloroformate, benzyl chloroformate, Boc-anhydride.

[0030] The molar ratio of the compound of general formula (IV) to the compound of general formula (V) is in the range of about 1:0.9 to 1:2, preferably 1:1 to 1:1.5.

[0031] Acylation can be carried out with or without a base. It may be surprising that it is also possible to use a salt of the compound of general formula (IV) (especially an HCl salt) in the acylation step. When a base is used, the molar ratio of the compound of general formula (IV) to the base is 1:0.5 to 1:3. Organic or inorganic compounds are suitable as bases.

[0032] The organic base is triethylamine, tributylamine, Hunig's base, pyridine, alkylpyridine, dimethylcyclohexylamine. Preferred bases are triethylamine, Hunig's base, 2-methyl-5-ethylpyridine, 3-picoline, dimethylcyclohexylamine.

[0033] Possible inorganic bases are potassium, Na2CO3, NaOAc.

[0034] Reaction step 3 is typically carried out in the temperature range of 10° C. to 40° C., optionally in the presence of a solvent or diluent. The reaction is preferably carried out in a solvent at about room temperature (RT).

[0035] Preferred solvents are toluene, chlorobenzene, acetonitrile, ether, dimethylacetamide, ethyl acetate, isopropyl acetate, dichloromethane, etc. The compound of formula (I) is isolated by filtration of the product or by extraction with an organic solvent (see Examples).

[0036] Description of Methods and Intermediates Example The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[0037] Measurement method The product 1 H NMR spectroscopy / 13 Characterized by C NMR spectroscopy and / or LC-MS (liquid chromatography mass spectrometry).

[0038] NMR spectra were measured using a Bruker Avance 400 equipped with a flow probe head (volume 60 μl). In individual cases, NMR spectra were measured using a Bruker Avance II 600.

[0039] Example 1 Methyl 4-aminofuran-2-carboxylate hydrochloride (HCl salt of the compound of formula (IV)). 15.9 g (0.1 mol) of methyl 4-amino-5-hydroxy-2-oxopent-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 at 10°C for an additional 5 hours, and the precipitate was filtered off, washed with 5 mL of methanol, and dried. This yielded 16.8 g (95%) of pale beige crystals. 1 H-NMR (400MHz, CDCl3):δ 10.07 (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.

[0040] Example 2 Conversion of methyl 4-aminofuran-2-carboxylate hydrochloride (salt of formula (IV)) to methyl 4-aminofuran-2-carboxylate (product of formula (IV) without salt) 9.2 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 50 ml of ethyl acetate and 15.7 g of EtN was added. The mixture was stirred at room temperature for 3 hours, the precipitate was filtered off, and the ethyl acetate was completely concentrated under vacuum. This gave 6.96 g, 95%, of beige crystals. 1 H-NMR (400MHz, CDCl3):δ:7.24 (1H, d); 6.8 (1H, d); 4.3 (2H,s ) 3.75 (3H, s) ppm.

[0041] Example 3 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate methyl ester 0.5 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate, and 1 g of (CFCO)O was added at 10° C. The mixture was stirred at RT for 5 h, and the precipitate was filtered off, yielding 0.55 mg of the product as a solid. 1 H-NMR (400MHz, CDCl3):δ 11.76 (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.

[0042] Example 4 4-[(2-Methoxy-2-oxoacetyl)amino]furan-2-carboxylate methyl ester 0.5 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate, and 0.5 g of methyloxalyl chloride was added at 10° C. The mixture was stirred at RT for 15 h, and the precipitate was filtered off, yielding 0.5 g (79%) of the product. Mass spectrum m / z 227. 1 H-NMR (400MHz, CDCl3):δ 11.56 (1H, s, br.); 8.32 (1H, d); 7.36 (1H, d); 3.82 (3H, s), 3.32 (3H,s) ppm.

[0043] Example 5 4-(Methoxycarbonylamino)furan-2-carboxylic acid methyl ester 0.5 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate, and 0.5 g of methyl chloroformate was added at 10 °C. The mixture was stirred at RT for 30 min, and 0.5 g of NEt was added in portions. The mixture was stirred at RT for 10 h and diluted with 30 ml of ethyl acetate. The organic phase was washed with water and evaporated. This gave 0.54 g of product. 1 H-NMR (400MHz, CDCl3):δ 9.82 (1H, s, br.); 7.99 (1H, d); 7, 15 (1H, d); 3.86 (3H, s), 3.73 ppm

[0044] Example 6 4-(benzyloxycarbonylamino)furan-2-carboxylic acid methyl ester This was carried out as described in Example 5, but using 1.5 equivalents of benzyl chloroformate. Yield 96%; m / z 275. 1H-NMR (400MHz, CDCl3):δ 9.85 (1H, s, br.); 7.95 (1H, d); 7.4-7.15 (5H, m); 7.2 (1H, d), 5.2 (2H. s) 3.75 (3H, s) ppm.

[0045] Example 7 4-[(2,2,2-trichloroacetyl)amino]furan-2-carboxylate methyl ester This was carried out as described in Example 4, but using 1.2 equivalents of CCl3COCl. Yield 88%; m / z 286. 1 H-NMR (400MHz, CDCl3):δ 11.2 (1H, s, br.); 8.45 (1H, d); 7, 45 (1H, d); 3.80 (3H, s), 3.73 ppm

Claims

1. General formula (I) 【Chemical 1】 (In the formula, R 1 CF 3 , CF 2 H, C 2 F 5 , CF 2 Cl, -COO- (C 1 ~C 6 )-alkyl, COOH; R 2 is H, (C 1 ~C 6 )-Alkyl, Cl, F, CF 3 , CF 2 Cl, CCl 3 , -O-(C 1 ~C 6 )-alkyl, -O-(C 1 ~C 6 )-Alkylaryl, -COO-(C 1 ~C 6 )-alkyl) A method for preparing a compound of the formula In the first step, a compound of general formula (II) 【Chemistry 2】 (In the formula, R 3 and R 4 are each independently H and (C 1 ~C 6 )-alkyl, R 1 has the definition above) with ammonia to form a compound of the general formula (III) 【Chemistry 3】 (In the formula, R 1 has the definition above) is converted into the compound In a second reaction step, they are reacted in the presence of a dehydrating reagent to give a compound of general formula (IV): 【Chemistry 4】 (In the formula, R 1 has the definition above) to obtain a compound of Then, in the third reaction step, they are reacted with the compound of formula (V) R 2 COX （V） (In the formula, R 2 is as defined above, X is F, Cl, Br, H 3 CSO 2 O, p-TolSO 2 O, -OCOR 2 is) to obtain a compound of general formula (I).

2. 2. The method according to claim 1, characterized in that the radical definitions of the compounds of general formulae (I), (II), (III), (IV) and (V) are as follows: R 1 CF 3 , CF 2 H, CF 2 Cl, C 2 F 5 , COOCH 3 , COOC 2 H 5 and R 2 is H, -(C 1 ~C 4 )-Alkyl, Cl, CF 3 , CF 2 Cl, CCl 3 , -O-(C 1 ~C 4 )-alkyl, -O-CH 2 - Phenyl, COOCH 3 , COOC 2 H 5 and R 3 and R 4 are each independently H or CH 3 and X is F, Cl, -OCOR 2 , H 3 CSO 2 O, p-TolSO 2 It is O.

3. 2. The method according to claim 1, characterized in that the radical definitions of the compounds of general formulae (I), (II), (III), (IV) and (V) are as follows: R 1 COOCH 3 , COOC 2 H 5 and R 2 is methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, CF 3 , -O-methyl, -O-ethyl, -O-propyl, -O-1-methylethyl, -O-butyl, -O-1-methylpropyl, -O-2-methylpropyl, -O-1,1-dimethylethyl, -O-pentyl, -O-1-methylbutyl, -O-2-methylbutyl, -O-3-methylbutyl, -O-2,2-dimethylpropyl, -O-1-ethylpropyl, COOCH 3 and R 3 and R 4 are each independently H or CH 3 and X is Cl, -OCOR 2 , H 3 CSO 2 It is O.

4. 2. The method according to claim 1, characterized in that the radical definitions of the compounds of general formulae (I), (II), (III), (IV) and (V) are as follows: R 1 COOCH 3 , COOC 2 H 5 and R 2 H, CH 3 , CF 3 , -OCH 3 , -OC 2 H 5 , (CH 3 ) 3 CO-, CCl 3 , COOCH 3 , -O-CH 2 -phenyl, R 3 and R 4 is CH 3 and X is Cl, -OCOR 2 is.

5. 2. The method according to claim 1, characterized in that the radical definitions of the compounds of general formulae (I), (II), (III), (IV) and (V) are as follows: R 1 COOCH 3 , COOC 2 H 5 and R 2 CF 3 , -OCH 3 , -OC 2 H 5 , (CH 3 ) 3 CO-, CCl 3 , COOCH 3 , -O-CH 2 -phenyl, R 3 and R 4 is CH 3 and X is Cl.

6. 6. The method according to claim 1, wherein 1:0.1 to 1:5 equivalents of a cyclization reagent are used relative to the compound of general formula (III).

7. The cyclization reagent is SOCl 2 , POCl 3 7. The method according to claim 1, wherein the solvent is oxalyl chloride, phosgene, or HCl.

8. 8. The method according to claim 1, wherein 1:0.9 to 1:2 equivalents of the compound of general formula (IV) are used relative to the compound of general formula (V).

9. 9. The method according to claim 1, wherein triethylamine, Hunig's base, 2-methyl-5-ethylpyridine, 3-picoline, or dimethylcyclohexylamine is used as the base in step 3.

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