TW202222790A - Method for preparing 4-bromofuran-2- carboxylates - Google Patents

Abstract

The present invention relates to a method for preparing 4-bromofuran-2-carboxylates of the general formula ( I) and to the use thereof as important precursors for the synthesis of agrochemical and pharmaceutical active substances.

Description

Process for preparing 4-bromofuran-2-carboxylate

The present invention relates to a method for preparing 4-bromofuran-2-carboxylate of general formula ( I ) and its use as an important precursor for synthesizing agrochemical and pharmaceutical active substances.

4-Bromofuran-2-carboxylates of general formula ( I ) (especially R ¹ =COO methyl) are important precursors for agrochemicals (see WO 2018/228985) and pharmaceutically active substances (Craig et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002 ; F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 ).

4-Bromofuran-2-carboxylates of general formula ( I ) were used as starting materials for the preparation of tetrahydro and dihydrofuran carboxylic acids and esters (F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6) , 2019-2024; 2012 ).

The reaction for methyl 4,5-dibromofuran-2-carboxylate is described in European Journal of Medicinal Chemistry, 2016 , 117 , 47, Journal of Agricultural and Food Chemistry, 2017 , 65 , 5397 and CN105503832. The reaction used 2.2 equivalents of aluminum chloride. The maximum yield was 78%. However, these conditions result in the formation of relatively large amounts (20-30%) of by-products that cannot be removed or are difficult to remove. In addition, lower reaction temperatures can result in substantial fouling of the reactor walls and incomplete conversion due to impeded agitation.

The preparation of methyl 4-bromofuran-2-carboxylate can additionally be achieved by the reaction of methyl 4,5-dibromofuran-2-carboxylate with isopropylmagnesium chloride. This reaction is described in European Journal of Medicinal Chemistry, 2016 , 117 , 47, CN105503832 and WO 2008/98104. Disadvantages are relatively low yields, the need for low reaction temperatures and intensive wastewater treatment. Furthermore, processing isopropylmagnesium chloride on an industrial scale is challenging and expensive.

As an alternative, it is also possible to synthesize methyl 4-bromofuran-2-carboxylate from tertiary butyllithium. This reaction is found in documents such as EP1489077. However, it is known that butyllithium - also due to the low temperature - can only be processed on a large scale to a limited extent and with difficulty.

A further option is to synthesize methyl 4-bromofuran-2-carboxylate using ammonium chloride and zinc as reagents. This reaction is described in F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 and US 2016/0264544, with low yields and requiring large amounts of salt.

In view of the above-mentioned prior art, the object of the present invention is to find a process for the preparation of the so-called compounds, so that the compounds of general formula ( I ) can be obtained in higher yields, in high purity and in an environmentally friendly manner, in Important intermediates for the preparation of active substances are produced on an industrial scale.

( I)， 其中 R ¹為COO(C ₁-C ₄)烷基， 其特徵在於通式( II)化合物

( II)， 其中 R ¹係如上面之定義， 在1.0至1.8當量之氯化鋁 – 以通式( II)化合物為基準 – 與溴存在下反應以形成通式( III)化合物，

( III) 其中 R ¹係如上面之定義， 且係進一步與1.0至1.5當量之鋅和氯化銨反應以形成式( I)化合物。 The above objects are achieved by a method for the preparation of compounds of general formula ( I )

( I ), wherein R ¹ is COO(C ₁ -C ₄ ) alkyl, which is characterized by a compound of general formula ( II )

( II ), wherein R1 is as defined above, and 1.0 to ^1.8 equivalents of aluminum chloride - based on the compound of general formula ( II ) - is reacted with bromine to form the compound of general formula ( III ),

( III ) wherein R1 is as defined above, and is further reacted with 1.0 to ^1.5 equivalents of zinc and ammonium chloride to form compounds of formula ( I ).

Preferred definitions of the groups in the compounds of general formula ( I ), ( II ) and ( III ) are as follows: R ¹ is COOCH ₃ , COOC ₂ H ₅ .

Particularly preferred definitions of the groups in the compounds of formula ( I ), ( II ) and ( III ) are as follows: R ¹ is COOCH ₃ .

Illustration of methods and intermediates Flowchart 1

A compound of general formula ( II ) is reacted in the presence of 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of general formula ( II ) - with bromine to form a compound of general formula ( III) which is further combined with 1.0 to 1.5 equivalents of zinc and ammonium chloride to form compounds of formula ( I ). Step 1

1.0 to 1.8 equivalents of aluminium chloride are used - based on the compound of general formula ( II ), preferably 1.2 to 1.5 equivalents, very particularly preferably 1.3 to 1.4 equivalents.

1.8 to 3.0 equivalents of bromine are used - based on the compound of general formula ( II ), preferably 1.9 to 2.2 equivalents, very particularly preferably 2.0 equivalents.

The reaction is usually carried out at a temperature ranging from -10 to 30°C. The reaction is preferably carried out at 0 to 30°C, very particularly preferably within 5 to 20°C.

The reaction is generally carried out in a chlorinated solvent, preferably dichloromethane or dichloroethane, very particularly preferably dichloromethane.

Reducing the number of equivalents of aluminium chloride used - based on the compound of general formula ( II ) - increased the yield of ( III ) obtained to > 85% compared to the previous technique (see max. 78%). Furthermore, the amount of by-products formed is reduced to 5 to 10%, making the handling/isolation of the compound of general formula ( III ) easier. Isolation can be accomplished by methods known to those of ordinary skill in the art, eg, extraction, distillation of solvent, and crystallization. However, in the context of the present invention it is preferred - after switching to the preferred solvent in step 2 - to further use the crude product directly. Step 2

1.0 to 1.5 equivalents of zinc are used - based on the compound of general formula ( II ), preferably 1.1 to 1.3 equivalents, very particularly preferably 1.1 to 1.2 equivalents.

2.0 to 4.0 equivalents of ammonium chloride are used - based on the compound of general formula ( II ), preferably 2.5 to 3.5 equivalents, very particularly preferably 2.8 to 3.2 equivalents.

The reaction is usually carried out in the temperature range of -10 to 60°C. The reaction is preferably carried out at 10 to 50°C, very particularly preferably within 30 to 50°C.

The reaction is usually carried out in a solvent, preferably methanol.

The isolated material of the compound of general formula ( III ) can be converted to the compound of general formula ( I ) according to the preferred reaction conditions. Preferably, the compound of general formula ( II ) in step 1 is directly used in step 2 without intermediate separation after solvent distillation conversion. Solvent exchange is preferably carried out at a temperature of 20°C to 100°C, most preferably 30°C to 60°C. The distillation can be carried out under standard conditions or under reduced pressure, particularly preferably at 50 mbar to 1000 mbar, very particularly preferably at 200 mbar to 550 mbar.

It has now surprisingly been found that substoichiometric addition of a desiccant, such as sodium sulfate, is advantageous in reducing the amount of zinc and in high yields. Although small amounts of water can be tolerated in the system, large amounts can cause the added zinc to agglomerate. As a result, sufficient reactivity is no longer achieved, meaning that a considerable amount of zinc is required for complete conversion. A further advantage of this is that the laborious drying and distillation process between steps 1 and 2 is no longer required.

Using the compound of general formula ( III ) directly without intermediate isolation, and reducing starting material, the overall yield in two steps increased to > 80% in two steps, with high purity. The waste volume is also significantly reduced, thereby improving the environmental impact of the method. Example

The invention is illustrated in more detail by the following examples, but the invention is not limited thereto. Measurement methods

The product was confirmed by ¹ H NMR. Example 1 Step 1 : Methyl 4,5 -dibromofuran -2- carboxylate (III-1)

A 2-liter jacketed reactor equipped with a mechanical stirrer was charged with 1100 mL of dichloromethane under argon, and 296.0 g (1.4 equiv.) of aluminum trichloride was suspended therein. The suspension was cooled and 200.0 g (1.0 equiv.) of methyl 2-furancarboxylate were metered in over a period of 45 minutes at <5°C. At the end of the metered addition, the reaction mixture was warmed to 22° C. and stirred at this temperature for 60 minutes. After cooling to 14 to 15°C again, 499.2 g (2.0 equiv.) of bromine are metered in over a period of 2.5 hours at this temperature, while the acid gas is passed through the alkaline gas scrubber. At the end of the metered addition, the reaction mixture was stirred for a further 1.5 hours at this temperature, and then 1500 ml of an aqueous solution containing 32.5 g (0.1 eq) of sodium metabisulfite was metered in over a period of 2 hours at <10°C. At the end of the addition, the mixture was warmed to 22°C, the phases were separated and the organic phase was washed with 300 mL of water. The organic phase was washed again with 230 mL of saturated sodium bicarbonate solution, the solvent was removed under reduced pressure, and the residue was dissolved in 2400 mL of methanol and used directly in the second step without further purification: conversion 97 Area % (HPLC).

Analytical samples of pure compounds were taken after isolation by distillative removal of the solvent and drying of the solids under reduced pressure at 30°C.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 3.90 (s, 3H), 7.46 (s, 1H) ppm. Step 2 : Methyl 5- bromofuran -2- carboxylate (I-1)

A solution of 4,5-dibromofuran-2-carboxylate (1.0 equiv) in methanol containing 2400 mL of methyl 4,5-dibromofuran-2-carboxylate (1.0 equiv) from step 1 (Example 1, (III-1)) was loaded into 4 equipped with a mechanical stirrer. A jacketed reactor was added and 232.8 grams (3.0 equiv.) of ammonium chloride was added. The suspension was warmed to 30°C and, after adding 51.5 g (0.25 equiv) of sodium sulfate, was stirred at this temperature for 45 minutes. Subsequently, 106.4 grams (1.1 equiv) of zinc powder was added in 6 portions over 2 hours. At the end of the addition, the mixture was heated to 45°C and stirred at this temperature for 30 minutes. Once the reaction was complete (monitored by HPLC), the suspension was cooled to <10°C, filtered, and the filter cake was washed with 300 mL of ice-cold methanol. The combined filtrates were concentrated at 200 mbar and 35°C, and the residue was dissolved in 1000 ml of n-heptane at 35°C. After removal of residual methanol and azeotropic drying of the organic phase, 175 mL of tert-butyl methyl ether was added to the organic phase and washed with two 300 mL portions of 10% (by weight) HCl at 40°C . After re-azeotropic drying of the organic phase and partial removal of the solvent under reduced pressure at 40°C, the organic phase was cooled to 30°C and the product crystallized at 25°C to 30°C. Seeding can be optionally performed at 30°C. Subsequently, cooling to 0°C over a period of 6 hours, and after filtration and washing of the filter cake with two 75 ml portions of cold n-heptane, the product was obtained as a colourless to pale beige solid: yield 248 g (in 83% of theory in 2 steps, > 99% by weight).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 3.90 (s, 3H), 7.18 (s, 1H), 7.57 (s, 1H) ppm. Comparative example with 2.2 equivalents of _AlCl

A 250 mL 4-neck round bottom flask was charged with 50 mL of dichloromethane under argon, 10.0 g (1.0 equiv) of methyl 2-furancarboxylate was added, and the solution was cooled to <5°C. 23.0 g (2.2 equiv.) of aluminium trichloride were added portionwise at this temperature and the suspension was stirred for 15 minutes. Subsequently, 25.0 g (2.0 equiv.) of bromine are metered in over a period of 30 minutes at the same temperature, and at the end of the metered addition, the reaction mixture is warmed to 20 to 22° C., stirred at this temperature for 1 hour, and heated at this temperature for 1 hour. Store under argon overnight. Subsequently, the reaction mixture was added portionwise to a mixture of 60 g of ice, 10 g of water and 10 ml of saturated sodium sulfite solution. The phases were separated, the organic phase was diluted with 100 mL of ethyl acetate and washed with 50 mL of water. The solvent was removed under reduced pressure at 30°C to obtain the product as a dark orange solid: 17.4 g yield.

¹ H-NMR analysis showed about 24% methyl 4,5-dibromo-2-carboxylate and 75% methyl 4-bromo-5-chloro-2-carboxylate. Omitting the overnight storage of the reaction mixture under argon increased the separation of the target product by 60 to 70%. However, comparable chemistry means that about 20 to 30% of the by-product components may be depleted only when there is a significant loss of product.

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Claims (9)

A kind of method for preparing compound of general formula ( I )

( I ), wherein R ¹ is COO(C ₁ -C ₄ ) alkyl, which is characterized by a compound of general formula ( II )

( II ), wherein R1 is as defined above, and 1.0 to ^1.8 equivalents of aluminum chloride - based on the compound of general formula ( II ) - is reacted with bromine to form the compound of general formula ( III ),

( III ) wherein R1 is as defined above, and is further reacted with 1.0 to ^1.5 equivalents of zinc and ammonium chloride to form compounds of formula ( I ). The method of claim 1, characterized in that the groups in the compounds of general formula ( I ), ( II ) and ( III ) are defined as follows: R ¹ is COOCH ₃ , COOC ₂ H ₅ . The method of claim 1, characterized in that the groups in the compounds of general formula ( I ), ( II ) and ( III ) are defined as follows: R ¹ is COOCH ₃ . The method according to any one of claims 1 to 3, characterized in that 1.3 to 1.4 equivalents of aluminum chloride are used, based on the compound of general formula ( II ). The method of any one of claims 1 to 4, characterized in that 1.9 to 2.2 equivalents of bromine are used, based on the compound of general formula ( II ). The method according to any one of claims 1 to 5, characterized in that 1.1 to 1.2 equivalents of zinc are used, based on the compound of general formula ( II ). The method according to any one of claims 1 to 6, characterized in that 2.8 to 3.2 equivalents of ammonium chloride are used, based on the compound of general formula ( II ). The method according to any one of claims 1 to 7, characterized in that the solvent in the first reaction step is dichloromethane. The method according to any one of claims 1 to 8, characterized in that the solvent in the second reaction step is methanol.