WO2022069554A1 - Method for producing 4-bromfuran-2-carboxylates - Google Patents

Abstract

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

Description

Process for preparing 4-bromofuran-2-carboxylates

The present invention relates to a process for the preparation of 4-bromofuran-2-carboxylates of the general formula (I) and their use as important precursors for the synthesis of agrochemical and pharmaceutical active ingredients.

4-Bromofuran-2-carboxylates of the general formula (I), especially R ^{1 =} COOmethyl, are important precursors of agrochemical (cf. WO 2018/228985) and pharmaceutical active substances (e.g. 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 the general formula (I) are used as starting materials for the production of tetrahydro- and dihydrofurancarboxylic acids and esters (F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 ).

The reaction to form methyl 4,5-dibromofuran-2-carboxylate is described in the European Journal of Medicinal Chemistry, 2016, 117, 47 and Journal of Agricultural and Food Chemistry, 2017, 65, 5397 and in CN105503832. 2.2 equivalents of aluminum chloride are used here. The maximum yield is 78%. Under these conditions, however, large amounts of a secondary component (20-30%) are formed which cannot be separated or can only be separated with difficulty. In addition, the lower reaction temperatures lead to severe incrustations on the reactor wall and incomplete conversions as a result of impeded stirrability.

Alternatively, the preparation of methyl 4-bromofuran-2-carboxylate can be achieved by reacting 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. The disadvantages are lower yields, the necessary low reaction temperatures and the waste-intensive aqueous work-up. In addition, working with isopropylmagnesium chloride on a commercial scale is difficult and expensive.

Alternatively, butyllithium can be used for the synthesis of methyl 4-bromofuran-2-carboxylate. This reaction can be found in the literature, for example in EP1489077. However, it is known that butyllithium can only be handled to a limited extent and is difficult to handle on a large scale, also due to the low temperatures.

Another possibility is the preparation of methyl 4-bromofuran-2-carboxylate using ammonium chloride and zinc as reagents. This reaction is described in F. Brucoli, et al. organic & Medicinal Chemistry, 20(6), 2019-2024; 2012 and US 2016/0264544, the yields are lower and large amounts of salt have to be used.

In the light of the prior art described above, the present invention has the object of finding a process for preparing the compounds mentioned, so that the compounds of general formula (I) can be obtained in higher yield, in high purity and in an environmentally friendly manner, so that important Intermediates for the production of active ingredients can be produced on an industrial scale.

worin The object described above is achieved by a process for preparing compounds of the general formula (I)

wherein

worin R ¹ is COO(Ci-C ₄ )-alkyl, characterized in that the compounds of general formula (II)

wherein

worin R ¹ has the meanings given above in the presence of 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of the general formula (II) - and bromine to form compounds of the general formula (III).

wherein

R ¹ has the meanings given above and reacted further with 1.0 to 1.5 equivalents of zinc and ammonium chloride to give compounds of the formula (I).

Preferred radical definitions for the compounds of the general formulas (I), (II) and (III) are the following:

R1 represents _COOCH3 , ^COOC2 _H5 .

Particularly preferred radical definitions for the compounds of the general formulas (I), (II) and (HI) are the following:

R1 represents ^COOCH3 .

Explanation of the processes and intermediates

Scheme 1

The compounds of the general formula (II) react in the presence of 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of the general formula (II) - and bromine to give compounds of the general formula (III), which further react with 1.0 to 1.5 equivalents of zinc and ammonium chloride are converted into compounds of the formula (I).

Step 1

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

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

The reaction is usually carried out in a temperature range of -10 - 30°C. The reaction is preferably carried out at 0-30.degree. C., very particularly preferably at 5-20.degree.

The reaction is usually carried out in a chlorinated solvent, preferred are dichloromethane and dichloroethane, most preferred is dichloromethane.

By reducing the equivalents of aluminum chloride used, based on the compound of the general formula (II), the yields of (II) achieved could be increased to >85% compared to the prior art (about a maximum of 78%). In addition, the amount of secondary components formed could be reduced to 5-10% and the compounds could therefore be worked up or isolated of the general formula (II) can be significantly simplified. Isolation can be carried out by methods well known to those skilled in the art, for example extraction, distillation of the solvent and crystallization. However, in the context of the present invention, the crude product is preferably used further directly after changing to a solvent that is preferred in step 2.

step 2

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

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

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

The reaction is usually carried out in a solvent, preference being given to methanol.

The conversion into compounds of the general formula (I) can be carried out from isolated material of the compounds of the general formula (II) according to the preferred reaction conditions. The compounds of the general formula (II) from step 1 are preferably used directly in step 2 without intermediate isolation after a distillative change of the solvent. The solvent is preferably exchanged at temperatures from 20.degree. C. to 100.degree. C., very preferably from 30.degree. C. to 60.degree. The distillation can be carried out under standard conditions or reduced pressure, particularly preferably at 50 mbar to 1000 mbar, very particularly preferably at 200 mbar to 550 mbar.

Surprisingly, it has now been found that the sub-stoichiometric addition of a desiccant, for example sodium sulfate, is advantageous in terms of reducing the amount of zinc and increasing the yield. Although small traces of water can be tolerated in the system, larger amounts lead to sticking of the added zinc. The consequence of this is that there is no longer sufficient reactivity and therefore significantly higher amounts of zinc are required for complete conversion. This also has the advantage that complex drying and distillation processes between stages 1 and 2 are no longer necessary.

The direct use of the compounds of the general formula (II) without intermediate isolation and the reduction in the starting materials enabled the overall yield to be compared to the prior art (cf. max. 70%) can be increased to >80% over both stages with high purity. In addition, the amount of waste was significantly reduced, thereby improving the impact of the process on the environment.

examples

The present invention is explained in more detail using the following examples, without restricting the invention to these.

measurement method

The products were characterized by ¹ H NMR.

example 1

Step 1: Methyl 4,5-dibromofuran-2-carboxylate (111-1)

In a 2L jacketed reactor with a mechanical stirrer, 1100 mL of dichloromethane were placed under argon and 296.0 g (1.4 eq) of aluminum trichloride were suspended. With cooling, 200.0 g (1.0 eq) of methyl 2-furancarboxylate were metered in at <5° C. over a period of 45 minutes. After the metered addition was complete, the mixture was heated to 22° C. and stirred at this temperature for 60 minutes. It was then cooled again to 14-15° C. and 499.2 g (2.0 eq) of bromine were metered in at this temperature over a period of 2.5 h, while the acidic waste gases formed were discharged through a basic gas scrubber. After the metering was complete, stirring was continued at this temperature for a further 1.5 h and the reaction mixture was then metered over 2 h at <10° C. to 32.5 g (0.1 eq) of sodium pyrosulfite, dissolved in 1500 mL of water. After the addition was complete, the mixture was heated to 22° C., the phases were separated and the organic phase was washed with 300 mL 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 taken up in 2400 mL of methanol and used directly in the second stage without further purification: conversion 97 area% (HPLC)

An analytical sample of the pure compound was obtained after isolation by removing the solvent by distillation and drying the solid in vacuo at 30°C.

'H-NMR (400MHz, CDC1 ₃ ): 5 = 3.90 (s, 3H), 7.46 (s, 1H) ppm.

Step 2: Methyl 5-bromofuran-2-carboxylate (1-1)

The solution of methyl 4,5-dibromofuran-2-carboxylate (1.0 eq) in 2400 mL of methanol from step 1 (Example 1, (III-l)) was prepared in a 4L jacketed reactor with a mechanical stirrer. submitted and treated with 232.8 g (3.0 eq) of ammonium chloride. The suspension was heated to 30° C. and, after the addition of 51.5 g (0.25 eq) sodium sulfate, stirred at this temperature for 45 min. Then 106.4 g (1.1 eq) of zinc powder were added in 6 portions over 2 hours. After the addition was complete, the mixture was heated to 45° C. and stirred at this temperature for 30 min. After the conversion was complete (HPLC check), the suspension was cooled to <10° C., filtered and the filter cake rinsed with 300 mL ice-cold methanol. The combined filtrates were concentrated at 200 mbar and 35° C., and the residue was taken up in 1000 mL of n-heptane at 35° C. After removal of the remaining methanol and azeotropic drying of the organic phases, the organic phase was washed twice at 40° C. with 300 ml of 10% by weight HCl each time after addition of 175 ml of /e/7-butyl methyl ether. After renewed 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. Inoculation can optionally be carried out at 30 °C. It was then cooled to 0 °C for 6 h and the product was obtained as a colorless to slightly beige solid after filtration and washing the filter cake twice with 75 mL cold n-heptane each time: Yield 248 g (83% of theory over 2 stages, > 99 wt.%).

'H-NMR (400MHz, CDC1 ₃ ): 5 = 3.90 (s, 3H), 7.18 (s, 1H), 7.57 (s, 1H) ppm.

Comparative example with 2.2 eq AICI3

In a 250 mL 4-neck round bottom flask, 50 mL dichloromethane were placed under argon and the solution was cooled to <5° C. after the addition of 10.0 g (1.0 eq) methyl 2-furancarboxylate. At this temperature, 23.0 g (2.2 eq) of aluminum trichloride were added in portions and the suspension was stirred for 15 minutes. At the same temperature, 25.0 g (2.0 eq) of bromine were metered in over 30 minutes, the reaction mixture was heated to 20-22° C. after metering was complete and stirred at this temperature for 1 hour and stored under argon overnight. The reaction mixture was then added in portions 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 ethyl acetate and the organic phase was washed with 50 mL water. Removal of the solvent under reduced pressure at 30°C afforded the product as a dark orange solid: yield 17.4 g

1H-NMR analysis showed about 24% methyl 4,5-dibromo-2-carboxylate together with 75% methyl 4-bromo-5-chloro-2-carboxylate. Without storing the reaction mixture overnight under argon, the proportion of the target product can be increased to 60-70%. A depletion of approx. However, due to the comparable chemical properties, 20-30% of the secondary component is only possible with large losses of the product.

Claims

Patent Claims: 1. Process for preparing compounds of general formula (I)

(I), wherein R ¹ is COO(Ci-C ₄ )-alkyl, characterized in that the compounds of general formula (II)

(II), wherein R ¹ has the meanings given above in the presence of 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of the general formula (II) - and bromine to form compounds of the general formula (III).

wherein R ¹ has the meanings given above and are further reacted with 1.0 to 1.5 equivalents of zinc and ammonium chloride to give compounds of the formula (I). 2. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II) and (III) are the following: R ¹ represents COOCH ₃ , COOC ₂ H ₅ . 3. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II) and (III) are the following: R1 represents ^COOCH3 . 4. The method according to any one of claims 1 to 3, characterized in that 1.3 - 1.4 equivalents of aluminum chloride based on the compounds of general formula (II) are used. 5. The method according to any one of claims 1 to 4, characterized in that 1.9 - 2.2 equivalents of bromine are used based on the compounds of general formula (II). 6. The method according to any one of claims 1 to 5, characterized in that 1.1 - 1.2 equivalents of zinc are used based on the compounds of general formula (II). 7. The method according to any one of claims 1 to 6, characterized in that 2.8 - 3.2 equivalents of ammonium chloride based on the compounds of general formula (II) are used. 8. The method according to any one of claims 1 to 7, characterized in that the Solvent in the first reaction step is dichloromethane. 9. The method according to any one of claims 1 to 8, characterized in that the Solvent in the second reaction step is methanol.