Preparation method of 5-bromo-2-chloro-4 '-ethyoxyl diphenylmethane

Abstract

The invention discloses a preparation method of a dapagliflozin intermediate 5-bromine-2-chlorine-4 '-ethyoxyl diphenylmethane, which comprises the following steps: carrying out nucleophilic substitution reaction on 4-bromine-1-chlorine-2-fluorobenzene and 4-ethyoxyl phenylacetate, and then hydrolyzing and decarboxylating to obtain the dapagliflozin intermediate 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane. By optimizing the preparation route, the reaction utilization rate, the product yield and the product purity of the raw materials are improved, high-risk and high-pollution chemicals are prevented from being used, and the method is convenient to operate, safe, environmentally friendly, efficient in reaction and beneficial to industrial implementation.

Description

Technical Field

[0001] The present invention relates to a method for preparing a dapagliflozin intermediate 5-bromo-2-chloro-4'-ethoxydiphenylmethane, and in particular to an efficient and convenient method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane. Background Art

[0002] Dapagliflozin is a SGLT-2 inhibitor, a novel antidiabetic drug used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. 5-Bromo-2-chloro-4′-ethoxydiphenylmethane (4-Bromo-1-chloro-2-(4-ethoxybenzyl)benzene) (Compound 4) is an important intermediate in the preparation of SGLT-2 inhibitors such as dapagliflozin. It is primarily prepared by the Friedel-Crafts reaction of a dihalogenated benzoic acid with phenethyl ether, followed by reduction.

[0003]

[0004] WO2010022313 discloses the reaction of 2-chloro-5-bromobenzoic acid with oxalyl chloride to produce 2-chloro-5-bromobenzoyl chloride, followed by a Friedel-Crafts reaction catalyzed by aluminum chloride, and then a sodium borohydride / aluminum chloride system to reduce the carbonyl group to a methylene group, thereby preparing the aforementioned dapagliflozin intermediate. WO2010009243 discloses the use of triethylsilane / trifluoromethanesulfonic acid to catalyze the reduction of the carbonyl group to a methylene group. This type of preparation method generates large amounts of halogen waste liquid and acidic gases, which are difficult to dispose of, have a significant impact on the environment, and are not conducive to industrialization.

[0005]

[0006] CN114044739 discloses the reaction of 2-chlorobenzoic acid with oxalyl chloride to produce 2-chlorobenzoyl chloride, which is then reacted with iodobenzene via a Friedel-Crafts reaction catalyzed by aluminum trichloride, followed by bromination, reduction, and etherification to produce the aforementioned dapagliflozin intermediate. However, this preparation method does not avoid the production of halogen wastewater, and the bromination reaction exhibits multiple regioselectivities, produces a large number of byproducts, and is difficult to purify, hindering industrialization.

[0007] Summary of the Invention

[0008] Purpose of the invention: The present invention aims to provide a convenient, efficient, safe, environmentally friendly and industrially applicable method for preparing 5-bromo-2-chloro-4′-ethoxydiphenylmethane.

[0009] Technical solution: The preparation method of 5-bromo-2-chloro-4′-ethoxydiphenylmethane of the present invention comprises the following steps:

[0010]

[0011] (1) Compound 1 and Compound 2 undergo a substitution reaction catalyzed by a first base to obtain Compound 3;

[0012] (2) hydrolyzing the compound 3 obtained in step (1) with a second base, and then decarboxylating it with an acid catalysis to obtain 5-bromo-2-chloro-4′-ethoxydiphenylmethane (compound 4);

[0013] In the above synthesis route, the ester groups on compound 2 and compound 3 can be removed by subsequent hydrolysis and decarboxylation reactions, preferably but not limited to methyl ester or ethyl ester.

[0014] Preferably, the first base in step (1) is selected from sodium tert-butoxide, potassium tert-butoxide or sodium hydride.

[0015] More preferably, the first base is sodium hydride.

[0016] Preferably, the molar ratio of compound 1, compound 2 and the first base in step (1) is 1:(1.05-1.3):(1.1-1.4).

[0017] More preferably, the molar ratio of compound 1, compound 2 and the first base is 1:1.1:1.2.

[0018] Preferably, the reaction solvent of step (1) is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

[0019] More preferably, the reaction solvent is dimethyl sulfoxide.

[0020] Preferably, the reaction temperature in step (1) is 50-80°C.

[0021] More preferably, the reaction temperature is 55-75°C.

[0022] Preferably, the second base in step (2) is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0023] More preferably, the second base is selected from sodium hydroxide or potassium hydroxide.

[0024] Preferably, the acid in step (2) is selected from hydrochloric acid, trifluoroacetic acid or sulfuric acid.

[0025] Further preferably, the acid is selected from 36% hydrochloric acid or trifluoroacetic acid;

[0026] More preferably, the acid is 36% hydrochloric acid.

[0027] Preferably, the molar ratio of the compound 3, the second base and the acid in step (2) is 1: (1.5-2.5): (2.8-3.8).

[0028] More preferably, the molar ratio of the compound 3, the second base, and the acid in step (2) is 1:2:3.3.

[0029] Preferably, the reaction solvent for the hydrolysis reaction in step (2) is selected from methanol-water or ethanol-water;

[0030] More preferably, the reaction solvent of the hydrolysis reaction is ethanol-water.

[0031] More preferably, the mass ratio of the second alkali to water is 1:10.

[0032] More preferably, the reaction solvent of the hydrolysis reaction is ethanol-water with a mass ratio of 1: (0.8-1).

[0033] Still more preferably, the reaction solvent of the hydrolysis reaction is ethanol-water with a mass ratio of 1:0.9.

[0034] Preferably, the reaction temperature of the hydrolysis reaction in step (2) is 40-50°C.

[0035] More preferably, the reaction temperature of the hydrolysis reaction is 45°C.

[0036] Preferably, the reaction temperature of the decarboxylation reaction in step (2) is 80-85°C.

[0037] Preferably, the preparation method of the present invention further comprises a crystallization purification step.

[0038] Preferably, the crystallization solvent for the crystallization purification is selected from methanol or ethanol.

[0039] More preferably, the crystallization solvent is ethanol.

[0040] More preferably, the crystallization purification method is to dissolve the crude product at 60-65°C, filter, and then crystallize the filtrate at -10-0°C to obtain the refined product of compound 4.

[0041] Still more preferably, the ratio of the crude product to ethanol is 2.0 to 2.5 m / V.

[0042] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0043] The present invention improves the reaction utilization rate of raw materials, product yield and product purity by optimizing the preparation route, and avoids the use of highly dangerous and highly polluting chemicals. It is convenient to operate, safe and environmentally friendly, and has a high reaction efficiency, which is conducive to industrial implementation. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 HPLC spectrum for purity detection of the target product obtained in reaction 1 of Example 2;

[0045] Figure 2 The target product obtained by reaction 1 in Example 2 1 H-NMR spectrum;

[0046] Figure 3 This is the HPLC spectrum for purity detection of the target product obtained in reaction 2 of Example 2. DETAILED DESCRIPTION

[0047] The technical solution of the present invention will be further described below in conjunction with embodiments.

[0048] Example 1: Preparation of Compound 3

[0049] (1) Reaction 1

[0050]

[0051] To a four-necked flask, add 22.9g of compound 2 and 69g of dimethyl sulfoxide (DMSO) and stir to dissolve. Then, add 4.8g of sodium hydride, and then add 20.7g of compound 1 to the reaction mixture. After the addition of compound 1, incubate at 55°C for 1 hour. The reaction mixture is then added dropwise to 200g of 1N HCl aqueous solution. The mixture is separated, and the organic phase is washed with saturated sodium bicarbonate aqueous solution. The solvent is concentrated under reduced pressure until essentially no fraction remains, at which point concentration is terminated to yield 41.1g of compound 3, a yield exceeding 100%.

[0052] (2) Reaction 2

[0053] To a four-necked flask, add 22.9g of compound 2 and 69g of dimethyl sulfoxide (DMSO) and stir to dissolve. Then, add 11.5g of sodium tert-butoxide, and then add 20.7g of compound 1 to the reaction mixture. After the addition of compound 1, incubate at 75°C for 5 hours. The reaction mixture is then added dropwise to 200g of 1N HCl aqueous solution. The mixture is separated, and the organic phase is washed with saturated sodium bicarbonate aqueous solution. The solvent is concentrated under reduced pressure until virtually no fraction remains, at which point concentration is terminated to yield 39.5g of compound 3 (99.2% yield).

[0054] Example 2: Preparation of Compound 4

[0055]

[0056] (1) Reaction 1

[0057] To a reaction flask, 41.1 g of compound 3 and 120 g of ethanol were added, the temperature was lowered to 15°C, and a solution of 11.2 g of potassium hydroxide and 112.0 g of water was added dropwise. After the addition was complete, the mixture was kept at 45°C for 3 h. 66.7 g of 36% hydrochloric acid was added, the temperature was raised to 85°C, and the reaction was kept at this temperature for 5 h. The ethanol solvent was removed by concentration under reduced pressure, and the mixture was extracted with ethyl acetate (100 g x 2), then washed once with 5% sodium bicarbonate, and concentrated to remove the organic solvent, yielding 38.2 g of an oil. 90 g of ethanol was added to the oil, the temperature was raised to 60°C, and the mixture was filtered while hot. The resulting filtrate was slowly cooled to -10°C for crystallization, filtered, and the filter cake dried to yield 28.5 g of the product, with a yield of 87.7% and a purity of 99.97% (Table 1). 1 H-NMR (DMSO 500MHZ), 6: 7.488 (d, 1H), 7.423 (dd, 1H), 7.373 (d, 1H), 7.118 (d, 2H), 6.845 (d, 2H), 3.985~3.944 (m, 4H), 1.300 (t, 3H).

[0058] Table 1 Purity test results of reaction 1 product

[0059]

[0060] (2) Reaction 2

[0061] To a reaction flask, 39.5 g of compound 3 and 120 g of ethanol were added, the temperature was lowered to 15°C, and a solution of 11.2 g of potassium hydroxide and 112.0 g of water was added dropwise. After the addition was complete, the mixture was kept at 45°C for 3 h. 45.6 g of trifluoroacetic acid was added, the temperature was raised to 85°C, and the reaction was kept at this temperature for 3 h. The ethanol solvent was removed by concentration under reduced pressure, and the mixture was extracted with ethyl acetate (100 g x 2), then washed once with 5% sodium bicarbonate and concentrated to remove the organic solvent, yielding 38.2 g of an oil. 90 g of ethanol was added to the oil, the temperature was raised to 60°C, and the mixture was filtered while hot. The resulting filtrate was slowly cooled to -10°C for crystallization, filtered, and the filter cake dried to yield 25.3 g of the product, with a yield of 77.8% and a purity of 99.97% (Table 2).

[0062] Table 2 Purity test results of reaction 2 products

[0063]

Claims

1. A method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane, characterized in that: The following steps are involved: (1) Compound 1 and Compound 2 undergo a substitution reaction catalyzed by a first base to obtain Compound 3; (2) The compound 3 obtained in step (1) is hydrolyzed by a second base, and then decarboxylated by an acid to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane.

2. The preparation method according to claim 1, characterized in that The first base described in step (1) is selected from sodium tert-butoxide, potassium tert-butoxide or sodium hydride.

3. The preparation method according to claim 1, characterized in that The molar ratio of compound 1, compound 2 and the first base in step (1) is 1:(1.05-1.3):(1.1-1.4).

4. The preparation method according to claim 1, characterized in that The reaction solvent of step (1) is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

5. The preparation method according to claim 1, characterized in that The second base described in step (2) is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.

6. The preparation method according to claim 1, characterized in that The acid described in step (2) is selected from hydrochloric acid, trifluoroacetic acid or sulfuric acid.

7. The preparation method according to claim 1, characterized in that The reaction solvent described in step (2) is selected from methanol-water or ethanol-water.

8. The preparation method according to claim 1, characterized in that The reaction temperature of the decarboxylation reaction described in step (2) is 80-85°C.

9. The preparation method according to claim 1, characterized in that A crystallization purification step is also included.

10. The preparation method according to claim 9, characterized in that The crystallization solvent for the crystallization purification is selected from methanol or ethanol.

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