Preparation method of mandelic acid derivative

Abstract

The invention relates to a preparation method of a mandelic acid derivative, which adopts a commercially available conventional p-chlorphenyl magnesium bromide reagent as a raw material, the cost is low, the p-chlorphenyl magnesium bromide reagent is easy to obtain, the cost of the raw material is reduced by more than 40%, and the synthesis steps are simple, the cost is lower, the toxicity is lower, the operation is convenient, and the safety is high.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of mandelic acid derivatives. Background Art

[0002] As key organic synthesis intermediates, mandelic acid derivatives have important application values in the pharmaceutical and pesticide industries. A typical representative is the anti-gout drug arnofenate with its core structure.

[0003] The prior art discloses a synthesis method of (4-chlorophenyl)-prop-2-ynoxyacetate, which is obtained from p-chlorobenzaldehyde and propargyl ester through multiple steps such as addition, chlorination, cyanidation, and esterification. There are problems such as multiple steps, low overall yield, and high cost.

[0004] Therefore, a preparation method of mandelic acid derivatives is needed to reduce costs and be suitable for industrial production. Summary of the Invention

[0005] To solve the existing problems, the present invention provides a preparation method of mandelic acid derivatives. Starting from p-chlorophenylmagnesium bromide, the steps are significantly simplified and the cost is reduced. The reaction conditions are further optimized, and the reaction safety is improved at the same time. It is a new synthetic route suitable for industrial production.

[0006] The present invention relates to a preparation method of mandelic acid derivatives, and the mandelic acid derivative is shown as formula (Ⅰ):

[0007]

[0008] The method includes:

[0009] (1) Reacting p-chlorophenylmagnesium bromide with a compound of formula (Ⅳ) to obtain a compound of formula (Ⅲ);

[0010] (2) Reacting the compound of formula (Ⅲ) with a compound of formula (Ⅱ) in a basic environment to obtain a compound of formula (Ⅰ);

[0011] wherein, R is selected from methyl, ethyl, propyl, isopropyl or tert-butyl; and X is selected from chlorine or bromine;

[0012] .

[0013] Among them, in step (1), the solvent added in the reaction is selected from one or more of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, toluene or methylcyclopentyl ether;

[0014] Among them, in step (1), in terms of molar amount, the ratio of p-chlorophenylmagnesium bromide to the compound of formula (Ⅳ) is 1:1 - 1.3.

[0015] Among them, in step (1), the reaction temperature is -10 to 50 °C, preferably -5 to 15 °C.

[0016] Among them, in step (1), the reaction time is 1 to 10 hours, preferably 1 to 5 hours.

[0017] Preferably, in step (1), MPA (hexamethylphosphoric triamide) or DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone) can be added as an auxiliary agent.

[0018] Furthermore, in terms of molar amount, the ratio of p-chlorophenylmagnesium bromide to the auxiliary agent is 1:0.01 - 0.1, preferably 1:0.01 - 0.05.

[0019] Specifically, in step (1), p-chlorobromobenzene reacts with magnesium shavings in an organic solvent to obtain p-chlorophenylmagnesium bromide; then the p-chlorophenylmagnesium bromide is added dropwise to the solution of the compound of formula (IV), controlling the temperature at -10~50 °C. After the addition is completed, it is stirred well. After the reaction is completed, the reaction solution is poured into a mixture of ice and dilute sulfuric acid, and layered. The organic layer is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the compound of formula (III). Or the reaction is quenched with sulfuric acid, the pH is adjusted to acidic, ethyl acetate is added for extraction, and the organic phase is concentrated under reduced pressure to obtain the crude product of the compound of formula (III).

[0020] Among them, in step (2), the base added in the reaction is selected from one or more of sodium hydroxide, potassium hydroxide, and sodium hydride.

[0021] Among them, in step (2), the molar ratio of the compound of formula (III) to the compound of formula (II) is 1:1 - 1.5.

[0022] Among them, in step (2), the reaction temperature is -10 to 100 °C, preferably 0 to 60 °C.

[0023] Among them, in step (2), the reaction time is 1 to 10 hours, preferably 1 to 5 hours.

[0024] Among them, in step (2), the solvent added in the reaction is selected from one or more of toluene, water, chlorobenzene, DMF, DMAc, acetonitrile, N-methylpyrrolidone, or dimethyl sulfoxide.

[0025] Among them, when the reaction solvent in step (2) includes water, a phase transfer catalyst is added to the system, and the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium hydrogensulfate, polyethylene glycol 800, and crown ether.

[0026] Specifically, in step (2), the compound of formula (III) reacts with the compound of formula (II) in a strong base environment at -10 - 100 °C for 1 - 10 hours until the conversion of the compound of formula (III) is completed. The reaction system is added with water and separated into layers, and the organic phase is concentrated under reduced pressure to obtain the compound of formula (I).

[0027] Beneficial effects:

[0028] The present invention uses a commercially available conventional p-chlorophenylmagnesium bromide reagent as a raw material, which has low cost and is easy to obtain. The raw material cost is reduced by more than 40%. Moreover, the synthesis steps are simple, the cost is low, the toxicity is low, the operation is convenient, and the safety is high.

[0029] The present invention completes the synthesis of the target product through two-step reactions, shortening the process by more than 50% compared with the four-step reaction of the prior art. The total yield of the route of the present invention can reach up to 80% at most, and the total yield is increased by 10% - 15% compared with the prior art. Description of the drawings

[0030] Figure 1 1H NMR spectrum of the compound of formula (III) in Example 1 1 1H NMR spectrum.

[0031] Figure 2 1H NMR spectrum of the compound of formula (I) in Example 1 1 1H NMR spectrum. Detailed implementation manners

[0032] Example 1

[0033] 1) Synthesis of the compound of formula (III)

[0034] 215.7 g of p-chlorophenylmagnesium bromide Grignard reagent (1 mol, 1 eq) was added dropwise to a tetrahydrofuran solution of 95.1 g of methyl formylformate (1.08 mol, 1.08 eq) at a reaction temperature of 0 °C. After the addition was completed, the mixture was stirred and reacted for 2 h. After the reaction was completed, 200 g of 15% sulfuric acid was added to quench the reaction, and the pH was adjusted to 3 - 4. The mixture was extracted with ethyl acetate (3 × 250 mL), and the organic phase was concentrated under reduced pressure to obtain 167.5 g of methyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 83.5%.

[0035] 2) Synthesis of the compound of formula (I)

[0036] Under the protection of an inert gas, 167.5 g (0.835 mol, 1 eq) of the above product was mixed with 68.5 g of 3-chloropropyne (0.919 mol, 1.1 eq) in 300 ml of chlorobenzene, 47.6 g of potassium hydroxide (0.85 mol) was added, and the reaction was carried out at 0 °C for 3 h. Water was added and the layers were separated. The organic phase was concentrated under reduced pressure to obtain 190.1 g of methyl 2-(4-chlorophenyl)-2-(prop-2-ynyloxy)acetate, with a yield of 95.4%.

[0037] Example 2

[0038] 1) Synthesis of the compound of formula (III)

[0039] 215.7 g of p-chlorophenylmagnesium bromide Grignard reagent (1 mol, 1 eq) was added dropwise to a solution of 110.3 g of ethyl formylformate (1.08 mol, 1.08 eq) in tetrahydrofuran at a reaction temperature of 0 °C. After the addition was complete, the mixture was stirred for 2 h. After the reaction was completed, 200 g of 15% sulfuric acid was added to quench the reaction, and the pH was adjusted to 3-4. The mixture was extracted with ethyl acetate (3 × 250 mL), and the organic phase was concentrated under reduced pressure to obtain 181.5 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 84.6%.

[0040] 2) Synthesis of the compound of formula (I)

[0041] Under the protection of an inert gas, the above product 181.5 g (0.846 mol, 1 eq) and 68.5 g of 3-chloropropyne (0.919 mol, 1.1 eq) were mixed in 300 ml of chlorobenzene, and 47.6 g of potassium hydroxide (0.85 mol) was added. The reaction was carried out at 0 °C for 3 h. Water was added and the layers were separated. The organic phase was concentrated under reduced pressure to obtain 202.7 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-ynyloxy)acetate, with a yield of 94.8%.

[0042] z Example 3

[0043] 1) Synthesis of the compound of formula (III)

[0044] 215.7 g of p-chlorophenylmagnesium bromide Grignard reagent (1 mol, 1 eq) was added dropwise to a solution of 110.3 g of ethyl formylformate (1.08 mol, 1.08 eq) in tetrahydrofuran at a reaction temperature of 10 °C. After the addition was complete, the mixture was stirred for 1.5 h. After the reaction was completed, 200 g of 15% sulfuric acid was added to quench the reaction, and the pH was adjusted to 3-4. The mixture was extracted with ethyl acetate (3 × 250 mL), and the organic phase was concentrated under reduced pressure to obtain 176.6 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 82.3%.

[0045] 2) Synthesis of the compound of formula (I)

[0046] Under the protection of an inert gas, the above product 176.6 g (0.823 mol, 1 eq) was mixed with 68.5 g of 3-chloropropyne (0.919 mol, 1.1 eq) in 300 ml of chlorobenzene, and 47.6 g of potassium hydroxide (0.85 mol) was added. The reaction was carried out at 5 °C for 3 h. Water was added and the layers were separated. The organic phase was concentrated under reduced pressure to obtain 191.5 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-ynyloxy)acetate, with a yield of 92.1%.

[0047] Example 4

[0048] 215.7 g of p-chlorophenylmagnesium bromide Grignard reagent (1 mol, 1 eq) was added dropwise to a tetrahydrofuran solution of 95.1 g of methyl formylformate (1.08 mol, 1.08 eq), 1.8 g of MPA (hexamethylphosphoric triamide) was added, the reaction temperature was 10 °C. After the addition was completed, the mixture was stirred for 1 h. After the reaction was completed, 200 g of 15% sulfuric acid was added to quench the reaction, the pH was adjusted to 3-4, and the mixture was extracted with ethyl acetate (3×250 mL). The organic phase was concentrated under reduced pressure to obtain 181.3 g of methyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 90.4%.

[0049] Example 5

[0050] 215.7 g of p-chlorophenylmagnesium bromide Grignard reagent (1 mol, 1 eq) was added dropwise to a tetrahydrofuran solution of 110.3 g of ethyl formylformate (1.08 mol, 1.08 eq), 1.3 g of DMPU was added, the reaction temperature was 10 °C. After the addition was completed, the mixture was stirred for 1 h. After the reaction was completed, 200 g of 15% sulfuric acid was added to quench the reaction, the pH was adjusted to 3-4, and the mixture was extracted with ethyl acetate (3×250 mL). The organic phase was concentrated under reduced pressure to obtain 196.3 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 91.5%.

[0051] Example 6

[0052] 215.7 g of p-chlorophenylmagnesium bromide Grignard reagent (1 mol, 1 eq) was added dropwise to a tetrahydrofuran solution of 125.4 g of isopropyl formylformate (1.08 mol, 1.08 eq), the reaction temperature was 0 °C. After the addition was completed, the mixture was stirred for 2 h. After the reaction was completed, 200 g of 15% sulfuric acid was added to quench the reaction, the pH was adjusted to 3-4, and the mixture was extracted with ethyl acetate (3×250 mL). The organic phase was concentrated under reduced pressure to obtain 191.3 g of isopropyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 83.7%.

[0053] Example 7

[0054] 215.7 g of p-chlorophenylmagnesium bromide Grignard reagent (1 mol, 1 eq) was added dropwise to a tetrahydrofuran solution of 140.5 g of tert-butyl formylformate (1.08 mol, 1.08 eq), the reaction temperature was 0 °C. After the addition was completed, the mixture was stirred for 2 h. After the reaction was completed, 200 g of 15% sulfuric acid was added to quench the reaction, the pH was adjusted to 3-4, and the mixture was extracted with ethyl acetate (3×250 mL). The organic phase was concentrated under reduced pressure to obtain 206.4 g of tert-butyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 85.1%.

[0055] Example 8

[0056] Under the protection of inert gas, 167.5 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (0.835 mol, 1 eq) was mixed with 109.4 g of 3-bromopropyne (0.92 mol, 1.1 eq) in 300 ml of chlorobenzene, and 47.6 g of potassium hydroxide (0.85 mol) was added. The reaction was carried out at 0 °C for 3 h. The organic phase was separated, and 199.6 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-ynyloxy)acetate was obtained by distillation under reduced pressure, with a yield of 94.6%.

[0057] Example 9

[0058] Under the protection of inert gas, 167.5 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (0.835 mol, 1 eq) was mixed with 109.4 g of 3-bromopropyne (0.92 mol, 1.1 eq) in 300 ml of toluene and 200 ml of water, potassium carbonate (0.85 mol) was added, and 5 g of the phase transfer catalyst tetrabutylammonium bromide was added. The reaction was carried out at 40 °C for 3 h. The organic phase was separated, and 201.3 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-ynyloxy)acetate was obtained by distillation under reduced pressure, with a yield of 95.4%.

[0059] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A preparation method of a mandelic acid derivative, and the mandelic acid derivative is shown as formula (Ⅰ): It is characterized in that The method comprises: (1) Reacting p-chlorophenylmagnesium bromide with a compound of formula (Ⅳ) to obtain a compound of formula (Ⅲ); (2) Reacting the compound of formula (Ⅲ) with the compound of formula (Ⅱ) in an alkaline environment to obtain the compound of formula (Ⅰ); wherein, R is selected from methyl, ethyl, propyl, isopropyl or tert-butyl; and X is selected from chlorine or bromine; 。 2. The preparation method according to claim 1, characterized in that, In the step (1), the solvent added in the reaction is selected from one or more of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, toluene or methylcyclopentyl ether; in the step (2), the solvent added in the reaction is selected from one or more of toluene, water, chlorobenzene, DMF, DMAc, acetonitrile, N-methylpyrrolidone or dimethyl sulfoxide.

3. The preparation method according to claim 1, characterized in that, In the step (1), in terms of molar amount, the ratio of p-chlorophenylmagnesium bromide to the compound of formula (Ⅳ) is 1:1 - 1.3; in the step (2), the molar ratio of the compound of formula (Ⅲ) to the compound of formula (Ⅱ) is 1:1 - 1.

5.

4. The preparation method according to claim 1, wherein In the step (1), the reaction temperature is -10 - 50°C; in the step (2), the reaction temperature is -10 - 100°C.

5. The preparation method according to claim 1, characterized in that, In the step (1), the reaction time is 1 - 10 hours; in the step (2), the reaction time is 1 - 10 hours.

6. The preparation method according to claim 1, wherein, In the step (1), hexamethylphosphoric triamide or DMPU is added as an auxiliary agent.

7. The preparation method according to claim 1, wherein In the step (2), the base added in the reaction is selected from one or more of sodium hydroxide, potassium hydroxide, sodium hydride.

8. The preparation method according to claim 1, wherein In the step (2), when the reaction solvent includes water, a phase transfer catalyst is added to the system, and the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium hydrogensulfate, polyethylene glycol 800, crown ether.

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