A process for the preparation of mandelic acid derivatives

Abstract

This invention relates to a method for preparing mandelic acid derivatives. The invention uses commercially available conventional p-chlorophenyl magnesium bromide reagent as raw material, which is low in cost, readily available, and reduces raw material costs by more than 40%. Furthermore, the synthesis steps are simple, low in cost, low in toxicity, convenient to operate, and highly safe.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing a mandelic acid derivative. Background Technology

[0002] Mandelic acid derivatives, as key organic synthesis intermediates, have important applications in the pharmaceutical and pesticide industries. A typical example is anorexic ester, an anti-gout drug with mandelic acid as its core structure.

[0003] Existing technologies disclose a method for synthesizing (4-chlorophenyl)-prop-2-alkynoxyacetic acid ester, which uses p-chlorobenzaldehyde and propargyl ester as raw materials and obtains it through multiple steps of reaction such as addition, chlorination, cyanation, and esterification. This method has problems such as many steps, low overall yield, and high cost.

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

[0005] To address existing problems, this invention proposes a method for preparing mandelic acid derivatives. By using p-chlorophenyl magnesium bromide as a starting material, the method significantly simplifies the steps, reduces costs, further optimizes reaction conditions, and improves reaction safety. This is a new synthetic route suitable for industrial production.

[0006] This invention relates to a method for preparing a mandelic acid derivative, which is shown in formula (I):

[0007]

[0008] The method includes:

[0009] (1) Reaction of p-chlorophenyl magnesium bromide with compound (IV) yields compound (III);

[0010] (2) Compound (III) reacts with compound (II) in an alkaline environment to give compound (I);

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

[0012] .

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

[0014] In step (1), the ratio of p-chlorophenyl magnesium bromide and compound (IV) is 1:1-1.3 in molar amounts.

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

[0016] In step (1), the reaction time is 1-10 hours, preferably 1-5 hours.

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

[0018] Furthermore, the ratio of magnesium p-chlorophenyl bromide to the auxiliaries is 1:0.01-0.1, preferably 1:0.01-0.05, in molar amounts.

[0019] Specifically, in step (1), p-chlorobromobenzene reacts with magnesium shavings in an organic solvent to obtain p-chlorophenyl magnesium bromide; then, p-chlorophenyl magnesium bromide is added dropwise to the solution of compound (IV), with the temperature controlled at -10~50℃. After the addition is complete, the mixture is stirred thoroughly. After the reaction is complete, the reaction solution is poured into a mixture of ice and dilute sulfuric acid, and the layers are separated. The organic layer is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude compound (III). Alternatively, the reaction can be quenched with sulfuric acid, the pH adjusted to acidic, extracted with ethyl acetate, and the organic phase concentrated under reduced pressure to obtain crude compound (III).

[0020] In step (2), the alkali added to the reaction is selected from one or more of sodium hydroxide, potassium hydroxide, and sodium hydride.

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

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

[0023] In step (2), the reaction time is 1-10 hours, preferably 1-5 hours.

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

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

[0026] Specifically, in step (2), compound (III) reacts with compound (II) in a strongly alkaline environment at -10 to 100°C for 1 to 10 hours until the conversion of compound (III) is complete. Water is added to the reaction system to separate the layers, and the organic phase is concentrated under reduced pressure to obtain compound (I).

[0027] Beneficial effects:

[0028] This invention uses commercially available conventional p-chlorophenyl magnesium bromide reagent as a raw material, which is low in cost and easy to obtain, reducing the raw material cost by more than 40%. Furthermore, the synthesis steps are simple, low in cost, low in toxicity, easy to operate, and highly safe.

[0029] This invention synthesizes the target product through a two-step reaction, shortening the process by more than 50% compared to the four-step reaction of existing technologies. The overall yield of this invention can reach up to 80%, which is 10% to 15% higher than that of existing technologies. Attached Figures and Descriptions

[0030] Figure 1 Example 1: Compound of formula (III) 1 H NMR spectrum.

[0031] Figure 2 Example 1: Compound of formula (Ⅰ) 1 H NMR spectrum. Detailed Implementation

[0032] Example 1

[0033] 1) Synthesis of compound (III)

[0034] 215.7 g of 1 mol (1 eq) of magnesium p-chlorophenyl bromide Grignard reagent was added dropwise to a tetrahydrofuran solution containing 95.1 g (1.08 mol (1.08 eq) of methyl formate. The reaction was carried out at 0 °C, and the mixture was stirred for 2 h after the addition was complete. After the reaction was complete, 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 give 167.5 g of methyl 2-(4-chlorophenyl)-2-hydroxyacetic acid, with a yield of 83.5%.

[0035] 2) Synthesis of compound (Ⅰ)

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

[0037] Example 2

[0038] 1) Synthesis of compound (III)

[0039] 215.7 g of 1 mol (1 eq) of magnesium p-chlorophenyl bromide Grignard reagent was added dropwise to a tetrahydrofuran solution containing 110.3 g (1.08 mol (1.08 eq) of ethyl formate. The reaction was carried out at 0 °C, and the mixture was stirred for 2 h after the addition was complete. After the reaction was complete, 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 give 181.5 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 84.6%.

[0040] 2) Synthesis of compound (Ⅰ)

[0041] Under inert gas protection, 181.5 g (0.846 mol, 1 eq) of the above product and 68.5 g (0.919 mol, 1.1 eq) of 3-chloropropyne were mixed in 300 mL of chlorobenzene, and 47.6 g (0.85 mol) of potassium hydroxide were added. The mixture was reacted at 0 °C for 3 h. After adding water to separate the layers, the organic phase was concentrated under reduced pressure to give 202.7 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-alkynyloxy)acetate, with a yield of 94.8%.

[0042] Example 3

[0043] 1) Synthesis of compound (III)

[0044] 215.7 g of 1 mol (1 eq) of magnesium p-chlorophenyl bromide Grignard reagent was added dropwise to a tetrahydrofuran solution containing 110.3 g (1.08 mol (1.08 eq) of ethyl formate. The reaction was carried out at 10 °C, and the mixture was stirred for 1.5 h after the addition was complete. After the reaction was complete, 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 give 176.6 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 82.3%.

[0045] 2) Synthesis of compound (Ⅰ)

[0046] Under inert gas protection, 176.6 g (0.823 mol, 1 eq) of the above product was mixed with 68.5 g (0.919 mol, 1.1 eq) of 3-chloropropyne in 300 mL of chlorobenzene, and 47.6 g (0.85 mol) of potassium hydroxide was added. The mixture was reacted at 5 °C for 3 h. After adding water to separate the layers, the organic phase was concentrated under reduced pressure to give 191.5 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-alkynyloxy)acetate, with a yield of 92.1%.

[0047] Example 4

[0048] 215.7 g of 1 mol (1 eq) of magnesium p-chlorophenyl bromide Grignard reagent was added dropwise to a tetrahydrofuran solution of 95.1 g (1.08 mol (1.08 eq) of methyl formate, followed by the addition of 1.8 g of MPA (hexamethylphosphoric triamine). The reaction was carried out at 10 °C, and the mixture was stirred for 1 h after the addition was complete. After the reaction was complete, 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 give 181.3 g of methyl 2-(4-chlorophenyl)-2-hydroxyacetic acid, with a yield of 90.4%.

[0049] Example 5

[0050] 215.7 g of 1 mol (1 eq) of magnesium p-chlorophenyl bromide Grignard reagent was added dropwise to a tetrahydrofuran solution of 110.3 g (1.08 mol (1.08 eq) of ethyl formate. 1.3 g of DMPU was added, and the reaction was carried out at 10 °C. After the addition was complete, the mixture was stirred for 1 h. After the reaction was complete, 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 give 196.3 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate, with a yield of 91.5%.

[0051] Example 6

[0052] 215.7 g of 1 mol (1 eq) of magnesium p-chlorophenyl bromide Grignard reagent was added dropwise to a tetrahydrofuran solution containing 125.4 g (1.08 mol (1.08 eq) of isopropyl formylformate. The reaction was carried out at 0 °C, and the mixture was stirred for 2 h after the addition was complete. After the reaction was complete, 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 give 191.3 g of isopropyl 2-(4-chlorophenyl)-2-hydroxyacetic acid, with a yield of 83.7%.

[0053] Example 7

[0054] 215.7 g of 1 mol (1 eq) of magnesium p-chlorophenyl bromide Grignard reagent was added dropwise to a tetrahydrofuran solution containing 140.5 g (1.08 mol (1.08 eq) of tert-butyl formate. The reaction was carried out at 0 °C, and the mixture was stirred for 2 h after the addition was complete. After the reaction was complete, 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 give 206.4 g of tert-butyl 2-(4-chlorophenyl)-2-hydroxyacetic acid, with a yield of 85.1%.

[0055] Example 8

[0056] Under an inert gas atmosphere, 167.5 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (0.835 mol, 1 eq) and 109.4 g of 3-bromopropyne (0.92 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. The organic phase was separated, and the mixture was distilled under reduced pressure to give 199.6 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-alkynyloxy)acetate, with a yield of 94.6%.

[0057] Example 9

[0058] Under an inert gas atmosphere, 167.5 g of ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (0.835 mol, 1 eq) and 109.4 g of 3-bromopropyne (0.92 mol, 1.1 eq) were mixed in 300 mL of toluene and 200 mL of water. Potassium carbonate (0.85 mol) and 5 g of tetrabutylammonium bromide, a phase transfer catalyst, were added, and the mixture was reacted at 40 °C for 3 h. The organic phase was separated, and the mixture was distilled under reduced pressure to give 201.3 g of ethyl 2-(4-chlorophenyl)-2-(prop-2-alkynyloxy)acetate, with a yield of 95.4%.

[0059] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a mandelic acid derivative, the mandelic acid derivative being as shown in formula (Ⅰ): Its features are, The method includes: (1) Reaction of p-chlorophenyl magnesium bromide with compound (IV) yields compound (III); (2) Compound (III) reacts with compound (II) in an alkaline environment to give compound (I); Wherein, R is selected from methyl, ethyl, propyl, isopropyl, or tert-butyl; and X is selected from chlorine or bromine. ， In step (1), the reaction temperature is -5 to 15℃; in step (2), the reaction temperature is 0 to 60℃. In step (1), the reaction time is 1-10 hours; in step (2), the reaction time is 1-10 hours. In step (1), hexamethylphosphoric acid triamine or DMPU is added as an adjuvant, and the ratio of p-chlorophenyl magnesium bromide to the adjuvant is 1:0.01 in molar amount; In step (2), the solvents added to the reaction are toluene and water, and a phase transfer catalyst is added to the system. The phase transfer catalyst is selected from tetrabutylammonium bromide.

2. The preparation method according to claim 1, characterized in that, In step (1), the solvent added to the reaction is selected from one or more of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, toluene, or methyl cyclopentyl ether.

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

5.

4. The preparation method according to claim 1, characterized in that, In step (2), the alkali added to the reaction is selected from one or more of sodium hydroxide, potassium hydroxide, and sodium hydride.

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