CN114890988A - A kind of chemical synthesis method of thalidomide - Google Patents

Abstract

The invention discloses a chemical synthesis method of thalidomide, which comprises the following steps:

Description

A kind of chemical synthesis method of thalidomide

technical field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a chemical synthesis method of thalidomide.

Background technique

Thalidomide (Thaiidomide) alias: reaction stop, phthalimide, is a synthetic glutamic acid derivative. In May 2006, the FDA approved it for the treatment of multiple myeloma. In 2010, thalidomide was approved for marketing in China. In addition to the treatment of erythema nodosum leprosy, thalidomide can treat multiple myeloma in the Clinical Diagnosis and Treatment Guideline of Hematology. Its structural formula is as follows:

In the prior art, the synthetic method of thalidomide mainly contains the following several:

Method 1: (CN102863424A)

In this route, phthalic anhydride and glutamic acid are used as raw materials, and N-phthaloyl glutamic acid is obtained by heating and condensation, and then thalidomide is obtained by condensation of acetic anhydride and ammonia ammoniation.

Method 2: (WO2017/081701Al)

This route uses phthalic anhydride and 3-amino-piperidinedione hydrochloride as raw materials, reacts in a mixed solvent of acetic acid and triethylamine to obtain thalidomide.

Method 3: (10.1021/op980201b)

This route uses L-glutamine as raw material, reacts with N-ethoxycarbonyl phthalimide to obtain N-phthaloyl-L-glutamine, and cyclizes in the presence of carbonyldiimidazole to prepare into racemic thalidomide.

In the above-mentioned method, the first method requires high temperature for ammonia gas melting, which requires higher equipment, and the production is not easy to operate and control, which is not conducive to safe production. In the second method, 3-amino-piperidinedione hydrochloride is used as a raw material, the preparation steps are complicated, and the production cost is high. The N-ethoxycarbonyl phthalimide in the third method is expensive and has few commercial sources, so it is not suitable for large-scale application. In short, the above methods have disadvantages such as difficult to obtain raw materials, high cost or difficult realization of the process, or harsh production environment.

Therefore, there is still a need in the art to develop a method for synthesizing thalidomide that is more suitable for industrial production.

SUMMARY OF THE INVENTION

In view of the problems in the background technology, the object of the present invention is to provide a chemical synthesis method of thalidomide, the preparation process is simple, the product purity and yield are high, and it is suitable for industrial production.

To achieve the above object, the present invention proposes the following technical solutions:

A kind of chemical synthesis method of thalidomide, synthesis route is as follows:

，

,

Specifically include the following steps:

Step 1): in an organic solvent, under the action of an oxidant and a catalyst, the compound represented by formula (I) is subjected to an oxidative dehydrogenation coupling reaction with cyclopentene to obtain a compound represented by formula (II);

Step 2): in the mixed solvent system, under the action of an oxidant and a catalyst, the compound represented by formula (II) is subjected to an oxidation reaction to obtain a compound represented by formula (III);

Step 3): firstly, under the action of a condensing agent, the compound represented by the formula (III) undergoes self-condensation reaction, and then is concentrated under reduced pressure, the residue is dissolved in an organic solvent, and an aminolysis agent is added to undergo an aminolysis reaction to obtain the formula (IV) the compound shown;

Step 4): in an organic solvent, under the action of a base and acetic anhydride, the compound represented by the formula (IV) undergoes a cyclization reaction to obtain the compound represented by the formula (V).

Further, in step 1), the oxidant is di-tert-butyl peroxide, tert-butyl hydroperoxide, and the molar ratio of the oxidant to the compound represented by formula (I) is 1:1-5:1 The catalyst is tetrabutylammonium iodide, and the molar ratio of the catalyst to the compound shown in formula (I) is 0.1:1 to 0.5:1.

Further, in step 1), the molar ratio of the cyclopentene to the compound represented by formula (I) is 1:1 to 6:1; the organic solvent is toluene, benzene, dichloroethane Or chlorobenzene, the mass ratio of the volume of the organic solvent to the compound represented by formula (I) is 5~10:1, the volume unit is mL, and the mass unit is g; the reaction temperature is 80°C~120°C; the reaction time is 12 to 24 hours.

Further, in step 2), the oxidant is sodium periodate, potassium permanganate, potassium periodate or periodic acid, and the molar ratio of the oxidant to the compound shown in formula (II) is 3:1 ~5:1; the catalyst is ruthenium oxide or ruthenium trichloride, and the catalyst is 1% to 5% of the molar amount of the compound represented by formula (II).

Further, in step 2), the mixed solvent is an organic mixed solvent and water, the organic mixed solvent is ethyl acetate and acetonitrile or ethyl acetate and carbon tetrachloride, and the volume of the organic mixed solvent is the same as that of formula (II). ), the mass ratio of the compounds shown is 5~10:1, the volume unit is mL, the mass unit is g, the volume of the organic mixed solvent and water in the mixed solvent is 3:1~8:1, and the reaction temperature is 20℃~40℃; the reaction time is 40~48 h.

Further, in step 3), the condensing agent is acetic anhydride or acetyl chloride, the mass ratio of the volume of the condensing agent to the compound represented by formula (III) is 10-15:1, the volume unit is mL, and the mass The unit is g; the ammonolytic agent is ammonia water, ammonia gas, ammonium formate or ammonium acetate, and the molar ratio of the ammonolytic agent to the compound represented by formula (III) is 1:1~10:1.

Further, in step 3), the organic solvent is tetrahydrofuran, dichloroethane, 1,4-dioxane or methanol, and the volume of the organic solvent and the mass ratio of the compound shown in formula (III) are: 1~20:1, the volume unit is mL, the mass unit is g; the condensation reaction temperature is 60℃~100℃, the aminolysis reaction temperature is 0℃~30℃, and the total reaction time is 3~5 h.

Further, in step 4), the base is triethylamine, diethylamine, pyridine, potassium tert-butoxide, N,N-diisopropylethylamine, potassium carbonate or 1,8-diazo Bispiro[5.4.0]undec-7-ene, the molar ratio of the base to the compound represented by the formula (IV) is 1:1 to 1:6; the acetic anhydride and the compound represented by the formula (IV) The molar ratio of the compounds is 1:1 to 8:1.

Further, in step 4), the organic solvent is tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethylene glycol dimethyl ether or diphenyl ether, and the organic solvent The mass ratio of the volume of the compound to the compound represented by the formula (IV) is 5~20:1, the volume unit is mL, and the mass unit is g; the reaction temperature is 80 ℃~130 ℃, and the reaction time is 10~16 h.

The beneficial effects of the invention are as follows: the invention has a novel process route, reasonable process conditions, simple operation, easy-to-obtain raw materials, reduced production cost, and is an economical and large-scale method for preparing thalidomide.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. However, these embodiments are only intended to illustrate the present invention rather than further limit the protection scope of the present invention.

Example 1

Preparation of 2-(cyclopenten-2-enyl)-isoindoline-1,3-dione (Ⅱ)

Phthalimide (1.47g, 10mmol) was added to the reaction flask, 14ml of chlorobenzene, tetrabutylammonium iodide (0.72g, 2mmol), cyclopentene (1.36g, 20mmol), tert-butyl base hydrogen peroxide (1.80 g, 20 mmol), sealed with nitrogen, and stirred at 120 °C for 12 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was extracted three times with 15 ml of ethyl acetate and 10 ml of water. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.27 g of a white solid with a yield of 60 %.

¹ (400 MHz, DMSO- d ₆ ) δ 7.81 (s, 4H), 6.03 (m, 1H), 5.70 – 5.62 (m, 1H), 5.23 (m, 1H), 2.65 (m, 1H), 2.37 ( m, 1H), 2.24 (m, 1H), 2.08 – 1.95 (m, 1H).

Example 2

Preparation of 2-(cyclopenten-2-enyl)-isoindoline-1,3-dione (Ⅱ)

Phthalimide (1.47g, 10mmol) was added to the reaction flask, 12ml of toluene, tetrabutylammonium iodide (0.37g, 1mmol), cyclopentene (0.68g, 10mmol), di-tert-butyl were added base peroxide (1.46 g, 10 mmol), sealed with nitrogen, and stirred at 110 °C for 16 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was extracted three times with 15 ml of ethyl acetate and 10 ml of water. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.81 g of a white solid with a yield of 85%. %.

Example 3

Preparation of 2-(cyclopenten-2-enyl)isoindoline-1,3-dione (Ⅱ)

Phthalimide (1.47g, 10mmol) was added to the reaction flask, 8ml of dichloroethane, tetrabutylammonium iodide (1.85g, 5mmol), cyclopentene (4.08g, 60mmol) were added, tert-Butyl hydroperoxide (4.5 g, 50 mmol), sealed with nitrogen, then stirred at 80 °C for 24 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was extracted three times with 15 ml of ethyl acetate and 10 ml of water. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.71 g of a white solid with a yield of 80 %.

Example 4

Preparation of N-phthaloyl-L-glutamic acid (Ⅲ)

2-(Cyclopentene-2-enyl)-isoindoline-1,3-dione (3.2 g, 15 mmol) was added to the reaction flask, and a mixture of ethyl acetate and acetonitrile in a volume ratio of 1:1 was added 26 ml of solvent, ruthenium trichloride (0.06 g, 2 mmol%), and 4 ml of an aqueous solution of sodium periodate (12.83 g, 60 mmol) were added and stirred at 25° C. for 48 h. After the reaction was completed, 25 ml of ethyl acetate was used. Extracted with 30 ml of water three times, combined the organic phases, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, poured the residual liquid into 30 ml of dilute hydrochloric acid with a pH value of less than 3, stirred for 1 h, suction filtered, and dried to obtain 3.12 g of a white solid with a yield of 3.12 g. 75%.

¹ (400 MHz, DMSO- d ₆ ) δ 12.69 (s, 2H), 7.97 – 7.84 (m, 4H), 4.87 – 4.78 (m, 1H), 2.45 – 2.19 (m, 4H).

Example 5

Preparation of N-phthaloyl-L-glutamic acid (Ⅲ)

Add 2-(cyclopenten-2-enyl)isoindoline-1,3-dione (3.2g, 15mmol) to the reaction flask, add ethyl acetate and carbon tetrachloride in a volume ratio of 1:1 16ml of mixed solvent, ruthenium oxide (0.1g, 5mmol%), then 4ml of potassium permanganate (7.1g, 45mmol) aqueous solution was added to it and stirred, and the reaction was carried out at 20°C for 40h. After the reaction was completed, 25ml of ethyl acetate was added. Extracted with 30 ml of water for three times, combined the organic phases, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, poured the residual liquid into 30 ml of dilute hydrochloric acid with a pH value of less than 3, stirred for 1 h, filtered with suction, and dried to obtain 3.32 g of white solid with a yield of 3.32 g. 80%.

Example 6

Preparation of N-phthaloyl-L-glutamic acid (Ⅲ)

2-(Cyclopentene-2-enyl)isoindoline-1,3-dione (3.2g, 15mmol) was added to the reaction flask, and a mixed solvent of ethyl acetate and acetonitrile in a volume ratio of 1:1 was added 32ml, ruthenium trichloride (0.03g, 1mmol%), and then 10ml of an aqueous solution of periodic acid (17.09g, 75mmol) was added to it and stirred, and reacted at 40°C for 45h. After the reaction was completed, 25ml of ethyl acetate and water were used. 30 ml was extracted three times, the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was poured into 30 ml of dilute hydrochloric acid with a pH value of less than 3, stirred for 1 h, suction filtered, and dried to obtain 3.53 g of a white solid with a yield of 85%. .

Example 7

Preparation of N-phthaloyl-L-glutamine (IV)

N-3-phthalic acid-L-glutamic acid (5.54g, 20mmol) was added to the reaction flask, 56ml of acetic anhydride was added, and the reaction was carried out at 80°C for 2h. The reaction was completed, concentrated under reduced pressure, and 1, 56ml of 4-dioxane was introduced into ammonia gas for 10min, the amount of ammonia gas was 100mmol, the reaction was carried out at 15°C for 1h, the reaction was completed, concentrated under reduced pressure, the residue was added to 30ml of dilute hydrochloric acid, stirred, filtered, and dried to obtain 5.41 g of white solid, yield 98%.

¹ (400 MHz, DMSO- d ₆ ) δ 13.18 – 13.13 (m, 1H), 7.90 (m, 4H), 7.21 (s, 1H), 6.74 (s, 1H), 4.76 (dd, J = 10.8, 4.6 Hz, 1H), 2.44 – 2.20 (m, 2H), 2.10 (t, J = 7.4 Hz, 2H).

Example 8

Preparation of N-phthaloyl-L-glutamine (IV)

N-3-phthalic acid-L-glutamic acid (5.54 g, 20 mmol) was added to the reaction flask, 66 ml of acetyl chloride was added, and the reaction was carried out at 60 °C for 2 h. The reaction was completed, concentrated under reduced pressure, and tetrahydrofuran was added to the residue. 6 ml was poured into ammonium formate (1.26 g, 20 mmol) and reacted at 0°C for 2 h. The reaction was completed, concentrated under reduced pressure, the residue was added to 30 ml of dilute hydrochloric acid, stirred, filtered and dried to obtain 4.86 g of white solid with a yield of 88%.

Example 9

Preparation of N-phthaloyl-L-glutamine (IV)

N-3-phthalic acid-L-glutamic acid (5.54 g, 20 mmol) was added to the reaction flask, 83 ml of acetic anhydride was added, and the reaction was carried out at 100 °C for 2 h. 110 ml of ethyl chloride was added with ammonium acetate (15.41 g, 200 mmol) and reacted at 30°C for 3 h. The reaction was completed, concentrated under reduced pressure, the residue was added to 30 ml of dilute hydrochloric acid, stirred, filtered and dried to obtain 4.97 g of white solid with a yield of 90 %.

Example 10

Preparation of Thalidomide (V)

Add N-3-phthalic acid-L-glutamine (2.6g, 9.4mmol) into the reaction flask, add 1,4-dioxane 13ml, triethylamine (0.19g, 1.88mmol), ethyl acetate Acid anhydride (0.96 g, 9.4 mmol) was heated to 80 °C and reacted for 16 h. The reaction was completed, cooled to room temperature, and suction filtered to obtain 1.46 g of a dark gray solid with a yield of 60%.

¹ (400 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 7.98 – 7.85 (m, 4H), 5.18 (dd, J = 13.0, 5.4 Hz, 1H), 2.91 (m, 1H), 2.67 – 2.47 (m, 2H), 2.13 – 2.02 (m, 1H).

Example 11

Preparation of Thalidomide (V)

N-3-phthalic acid-L-glutamine (2.6g, 9.4mmol) was added to the reaction flask, 52ml of N,N-dimethylformamide, N,N-diisopropylethylamine ( 1.2 g, 9.4 mmol), acetic anhydride (7.67 g, 75.2 mmol), the temperature was raised to 130 °C, and the reaction was carried out for 10 h. The reaction was completed, cooled to room temperature, and suction filtered to obtain 1.51 g of a dark gray solid with a yield of 62%.

Example 12

Preparation of Thalidomide (V)

N-3-phthalic acid-L-glutamine (2.6g, 9.4mmol) was added to the reaction flask, 26ml of diphenyl ether, potassium carbonate (0.65g, 4.7mmol), acetic anhydride (3.83g, 37.6ml) were added mmol), the temperature was raised to 100 °C, and the reaction was carried out for 12 h. The reaction was completed, cooled to room temperature, and suction filtered to obtain 1.57 g of a dark gray solid with a yield of 65%.

Claims (9)

1. The chemical synthesis method of thalidomide is characterized in that the synthesis route is as follows:

，

the method specifically comprises the following steps:

step 1): in an organic solvent, under the action of an oxidant and a catalyst, carrying out oxidative dehydrogenation coupling reaction on a compound shown as a formula (I) and cyclopentene to prepare a compound shown as a formula (II);

step 2): in a mixed solvent system, under the action of an oxidant and a catalyst, carrying out oxidation reaction on a compound shown as a formula (II) to prepare a compound shown as a formula (III);

step 3): firstly, carrying out self-condensation reaction on a compound shown as a formula (III) under the action of a condensing agent, then carrying out reduced pressure concentration, dissolving residues in an organic solvent, and adding an aminolysis agent to carry out an aminolysis reaction to obtain a compound shown as a formula (IV);

and 4) in an organic solvent, under the action of alkali and acetic anhydride, carrying out cyclization reaction on the compound shown as the formula (IV) to obtain the compound shown as the formula (V).

2. The chemical synthesis method of thalidomide according to claim 1, wherein in step 1), the oxidant is di-tert-butyl peroxide and tert-butyl hydroperoxide, and the molar ratio of the oxidant to the compound shown in formula (i) is 1:1 to 5: 1; the catalyst is tetrabutylammonium iodide, and the molar ratio of the catalyst to the compound shown in the formula (I) is 0.1: 1-0.5: 1.

3. The chemical synthesis method of thalidomide according to claim 1 or 2, wherein in step 1), the molar ratio of the cyclopentene to the compound represented by formula (i) is 1:1 to 6: 1; the organic solvent is toluene, benzene, dichloroethane or chlorobenzene, and the mass ratio of the volume of the organic solvent to the compound shown in the formula (I) is 5-10: 1, volume unit is mL, and mass unit is g; the reaction temperature is 80-120 ℃; the reaction time is 12-24 h.

4. The chemical synthesis method of thalidomide according to claim 1, wherein in step 2), the oxidizing agent is sodium periodate, potassium permanganate, potassium periodate or periodic acid, and the molar ratio of the oxidizing agent to the compound represented by formula (ii) is 3:1 to 5: 1; the catalyst is ruthenium oxide or ruthenium trichloride, and the molar weight of the catalyst is 1-5% of that of a compound shown as a formula (II).

5. The chemical synthesis method of thalidomide according to claim 1 or 4, characterized in that in step 2), the mixed solvent is an organic mixed solvent and water, the organic mixed solvent is ethyl acetate and acetonitrile or ethyl acetate and carbon tetrachloride, and the mass ratio of the volume of the organic mixed solvent to the compound represented by formula (II) is 5-10: 1, wherein the volume unit is mL, the mass unit is g, the volumes of the organic mixed solvent and water in the mixed solvent are 3: 1-8: 1, and the reaction temperature is 20-40 ℃; the reaction time is 40-48 h.

6. The chemical synthesis method of thalidomide according to claim 1, wherein in step 3), the condensing agent is acetic anhydride or acetyl chloride, and the mass ratio of the volume of the condensing agent to the compound represented by formula (iii) is 10-15: 1, the volume unit is ml, and the mass unit is g; the ammonolysis agent is ammonia water, ammonia gas, ammonium formate or ammonium acetate, and the molar ratio of the ammonolysis agent to the compound shown in the formula (III) is 1: 1-10: 1.

7. the chemical synthesis method of thalidomide of claim 1 or 6, wherein in step 3), the organic solvent is tetrahydrofuran, dichloroethane, 1, 4-dioxane or methanol, and the mass ratio of the volume of the organic solvent to the compound represented by formula (iii) is 1-20: 1, volume unit is mL, and mass unit is g; the condensation reaction temperature is 60-100 ℃, the ammonolysis reaction temperature is 0-30 ℃, and the total reaction time is 3-5 h.

8. The chemical synthesis method of thalidomide according to claim 1, wherein in step 4), the base is triethylamine, diethylamine, pyridine, potassium tert-butoxide, N-diisopropylethylamine, potassium carbonate or 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene, and the molar ratio of the base to the compound represented by formula (iv) is 1:1 to 1: 6; the molar ratio of the acetic anhydride to the compound shown as the formula (IV) is 1: 1-8: 1.

9. The chemical synthesis method of thalidomide according to claim 1 or 8, characterized in that in step 4), the organic solvent is tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, ethylene glycol dimethyl ether or diphenyl ether, and the mass ratio of the volume of the organic solvent to the compound represented by formula (iv) is 5-20: 1, volume unit is mL, and mass unit is g; the reaction temperature is 80-130 ℃, and the reaction time is 10-16 h.