CN114890988A - Chemical synthesis method of thalidomide - Google Patents
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Abstract
The invention discloses a chemical synthesis method of thalidomide, which comprises the following steps:
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a chemical synthesis method of thalidomide.
Background
Thalidomide (Thaidomide), also known as thalidomide, is a synthetic glutamic acid derivative. In 2006, 5 months, FDA approved in the united states for the treatment of multiple myeloma. In 2010, thalidomide was approved for marketing in china, and in addition to treating erythema nodosum leprosum, thalidomide can treat multiple myeloma in the clinical guidelines blood book, with the following structural formula:
in the prior art, the synthesis methods of thalidomide mainly include the following methods:
the method comprises the following steps: (CN102863424A)
The method comprises the steps of taking phthalic anhydride and glutamic acid as raw materials, heating and condensing to obtain N-phthalandiyl glutamic acid, condensing with acetic anhydride, and ammoniating with ammonia to obtain thalidomide.
The second method comprises the following steps: (WO2017/081701Al)
The method takes phthalic anhydride and 3-amino-piperidedione hydrochloride as raw materials to react in a mixed solvent of acetic acid and triethylamine to prepare the thalidomide.
The third method comprises the following steps: (10.1021/op980201b)
The method takes L-glutamine as a raw material, reacts with N-ethoxycarbonylphthalimide to prepare N-phthaloyl-L-glutamine, and cyclizes in the presence of carbonyldiimidazole to prepare racemic thalidomide.
In the method, the ammonia gas is introduced for melting, the high temperature is required, the requirement on equipment is high, the production is not easy to operate and control, and the safety production is not facilitated. In the second method, 3-amino-piperidedione hydrochloride is used as a raw material, the preparation steps are complex, and the production cost is high. In the third method, the N-ethoxycarbonylphthalimide is expensive and has few commercial sources, so that the method is not suitable for large-scale application. In a word, the method has the defects of difficult acquisition of raw materials, high cost, difficult realization of the process, severe production environment and the like.
Therefore, the need still exists in the art to develop a synthetic method of thalidomide which is more suitable for industrial production.
Disclosure of Invention
Aiming at the problems in the background art, the invention aims to provide a chemical synthesis method of thalidomide, which has the advantages of simple and convenient preparation process, high product purity and yield and suitability for industrial production.
In order to achieve the purpose, the invention provides the following technical scheme:
a chemical synthesis method of thalidomide comprises the following steps:
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).
Further, in the step 1), the oxidant is di-tert-butyl peroxide or tert-butyl hydroperoxide, and the molar ratio of the oxidant to the compound shown in the formula (I) is 1: 1-5: 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.
Further, in the step 1), the molar ratio of the cyclopentene to the compound shown as the formula (I) is 1: 1-6: 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.
Further, in the 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 shown in the formula (II) is 3: 1-5: 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).
Further, in the 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 shown in the 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.
Further, in the 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 shown in the formula (III) is 10-15: 1, volume unit is mL, and 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.
further, in the 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 shown in the 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.
Further, in the 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 shown in the formula (IV) is 1: 1-1: 6; the molar ratio of the acetic anhydride to the compound shown as the formula (IV) is 1: 1-8: 1.
Further, in the 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 shown in the 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.
The invention has the beneficial effects that: the method has the advantages of novel process route, reasonable process conditions, simple operation, easily obtained raw materials and reduced production cost, and is an economic and large-scale method for preparing thalidomide.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. However, these examples are only illustrative and are not intended to limit the 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 a reaction flask, and 14ml of chlorobenzene, tetrabutylammonium iodide (0.72g, 2mmol), cyclopentene (1.36g, 20mmol), tert-butyl hydroperoxide (1.80g, 20mmol), nitrogen gas was added and then stirred at 120 ℃ for 12 hours. After the reaction is finished, the reaction product is cooled to room temperature, the reaction product is concentrated under reduced pressure, residual liquid is extracted for three times by 15ml of ethyl acetate and 10ml of water, organic phases are combined, the concentration under reduced pressure is carried out, and the residual liquid is purified by column chromatography to obtain 1.27g of white solid with the yield of 60 percent.
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 a reaction flask, 12ml of toluene, tetrabutylammonium iodide (0.37g, 1mmol), cyclopentene (0.68g, 10mmol), di-tert-butyl peroxide (1.46g, 10mmol), nitrogen gas sealed, and then stirred at 110 ℃ for 16 h. After the reaction is finished, the reaction product is cooled to room temperature, the reaction product is concentrated under reduced pressure, residual liquid is extracted for three times by 15ml of ethyl acetate and 10ml of water, organic phases are combined, the concentration under reduced pressure is carried out, and the residual liquid is purified by column chromatography to obtain 1.81g of white solid with the yield of 85 percent.
Example 3
Preparation of 2- (cyclopenten-2-enyl) isoindoline-1, 3-dione (II)
Phthalimide (1.47g, 10mmol) was added to a reaction flask, 8ml of dichloroethane, tetrabutylammonium iodide (1.85g, 5mmol), cyclopentene (4.08g, 60mmol), t-butyl hydroperoxide (4.5g, 50mmol) were added, nitrogen was sealed, and stirring was carried out at 80 ℃ for 24 hours. After the reaction, the reaction mixture is cooled to room temperature, the reaction mixture is concentrated under reduced pressure, residual liquid is extracted for three times by 15ml of ethyl acetate and 10ml of water, organic phases are combined, the concentration is carried out under reduced pressure, and the residual liquid is purified by column chromatography to obtain 1.71g of white solid with the yield of 80 percent.
Example 4
Preparation of N-phthaloyl-L-glutamic acid (III)
Adding 2- (cyclopentene-2-alkenyl) -isoindoline-1, 3-dione (3.2g and 15mmol) into a reaction bottle, adding 26ml of mixed solvent of ethyl acetate and acetonitrile in a volume ratio of 1:1 and 0.06g and 2mmol% of ruthenium trichloride, adding 4ml of aqueous solution of sodium periodate (12.83g and 60mmol) into the reaction bottle, stirring, reacting at 25 ℃ for 48 h, extracting with 25ml of ethyl acetate and 30ml of water for three times after the reaction is finished, combining organic phases, drying by anhydrous magnesium sulfate, concentrating under reduced pressure, pouring the residual solution into 30ml of dilute hydrochloric acid with the pH value of less than 3, stirring for 1h, filtering, and drying to obtain a white solid of 3.12g and the yield of 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)
Adding 2- (cyclopentene-2-alkenyl) isoindoline-1, 3-dione (3.2g and 15mmol) into a reaction bottle, adding 16ml of mixed solvent of ethyl acetate and carbon tetrachloride in a volume ratio of 1:1 and ruthenium oxide (0.1g and 5mmol%), adding 4ml of aqueous solution of potassium permanganate (7.1g and 45mmol) into the reaction bottle, stirring, reacting at 20 ℃ for 40 hours, extracting with 25ml of ethyl acetate and 30ml of water for three times after the reaction is finished, combining organic phases, drying by anhydrous magnesium sulfate, concentrating under reduced pressure, pouring the residual solution into 30ml of dilute hydrochloric acid with the pH value of less than 3, stirring for 1 hour, filtering, and drying to obtain a white solid of 3.32g and the yield of 80%.
Example 6
Preparation of N-phthaloyl-L-glutamic acid (III)
Adding 2- (cyclopentene-2-alkenyl) isoindoline-1, 3-dione (3.2g and 15mmol) into a reaction bottle, adding 32ml of a mixed solvent of ethyl acetate and acetonitrile in a volume ratio of 1:1 and 0.03g and 1mmol of ruthenium trichloride, adding 10ml of an aqueous solution of periodic acid (17.09g and 75mmol) into the reaction bottle, stirring, reacting at 40 ℃ for 45 hours, extracting with 25ml of ethyl acetate and 30ml of water for three times after the reaction is finished, combining organic phases, drying by anhydrous magnesium sulfate, concentrating under reduced pressure, pouring the residual liquid into 30ml of dilute hydrochloric acid with the pH value of less than 3, stirring for 1 hour, filtering, and drying to obtain a white solid of 3.53g and the yield of 85 percent.
Example 7
Preparation of N-phthaloyl-L-glutamine (IV)
Adding N-3-phthalic acid-L-glutamic acid (5.54g, 20mmol) into a reaction bottle, adding 56ml of acetic anhydride, reacting for 2h at 80 ℃, completing the reaction, concentrating under reduced pressure, adding 56ml of 1, 4-dioxane into the residue, introducing ammonia gas for 10min, wherein the introduction amount of the ammonia gas is 100mmol, reacting for 1h at 15 ℃, completing the reaction, concentrating under reduced pressure, adding the residue into 30ml of diluted hydrochloric acid, stirring, filtering, and drying to obtain 5.41g of white solid, wherein the yield is 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)
Adding N-3-phthalic acid-L-glutamic acid (5.54g, 20mmol) into a reaction bottle, adding 66ml of acetyl chloride, reacting for 2h at 60 ℃, completing the reaction, concentrating under reduced pressure, adding 6ml of tetrahydrofuran into the residue, introducing ammonium formate (1.26 g, 20mmol), reacting for 2h at 0 ℃, completing the reaction, concentrating under reduced pressure, adding the residue into 30ml of diluted hydrochloric acid, stirring, filtering, and drying to obtain 4.86g of white solid with the yield of 88%.
Example 9
Preparation of N-phthaloyl-L-glutamine (IV)
Adding N-3-phthalic acid-L-glutamic acid (5.54g, 20mmol) into a reaction bottle, adding 83ml of acetic anhydride, reacting for 2h at 100 ℃, concentrating under reduced pressure after the reaction is finished, adding 110ml of dichloroethane into the residue, adding ammonium acetate (15.41 g, 200mmol), reacting for 3h at 30 ℃, concentrating under reduced pressure after the reaction is finished, adding the residue into 30ml of diluted hydrochloric acid, stirring, filtering, and drying to obtain 4.97g of white solid with the yield of 90%.
Example 10
Preparation of thalidomide (V)
N-3-phthalic acid-L-glutamine (2.6g, 9.4mmol) was added to a reaction flask, 13ml of 1, 4-dioxane, triethylamine (0.19 g, 1.88 mmol), acetic anhydride (0.96g, 9.4mmol) were added, the temperature was raised to 80 ℃ and reaction was carried out for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered with suction to obtain 1.46g 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 a reaction flask, and 52ml of N, N-dimethylformamide, 1.2g, 9.4mmol of N, N-diisopropylethylamine (1.67 g, 75.2mmol) and acetic anhydride (7.67g, 75.2mmol) were added thereto, and the reaction was carried out at 130 ℃ for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered with suction to obtain 1.51g of a dark gray solid with a yield of 62%.
Example 12
Preparation of thalidomide (V)
Adding N-3-phthalic acid-L-glutamine (2.6g, 9.4mmol) into a reaction bottle, adding diphenyl ether 26ml, potassium carbonate (0.65g, 4.7mmol) and acetic anhydride (3.83g, 37.6mmol), heating to 100 ℃ and reacting for 12 h. After the reaction was complete, the reaction was cooled to room temperature and filtered with suction to give 1.57g of a dark grey 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.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035378A2 (en) * | 2006-09-20 | 2008-03-27 | Matrix Laboratories Ltd | An improved process for the preparation of thalidomide |
| JP2010202544A (en) * | 2009-03-02 | 2010-09-16 | Osaka Prefecture Univ | Method for producing thalidomide derivative |
| CN113574055A (en) * | 2019-01-18 | 2021-10-29 | 阿斯利康(瑞典)有限公司 | PCSK9 inhibitors and methods of use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035378A2 (en) * | 2006-09-20 | 2008-03-27 | Matrix Laboratories Ltd | An improved process for the preparation of thalidomide |
| JP2010202544A (en) * | 2009-03-02 | 2010-09-16 | Osaka Prefecture Univ | Method for producing thalidomide derivative |
| CN113574055A (en) * | 2019-01-18 | 2021-10-29 | 阿斯利康(瑞典)有限公司 | PCSK9 inhibitors and methods of use thereof |
Non-Patent Citations (1)
| Title |
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| 钱绍松等: "D-谷氨酰胺的制备", 《有机化学》, no. 2006, pages 514 - 517 * |
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