CN1164586C - Thalidomide and its derivatives preparation method - Google Patents
Thalidomide and its derivatives preparation method Download PDFInfo
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- CN1164586C CN1164586C CNB021460507A CN02146050A CN1164586C CN 1164586 C CN1164586 C CN 1164586C CN B021460507 A CNB021460507 A CN B021460507A CN 02146050 A CN02146050 A CN 02146050A CN 1164586 C CN1164586 C CN 1164586C
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- phthalic anhydride
- glutamine
- thalidomide
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- hydro phthalic
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Abstract
The present invention relates to a method for synthesizing thalidomide and derivants thereof. Phthalic anhydride and glutamine are added under 120 to 150 DEG C, the addition weight of phthalic anhydride is one to four times than that of glutamine, phthalic anhydride and glutamine are heated and stirred, and temperature is slowly raised to 160 to 220 DGE C after reaction is carried out for 20 to 40 minutes; vacuum pumping is carried out to a system, and reaction is stopped after 2 to 20 hours; 1, 4-dioxane is added, heated and stirred until the system is converted into solution, dioxane is streamed by reducing pressure, acetone is added, the solution is stirred, filtered, washed and precipitated and than is wahsed by acetone, and thalidomide is obtained by vacuum drying. Corresponding derivants of thalidomide can be obtained by that phthalic anhydride substituted by 3-bit or 4-bit CH3, CH2 CH3, OCH3, F, Cl, Br or NO2 reacts with glutamine together.
Description
Technical field
The present invention relates to the preparation method of a kind of Thalidomide and derivative thereof.
Background technology
Thalidomide (Thalidomide) has another name called thalidomide.Be synthetic in nineteen fifty-three by the Chem.Gr ǔ nenthal company of West Germany at first, listing in October nineteen fifty-seven is used for the conceived antiemetic when early stage of calmness, hypnosis and women.Compare with barbiturate(s), the sedative effect of Thalidomide is not followed anesthetic action, and not resembling barbiturate(s) has an excitement earlier, the process that the back is calm, and clinical experiment at that time shows that Thalidomide is very low to the toxicity of organs such as liver, thereby has obtained very high evaluation.But in subsequently several years, this medicine has caused the birth of tens0000 teratogenesiss in Europe and North America, and from then on this medicine is in the use that all is under an embargo of a lot of countries.But in recent years owing to having found that the physiologically active of this medicine at aspects such as anticancer, immunosuppression, anti HIV-1 virus receives much attention.Again become the focus of research.Again allowed to be used for the treatment of some disease in some country.1998, FDA (U.S. food and drug administration) ratified Thalidomide and has been used for the treatment of leprosy and follows disease.In China, Thalidomide is the national essential drugs that the treatment leprosy is followed disease.Therefore, the synthetic and biological activity of Thalidomide and derivative thereof very important scientific research and practical value have been studied.
The traditional synthetic method of Thalidomide adopt Tetra hydro Phthalic anhydride and L-glutamic acid three-step approach synthetic (Muller, G.W.Org.Process.Res.Dev.1999.3 (2), 139-140).The product that this method obtains needs the multistep recrystallization to purify, thereby overall yield is low.Muller.G.W replaced Tetra hydro Phthalic anhydride with N-carbonyl oxyethyl group phthalic imidine in 1999; glutamine replaces L-glutamic acid and reacts the intermediate N phthalyl base glutamine that obtains Thalidomide; again with N; N-lutidine (DMAP) is made catalyzer; do the dewatering agent cyclisation with carbonyl dimidazoles (CDI) and obtain Thalidomide (Muller; G.W.Org.Process.Res.Dev.1999.3 (2), 139-140).But the price of the N-carbonyl oxyethyl group phthalic imidine that uses in this method, carbonyl dimidazoles (CDI) all compares expensive, so this method is not suitable for producing.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of Thalidomide and derivative thereof.
After the α of glutamine Tetra hydro Phthalic anhydride amino and Tetra hydro Phthalic anhydride or replacement was dehydrated into ring under vacuum heating conditions, the carboxyl of glutamine and its amide group were dehydrated into ring again, and a step can obtain Thalidomide and derivative thereof.
For achieving the above object, the present invention adopts L-glutamic acid and Tetra hydro Phthalic anhydride or 3 or 4 CH in the glutamine replacement prior synthesizing method
3, CH
2CH
3, OCH
3, F, Cl, Br or NO
2The Tetra hydro Phthalic anhydride that replaces is done raw material, and under the vacuum heating conditions, a step obtains the Thalidomide and the derivative thereof of following structure:
Wherein, R=H, CH
3, CH
2CH
3, OCH
3, F, Cl, Br or NO
2Technological process is as follows: add down Tetra hydro Phthalic anhydride and glutamine at 120-150 ℃, the add-on of Tetra hydro Phthalic anhydride be glutamine add weight 1-4 doubly, heated and stirred is reacted and after 20-40 minute temperature is slowly risen to 160-220 ℃; System is vacuumized, and stopped reaction after 2-20 hour adds 1,4-dioxane, add-on are reactant Tetra hydro Phthalic anhydride and glutamine gross weight 3-10 times, and heated and stirred to system becomes solution, decompression steams dioxane, add acetone, add-on is reactant Tetra hydro Phthalic anhydride and glutamine gross weight 3-10 a times, stirs, filter and water washing and precipitating, use washing with acetone again, vacuum-drying gets Thalidomide; Be used in 3 or 4 by CH
3, CH
2CH
3, OCH
3, F, Cl, Br or NO
2The Tetra hydro Phthalic anhydride that replaces replaces Tetra hydro Phthalic anhydride and glutamine to react under these conditions, obtains the derivative of corresponding Thalidomide.
Make the excessive 1-4 of Tetra hydro Phthalic anhydride or derivatives thereof appropriateness doubly in the reaction, the transformation efficiency of the relatively costly glutamine that helps improving price.
The Thalidomide that the present invention makes and the fusing point of derivative, thin-layer chromatography and nuclear magnetic data are consistent with literature value.
Embodiment:
Embodiment 1:
Add 2.0g Tetra hydro Phthalic anhydride and 2.0g glutamine, heated and stirred in 120 ± 10 ℃ the reactor toward being heated in advance, react and after 40 minutes temperature is slowly risen to 200 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 2 hours obtains yellow solid.Add 15g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 15g acetone, stirs, have precipitation to generate, filter, washing repeatedly, wash repeatedly with acetone again, vacuum-drying obtains pure white solid 0.85g, productive rate: 24.1%, thin-layer chromatography shows that this material has only a point, fusing point 273-274 ℃ (literature value 273-275 ℃).
1HNMR (DMSO-d6): σ 11.12 (s, 1H), 7.94-7.88 (m, 4H), 5.18-5.14 (dd, 1H), 3.00-2.80 (m, 1H), 2.65-2.50 (m, 2H), 2.15-2.00 (m, 1H), consistent with the nuclear magnetic spectrogram of Thalidomide in the document.
Embodiment 2:
Add 3.0g3-methylphthalic acid acid anhydride and 2.0g glutamine in 140 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 30 minutes temperature is slowly risen to 180 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 6 hours obtains white solid.Add 24g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 24g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.09g of 3 methyl substituted Thalidomides, productive rate 29.0%, fusing point: 254-256 ℃.
1HNMR(DMSO-d6)：σ11.14(s，1H)，7.68-7.56(m，3H)，5.21-5.16(dd，1H)，2.90-2.86(m，1H)，2.76(s，3H)，2.64-2.54(m，2H)，2.10-2.06(m，1H)。
Embodiment 3:
Add 3.0g4-methylphthalic acid acid anhydride and 2.0g glutamine in 130 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 40 minutes temperature is slowly risen to 170 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 10 hours obtains white solid.Add 21g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 21g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.21g of 4 methyl substituted Thalidomides, productive rate 32.2%, fusing point: 197-199 ℃.
1HNMR(DMSO-d6)：σ11.18(s，1H)，7.98-7.85(m，3H)，5.21-5.16(dd，1H)，2.90-2.86(m，1H)，2.75(s，3H)，2.64-2.55(m，2H)，2.09-2.07(m，1H)。
With 3 or 4 CH
2CH
3, OCH
3The Tetra hydro Phthalic anhydride that replaces replaces 4-methylphthalic acid acid anhydride to react the derivative that then can obtain corresponding Thalidomide under these conditions.
Embodiment 4:
Add 3.0g3-difluorophthalic anhydride and 2.0g glutamine in 140 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 30 minutes temperature is slowly risen to 190 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 20 hours obtains white solid.Add 15g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 15g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.34g of 3 fluoric Thalidomides, productive rate 35.4%, fusing point: 286-288 ℃.
1HNMR(DMSO-d6)：611.16(s，1H)，8.35-8.26(m，3H)，5.19-5.14(dd，1H)，2.93-2.88(m，1H)，2.65-2.53(m，2H)，2.11-2.08(m，1H)。
Embodiment 5:
Add 3.0g4-difluorophthalic anhydride and 2.0g glutamine in 120 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 30 minutes temperature is slowly risen to 160 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 20 hours obtains white solid.Add 15g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 15g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.66g of 4 fluoric Thalidomides, productive rate 43.9%, fusing point: 224-227 ℃.
1HNMR(DMSO-d6)：σ11.13(s，1H)，8.38-8.26(m，3H)，5.25-5.18(dd，1H)，2.89-2.46(m，1H)，2.66-2.59(m，2H)，2.14-2.05(m，1H)。
Embodiment 6:
Add 4.0g3-monochloro phthalic anhydride and 2.0g glutamine in 130 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 40 minutes temperature is slowly risen to 190 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 8 hours obtains white solid.Add 42g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 42 g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.88g of the Thalidomide of 3 chloros, productive rate 46.9%, fusing point: 303-305 ℃.
1HNMR(DMSO-d6)：σ11.14(s，1H)，8.29-7.88(m，3H)，5.24-5.16(dd，1H)，2.93-2.85(m，1H)，2.65-2.55(m，2H)，2.08-2.02(m，1H)。
Embodiment 7:
Add 4.0g4-monochloro phthalic anhydride and 2.0g glutamine in 150 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 40 minutes temperature is slowly risen to 190 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 10 hours obtains white solid.Add 42g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 42g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.67g of the Thalidomide of 4 chloros, productive rate 41.7%, fusing point: 289-291 ℃ (distillation).
1HNMR(DMSO-d6)：σ11.19(s，1H)，8.22-8.02(m，3H)，5.25-5.18(dd，1H)，2.90-2.81(m，1H)，2.62-2.51(m，2H)，2.20-2.09(m，1H)。
Tetra hydro Phthalic anhydride with 3 or 4 Br replacements replaces the 4-monochloro phthalic anhydride to react the derivative that then can obtain corresponding Thalidomide under these conditions.
Embodiment 8:
Add 4.0g3-nitrophthalic acid acid anhydride and 2.0g glutamine in 140 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 40 minutes temperature is slowly risen to 180 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 10 hours obtains white solid.Add 24g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 24 g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.46g of the Thalidomide of 3 nitros replacements, productive rate 35.2%, fusing point: 297-299 ℃.
1HNMR(DMSO-d6)：σ 11.16(s，1H)，8.18-7.96(m，3H)，5.26-5.18(dd，1H)，2.96-2.87(m，1H)，2.68-2.56(m，2H)，2.15-2.08(m，1H)。
Embodiment 9:
Add 4.0g4-nitrophthalic acid acid anhydride and 2.0g glutamine in 130 ± 10 ℃ the reactor toward being heated in advance, heated and stirred is reacted and after 40 minutes temperature is slowly risen to 190 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 6 hours obtains white solid.Add 28g1, the 4-dioxane, heated and stirred makes system become solution, decompression steams dioxane, adds 28g acetone, stirs, there is precipitation to generate, filter, washing is repeatedly washed repeatedly with acetone again, vacuum-drying, obtain the derivative 1.38g of the Thalidomide of 4 nitros replacements, productive rate 33.2%, fusing point: 245-247 ℃.
1HNMR(DMSO-d6)：σ11.21(s，1H)，8.26-8.16(m，3H)，5.25-5.15(dd，1H)，2.99-2.89(m，1H)，2.64-2.51(m，2H)，2.15-2.05(m，1H)。
Embodiment 10:
The excessive influence to productive rate of Tetra hydro Phthalic anhydride is an example with synthetic Thalidomide, according to the method among the embodiment 1, make Tetra hydro Phthalic anhydride respectively with 0,0.5,1,2,3,4 times excessive, reacts the excessive influence to productive rate (with respect to glutamine) of research Tetra hydro Phthalic anhydride under the identical situation of other condition.The result is shown in table-1.
Table 1
| The excessive multiple of Tetra hydro Phthalic anhydride | Productive rate (%) |
| 0 0.5 1 2 3 4 | 24.1 31.5 35.2 37.9 38.7 39.3 |
The result shows, the excessive productive rate that helps improving with respect to glutamine of Tetra hydro Phthalic anhydride.More reasonable in the time of excessive 1-2 times.
Claims (2)
1. the method for synthetic Thalidomide and derivative thereof, it is characterized in that adopting glutamine and Tetra hydro Phthalic anhydride or 3 or 4 by CH
3, CH
2CH
3, OCH
3, F, Cl, Br or NO
2The Tetra hydro Phthalic anhydride that replaces is done raw material, and under the vacuum heating conditions, a step obtains the Thalidomide and the derivative thereof of following structure:
Wherein, R=H, CH
3, CH
2CH
3, OCH
3, F, Cl, Br or NO
2
Technological process: add down Tetra hydro Phthalic anhydride and glutamine at 120-150 ℃, the add-on of Tetra hydro Phthalic anhydride be glutamine add weight 1-4 doubly, heated and stirred is reacted and after 20-40 minute temperature is slowly risen to 160-220 ℃; System is vacuumized, and stopped reaction after 2-20 hour adds 1, the 4-dioxane, 1,4-dioxane add-on is reactant Tetra hydro Phthalic anhydride and glutamine gross weight 3-10 a times, heated and stirred, decompression steams dioxane, adds acetone, the acetone add-on is Tetra hydro Phthalic anhydride and glutamine gross weight 3-10 a times, stir, filter and water washing and precipitating, use washing with acetone again, vacuum-drying gets Thalidomide; Be used in 3 or 4 by CH
3, CH
2CH
3, OCH
3, F, Cl, Br or NO
2The Tetra hydro Phthalic anhydride that replaces replaces Tetra hydro Phthalic anhydride and glutamine to react under these conditions, obtains the derivative of corresponding Thalidomide.
2. the method for synthetic Thalidomide as claimed in claim 1 and derivative thereof, it is characterized in that Tetra hydro Phthalic anhydride or 3 or 4 by CH
3, CH
2CH
3, OCH
3, F, Cl, Br or NO
2The add-on of the Tetra hydro Phthalic anhydride that replaces is 1-2 a times of glutamine weight.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021460507A CN1164586C (en) | 2002-10-28 | 2002-10-28 | Thalidomide and its derivatives preparation method |
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|---|---|---|---|
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100398534C (en) * | 2003-09-15 | 2008-07-02 | 天津和美生物技术有限公司 | New method of synthesizing thalidomide and its derivative |
| CN101716178B (en) * | 2008-01-31 | 2011-06-01 | 上海交通大学 | Antitumor medicament |
| AU2011263493B2 (en) * | 2010-06-09 | 2015-08-06 | Generics [Uk] Limited | Crystalline forms of thalidomide and processes for their preparation |
| CN102863425A (en) * | 2012-09-18 | 2013-01-09 | 宁波立华制药有限公司 | One-step synthetic method of thalidomide and derivative thereof |
| CN102924432A (en) * | 2012-11-09 | 2013-02-13 | 常州制药厂有限公司 | Preparation method of high-purity thalidomide |
| CN104016967A (en) * | 2014-04-04 | 2014-09-03 | 南京工业大学 | Synthetic method of pomalidomide |
| CA3119343C (en) | 2018-11-13 | 2024-01-16 | Biotheryx, Inc. | Substituted isoindolinones |
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