CN103130855B - Preparation method of decitabine - Google Patents
Preparation method of decitabine Download PDFInfo
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- CN103130855B CN103130855B CN201110389414.4A CN201110389414A CN103130855B CN 103130855 B CN103130855 B CN 103130855B CN 201110389414 A CN201110389414 A CN 201110389414A CN 103130855 B CN103130855 B CN 103130855B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to a preparation method of decitabine. When a protecting group is got out of the middle body of double-protection decitabine, a middle body of single-protection decitabine is obtained by controlling testing conditions. High-optical-pure decitabine is obtained by using the solubility difference of alpha-type single-protection decitabine and beta-type single-protection decitabine in alcohol solvent. The preparation method of the decitabine is simple in operation and free of too-high requirements of purity of mixing and spinning of the middle body, has lower cost and broader application and is particularly applied to industrial production.
Description
Technical field
The present invention relates to organic synthesis field, in particular to the preparation method of cancer therapy drug Decitabine.
Background technology
Decitabine, chemistry 4-amino-1-(2-deoxidation-β-D-erythro ribofuranose)-1,3,5-triazines-2 (1H)-one by name, also referred to as decitabine, structure is such as formula shown in I β.
Decitabine is the cancer therapy drug that Supergen Inc. (SuperGen) develops, and is a non-selective DNA methylation inhibitor, as dnmt rna inhibitor, can stop methylating of cytosine residues in DNA.Research finds, Decitabine has the effect of highly significant to acute myelocytic cells leukemia (AML), chronic myelocytic leukemia (CML) and myelodysplastic syndrome (MDS).
The document relating to Decitabine preparation method is a lot; conventional synthetic route is: the 2-deoxyribosyl of formula II and the 5-azepine cytosine(Cyt) of formula III react; (P, R are protecting group to obtain the mixture of the intermediate formula IV α of the two protection of hydroxyl and formula IV β; L is leavings group); then directly remove two protecting groups through single step reaction, obtain the mixture of I α and I β.Wherein I α is non-activity, is the major impurity needing in preparation to be separated.
Patent application CN101899079A is after the mixture preparing formula IV α and formula IV β; first through plug of celite and silicagel column separation and purification; then remove the protecting group of two hydroxyls through reaction, and by crystallization step by step and repeatedly recrystallizing methanol obtain β type Decitabine." synthesis of Decitabine "; Ji Jingjing, Yang Shouning, Dong Dongyin; poplar Li apple; Chinese Journal of Pharmaceuticals, 2007,38 (7); 468-469; after the α/β mixture preparing diacetyl group protection, carry out ammonia solution and directly remove two protecting groups, then obtain Decitabine through flash column chromatography and recrystallizing methanol.
Summary of the invention
The invention provides a kind of method preparing Decitabine, comprising:
(1) compound reaction under alcoholic solvent and sodium alkoxide exist of formula V, forms the precipitation of formula VI, precipitation separation, obtains the compound of formula VI in system;
(2) remove the protecting group of the compound of formula VI, obtain Decitabine,
Wherein R be ethanoyl, benzoyl, to chlorobenzene formacyl, to anisoyl, to methyl benzoyl, p-nitrophenyl formyl radical, fluorenes methoxy carbonyl acyl group, Methoxyacetyl, be preferably to methyl benzoyl.
R
1, R
2one of them is hydrogen, another be ethanoyl, benzoyl, to chlorobenzene formacyl, to anisoyl, to methyl benzoyl, p-nitrophenyl formyl radical, fluorenes methoxy carbonyl acyl group, Methoxyacetyl, be preferably to methyl benzoyl.Preferred, R
1for hydrogen, R
2for to methyl benzoyl.
Described formula V compound is the mixture of α and beta comfiguration, and those skilled in the art are known, when the mol ratio change of α, β, is all included in protection scope of the present invention.
Alcoholic solvent refers to C
1~ C
6alcohol, comprise methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol, Pentyl alcohol, 2-hexanol, particular methanol, ethanol, n-propyl alcohol, Virahol, more preferably methyl alcohol.
Described sodium alkoxide, comprises above-mentioned C
1~ C
6the sodium salt of alcohol, particular methanol sodium, sodium ethylate, more preferably sodium methylate.
The mol ratio of formula V compound and sodium alkoxide is 1: 0.01 ~ 0.2, is preferably 1: 0.02 ~ 0.09, is more preferably 1: 0.03 ~ 0.08, most preferably is 1: 0.03 ~ 0.06.
The compound of described formula VI comprises R
1for compound, the R of hydrogen up-to-date style VI
2for compound and the two mixture of hydrogen up-to-date style VI.
During the further deprotection base of the formula VI compound of step (2), method well known in the art can be adopted carry out, such as, react under the existence of triethylamine/pyridine, or NH
3/ CH
3react under the condition of OH, or react under the existence of ethanol/sodium ethylate, methyl alcohol/sodium methylate, after reaction terminates, adopt the general post-treating method in this area to obtain Decitabine.
After step (2) prepares Decitabine, optionally, the method by recrystallization is further purified, such as, be recrystallization solvent with anhydrous methanol, carries out a recrystallization.
Compared with existing preparation method; when of the present invention pair of his middle Binhai mesosome of protecting field west carries out Deprotection; adopt the method for substep deprotection base; first his middle Binhai mesosome of two protecting field west obtains the Decitabine intermediate of single protection by alcoholysis reaction; because the α type of this intermediate and the solubleness of β type in alcoholic solvent have very large difference; β type intermediate is insoluble to alcoholic solvent and α type intermediate is soluble in alcoholic solvent; by precipitate and separate out after; further deprotection base, obtains Decitabine again.Preparation method of the present invention is simple to operate, to the purity of DL intermediate without excessive demand, has lower cost, widely suitability, is particularly suitable for suitability for industrialized production.
The present invention can be described in detail by the following example.The object of specific embodiment further illustrates content of the present invention, but and do not mean that and limit the invention.
Embodiment
The preparation of example 1:1-(3,5-bis--O-is to toluyl-DRI)-5-azepine cytosine(Cyt)
In anhydrous methanol, logical hydrogen chloride gas, stand-by; Separately 40g DRI and 120g anhydrous methanol are put in reaction flask, after stirring, add hydrogen chloride methanol solution.Room temperature reaction is about 1h, adds triethylamine, make pH=7 ~ 8 in the backward system that reacts completely, and obtains dark red-brown liquid and is about 46g, be 1-methoxyl group-DRI in 40 DEG C of decompression steamings to constant weight.
Upper step product 500mL methylene dichloride is dissolved, adds 130mL triethylamine, under stirring cooling, drip 128g to methyl benzoyl chloride, control to drip process temperature 20 ~ 30 DEG C, drip and finish, spend the night in about 30 DEG C confined reactions.Reaction solution is joined in water and methylene dichloride mixed solution; stir; stratification, first washs with the dilute hydrochloric acid of 5%, and then washes 1 time with sodium hydrogen carbonate solution; purifying washes 2 times; anhydrous sodium sulfate drying, 30 DEG C are concentrated dry, obtain dark red-brown liquid and are about 112g; be 1-methoxyl group-3,5-bis--O-to methyl benzoyl-DRI.
Pass into hydrogen chloride gas under 350mL glacial acetic acid cooling and stirring, seal for subsequent use.By upper step intermediate 1-methoxyl group-3,5-bis--O-to the 40mL glacial acetic acid dilution of methyl benzoyl-DRI, join in above-mentioned hydrogenchloride glacial acetic acid solution in 15 ~ 20 DEG C; airtight stirring reaction; about 5 ~ 10min and adularescent solid occur, after there is a large amount of solid very soon, stirring reaction 1h; leach solid; with isopropyl ether making beating washing 3 times, 30 ~ 40 DEG C of forced air drying 3h, obtain off-white color solid 61g; be chloro-3, the 5-bis--O-of 1-to methyl benzoyl-DRI.
200g hexamethyldisilazane is added in reaction flask, 18.9g azepine cytosine(Cyt) and 2g ammonium sulfate, oil bath 170 DEG C backflow 6h clarifies to solution, revolve inspissation in 70 DEG C to do, add 200mL methylene dichloride to dissolve, logical nitrogen protection, add 1-chloro-3 again, 5-bis--O-is to the dichloromethane solution (60g/300g) of methyl benzoyl-DRI, add the dichloromethane solution (8g/40g) of tin tetrachloride, in 20 ~ 25 DEG C of reactions more than 3 hours, it is complete that TLC tracks to raw material primitive reaction, add methylene dichloride and water, stir layering, organic phase washes 1 time with saturated sodium bicarbonate aqueous solution again, wash 1 time, anhydrous sodium sulfate drying, be evaporated to dry, obtain the title compound of 51g.
Embodiment 2: the preparation of Decitabine
370ml anhydrous methanol and 0.3g sodium methylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-is to toluyl-DRI)-5-azepine cytosine(Cyt); be warming up to 52 ~ 58 DEG C of reactions 1 hour; add 0.4g Glacial acetic acid; be chilled to 10 ~ 30 DEG C of filtrations, after filter cake is dried, obtain the intermediate of single protection.
1H-NMR(DMSO-d
6)δ：2.40(3H，s)，3.30(2H，s)，3.70(2H，s)，4.22(1H，s)，5.19(1H，s)，5.47(1H，s)，6.15(1H，t，J＝6.5Hz，1H)，7.36(2H，d，J＝7.6Hz)，7.54(2H，s)，7.90(2H，d，J＝7.6Hz)，8.54(1H，s)。
MS：m/z，369.1(M+Na)。
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g); 52 ~ 58 DEG C are reacted 2 hours; add 1.2g glacial acetic acid; be chilled to 0 ~ 10 DEG C of stirring and crystallizing more than 8 hours; filter; 40 ~ 50 DEG C of decompression dryings obtain 5.1g Decitabine crude product, beta isomer 97.64%.Crude product 350ml anhydrous methanol recrystallization is obtained 4.1g white solid, beta isomer 99.98% 1 time.
1H-NMR(DMSO-d
6)δ：2.11-2.24(2H，m)，3.52-3.64(2H，m)，3.82(1H，q，J＝3.6Hz)，4.22-4.26(1H，m)，5.00(1H，t，J＝5.2Hz)，5.24(1H，d，J＝4.3Hz)，6.03(1H，t，J＝6.5Hz)，7.46(2H，d，J＝14.5Hz)，8.50(1H，s)。
Embodiment 3: the preparation of Decitabine
370ml anhydrous methanol and 0.06g sodium methylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-is to toluyl-DRI)-5-azepine cytosine(Cyt); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.4g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 369.1 (M+Na).
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g), and 52 ~ 58 DEG C are reacted 2 hours, add 1.2g glacial acetic acid; separate out solid; filter, filter cake dries to obtain 4.1g Decitabine crude product, beta isomer 97.2%.Crude product 300ml anhydrous methanol recrystallization is obtained 3.8g white solid, beta isomer 99.86% 1 time.
Embodiment 4: the preparation of Decitabine
370ml dehydrated alcohol and 0.66g sodium ethylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-is to toluyl-DRI)-5-azepine cytosine(Cyt); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.4g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 369.1 (M+Na).
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g), and 52 ~ 58 DEG C are reacted 2 hours, add 1.2g glacial acetic acid; separate out solid; filter, filter cake dries to obtain 4.5g Decitabine crude product, beta isomer 97.8%.Crude product 300ml anhydrous methanol recrystallization is obtained 4.1g white solid, beta isomer 99.82% 1 time.
Example 5: the preparation of Decitabine
370ml anhydrous methanol and 0.44g sodium methylate is added in reaction flask; 32g 1-(3 is added under stirring at room temperature; 5-bis--O-ethanoyl-DRI)-5-azepine cytosine(Cyt) (prepared by the method disclosed in the method for embodiment 1 or existing document that can refer to); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.4g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 271.1 (M+H).
Above-mentioned intermediate joins in anhydrous methanol (50ml) solution of sodium methylate (1g), 52 ~ 58 DEG C are reacted 2 hours, add 1.2g glacial acetic acid, be chilled to 0 ~ 10 DEG C of stirring and crystallizing 4 hours, filter, 40 ~ 50 DEG C of decompression dryings obtain 4.9g Decitabine crude product, beta isomer 96.98%.Crude product 290ml anhydrous methanol recrystallization is obtained 3.9g white solid, beta isomer 99.79% 1 time.
Example 6: the preparation of Decitabine
370ml dehydrated alcohol and 1.2g sodium ethylate is added in reaction flask; 40g 1-(3 is added under stirring at room temperature; 5-bis--O-benzoyl base-DRI)-5-azepine cytosine(Cyt) (prepared by the method disclosed in the method for embodiment 1 or existing document that can refer to); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.4g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 333.1 (M+H).
Above-mentioned intermediate joins in anhydrous methanol (50ml) solution of sodium methylate (1g), 52 ~ 58 DEG C are reacted 2 hours, add 1.2g glacial acetic acid, be chilled to 0 ~ 10 DEG C of stirring and crystallizing 2 hours, filter, 40 ~ 50 DEG C of decompression dryings obtain 4.2g Decitabine crude product, beta isomer 96.54%.Crude product 390ml anhydrous methanol recrystallization is obtained 3.9g white solid, beta isomer 99.87% 1 time.
Embodiment 7: the preparation of Decitabine
370ml anhydrous methanol and 0.53g sodium methylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-is to chlorobenzoyl-DRI)-5-azepine cytosine(Cyt) (prepared by the method disclosed in the method for embodiment 1 or existing document that can refer to); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.4g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 367.1 (M+H).
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g), and 52 ~ 58 DEG C are reacted 2 hours, add 1.2g glacial acetic acid; separate out solid; filter, filter cake dries to obtain 4g Decitabine crude product, beta isomer 96.6%.Crude product 300ml anhydrous methanol recrystallization is obtained 3.1g white solid, beta isomer 99.82% 1 time.
Embodiment 8: the preparation of Decitabine
370ml anhydrous methanol and 0.43g sodium methylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-is to methoxybenzoyl-DRI)-5-azepine cytosine(Cyt) (prepared by the method disclosed in the method for embodiment 1 or existing document that can refer to); be warming up to 52 ~ 58 DEG C of reactions 1 hour; be chilled to 10 ~ 30 DEG C of filtrations, after filter cake is dried, obtain the intermediate of single protection; MS:m/z, 363.1 (M+H).
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g), and 52 ~ 58 DEG C are reacted 2 hours, add 1.2g glacial acetic acid; separate out solid; filter, filter cake dries to obtain 3.8g Decitabine crude product, beta isomer 96.2%.Crude product 300ml anhydrous methanol recrystallization is obtained 3.2g white solid, beta isomer 99.81% 1 time.
Embodiment 9: the preparation of Decitabine
370ml anhydrous methanol and 0.15g sodium methylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-p-nitrophenyl formyl-DRI)-5-azepine cytosine(Cyt) (prepared by the method disclosed in the method for embodiment 1 or existing document that can refer to); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.5g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 378.1 (M+H).
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g), and 52 ~ 58 DEG C are reacted 2 hours, add 1g glacial acetic acid; separate out solid; filter, filter cake dries to obtain 4.7g Decitabine crude product, beta isomer 96.5%.Crude product 300ml anhydrous methanol recrystallization is obtained 4.1g white solid, beta isomer 99.9% 1 time.
Embodiment 10: the preparation of Decitabine
370ml anhydrous methanol and 0.51g sodium methylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-Methoxyacetyl-DRI)-5-azepine cytosine(Cyt) (prepared by the method disclosed in the method for embodiment 1 or existing document that can refer to); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.3g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 301.1 (M+H).
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g); 52 ~ 58 DEG C are reacted 2 hours; add 1.2g glacial acetic acid; be chilled to 0 ~ 10 DEG C of stirring and crystallizing more than 6 hours; filter; 40 ~ 50 DEG C of decompression dryings obtain 3.9g Decitabine crude product, beta isomer 98.0%.Crude product 300ml anhydrous methanol recrystallization is obtained 3.5g white solid, beta isomer 99.9% 1 time.
Embodiment 11: the preparation of Decitabine
370ml anhydrous methanol and 0.48g sodium methylate is added in reaction flask; 50g 1-(3 is added under stirring at room temperature; 5-bis--O-fluorenes methoxy carbonyl acyl group-DRI)-5-azepine cytosine(Cyt) (prepared by the method disclosed in the method for embodiment 1 or existing document that can refer to); be warming up to 52 ~ 58 DEG C of reactions 1 hour, add 0.6g Glacial acetic acid, be chilled to 10 ~ 30 DEG C of filtrations; after filter cake is dried; obtain the intermediate of single protection, MS:m/z, 451.2 (M+H).
The intermediate of above-mentioned single protection joins in anhydrous methanol (50ml) solution of sodium methylate (1g), and 52 ~ 58 DEG C are reacted 2 hours, add 1.5g glacial acetic acid; separate out solid; filter, filter cake dries to obtain 4.6g Decitabine crude product, beta isomer 97.9%.Crude product 300ml anhydrous methanol recrystallization is obtained 3.9g white solid, beta isomer 99.8% 1 time.
Claims (11)
1. prepare a method for Decitabine, comprising:
(1) compound reaction under alcoholic solvent and sodium alkoxide exist of formula V, forms the precipitation of formula VI, precipitation separation, obtains the compound of formula VI in system;
(2) remove the protecting group of the compound of formula VI, obtain Decitabine;
Wherein R be ethanoyl, benzoyl, to chlorobenzene formacyl, to anisoyl, to methyl benzoyl, p-nitrophenyl formyl radical, fluorenes methoxy carbonyl acyl group, Methoxyacetyl; R
1, R
2one of them is hydrogen, another be ethanoyl, benzoyl, to chlorobenzene formacyl, to anisoyl, to methyl benzoyl, p-nitrophenyl formyl radical, fluorenes methoxy carbonyl acyl group, Methoxyacetyl; The mol ratio of formula V compound and sodium alkoxide is 1:0.01 ~ 0.2; Described alcoholic solvent is C
1~ C
6alcohol; Sodium alkoxide is C
1~ C
6the sodium salt of alcohol.
2. method according to claim 1, is characterized in that, R is to methyl benzoyl; R
1, R
2one of be hydrogen, another is to methyl benzoyl.
3. the method described in claim 1 or 2, is characterized in that, R
1for hydrogen, R
2for to methyl benzoyl.
4. method described in claim 1, is characterized in that, the mol ratio of formula V compound and sodium alkoxide is 1:0.02 ~ 0.09.
5. method described in claim 1, is characterized in that, the mol ratio of formula V compound and sodium alkoxide is 1:0.03 ~ 0.08.
6. method described in claim 1, is characterized in that, the mol ratio of formula V compound and sodium alkoxide is 1:0.03 ~ 0.06.
7. method according to claim 1, is characterized in that, alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol, Pentyl alcohol, 2-hexanol.
8. method described in claim 1, is characterized in that, alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol.
9. method according to claim 1, is characterized in that, alcoholic solvent is methyl alcohol.
10. method described in claim 1, is characterized in that, sodium alkoxide is sodium methylate, sodium ethylate.
11. methods according to claim 1, is characterized in that, alcoholic solvent is methyl alcohol, and sodium alkoxide is sodium methylate.
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| CN105777830A (en) * | 2015-04-03 | 2016-07-20 | 杭州华东医药集团新药研究院有限公司 | Decitabine impurity, and preparation and HPLC detection method thereof |
| CN112424211B (en) * | 2018-07-24 | 2021-12-24 | 正大天晴药业集团股份有限公司 | Preparation method of trifluridine |
| CN110054654B (en) * | 2019-05-27 | 2022-12-27 | 武汉百科药物开发有限公司 | Synthetic method of decitabine intermediate alpha-substituted deoxyribose |
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| CN101560232A (en) * | 2009-05-15 | 2009-10-21 | 上海清松制药有限公司 | Method for preparing improved decitabine |
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| CN101560232A (en) * | 2009-05-15 | 2009-10-21 | 上海清松制药有限公司 | Method for preparing improved decitabine |
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Effective date of registration: 20150504 Address after: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee after: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Address before: Bridge 222069 Jiangsu city of Lianyungang province Lianyungang economic and Technological Development Zone Dapu Industrial Zone, Road No. 16 Patentee before: Lianyungang Runzhong Pharmaceutical Co.,Ltd. |
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Effective date of registration: 20180809 Address after: 211122 1099 Fu Ying Road, Jiangning District, Nanjing, Jiangsu (Jiangning Gao Xinyuan) Co-patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee after: Zhengda sunny Pharmaceutical Group Nanjing Shun Xin Pharmaceutical Co., Ltd. Co-patentee after: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Address before: 222006 No. 8 Julong North Road, Sinpo District, Jiangsu, Lianyungang Co-patentee before: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Patentee before: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. |