CN101768197A - Preparation method for nelarabine - Google Patents
Preparation method for nelarabine Download PDFInfo
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- CN101768197A CN101768197A CN200810246549A CN200810246549A CN101768197A CN 101768197 A CN101768197 A CN 101768197A CN 200810246549 A CN200810246549 A CN 200810246549A CN 200810246549 A CN200810246549 A CN 200810246549A CN 101768197 A CN101768197 A CN 101768197A
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method for a compound of nelarabine with formula (I), which obtains the nelarabine with high yield by using compounds with formulas (II) and (III) as initial raw materials.
Description
Technical field
The present invention relates to the preparation method of the Arabic ribofuranosyl of a kind of 2-amino-9-β-D--6-methoxyl group-purine (Nelzarabine):
Background technology
Nelzarabine is a kind of good antitumor drug, is mainly used in leukemic treatment, has of great value pharmacological properties.
About the preparation of Nelzarabine, EP0294114A2 has reported a kind of route that utilizes biological enzyme to prepare Nelzarabine, and is specific as follows:
This route is a raw material with the Arabic ribose of uridylic, is saccharase through 26 days fermentation with purine nucleoside phosphorylase and uridine Starch phosphorylase, obtains crude product and adopts ion exchange resin to separate to obtain pure product, and total recovery can reach 15%.But the saccharase that this route is not only used costs an arm and a leg and is difficult for buying, and reaction time while, long, purification difficult all was unfavorable for suitability for industrialized production.
And CN 200710119140 discloses a kind of novel method for preparing Nelzarabine, and its preparation route is as follows:
Above-mentioned route reaction step is more, and aftertreatment is also more loaded down with trivial details, and total recovery is lower, is unfavorable for technology production.
Based on the pharmacy value of Nelzarabine and good market outlook, seeking a kind of can be imperative with the effective ways of strong synthesis type (I) compound of good yield and controllability.
Summary of the invention
The invention provides a kind of preparation method of Nelzarabine, with formula (II) compound and formula (III) compound be starting raw material, with the Nelzarabine that obtains of the yield of excellence.
The invention provides a kind of preparation method of Nelzarabine more specifically; employing formula (II) compound and formula (III) compound; wherein R represents acyl group protecting group such as ethanoyl, methoxyl group ethanoyl, benzoyl and to chlorobenzene formacyl, obtains formula (IV) compound through the butt joint reaction:
Wherein R as above defines, and this compound obtains the formula V compound under base catalysis:
This compound removes by filter and obtains Nelzarabine after catalyzer also separates through hydrogenation.
Formula (II) compound can be the molecular sieve in different apertures with formula (III) compound butt joint catalyst for reaction, preferential 4A molecular sieve.
Formula (II) compound and formula (III) compound butt joint temperature of reaction are 40-100 ℃, preferred 60-80 ℃.
Formula (II) compound and formula (III) compound butt joint reaction is preferably finished in alkane solvents, and is preferred 1, and 2-ethylene dichloride, chloroform and methylene dichloride are made solvent, 1 after more preferably heavily steaming, 2-ethylene dichloride.
Formula (IV) compound can be sodium methylate, sodium ethylate, potassium tert.-butoxide and ammonia, particular methanol sodium to the basic catalyst that the formula V compound transforms.
Formula (IV) compound is 40-100 ℃ to the temperature of reaction that the formula V compound transforms, preferred 60-80 ℃.
In the catalyzer of the hydrogenation of formula V compound, can be palladium, platinum, nickel, rhodium and their compound, the spy be the form or the oxide form of load fully, is preferably the palladium charcoal.
The pressure of formula (II) hydrogenation of compounds reaction is 1-10atm, preferred normal pressure.
The temperature of formula (II) hydrogenation of compounds reaction is 20-100 ℃, preferred 60-80 ℃.
In the method according to the invention, wherein use the special case of formula (III) compound and formula (IV) compound, R wherein represents acyl group protecting group such as ethanoyl, methoxyl group ethanoyl, benzoyl and to chlorobenzene formacyl.
The special case of formula (III) compound and formula (IV) compound; R wherein represents acyl group protecting group such as ethanoyl, methoxyl group ethanoyl, benzoyl and to chlorobenzene formacyl; they are in chemistry or pharmaceutical industry; particularly in Nelzarabine synthetic; can be used as intermediate, they have constituted integral part of the present invention thus.
According to formula (I) Nelzarabine and one or more pharmaceutically acceptable inert non-toxic carriers of the present invention's preparation, purposes in the medicine of leukemia and lymphoma.
Method yield of the present invention is higher, and controllability is strong, and the purity height and the cost of product are lower.
Embodiment
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Synthesizing of embodiment 1:2-acetylaminohydroxyphenylarsonic acid 6-methoxyl group purine
In the bottle, add 2-amino-6-methoxyl group purine 100g successively in 2L three, pyridine 1L stirs insoluble.System is cooled to below 0 ℃, slowly drips the 144g Acetyl Chloride 98Min., temperature control 0～-10 ℃.Dropwise, rise to stirring at room 2h naturally.Suction filtration, filter cake stirs 0.5h, suction filtration with the mixed solution of dehydrated alcohol and water.Get white solid 91.4g, yield 72.1%.
Embodiment 2:1-chloro-2,3, the Arabic ribofuranose of 5-three benzyloxies-β-D-synthetic
In the 2L there-necked flask, add 2,3 successively; the Arabic ribofuranose 100.0g of 5-three benzyloxies-1-O-p-nitrophenyl formyl radical-D-, 1,2-ethylene dichloride 1L; stirring and dissolving. be cooled to below 0 ℃; the adularescent solid is separated out in the feeding hydrogen chloride gas precursor reactant 4h. reaction process. and reaction finishes, and stops ventilation. keep 0 ℃ of left and right sides suction filtration, 1; 2-ethylene dichloride drip washing filter cake. filtrate is revolved steaming; obtain light yellow oil 116.1g,, be directly used in next step reaction without purification process.
Synthesizing of embodiment 3:2-acetylaminohydroxyphenylarsonic acid 6-methoxyl group-9-(2,3, the Arabic ribofuranosyl of 5-three-O-benzyl-β-D-)-purine
N
2Protection in the 2L there-necked flask, adds 1-chloro-2,3 down successively, the Arabic ribofuranose 77.1g of 5-three benzyloxies-β-D-, 2-acetylaminohydroxyphenylarsonic acid 6-methoxyl group purine 36.4g, 1,2-ethylene dichloride 770mL and 4A molecular sieve 144g, temperature rising reflux reaction 72 hours.Naturally cool to room temperature, suction filtration with 50mL chloroform drip washing filter cake, revolves and steams filtrate, and the brown oil that obtains obtains brown oil 25.0g through column chromatography, and yield is 35.6%.
Synthesizing of embodiment 4:2-amino-6-methoxyl group-9-(2,3, the Arabic ribofuranosyl of 5-three-O-benzyl-β-D-)-purine
In 500mL single port bottle, add 2-acetylaminohydroxyphenylarsonic acid 6-methoxyl group-9-(2,3, the Arabic ribofuranosyl of 5-three-O-benzyl-β-D-)-purine 13.2g successively, sodium methylate 2.9g and methyl alcohol 135mL, temperature rising reflux reaction 3h.Naturally cool to room temperature, suction filtration with 30mL methyl alcohol drip washing filter cake, revolves and steams filtrate, revolve to steam the making beating of residuum adding 66mL chloroform, and suction filtration, filtrate is revolved to steam and is obtained brown oil 11.5g, and yield is 92.1%,
1H-NMR (CDCl
3, 400MHz), and δ 3.65-3.66 (d, 2H), 4.01-4.09 (t, 3H), 4.11-4.17 (m, 2H), 4.21-4.24 (q, 3H), 4.53-4.60 (m, 4H), 4.88 (s, 2H), 6.34-6.35 (d, 1H), 6.97-6.99 (q, 4H), 7.21-7.27 (m, 13H), 7.97 (s, 1H).
Embodiment 5: Nelzarabine synthetic
In the 100mL there-necked flask, add 2-amino-6-methoxyl group-9-(2,3, the Arabic ribofuranosyl of 5-three-O-benzyl-β-D-)-purine 5.0g successively, methyl alcohol 50mL and 10%Pd/C 1.0g keep 40 ℃ and continue logical H
224h.Suction filtration with 10mL methyl alcohol drip washing filter cake, revolves and steams filtrate, the making beating of resistates ethyl acetate, and suction filtration, filter cake water and recrystallizing methanol obtain the 1.8g white solid, yield 53.7%, m.p.128.3 ℃, [a]
20D=+55.3 ° (c=0.27, DMF),
1H-NMR (DMSO, 400MHz), δ 3.58-3.64 (m, 2H), 3.73-3.74 (d, 1H), 3.94 (s, 3H), 4.03-4.07 (q, 2H), 5.01-5.04 (t, 1H), 5.46-5.47 (d, 1H), 5.58-5.59 (d, 1H), 5.73 (s, 1H), 6.09-6.11 (d, 1H), 6.40-6.41 (d, 2H), 7.90 (s, 1H).
Claims (10)
1. a novel method for preparing Nelzarabine is characterized in that obtaining formula (IV) compound with formula (II) compound and formula (III) compound through the butt joint reaction, under base catalysis, obtain the formula V compound, through hydrogenation, remove by filter and obtain Nelzarabine after catalyzer also separates again
Wherein R represents acyl group protecting group such as ethanoyl, methoxyl group ethanoyl, benzoyl and to chlorobenzene formacyl.
2. according to the preparation method of claim 1, the catalyzer of its Chinese style (II) compound and formula (III) compound butt joint prepared in reaction formula (IV) compound is a molecular sieve.
3. according to the preparation method of claim 1, its Chinese style (II) compound and formula (III) compound butt joint temperature of reaction are 40-100 ℃.
4. according to the preparation method of claim 1, wherein do not separate purifying formula (IV) compound.
5. according to the preparation method of claim 1, its Chinese style (IV) compound is sodium methylate, sodium ethylate, potassium tert.-butoxide or ammonia to the basic catalyst that the formula V compound transforms.
6. according to the preparation method of claim 1, its Chinese style (IV) compound is 40-100 ℃ to the temperature of reaction that the formula V compound transforms.
7. according to the preparation method of claim 1, wherein the catalyzer of the hydrogenation of formula V compound is the palladium charcoal.
8. according to the preparation method of claim 1, the pressure of its Chinese style (II) hydrogenation of compounds reaction is 1-10atm.
9. according to the preparation method of claim 1, the temperature of its Chinese style (II) hydrogenation of compounds reaction is 20-100 ℃.
10. according to the preparation method of claim 1, the R of its Chinese style (III) compound and formula (IV) compound represents acyl group protecting group such as ethanoyl, methoxyl group ethanoyl, benzoyl and to chlorobenzene formacyl.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200810246549A CN101768197A (en) | 2008-12-29 | 2008-12-29 | Preparation method for nelarabine |
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| CN200810246549A CN101768197A (en) | 2008-12-29 | 2008-12-29 | Preparation method for nelarabine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172687A (en) * | 2013-03-28 | 2013-06-26 | 山东罗欣药业股份有限公司 | Nelarabine crystalline compound and preparation method thereof |
| CN103483409A (en) * | 2013-09-24 | 2014-01-01 | 北京满格医药科技有限公司 | Synthetic method for preparing nelarabine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87108265A (en) * | 1986-12-15 | 1988-07-13 | 惠尔康基金会集团公司 | Antiviral compound |
| CN88102038A (en) * | 1987-04-10 | 1988-10-26 | 曼海姆泊灵格股份公司 | Deazapurine nucleoside derivates and preparation method thereof pharmaceutical composition, be used for nucleic acid sequence and as antiviral agent |
| CN1031233A (en) * | 1987-05-30 | 1989-02-22 | 惠尔康基金会集团公司 | Antiviral compound |
| WO1992001456A1 (en) * | 1990-07-19 | 1992-02-06 | The Wellcome Foundation Limited | Heterocyclic compounds |
| CN101092441A (en) * | 2007-07-17 | 2007-12-26 | 北京本草天源药物研究院 | Method for synthesizing nelarabine |
-
2008
- 2008-12-29 CN CN200810246549A patent/CN101768197A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87108265A (en) * | 1986-12-15 | 1988-07-13 | 惠尔康基金会集团公司 | Antiviral compound |
| CN88102038A (en) * | 1987-04-10 | 1988-10-26 | 曼海姆泊灵格股份公司 | Deazapurine nucleoside derivates and preparation method thereof pharmaceutical composition, be used for nucleic acid sequence and as antiviral agent |
| CN1031233A (en) * | 1987-05-30 | 1989-02-22 | 惠尔康基金会集团公司 | Antiviral compound |
| WO1992001456A1 (en) * | 1990-07-19 | 1992-02-06 | The Wellcome Foundation Limited | Heterocyclic compounds |
| US5821236A (en) * | 1990-07-19 | 1998-10-13 | Glaxo Wellcome Inc. | Tumor treatment with arabinofuranosyl purine derivatives |
| CN101092441A (en) * | 2007-07-17 | 2007-12-26 | 北京本草天源药物研究院 | Method for synthesizing nelarabine |
Non-Patent Citations (3)
| Title |
|---|
| TADEUSZ BIEG，等: "Removal of O-benzyl Protective groups by catalytic transfer hydrogenation", 《SYNTHESIS-STUTTGART》 * |
| 李天全: "《有机合成化学基础》", 30 June 1992, 高等教育出版社 * |
| 梁平，等: "奈拉滨的合成研究进展", 《精细化工中间体》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172687A (en) * | 2013-03-28 | 2013-06-26 | 山东罗欣药业股份有限公司 | Nelarabine crystalline compound and preparation method thereof |
| CN103172687B (en) * | 2013-03-28 | 2015-07-08 | 山东罗欣药业集团股份有限公司 | Nelarabine crystalline compound and preparation method thereof |
| CN103483409A (en) * | 2013-09-24 | 2014-01-01 | 北京满格医药科技有限公司 | Synthetic method for preparing nelarabine |
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Application publication date: 20100707 |