CN1563030A - Method for preparing 2',3'2-dideoxycytidine - Google Patents
Method for preparing 2',3'2-dideoxycytidine Download PDFInfo
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- CN1563030A CN1563030A CN 200410014350 CN200410014350A CN1563030A CN 1563030 A CN1563030 A CN 1563030A CN 200410014350 CN200410014350 CN 200410014350 CN 200410014350 A CN200410014350 A CN 200410014350A CN 1563030 A CN1563030 A CN 1563030A
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- dideoxycytidine
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- acetyl
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- 229960000523 zalcitabine Drugs 0.000 title claims description 13
- 238000000034 method Methods 0.000 title abstract description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 10
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 9
- NIDVTARKFBZMOT-PEBGCTIMSA-N N(4)-acetylcytidine Chemical compound O=C1N=C(NC(=O)C)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NIDVTARKFBZMOT-PEBGCTIMSA-N 0.000 claims abstract description 8
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 8
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims abstract description 4
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 229910001115 Zinc-copper couple Inorganic materials 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- QXHMWMKHGRRAJZ-NKOUKZSMSA-N 2-[2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-oxopurin-5-yl]acetic acid Chemical compound C1=NC2(C(=NC(=NC2=O)N)N1[C@H]3[C@@H]([C@@H]([C@H](O3)CO)O)O)CC(=O)O QXHMWMKHGRRAJZ-NKOUKZSMSA-N 0.000 abstract 1
- IYKLQEMQEGWXOQ-UHFFFAOYSA-N 3-(7-amino-4-chloro-1-oxoisochromen-3-yl)oxypropyl carbamimidothioate Chemical compound NC1=CC=C2C(Cl)=C(OCCCSC(=N)N)OC(=O)C2=C1 IYKLQEMQEGWXOQ-UHFFFAOYSA-N 0.000 abstract 1
- 229910007565 Zn—Cu Inorganic materials 0.000 abstract 1
- 229940087646 methanolamine Drugs 0.000 abstract 1
- 239000012047 saturated solution Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 5
- 239000012265 solid product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
In this invention, cytidine reacts with acetic oxide to produce 4-N-acetylcytidine, then reacting with hydrogen bromide in acetic acid saturated solution, in the presence of acitic oxide as catalyst to produce bromo-mixture; then reacting in the presence of Zn-Cu couple as catalyst to produce 4-N-acetyl-2,3-dihydro-2,3-didioxy cytidine-5-acetate; then, reacting, to proceed hydrogenation reaction, in the presence of Pd/C, to produce 4-N-acetyl-2,3-dideoxy guanosine-5-acetate; then, reacting in the presence of methanol and triethylamine to produce 2,3-dideoxy cytidine. This invention has advantages of: simple process, easy to operate, available raw material, high yield over 90%.
Description
Technical field:
The present invention relates to a kind of medicine, is a kind of medicine of AIDS resisting.
Background technology:
Existing 2 ＇, the production method of 3 ＇-dideoxycytidine, complex process, the product yield is low.
Summary of the invention:
The object of the present invention is to provide a kind of technology simple, easy to operate, 2 ＇ that the product yield is high, the production method of 3 ＇-dideoxycytidine.
Technical solution of the present invention is:
A kind of 2 ＇, the production method of 3 ＇-dideoxycytidine is characterized in that: comprise the following steps: successively
1. cytidine and aceticanhydride reaction are generated the 4-N-acetylcytidine;
2. with the saturated acetic acid solution of 4-N-acetylcytidine and hydrogen bromide under the condition of aceticanhydride as catalyzer, reaction generates the bromo mixture, is a pair of isomer;
3. be under the condition of catalyzer with the zinc copper couple with above-mentioned bromo mixture, reaction generates 4-N-acetyl-2 ＇, 3 ＇-two dehydrogenations-2 ＇, 3 ＇-dideoxycytidine 5 ＇-acetic ester;
4. with above-mentioned 4-N-acetyl-2 ＇, 3 ＇-two dehydrogenations-2 ＇, 3 ＇-dideoxycytidine 5 ＇-acetic ester carries out hydrogenation reaction under the condition that Pd/C exists, generate 4-N-acetyl-2 ＇, 3 ＇-dideoxyguanosine 5 ＇-acetic ester;
5. with 4-N-acetyl-2 ＇, 3 ＇-dideoxyguanosine 5 ＇-acetic ester is under the condition that methyl alcohol, triethylamine exist, and reaction generates 2 ＇, 3 ＇-dideoxycytidine.
Step reaction is 1. carried out under the reflux condition.Step temperature of reaction 2. is 40～60 ℃.Step 3. be with the bromo mixture under argon shield, be dissolved in the anhydrous acetonitrile with the zinc copper couple reaction.Step hydrogenation reaction is 4. carried out at normal temperatures and pressures.5. step is to carry out under 50～70 ℃ of water bath condition.
Technology of the present invention is simple, and is easy to operate, and raw material is easy to get, and product yield height reaches more than 90%.
The invention will be further described below in conjunction with embodiment.
Embodiment:
Embodiment:
A kind of 2 ＇, the production method of 3 ＇-dideoxycytidine comprises the following steps: successively
1. the reaction of cytidine and aceticanhydride is generated the 4-N-acetylcytidine: with 10 gram cytidines and 12～30ml (can be 12,18,25,30ml) aceticanhydride under mechanical stirring, heating reflux reaction 10～20 hours (example 10,15,20 hours), removal of solvent under reduced pressure then, add toluene 50 * 2 azeotropic again and remove residue, obtain the colourless powder product.Reaction formula:
2. with the saturated acetic acid solution of above-mentioned 4-N-acetylcytidine that obtains and hydrogen bromide under the condition of aceticanhydride as catalyzer, reaction generates the bromo mixture, be a pair of isomer: with 10 gram 4-N-acetylcytidines, add 5～15ml (example 5,10,15ml) the saturated acetic acid solution of hydrogen bromide and 5～15ml (example 5,10,15ml) the new aceticanhydride that steams, oil bath is heated to 40～60 ℃ of (examples 40,50,60 ℃), reacting 1～4 hour (can be 1,2,3,4 hours), the black product that obtains after the cooling is poured in the 250ml0.05M potassiumphosphate aqueous solution, use the 250ml dichloromethane extraction, further use anhydrous sodium sulfate drying, obtain solid product.Reaction formula:
3. be under the condition of catalyzer with the zinc copper couple with above-mentioned bromo mixture; reaction generates 4-N-acetyl-2 ＇; 3 ＇-two dehydrogenations-2 ＇; 3 ＇-dideoxycytidine 5 ＇-acetic ester: under argon shield; the above-mentioned bromo mixture of 3 grams is dissolved in 30～80ml (example 30,50,80ml) anhydrous acetonitrile; the zinc copper couple that adds 700～1000mg (example 700,800,900,1000mg); 3～10 hours (example 3,6,8,10 hours) of stirring at room reaction; remove unreacted zinc copper couple with diatomite filtration then, the dry gray solid product that gets.Reaction formula:
4. with above-mentioned 4-N-acetyl-2 ＇, 3 ＇-two dehydrogenations-2 ＇, 3 ＇-dideoxycytidine 5 ＇-acetic ester is under the condition that Pd/C exists, carry out hydrogenation reaction, generate 4-N-acetyl-2 ＇, 3 ＇-dideoxyguanosine 5 ＇-acetic ester: with 1 gram 4-N-acetyl-2 ＇, 3 ＇-two dehydrogenations-2 ＇, 3 ＇-dideoxycytidine 5 ＇-acetic ester is transferred to the hydrogenation bottle with 50ml methyl alcohol, obtain suspension, add 30～80mg (example 30,60, catalyst P d/C 80mg), reaction system is carried out the excluding air operation, stir at normal temperatures and pressures then and carry out hydrogenation, react 0.5～2 hour (example 0.5,1,2 hours), with diatomite filtering Pd/C, remove solvent under reduced pressure, the dry white solid product that gets.Reaction formula:
5. with 4-N-acetyl-2 ＇, 3 ＇-dideoxyguanosine 5 ＇-acetic ester is under the condition that methyl alcohol, triethylamine exist, and reaction generates 2 ＇, 3 ＇-dideoxycytidine.With 500mg4-N-acetyl-2 ＇, 3 ＇-dideoxyguanosine 5 ＇-acetic ester stir and are dissolved in the mixed solution that 15～30ml (example 15,20,25,30ml) methyl alcohol, 3～10ml (example 3,6,8,10ml) triethylamine and 1～6ml (example 1,3,6ml) deionized water be made into, 50～70 ℃ of (50,60,70 ℃ of examples) water-baths 1～6 hour (example 1,3,6 hours), removal of solvent under reduced pressure obtains solid product.Productive rate is more than 90%.Reaction formula:
Claims (6)
1, a kind of 2 ', 3 '-production method of dideoxycytidine, it is characterized in that: comprise the following steps: successively
1. cytidine and aceticanhydride reaction are generated the 4-N-acetylcytidine;
2. with the saturated acetic acid solution of 4-N-acetylcytidine and hydrogen bromide under the condition of aceticanhydride as catalyzer, reaction generates the bromo mixture, is a pair of isomer;
3. be under the condition of catalyzer with the zinc copper couple with above-mentioned bromo mixture, reaction generation 4-N-acetyl-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxycytidine 5 '-acetic ester;
4. with above-mentioned 4-N-acetyl-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxycytidine 5 '-acetic ester under the condition that Pd/C exists, carry out hydrogenation reaction, generate 4-N-acetyl-2 ', 3 '-dideoxyguanosine 5 '-acetic ester;
5. with 4-N-acetyl-2 ', 3 '-dideoxyguanosine 5 '-acetic ester under the condition that methyl alcohol, triethylamine exist, reaction generates 2 ', 3 '-dideoxycytidine.
2, according to claim 12 ', 3 '-production method of dideoxycytidine, it is characterized in that: step reaction is 1. carried out under the reflux condition.
3, according to claim 1 and 22 ', 3 '-production method of dideoxycytidine, it is characterized in that: step temperature of reaction 2. is 40～60 ℃.
4, according to claim 1 and 22 ', 3 '-production method of dideoxycytidine, it is characterized in that: step 3. be with the bromo mixture under argon shield, be dissolved in the anhydrous acetonitrile with the zinc copper couple reaction.
5, according to claim 1 and 22 ', 3 '-production method of dideoxycytidine, it is characterized in that: step hydrogenation reaction is 4. carried out at normal temperatures and pressures.
6, according to claim 1 and 22 ', 3 '-production method of dideoxycytidine, it is characterized in that: 5. step is to carry out under 50～70 ℃ of water bath condition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410014350XA CN1297565C (en) | 2004-03-15 | 2004-03-15 | Method for preparing 2',3'2-dideoxycytidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410014350XA CN1297565C (en) | 2004-03-15 | 2004-03-15 | Method for preparing 2',3'2-dideoxycytidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1563030A true CN1563030A (en) | 2005-01-12 |
| CN1297565C CN1297565C (en) | 2007-01-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200410014350XA Expired - Fee Related CN1297565C (en) | 2004-03-15 | 2004-03-15 | Method for preparing 2',3'2-dideoxycytidine |
Country Status (1)
| Country | Link |
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| CN (1) | CN1297565C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584922A (en) * | 2011-12-30 | 2012-07-18 | 杭州科本药业有限公司 | Method for preparing stavudine |
| CN102690310A (en) * | 2011-10-14 | 2012-09-26 | 珍奥集团股份有限公司 | Preparation method of N4-acetylcytidine |
| CN107033205A (en) * | 2017-06-12 | 2017-08-11 | 上海兆维科技发展有限公司 | A kind of preparation method of 3 ' BrdUs |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0692394B2 (en) * | 1987-06-23 | 1994-11-16 | 日本たばこ産業株式会社 | Method for producing 2 ', 3'-dideoxycytidine |
| US4900828A (en) * | 1988-05-12 | 1990-02-13 | Hoffmann-Laroche Inc. | Intermediate compounds and an improved procedure for the synthesis of 2',3'-dideoxycytidine |
| US5506349A (en) * | 1992-05-13 | 1996-04-09 | Ribozyme Pharmaceuticals, Inc. | Chemical synthesis of 2', 3'-dideoxycytidine |
-
2004
- 2004-03-15 CN CNB200410014350XA patent/CN1297565C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690310A (en) * | 2011-10-14 | 2012-09-26 | 珍奥集团股份有限公司 | Preparation method of N4-acetylcytidine |
| CN102690310B (en) * | 2011-10-14 | 2015-05-13 | 珍奥集团股份有限公司 | Preparation method of N4-acetylcytidine |
| CN102584922A (en) * | 2011-12-30 | 2012-07-18 | 杭州科本药业有限公司 | Method for preparing stavudine |
| CN107033205A (en) * | 2017-06-12 | 2017-08-11 | 上海兆维科技发展有限公司 | A kind of preparation method of 3 ' BrdUs |
| CN107033205B (en) * | 2017-06-12 | 2020-05-19 | 上海兆维科技发展有限公司 | A kind of preparation method of 3'-deoxyuridine |
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| Publication number | Publication date |
|---|---|
| CN1297565C (en) | 2007-01-31 |
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Assignee: NANTONG HONGCI PHARMACEUTICAL CO., LTD. Assignor: Lu Jinkang Contract fulfillment period: 2009.7.18 to 2024.3.1 contract change Contract record no.: 2009320001484 Denomination of invention: Method for producing 2 ', 3' - deoxycytidine Granted publication date: 20070131 License type: Exclusive license Record date: 2009.8.11 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.7.18 TO 2024.3.1; CHANGE OF CONTRACT Name of requester: NANTONG HONGCI MEDICINE CO., LTD. Effective date: 20090811 |
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