CN101565440A - Novel preparation method of telbivudine - Google Patents
Novel preparation method of telbivudine Download PDFInfo
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- CN101565440A CN101565440A CNA2009100525649A CN200910052564A CN101565440A CN 101565440 A CN101565440 A CN 101565440A CN A2009100525649 A CNA2009100525649 A CN A2009100525649A CN 200910052564 A CN200910052564 A CN 200910052564A CN 101565440 A CN101565440 A CN 101565440A
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- telbivudine
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- 229960005311 telbivudine Drugs 0.000 title claims abstract description 42
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 title claims abstract description 41
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 6
- 238000005695 dehalogenation reaction Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- -1 carboxylic acid halides Chemical class 0.000 claims description 5
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical compound C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- RIBFXMJCUYXJDZ-UHFFFAOYSA-N propanoyl bromide Chemical compound CCC(Br)=O RIBFXMJCUYXJDZ-UHFFFAOYSA-N 0.000 claims description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000990 Ni alloy Inorganic materials 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 9
- 230000018044 dehydration Effects 0.000 abstract description 2
- 238000006297 dehydration reaction Methods 0.000 abstract description 2
- 238000005658 halogenation reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000003147 glycosyl group Chemical group 0.000 description 5
- 239000002777 nucleoside Substances 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 150000008131 glucosides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000007348 radical reaction Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 239000003390 Chinese drug Substances 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 235000019082 Osmanthus Nutrition 0.000 description 1
- 241000333181 Osmanthus Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- RNJCXDJXPXWMDK-UHFFFAOYSA-N [AlH3].COCCO[Na] Chemical compound [AlH3].COCCO[Na] RNJCXDJXPXWMDK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel preparation method of telbivudine. The preparation method of telbivudine uses 5-methyl-L-uridine as initial raw material, and makes it undergo the processes of dehydration, acylation-halogenation, catalytic hydrogenation dehalogenation reaction and four-step reaction for finally removing protective group from sugar so as to obtain the telbivudine. The method has mild reaction conditions, higher yield than the existing preparation method, economy and effectiveness, and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the new preparation method's technical field of a kind of Telbivudine.
Background technology
Telbivudine is by Idenix Pharmaceuticals company research and development, goes on the market with trade(brand)name Sebivor in Switzerland in 2006.Chinese drug and food Surveillance Authority in 2007 ratifies this medicine and is used to treat chronic HBV.Telbivudine is the 4th medicine that is used for the treatment of chronic hepatitis B of FDA approval, be used for the treatment of adult's chronic hepatitis B, decompensated cirrhosis clinically, effect is better than lamivudine, and tolerance height, security are good, are nucleoside medicines that DEVELOPMENT PROSPECT is arranged.The chemical name of Telbivudine is 1-(2-deoxidation-β-L-furan type ribosyl)-5-methyl-2,4-(1H, 3H)-pyrimidine dione, structure is as follows:
The synthetic method of Telbivudine is a lot, bibliographical information mainly contain following two classes:
(1) glucosides method
The glucosides method is the common method of preparation Telbivudine; be starting raw material generally with 2-deoxidation-L-ribose; generate 1-chloro-2-deoxidation-3 through three-step reaction; 5-two-O-is to toluyl-α-L-ribofuranose; carry out glycosylation reaction with two TMS thymus pyrimidines again, remove that protecting group promptly gets Telbivudine on the glycosyl.[reference: Fujimori, S.; Iwanami, N.; Hashimoto, Y.; Shudo, K; A conventient and stereoselectivesynthesis of 2 '-deoxy-β-L-ribonucleosides.Nucleosides﹠amp; Nucleotides, 1992,11 (2-4), 341] raw material 2-deoxidation-L-ribose needs synthetic because occurring in nature does not exist in this method, though multiple synthetic method report is arranged, yield is all lower.In the glycosylation reaction, because glycosyl 2-position deoxidation, the nucleosides of generation is α, beta isomer mixture, and is not easily separated, influenced the purity of final product.The reaction scheme report is as follows:
Wherein, the synthetic route of 2-deoxidation-L-ribose summary can be referring to document [" the synthetic method general introduction of 2-deoxidation-L-ribose ", Han Suhui, the honor of canal osmanthus and Li Yong, organic chemistry, 2005,25 (5), 526-531]
(2) 2 deoxidation methods of glycosyl
US6395716 reported with 2 '-O-ethanoyl-3 '; the Arabic uridine of 5 '-two-O-benzoyl-β-L-is a starting raw material; according to its 2 '-the acid stronger character in position; with the hydrazine hydrate list take off 2 '-protecting group; utilize the free radical reaction deoxidation again; iodo is carried out in base 5-position, and methylation reaction is sloughed the sugared protecting group that goes up and got Telbivudine.This route steps is longer, owing to selected for use uridylic to carry out glycosylation reaction, the nucleoside base of generation also needs to carry out methyl substituted, the step complexity, and route is tediously long, and total recovery low (about 10～12%) is with high costs, does not have actual use meaning.
WO2001034618 has reported route of short synthetic Telbivudine:
This method is to be raw material with 5-methyl-L-uridine, protection 3 earlier ', 5 '-hydroxyl, 2 '-a position hydroxyl carry out sulfonylization, deoxidation under the free radical reaction condition obtains silanization-L-thymidine, slough again silylation protect Telbivudine.Though this reaction scheme reactions steps is short, because silylation protection reagent (TIPDSCl) costs an arm and a leg, this route is difficult to industrialization at present.
WO2005003374 has reported that a new legal system is equipped with Telbivudine, promptly adopt two (2-methoxy ethoxy) sodium aluminum hydride (Red-Al) reductase 12s, 2 '-dehydration-5-methyluridine, generation 2 '-deoxidation-β-L-nucleosides, but because Red-Al reagent costs an arm and a leg, cost is greater than value of the product, and industrial being difficult to used.
In sum, in view of the good prospect in medicine of Telbivudine, therefore need the method for preparing Telbivudine of economy of exploitation, safety.
Summary of the invention
Purpose of the present invention just provides a kind of new Telbivudine preparation method, uses the synthetic Telbivudine of this method to overcome the above-mentioned defective of prior art, and reaction scheme is short, uses reagent common, be fit to very much suitability for industrialized production, and yield is also than existing method height.
The present inventor has found a kind of suitable Telbivudine preparation method through experiment repeatedly, and concrete technical scheme is as follows:
The preparation method of Telbivudine comprises
Step 1: formula (I) compound is production (II) compound under the dewatering agent effect:
Step 2: formula (II) compound is through acidylate-halogenating reaction production (III) compound:
Wherein, X represents Cl or Br, and R represents alkyloyl;
Step 3: formula (III) compound is dehalogenation production (IV) compound under the condition of catalytic hydrogenation:
Wherein, R represents alkyloyl;
Step 4: formula (IV) compound removes under the alkali effect that protecting group gets Telbivudine (V) on the sugar.
The dewatering agent that uses when above-mentioned step 1 is reacted is selected methylcarbonate, diethyl carbonate, diphenyl carbonate etc. for use, wherein preferred diethyl carbonate or diphenyl carbonate.Use solvent to select C such as DMF for use during reaction
2-C
6Rudimentary acid amides, C
2-C
6Ester class (as methyl acetate, ethyl acetate etc.), C
2-C
6One or more mixed solvents in alkane, haloalkane, acetonitrile or the dioxane, wherein preferred DMF.Temperature is 100-150 ℃ during reaction.The alkali that uses as mineral alkali or organic bases all can, as sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood etc., most preferably sodium bicarbonate.
Acidylate-the halogenating agent that uses when above-mentioned step 2 is reacted is selected from C
3-C
6The fat carboxylic acid halides, wherein preferred propionyl bromide or propionyl chloride.Therefore the R in formula (III) compound of reaction back is C
3-C
6Alkyloyl, the preferred propionyl of R wherein.The solvent that uses during reaction is selected from C such as DMF
2-C
6Rudimentary acid amides, C
2-C
6Ester class (as methyl acetate, ethyl acetate etc.), C
2-C
6One or more mixed solvents in alkane, haloalkane, acetonitrile or the dioxane, wherein preferred acetonitrile.
The condition of catalytic hydrogenation was selected for use under the convenient pressure when above-mentioned step 3 was reacted, at catalyzer such as Pd-C, Pd-BaSO
4, carry out under the effect such as Raney-Ni or nickelalloy.
Remove on the glycosyl alkali of protecting group during the reaction of above-mentioned step 4 and be selected from C such as mineral alkali such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood or sodium methylate, sodium ethylate
1-C
3Rudimentary sodium alkoxide or ammoniacal liquor etc., wherein particular methanol sodium or ammoniacal liquor.Usedly during reaction remove that the solvent of protecting group is selected from C such as methyl alcohol, ethanol, propyl alcohol, Virahol on the glycosyl
1-C
6Lower aliphatic alcohols or water, wherein particular methanol.
Beneficial effect of the present invention: the present invention has found a new Telbivudine preparation method, with 5-methyl-L-uridine is starting raw material, make Telbivudine, the reaction conditions gentleness through dehydration, acidylate-halogenation, the catalytic hydrogenation dehalogenation reaction and the last sugared protecting group four-step reaction of going up that removes; Former, the auxiliary material that use all are common industrial chemicals commonly used, per step yield all 〉=90%, total recovery 65～67%, yield is than prior preparation method height; In addition, each step all is the conventional chemical reaction, uses general chemical device, is suitable for large-scale industrial production, economical and effective.
Embodiment
For specifically illustrating implementation process of the present invention, the spy enumerates several preferred case study on implementation.Listed concrete data of following embodiment and raw material only are to describe implementation process of the present invention in detail, and do not lie in restriction interest field of the presently claimed invention.
Embodiment 1
2,2 '-preparation of dehydration-5-methyl-β-L-uridine (II):
5-methyl-β-L-uridine (2.6g) is dissolved among the DMF (6ml), add diphenyl carbonate (2.8g) and solid sodium bicarbonate (0.1g), mixture is warming up to 120 ℃ of reactions 90 minutes, naturally cools to room temperature, pour in the ether (25ml), stir, gradually have solids to separate out, filter, ether (5ml) is washed, ethyl alcohol recrystallization gets 2,2 '-dehydration-5-methyl-β-L-uridine (2.2g), yield is (91%).mp：218～224℃
Embodiment 2
2 '-bromo-2 '-deoxidation-3 ', the preparation of 5 '-two-O-propionyl-5-methyl-β-L-uridine (III):
With 2,2 '-dehydration-5-methyl-β-L-uridine (1.4g) is dissolved in the acetonitrile (110ml), stirs and be warming up to 40 ℃, drip propionyl bromide (3.8ml), finish, the clarification of reaction solution color is gradually dark, be warming up to 50-65 ℃ of reaction, thin layer is followed the tracks of and is reacted to the completely dissolve of raw material point.Steaming desolventizes, and resistates is dissolved in the methylene dichloride (10ml), and saturated sodium bicarbonate aqueous solution is given a baby a bath on the third day after its birth inferior, final saturation salt washing twice, and with methylene dichloride 10ml extraction once, organic phase merges wash water again, the adding activated carbon decolorizing.Filter, filtrate adds anhydrous magnesium sulfate drying.Filter, filtrate decompression is concentrated into dried enriched material 2.6g.Dehydrated alcohol (10ml) is added in the enriched material, and heating makes dissolving, puts coldly, has solid to generate.Filter 3 ', 5 '-two-O-propionyl-2 '-bromo-2 '-deoxidation-5-methyl-β-L-uridine (2.3g, yield 91.1%), mp:130-131 ℃.
1H-NMR(CDCl
3)δ：7.999(s，1H，NH)，7.255-7.163(d，1H，H-6)，6.219-6.203(d，1H，H-1′)，5.197-5.172(dd，1H，H-3′orH-4′)，4.539-4.509(t，1H，H-3′or?H-4′)，4.398-4.366(t，3H，H-3′orH-2′)，2.474-2.384(m，4H，2*CH
2)，1.946(s，3H，CH
3)，1.224-1.177(m，6H，2*CH
3)。
Embodiment 3
2 '-chloro-2 '-deoxidation-3 ', the preparation of 5 '-two-O-propionyl-5-methyl-β-L-uridine (III):
2 ' 2-dehydration-5-methyl-β-L-uridine (2.4g) is dissolved in the acetonitrile (25ml), stirs and be warming up to 40 ℃, drip propionyl chloride (5ml), finish, the clarification of reaction solution color is warming up to 50-65 ℃ of reaction, and thin layer is followed the tracks of and reacted to the completely dissolve of raw material point.Steaming desolventizes, and resistates is dissolved in the methylene dichloride (10ml), and saturated sodium bicarbonate aqueous solution is given a baby a bath on the third day after its birth inferior, final saturation salt washing twice, and with methylene dichloride 10ml extraction 1 time, organic phase merges wash water again, the adding activated carbon decolorizing.Filter, filtrate adds anhydrous magnesium sulfate drying.Filter, filtrate decompression is concentrated into dried colorless oil 3.8g.Oily matter is dissolved in the dehydrated alcohol (15ml), and heating makes dissolving, puts coldly, has solid to generate, filter 2 '-chloro-2 '-deoxidation-3 ', 5 '-two-O-propionyl-5-methyl-β-L-uridine (3.5g, yield 90%), mp:150-152 ℃.
1H-NMR(CDCl
3)δ：7.999(s，1H，NH)，7.250-7.163(d，1H，H-6)，6.077-6.062(d，1H，H-1′)，5.268-5.243(dd，1H，H-3′orH-4′)，4.562-4.533(t，1H，H-3′or?H-4′)，4.398-4.355(t，3H，H-3′orH-2′)，2.484-2.377(m，4H，2*CH
2)，1.940(s，3H，CH
3)，1.220-1.177(m，6H，2*CH
3)。
Embodiment 4
3 ', 5 '-two-O-propionyl-2 '-preparation of deoxidation-5-methyl-β-L-uridine (IV):
Drop into 2 in the high-pressure hydrogenation still '-bromo-2 '-deoxidation-3 '; 5 '-two-O-propionyl-5-methyl-β-L-uridine (1.4g) is dissolved in the methyl alcohol (15ml), adds Raney-Ni (0.7g), sodium acetate (0.5g); lead to hydrogen to 0.4MPa, stirring reaction 1 2hr under the room temperature.Leave standstill and draw upper strata liquid, filter, it is colourless that catalyzer use methyl alcohol is washed till washing lotion, and filtrate is concentrated into dried, adds 5ml water, uses methylene dichloride 5ml * 2 extraction secondaries again, merges methane liquid, and reconcentration gets soup compound to doing, and directly drops into next step reaction.
Embodiment 5
2 '-preparation of deoxidation-5-methyl-β-L-uridine (being Telbivudine):
Get reactant among the embodiment 4 (3.5g), add and contain in the methanol solution (30ml) of sodium methylate (0.1g) stirring reaction under the room temperature.Thin layer detects to reacting completely.Dropping glacial acetic acid neutralization concentrates, ethyl alcohol recrystallization, filter Telbivudine (2.2g, yield 92.1%), mp:183-188 ℃.
Embodiment 6
2 '-preparation of deoxidation-5-methyl-β-L-uridine (being Telbivudine):
Drop into reaction product (3.2g) among the embodiment 4, add dehydrated alcohol (30ml) and 25% ammoniacal liquor (0.6ml), the stirring at room reaction, complete to the thin layer detection reaction.Cold leaving standstill below 5 ℃ 10 hours falls in the neutralization of dropping glacial acetic acid, filters, and oven dry gets Telbivudine 2.0g, yield 91.5%.mp：183-188℃。
Claims (11)
1. the preparation method of Telbivudine comprises
Step 1: formula (I) compound is production (II) compound under the dewatering agent effect:
Step 2: formula (II) compound is through acidylate-halogenating reaction production (III) compound:
Wherein, X represents Cl or Br, and R represents alkyloyl;
Step 3: formula (III) compound is dehalogenation production (IV) compound under the condition of catalytic hydrogenation:
Wherein, R represents alkyloyl;
Step 4: formula (IV) compound removes under the alkali effect that protecting group gets Telbivudine (V) on the sugar.
2. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: the dewatering agent that uses during the step 1 reaction is methylcarbonate, diethyl carbonate or diphenyl carbonate.
3. the preparation method of Telbivudine as claimed in claim 2 is characterized in that: the dewatering agent that uses during the step 1 reaction is diethyl carbonate or diphenyl carbonate.
4. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: use alkali during the step 1 reaction, comprise sodium bicarbonate, yellow soda ash, saleratus and salt of wormwood.
5. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: the solvent that uses during the step 1 reaction is DMF.
6. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: the acidylate-halogenating agent that uses during the step 2 reaction is C
3-C
6Fatty carboxylic acid halides.
7. the preparation method of Telbivudine as claimed in claim 6 is characterized in that: the acidylate-halogenating agent that uses during the step 2 reaction is propionyl bromide or propionyl chloride.
8. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: the solvent that uses during the step 2 reaction is acetonitrile.
9. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: the said catalytic hydrogenation condition of step 3 is meant at convenient pressure and has catalyzer such as Pd-C, Pd-BaSO
4, Raney-Ni or nickelalloy condition under.
10. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: the alkali that uses during the step 4 reaction comprises sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood, sodium methylate, sodium ethylate and C
1-C
3Rudimentary sodium alkoxide or ammoniacal liquor.
11. the preparation method of Telbivudine as claimed in claim 1 is characterized in that: the alkali that uses during the step 4 reaction is sodium methylate or ammoniacal liquor.
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|---|---|---|---|
| CNA2009100525649A CN101565440A (en) | 2009-06-05 | 2009-06-05 | Novel preparation method of telbivudine |
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650168A (en) * | 2013-11-23 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Telbivudine monohydrate compound |
| CN104817606A (en) * | 2015-05-02 | 2015-08-05 | 江苏诚信药业有限公司 | Process system for preparing telbivudine |
| CN105198948A (en) * | 2015-11-03 | 2015-12-30 | 郑州泰丰制药有限公司 | Telbivudine synthesis and treatment method |
-
2009
- 2009-06-05 CN CNA2009100525649A patent/CN101565440A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650168A (en) * | 2013-11-23 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Telbivudine monohydrate compound |
| CN104817606A (en) * | 2015-05-02 | 2015-08-05 | 江苏诚信药业有限公司 | Process system for preparing telbivudine |
| CN105198948A (en) * | 2015-11-03 | 2015-12-30 | 郑州泰丰制药有限公司 | Telbivudine synthesis and treatment method |
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Open date: 20091028 |