CN106117287B - The method for preparing 5- methyl deoxyuridine - Google Patents
The method for preparing 5- methyl deoxyuridine Download PDFInfo
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- CN106117287B CN106117287B CN201610229948.3A CN201610229948A CN106117287B CN 106117287 B CN106117287 B CN 106117287B CN 201610229948 A CN201610229948 A CN 201610229948A CN 106117287 B CN106117287 B CN 106117287B
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- 238000000034 method Methods 0.000 title claims abstract description 39
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 title claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims abstract description 27
- DWRXFEITVBNRMK-JXOAFFINSA-N ribothymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DWRXFEITVBNRMK-JXOAFFINSA-N 0.000 claims abstract description 24
- 230000018044 dehydration Effects 0.000 claims abstract description 20
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 16
- 230000002140 halogenating effect Effects 0.000 claims description 15
- 238000010792 warming Methods 0.000 claims description 15
- 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 claims description 14
- -1 hydrogen halides Chemical class 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- 238000009413 insulation Methods 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000012024 dehydrating agents Substances 0.000 claims description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 229910052759 nickel Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 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 claims description 7
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 7
- 229940045145 uridine Drugs 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 5
- VUPKGFBOKBGHFZ-UHFFFAOYSA-N dipropyl carbonate Chemical compound CCCOC(=O)OCCC VUPKGFBOKBGHFZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000002777 nucleoside Substances 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 239000002718 pyrimidine nucleoside Substances 0.000 claims 1
- 210000002700 urine Anatomy 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 17
- 235000011121 sodium hydroxide Nutrition 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 7
- 238000005352 clarification Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 4
- 229930182470 glycoside Natural products 0.000 description 4
- 150000002338 glycosides Chemical class 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 238000011953 bioanalysis Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention discloses a kind of methods of 5- methyl deoxyuridine shown in preparation formula (IV), it include: that 5-Methyluridine shown in formula (I) is dehydrated by following chemical equations, is halogenated, restores three-step reaction, 5- methyl deoxyuridine shown in formula (IV) is made, the dehydration, halogenated, reduction three-step reaction are completed by one kettle way.The method for preparing 5- methyl deoxyuridine of the invention, easy to operate, human cost is low, and equipment investment is few, and the production cycle is greatly reduced, and is suitable for industrial mass production, has a extensive future.
Description
Technical field
The present invention relates to medicine intermediate technical fields, and in particular to prepares 5- first by raw material of 5-Methyluridine
The method of base deoxyuridine.
Background technique
5- methyl deoxyuridine (Thymidine), popular method are referred to as deoxythymidine, belong to fudr,
It is the raw material of DNA.It is simultaneously also the important intermediate of synthesis anticancer drug stavudine, Zidovudine, no natural products exists.
It is mainly obtained at present by biological synthesis process (including DNA enzymatic solution, fermentation method, enzyme process) and chemical synthesis obtains.It makes a living at this stage
Object method and chemical method competitive coexistence stage, therefore with greater need for the competitiveness of novel synthesis raising product.
Bioanalysis based on biofermentation metabolic approach, although the method low raw-material cost, is disposably set now
Standby investment is huge, rear to extract difficulty, and there are also many technical problems are to be resolved.Up to the present, there is not yet patent report.
Chemical synthesis in the early time is either raw material still using 5-methyl-uridin as raw material using ribose, will be on ribose
Hydroxyl is protected, and protecting group, which is added and sloughed, needs more two-step reactions, and corresponding yield is lower therewith and higher cost.It is related
Patent has CN1055293C, CN1216766A, CN1539845A, CN1634959A, CN104513287A.Halogen used in simultaneously
It is acyl halides compound for reagent, causes production environment severe, it is big that waste post-processes environmental protection pressure.
As 5- methyl deoxyuridine demand is increasing, a large amount of 5- methyl deoxyuridine research and development money
Gold and manpower are and then put into wherein.It is subsequent and novel synthesis occur, with 5-methyl-uridin by dehydration, upper halogen, dehalogenation
Plain three steps synthesis, related patents such as CN102086222B.Such method has the advantage that halogenating agent compared to the method for early stage
It is cheap, such as hydrogen chloride, hydrogen bromide etc..Simultaneously it is this kind of it is halogenated can be recycled finally with halogenation salt form at waste,
There is no organic substance residues simultaneously.Cost of material and environmental protection pressure are greatly reduced, the use of protecting group is reduced.But such side
Method is there is separating for several times purification, the disadvantages of intermediate product stability is bad.
Summary of the invention
The invention solves the method for current production 5- methyl deoxyuridine, there are separating for several times purification, step are numerous
Technical problem trivial, intermediate product is unstable provides a kind of method for preparing 5- methyl deoxyuridine, this method operation
Simply, human cost is low, and equipment investment is few, and does not have to the stability problem for considering intermediate product.
In order to solve the above-mentioned technical problem, the present invention is achieved through the following technical solutions:
In one aspect of the invention, a kind of side of 5- methyl deoxyuridine shown in preparation formula (IV) is provided
Method, comprising: 5-Methyluridine shown in formula (I) is dehydrated by following chemical equations, is halogenated, reduction three steps it is anti-
It answers, 5- methyl deoxyuridine shown in formula (IV) is made, the dehydration, halogenated, reduction three-step reaction pass through one kettle way
It completes.
Term " one kettle way " refers in this application, in chemically synthesized each reaction step, the production of previous step reaction
Object needs not move through the processing such as separation, purification, directly as the reactant of next step reaction, reacts into next step.For example, above-mentioned
In reaction process, 5-Methyluridine shown in the formula (II) through dehydration generation needs not move through the step such as separation, purification
It is rapid to enter next step halogenating reaction, 5-Methyluridine halides shown in the formula (III) generated through halogenating reaction also without
Need to by separation, purification and etc. i.e. enter next step reduction reaction.
Specifically, the one kettle way is comprising steps of 5-Methyluridine shown in formula (I) and dehydrating agent are mixed in
In solvent, under inorganic base catalysis, 5-Methyluridine dehydrate shown in production (II)；Halogenating agent, example is added
Such as, hydrogen halides, 5-Methyluridine halides shown in production (III)；It is 5- first shown in formula (IV) through hydrogen reducing
Base deoxyuridine.
Dehydrating agent used in the dehydration includes dimethyl carbonate, diethyl carbonate or dipropyl carbonate, preferably
Ground, the dehydrating agent are dimethyl carbonate.
Inorganic base used in the dehydration include sodium hydroxide, sodium bicarbonate, potassium hydroxide, saleratus or
Calcium hydroxide, it is preferable that the inorganic base is sodium bicarbonate.
Solvent used in the reaction includes N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, methanol or tetrahydro
Furans, wherein solvent used in dehydration is n,N-Dimethylformamide, n,N-dimethylacetamide etc., halogenating reaction
Used in solvent be n,N-Dimethylformamide, n,N-dimethylacetamide, methanol, tetrahydrofuran etc., preferably N, N- diformazan
Base formamide.
Hydrogen halides used in the halogenating reaction includes hydrogen chloride or hydrogen bromide.
The dehydration is that 5-Methyluridine shown in formula (I) and dehydrating agent are mixed in solvent, is added
Inorganic base is warming up to 100~150 DEG C, for example, be warming up to 105 DEG C, 110 DEG C, 115 DEG C, 120 DEG C, 125 DEG C, 130 DEG C, 135 DEG C,
140 DEG C, 145 DEG C, 150 DEG C etc..Insulation reaction 2~12 hours, for example, insulation reaction 3 hours, 4 hours, 5 hours, 6 hours, 7
Hour, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours etc., the dehydration of 5-Methyluridine shown in production (II)
Object.The molar ratio of the 5-Methyluridine and dehydrating agent be 1:1~1:4, the 5-Methyluridine and
The molar ratio of inorganic base is 1:0.001~1:0.05.
The halogenating reaction be the reaction mixture after dehydration is cooled to 10~30 DEG C, for example, be cooled to 15 DEG C,
20 DEG C, 25 DEG C etc..The organic solvent solution of addition hydrogen halides, 30~80 DEG C (such as 35 DEG C, 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, 60
DEG C, 65 DEG C, 70 DEG C, 75 DEG C etc.) insulation reaction 6~12 hours (such as 7 hours, 8 hours, 9 hours, 10 hours, 11 hours etc.),
5- methyl deoxyuridine halides shown in production (III).
The reduction reaction is that the pH value of the reaction mixture after halogenating reaction is adjusted to 6.0~9.0, for example, adjusting
To 6.5,7.0,7.5,8.0,8.5 etc..In another example pH value is adjusted to 7.0-8.0.And the reaction mixture is cooled to 0~
30 DEG C or 0~20 DEG C, for example, being cooled to 5 DEG C, 10 DEG C, 15 DEG C, 16 DEG C, 17 DEG C, 18 DEG C, 19 DEG C etc..It is added and formula (I) institute
Show that 5-Methyluridine mass ratio is the reproducibility of 0.2~1 (for example, 0.3,0.4,0.5,0.6,0.7,0.8,0.9 etc.)
Metal, the reducing metal include zinc, nickel or palladium, are passed through hydrogen, obtain 5- methyl deoxyuridine shown in formula (IV).
Hydrogen Vapor Pressure be 0.1~0.9Mpa, for example, Hydrogen Vapor Pressure be 0.2Mpa, 0.3Mpa, 0.4Mpa, 0.5Mpa, 0.6Mpa,
0.7Mpa, 0.8Mpa, it is therefore preferable to 0.6Mpa.In one embodiment, reduction reaction is in low temperature, high pressure, high ph-values
Under the conditions of carry out.Specifically, in one embodiment, reduction reaction is by the pH value tune of the reaction mixture after halogenating reaction
Section is cooled to 0 DEG C to 8.0, and by the reaction mixture, and being added with 5-Methyluridine mass ratio shown in formula (I) is 0.5
Nickel, be passed through hydrogen so that Hydrogen Vapor Pressure be 0.6Mpa, obtain 5- methyl deoxyuridine shown in formula (IV).
The method that the present invention uses 5- methyl deoxyuridine shown in one kettle way preparation formula (IV), shown in formula (I)
5-Methyluridine is raw material, and directly synthesis 5- methyl deoxyuridine, in-between process do not have in separation and Extraction
Between product, until dehydration, it is halogenated, reduction three-step reaction be fully completed after, finally carry out first separation and purification.
The method that the present invention prepares 5- methyl deoxyuridine has the advantage that compared with existing production method
1. one pot process 5- methyl deoxyuridine of the present invention, although synthesis process is by dehydration, halogenated, reduction
Three-step reaction, but this three-step reaction is successively successively completed, centre eliminate the separation twice and purification after dehydration and after halogenated
Step, only first separation and purification after entire synthesis process only needs to restore, human cost substantially reduce.
2. existing method in same production capacity, needs a large amount of reaction kettle and separation equipment, and one pot of the invention
Method synthesizes 5- methyl deoxyuridine, and all reactions can react in the same reactor, and it is only necessary to one for separation equipment
Set, equipment investment reduce 2/3rds.
3. the method for the present invention only needs first separation and purification, greatly reduce the production cycle, when having saved a large amount of
Between cost.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail.
Embodiment 1 is by 5- methyl deoxyuridine shown in following chemical equation one kettle way preparation formulas (IV)
5-Methyluridine (type I compound) 100g, dimethyl carbonate 50g, potassium hydroxide 0.5g and N, N- diformazan
Base formamide 150ml is added in reactor, is warming up to 125 DEG C, insulation reaction 3h.After, reaction system is cooled to 10 DEG C,
The DMF solution of 200g HCl is added.40 DEG C are warming up to, 10h is reacted.Reaction terminates, solution 4mol/L sodium hydrate aqueous solution
Ph value is adjusted to 7.0.Reaction system is cooled to 20 DEG C, and nickel 50g, pure water 350ml is added, and is passed through hydrogen, keeps Hydrogen Vapor Pressure
The aqueous solution 97ml of 4mol/L sodium hydroxide is slowly added dropwise in 0.5Mpa.Reaction was completed after 12h.It is evaporated liquid, 100g is added in solid
Pure water heats dissolved clarification, is cooled to 4 DEG C of crystallizations, and methanol crystallizes again, dry, and 75g 5- methyl Brdurd core can be obtained
Glycosides (IV compound of formula), HPLC purity 99.1%.
2 one kettle way of embodiment prepares 5- methyl deoxyuridine (IV compound of formula)
5- methyl urinates uridine (type I compound) 100g, diethyl carbonate 80g, sodium bicarbonate 2.2g and N, N- bis-
Methylacetamide 100ml is added in reactor, is warming up to 100 DEG C, insulation reaction 12h.After, reaction system is cooled to 30
DEG C, the n,N-dimethylacetamide solution of 200g HCl is added.80 DEG C are warming up to, 12h is reacted.Reaction terminates, solution 4mol/
L sodium hydrate aqueous solution ph value is adjusted to 6.5.Reaction system is cooled to 30 DEG C, and palladium 10g is added, and pure water 350ml is passed through hydrogen,
Hydrogen Vapor Pressure 0.6Mpa is kept, the aqueous solution 97ml of 4mol/L sodium hydroxide is slowly added dropwise.Reaction was completed after 12h.Liquid is evaporated,
100g pure water is added in solid, heats dissolved clarification, is cooled to 4 DEG C of crystallizations, and methanol crystallizes again, dry, and 78g 5- methyl can be obtained
Deoxyuridine (IV compound of formula), HPLC purity 99.0%.
3 one kettle way of embodiment prepares 5- methyl deoxyuridine (IV compound of formula)
5- methyl urinates uridine (type I compound) 100g, dipropyl carbonate 80g, sodium hydroxide 0.4g and N, N- bis-
Methylformamide 150ml is added in reactor, is warming up to 150 DEG C, insulation reaction 10h.After, reaction system is cooled to 20
DEG C, the methanol solution of 500g HCl is added.30 DEG C are warming up to, 6h is reacted.Reaction terminates, and solution is water-soluble with 4mol/L sodium hydroxide
Liquid ph value is adjusted to 7.5.Reaction system is cooled to 0 DEG C, and nickel 50g, pure water 350ml is added, and is passed through hydrogen, keeps Hydrogen Vapor Pressure
The aqueous solution 97ml of 4mol/L sodium hydroxide is slowly added dropwise in 0.5Mpa.Reaction was completed after 12h.It is evaporated liquid, 100g is added in solid
Pure water heats dissolved clarification, is cooled to 4 DEG C of crystallizations, and methanol crystallizes again, dry, and 68g 5- methyl Brdurd core can be obtained
Glycosides (IV compound of formula), HPLC purity 98.4%.
4 one kettle way of embodiment prepares 5- methyl deoxyuridine (IV compound of formula)
5- methyl urinates uridine (type I compound) 100g, diethyl carbonate 60g, sodium bicarbonate 2.2g and N, N- bis-
Methylacetamide 100ml is added in reactor, is warming up to 100 DEG C, insulation reaction 12h.After, reaction system is cooled to 30
DEG C, the n,N-dimethylacetamide solution of 200g HCl is added.80 DEG C are warming up to, 12h is reacted.Reaction terminates, solution 4mol/
L sodium hydrate aqueous solution ph value is adjusted to 7.5.Reaction system is cooled to 15 DEG C, and palladium 10g is added, and pure water 350ml is passed through hydrogen,
Hydrogen Vapor Pressure 0.5Mpa is kept, the aqueous solution 97ml of 4mol/L sodium hydroxide is slowly added dropwise.Reaction was completed after 12h.Liquid is evaporated,
100g pure water is added in solid, heats dissolved clarification, is cooled to 4 DEG C of crystallizations, and methanol crystallizes again, dry, and 78g 5- methyl can be obtained
Deoxyuridine (IV compound of formula), HPLC purity 99.1%.
5 one kettle way of embodiment prepares 5- methyl deoxyuridine (IV compound of formula)
5- methyl urinates uridine (type I compound) 100g, dipropyl carbonate 90g, sodium hydroxide 0.4g and N, N- bis-
Methylformamide 100ml is added in reactor, is warming up to 110 DEG C, insulation reaction 8h.After, reaction system is cooled to 15 DEG C,
The methanol solution of 500g HCl is added.50 DEG C are warming up to, 8h is reacted.Reaction terminates, solution 4mol/L sodium hydrate aqueous solution
Ph value is adjusted to 8.0.Reaction system is cooled to 0 DEG C, and nickel 50g, pure water 350ml is added, and is passed through hydrogen, keeps Hydrogen Vapor Pressure
The aqueous solution 97ml of 4mol/L sodium hydroxide is slowly added dropwise in 0.6Mpa.Reaction was completed after 12h.It is evaporated liquid, 100g is added in solid
Pure water heats dissolved clarification, is cooled to 4 DEG C of crystallizations, and methanol crystallizes again, dry, and 68g 5- methyl Brdurd core can be obtained
Glycosides (IV compound of formula), HPLC purity 99.5%.
6 one kettle way of embodiment prepares 5- methyl deoxyuridine (IV compound of formula)
5- methyl urinates uridine (type I compound) 100g, dipropyl carbonate 80g, sodium hydroxide 0.4g and N, N- bis-
Methylformamide 100ml is added in reactor, is warming up to 140 DEG C, insulation reaction 6h.After, reaction system is cooled to 20 DEG C,
The methanol solution of 500g HCl is added.60 DEG C are warming up to, 10h is reacted.Reaction terminates, solution 4mol/L sodium hydrate aqueous solution
Ph value is adjusted to 8.5.Reaction system is cooled to 5 DEG C, and nickel 50g, pure water 350ml is added, and is passed through hydrogen, keeps Hydrogen Vapor Pressure
The aqueous solution 97ml of 4mol/L sodium hydroxide is slowly added dropwise in 0.7Mpa.Reaction was completed after 12h.It is evaporated liquid, 100g is added in solid
Pure water heats dissolved clarification, is cooled to 4 DEG C of crystallizations, and methanol crystallizes again, dry, and 68g 5- methyl Brdurd core can be obtained
Glycosides (IV compound of formula), HPLC purity 99.0%.
Embodiments of the present invention above described embodiment only expresses, the description thereof is more specific and detailed, but can not
Therefore limitations on the scope of the patent of the present invention are interpreted as.It should be pointed out that for those of ordinary skill in the art,
Without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection model of the invention
It encloses.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. a kind of method of 5- methyl deoxyuridine shown in preparation formula (IV), comprising: urinate 5- methyl shown in formula (I)
Pyrimidine nucleoside is dehydrated by following chemical equations, is halogenated, restoring three-step reaction, and 5- methyl deoxidation shown in formula (IV) is made
Uridine, which is characterized in that the dehydration, halogenated, reduction three-step reaction are completed by one kettle way, and the one kettle way includes
Step:
(1) dehydration: 5-Methyluridine shown in formula (I) and dehydrating agent are mixed in solvent, urged in inorganic base
Under change, it is warming up to 100~150 DEG C, insulation reaction 2~12 hours, 5-Methyluridine dehydration shown in production (II)
Object, wherein the molar ratio of 5-Methyluridine and the dehydrating agent shown in formula (I) is 1:1~1:4, formula (I) institute
The molar ratio of the 5-Methyluridine and the inorganic base shown is 1:0.001~1:0.05；
(2) halogenating reaction: the reaction mixture after dehydration is cooled to 10~30 DEG C, the organic solvent that hydrogen halides is added is molten
Liquid, 30~80 DEG C insulation reaction 6~12 hours, 5-Methyluridine halides shown in production (III)；
(3) reducing metal, the reducing metal and 5-Methyluridine shown in formula (I) reduction reaction: is added
Mass ratio is 0.2~1, is 5- methyl deoxyuridine shown in formula (IV) through hydrogen reducing, wherein the hydrogen reducing
Reaction is carried out under conditions of low temperature, high pressure, high ph-values, and the low temperature is 0~15 DEG C, and the high pressure is 0.4~0.9Mpa,
The high ph-values are that the pH value of the reaction mixture after halogenating reaction is adjusted to 7.5~9.0,
Wherein, 5-Methyluridine shown in the formula (II) generated through the dehydration needs not move through separation or purification i.e.
Into the halogenating reaction, 5-Methyluridine halides shown in the formula generated through the halogenating reaction (III) are without warp
It crosses separation or purification enters the reduction reaction,
2. the method according to claim 1, wherein the halogenating agent is hydrogen halides.
3. according to the method described in claim 2, it is characterized in that, the hydrogen halides is selected from hydrogen chloride or hydrogen bromide.
4. method according to claim 1 to 3, which is characterized in that dehydrating agent used in the dehydration
Selected from dimethyl carbonate, diethyl carbonate or dipropyl carbonate.
5. method according to claim 1 to 3, which is characterized in that inorganic base used in the dehydration
Selected from sodium hydroxide, sodium bicarbonate, potassium hydroxide, saleratus or calcium hydroxide.
6. method according to claim 1 to 3, which is characterized in that solvent used in the reaction is selected from N,
Dinethylformamide, DMAC N,N' dimethyl acetamide, methanol or tetrahydrofuran.
7. method according to claim 1 to 3, which is characterized in that the reduction reaction is will be after halogenating reaction
The pH value of reaction mixture be adjusted to 7.5~8.5, and the reaction mixture is cooled to 0~10 DEG C.
8. method according to claim 1 to 3, which is characterized in that the reducing metal is zinc, nickel or palladium.
9. the method according to claim 1, wherein the one kettle way is comprising steps of by 5- first shown in formula (I)
Base uridine and dehydrating agent dimethyl carbonate are mixed in solvent n,N-Dimethylformamide, under sodium bicarbonate catalysis,
5-Methyluridine dehydrate shown in production (II)；Hydrogen halides is added, the urine of 5- methyl shown in production (III) is phonetic
Pyridine nucleosides halides；The nickel for being 0.2~1 with 5-Methyluridine mass ratio shown in formula (I) is added, is passed through hydrogen and is gone back
Original, obtains 5- methyl deoxyuridine shown in formula (IV), and the Hydrogen Vapor Pressure is 0.4~0.9Mpa.
10. according to the method described in claim 9, it is characterized in that, the Hydrogen Vapor Pressure is 0.6~0.9Mpa.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216766A (en) * | 1998-10-06 | 1999-05-19 | 中国人民解放军第二军医大学 | Method for preparing beta-thymidine |
| CN1539845A (en) * | 2003-04-24 | 2004-10-27 | 浙江联化科技股份有限公司 | Method for preparing beta-thymidine |
| CN1634959A (en) * | 2004-10-28 | 2005-07-06 | 浙江沙星医药化工有限公司 | Industrial process for preparing beta-thymidine |
| CN102086222A (en) * | 2010-12-28 | 2011-06-08 | 浙江先锋科技有限公司 | Preparation method of beta-thymidine |
| CN104513287A (en) * | 2013-09-30 | 2015-04-15 | 上虞新和成生物化工有限公司 | Synthetic method of [beta]-thymidine |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216766A (en) * | 1998-10-06 | 1999-05-19 | 中国人民解放军第二军医大学 | Method for preparing beta-thymidine |
| CN1539845A (en) * | 2003-04-24 | 2004-10-27 | 浙江联化科技股份有限公司 | Method for preparing beta-thymidine |
| CN1634959A (en) * | 2004-10-28 | 2005-07-06 | 浙江沙星医药化工有限公司 | Industrial process for preparing beta-thymidine |
| CN102086222A (en) * | 2010-12-28 | 2011-06-08 | 浙江先锋科技有限公司 | Preparation method of beta-thymidine |
| CN104513287A (en) * | 2013-09-30 | 2015-04-15 | 上虞新和成生物化工有限公司 | Synthetic method of [beta]-thymidine |
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