CN101724001A - Method for synthesizing medicinal pyrimidine derivative - Google Patents
Method for synthesizing medicinal pyrimidine derivative Download PDFInfo
- Publication number
- CN101724001A CN101724001A CN200810171750A CN200810171750A CN101724001A CN 101724001 A CN101724001 A CN 101724001A CN 200810171750 A CN200810171750 A CN 200810171750A CN 200810171750 A CN200810171750 A CN 200810171750A CN 101724001 A CN101724001 A CN 101724001A
- Authority
- CN
- China
- Prior art keywords
- reaction
- pyrimidine
- reagent
- methyl
- phosphamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 8
- 150000003230 pyrimidines Chemical class 0.000 title abstract description 5
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- -1 phosphamide compound Chemical class 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims abstract 3
- 239000002994 raw material Substances 0.000 claims abstract 3
- 230000035484 reaction time Effects 0.000 claims abstract 2
- 238000012986 modification Methods 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 4
- 210000001541 thymus gland Anatomy 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 239000002718 pyrimidine nucleoside Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 229940035893 uracil Drugs 0.000 abstract 1
- SXUXMRMBWZCMEN-UHFFFAOYSA-N 2'-O-methyl uridine Natural products COC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 SXUXMRMBWZCMEN-UHFFFAOYSA-N 0.000 description 4
- SKUSIJOMOKTHIX-UHFFFAOYSA-N n-[di(propan-2-yl)amino]phosphanyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C(C)C)PN(C(C)C)C(C)C SKUSIJOMOKTHIX-UHFFFAOYSA-N 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- SXUXMRMBWZCMEN-ZOQUXTDFSA-N 2'-O-methyluridine Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 SXUXMRMBWZCMEN-ZOQUXTDFSA-N 0.000 description 3
- RKVHNYJPIXOHRW-UHFFFAOYSA-N 3-bis[di(propan-2-yl)amino]phosphanyloxypropanenitrile Chemical compound CC(C)N(C(C)C)P(N(C(C)C)C(C)C)OCCC#N RKVHNYJPIXOHRW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012795 verification Methods 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 2
- AOAMCUSCZLNQFN-XKBRQERYSA-N 1-[(2r,4s,5s)-4-hydroxy-5-(2,2,2-trifluoro-1-hydroxyethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](C(O)C(F)(F)F)O[C@H]1N1C(=O)NC(=O)C=C1 AOAMCUSCZLNQFN-XKBRQERYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 208000005100 Herpetic Keratitis Diseases 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 201000010884 herpes simplex virus keratitis Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for synthesizing a medicinal pyrimidine derivative. The method adopts a phosphamide compound as a reagent, uses 2'-O-methyl-uracil as a raw material, and performs reaction in an organic solvent in the presence of a catalyst. The mol ratio of a reactant to the reagent is between 1:1 and 1:50; the reaction time is 2 to 20 hours; the reaction temperature is between 50 and 200 DEG C; and the pressure is 1 to 10 MPa. The method has the advantages of simple operation, readily available raw materials, fewer reaction steps and high yield.
Description
Technical field:
The present invention relates to the synthetic of a class chemically modified Nucleotide, relate in particular to the method for the synthetic pyrimidine derivatives of a kind of catalysis.
Background technology:
Modification nucleotide is important medicine intermediate of a class and precursor, and has been widely used in treatment of diseases.For example, AZT, ddI, d4T etc. are used for the treatment of acquired immune deficiency syndrome (AIDS); 5 '-trifluormethyl-2 '-deoxyuridine is used for the treatment of herpetic keratitis; 5 '-iodo-1-(2-deoxy-2-fluoro-b-D-arabinofuranosyl) cytosine is used for the treatment of cytomegalovirus, simplexvirus, (Drug Design and Development such as the infection of Epstein-Barr virus etc., Povl Krogsgaard-Larsen and HansBundgaard, Eds, Harwood Academic Publishers, 1991, ch15).In addition, this compounds has also begun to be used to the antimycotic field of antibacterium.Explore new modification nucleotide route of synthesis and new nucleotide derivative will greatly enrich and expand the anti-infectives resource.
Summary of the invention:
The purpose of this invention is to provide low, the method for pyrimidine derivatives efficiently of a kind of reaction conditions gentleness, cost.Preferably, this compound is 5 '-Butylphosphate-2 '-O-methyl uridine-3 '-butyl phosphate.
For achieving the above object, technical scheme of the present invention is as follows: required the intermediate 2 '-O-methyl-Uridine of building-up reactions at first; (2-Cyanoethoxy) bis (N, N-diisopropylamino) phosphine; 2.2 (2-benzyloxy) bis (N, N-diisopropylamino) phosphine; 4-ter-butyldiphenylsiloxyl-1-butanol; 4-benzloxyl-butanol.Be reactant with 2 '-O-methyl-Uridine then, with 4-benzloxyl-butanol and 2.2 (2-benzyloxy) bis (N, N-diisopropylamino) phosphine is a reagent, synthetic 5 '-Butylphosphate-2 '-O-methyl uridine-3 '-butyl phosphate under tetrazole catalysis.
Specific implementation method:
Below by embodiment in detail the present invention is described in detail; But the present invention is not limited to following embodiment.
Embodiment 1.2 '-O-methyl-Uridine
2 '-O-methyl-Uridine compound can obtain by following reaction:
This reaction yield is 65%, through the NMR analysis verification exactness of product structure.
Embodiment 2. (2-Cyanoethoxy) bis (N, N-diisopropylamino) phosphine
(2-Cyanoethoxy) bis (N, N-diisopropylamino) phosphine can obtain by following reaction:
This reaction yield is 50%, through the exactness of NMR checking product structure.
Embodiment 3.2.2 (2-benzyloxy) bis (N, N-diisopropylamino) phosphine
2.2 (2-benzyloxy) bis (N, N-diisopropylamino) phosphine is obtained by following prepared in reaction:
This reaction yield is 70-90%
Embodiment 4.4-ter-butyldiphenylsiloxyl-1-butanol, 4-benzloxyl-butanol
4-ter-butyldiphenylsiloxyl-1-butanol, 4-benzloxyl-butanol can obtain by following reaction:
Exactness through its structure of NMR analysis verification.
Embodiment 5.4-benzloxyl-butanol
The synthetic of 4-benzloxyl-butanol carries out in the following manner:
Reaction product is a yellow oily, and reaction yield is 50%.
Embodiment 6.5 '-Butylphosphate-2 '-O-methyl uridine-3 '-butyl phosphate
5 '-Butylphosphate-2 '-O-methyl uridine-3 '-butyl phosphate obtains by following prepared in reaction:
This product warp
31P NMR and
1H NMR analysis verification, productive rate are 70%.Its purity is greater than 99%.
Claims (5)
1. the synthetic method of the synthetic pyrimidine nucleoside acid derivative of a catalysis, employings phosphamide compound is a reagent, is raw material with modification property pyrimidine, in the presence of catalyzer, reacts in organic solvent.The mol ratio of reactant and reagent is: 1: 1 to 1: 50; Reaction times is: 2～20 hours; Temperature of reaction is: 50～200 ℃; Pressure is: 1～10MPa.
2. the described modification pyrimidine of claim 1 is a uridylic; 2 '-O-6-Methyl Uracil; Thymus pyrimidine; 2 '-O-methyl thymus pyrimidine.
3. the described phosphamide compound of claim 1 is normal-butyl cyano ethyl-N, N-di-isopropyl phosphamide (n-butylcyanoethyl-N, N-diisopropyl phosphoramidite).
4. the described method of claim 1 is characterized in that, all organic solvents are one or more polarity or nonpolar inert solvent.
5. the described catalyzer of claim 1 is tetrazole or other short reaction reagent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810171750A CN101724001A (en) | 2008-10-24 | 2008-10-24 | Method for synthesizing medicinal pyrimidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810171750A CN101724001A (en) | 2008-10-24 | 2008-10-24 | Method for synthesizing medicinal pyrimidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101724001A true CN101724001A (en) | 2010-06-09 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810171750A Pending CN101724001A (en) | 2008-10-24 | 2008-10-24 | Method for synthesizing medicinal pyrimidine derivative |
Country Status (1)
| Country | Link |
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| CN (1) | CN101724001A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087096A (en) * | 2013-01-25 | 2013-05-08 | 苏州昊帆生物科技有限公司 | Preparation method of bis(diisopropylamine)(2-cyanoethoxy) phosphine |
| CN113476469A (en) * | 2017-03-10 | 2021-10-08 | 莱克伍德阿美达克斯股份有限公司 | Antimicrobial compounds, compositions and uses thereof |
| CN114369124A (en) * | 2022-01-21 | 2022-04-19 | 北京瑞博奥医药科技有限公司 | Preparation method of 2' -substituted pyrimidine nucleoside |
| US11795192B2 (en) | 2017-03-10 | 2023-10-24 | Lakewood Amedex, Inc. | Antimicrobial compounds, compositions, and uses thereof |
| US12030908B2 (en) | 2017-03-10 | 2024-07-09 | Lakewood Amedex, Inc. | Antimicrobial compounds, compositions, and uses thereof |
-
2008
- 2008-10-24 CN CN200810171750A patent/CN101724001A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087096A (en) * | 2013-01-25 | 2013-05-08 | 苏州昊帆生物科技有限公司 | Preparation method of bis(diisopropylamine)(2-cyanoethoxy) phosphine |
| CN113476469A (en) * | 2017-03-10 | 2021-10-08 | 莱克伍德阿美达克斯股份有限公司 | Antimicrobial compounds, compositions and uses thereof |
| US11795192B2 (en) | 2017-03-10 | 2023-10-24 | Lakewood Amedex, Inc. | Antimicrobial compounds, compositions, and uses thereof |
| CN113476469B (en) * | 2017-03-10 | 2024-04-19 | 莱克伍德阿美达克斯股份有限公司 | Antimicrobial compounds, compositions and uses thereof |
| US12030908B2 (en) | 2017-03-10 | 2024-07-09 | Lakewood Amedex, Inc. | Antimicrobial compounds, compositions, and uses thereof |
| US12054509B2 (en) | 2017-03-10 | 2024-08-06 | Lakewood Amedex, Inc. | Antimicrobial compounds, compositions, and uses thereof |
| CN114369124A (en) * | 2022-01-21 | 2022-04-19 | 北京瑞博奥医药科技有限公司 | Preparation method of 2' -substituted pyrimidine nucleoside |
| CN114369124B (en) * | 2022-01-21 | 2024-03-26 | 北京瑞博奥医药科技有限公司 | Preparation method of 2' -substituted pyrimidine nucleoside |
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Application publication date: 20100609 |