CN103848866A - Method for preparing sulfonyl oxymethyl diethyl phosphate compounds - Google Patents
Method for preparing sulfonyl oxymethyl diethyl phosphate compounds Download PDFInfo
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- CN103848866A CN103848866A CN201210514646.2A CN201210514646A CN103848866A CN 103848866 A CN103848866 A CN 103848866A CN 201210514646 A CN201210514646 A CN 201210514646A CN 103848866 A CN103848866 A CN 103848866A
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- diethyl phosphate
- formula
- diethyl ester
- described reaction
- acid diethyl
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- 0 C*COC[C@@](C)OC1OCCCC1 Chemical compound C*COC[C@@](C)OC1OCCCC1 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N C1COC=CC1 Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- UQKUUAUVNOCJBX-UHFFFAOYSA-N CC(C)COC(C(C)OC1OCCCC1)=O Chemical compound CC(C)COC(C(C)OC1OCCCC1)=O UQKUUAUVNOCJBX-UHFFFAOYSA-N 0.000 description 1
- OWSGIFOCFLHGTL-JWOPXBRZSA-N CC(C1)[C@H]1c(nc1N)nc2c1nc[n]2CC(O)[Ce] Chemical compound CC(C1)[C@H]1c(nc1N)nc2c1nc[n]2CC(O)[Ce] OWSGIFOCFLHGTL-JWOPXBRZSA-N 0.000 description 1
- RUFUQSSZNWPMGM-UHFFFAOYSA-N Nc1ncnc2c1nc[n]2CC1(C=CC1)OC1OCCCC1 Chemical compound Nc1ncnc2c1nc[n]2CC1(C=CC1)OC1OCCCC1 RUFUQSSZNWPMGM-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a method for preparing a sulfonyl oxymethyl diethyl phosphate compound as shown in a formula (1). The method is characterized in that the compound as shown in the formula (4) reacts with hydroxymethyl diethyl phosphate, wherein Y is selected from methyl, trifluoromethyl, phenyl, 4-trifluoromethyl phenyl or p-fluoro phenyl. The sulfonyl oxymethyl diethyl phosphate compounds as shown in the formula (1) are applied as intermediates for synthesizing compounds tenofovir for resisting hepatitis B virus and AIDS virus.
Description
Technical field
The present invention relates to a kind of method of intermediate sulphonyl oxygen methyl-phosphorous acid diethyl ester compounds of the compound tynofovir of preparing hepatitis B virus resisting and hiv virus.
Background technology
Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate, TDF), its structure is suc as formula shown in (5), to be researched and developed by Glead Scierices company of the U.S., it is a kind of novel nucleoside acids reverse transcriptase inhibitors, ratified to go on the market in the U.S. first by FDA October calendar year 2001, now in Europe, Australia and the countries and regions such as Canadian listing.Within 2008, FDA ratifies again its treatment adult chronic hepatitis B.TDF obtains medicinal ingredients tynofovir suc as formula shown in (3) after being hydrolyzed in vivo, it is the remarkable activity of inhibition HBV replication in vitro, and effective to most of HBV persisters, therefore in the treatment of infecting, has broad application prospects.
Shown in the formula (3) of existing bibliographical information, the synthetic route of compound has summed up 4 kinds, specific as follows.
Synthetic route 1
In whole route, repeatedly use protection and deprotection, synthetic route is longer, and complex operation is not suitable for suitability for industrialized production; total recovery only 14.3% (referring to, Holy A, Maso jidkova M.; CollectCzechChem Commun, 1995,60:1196～1212).
Synthetic route 2
In whole route, use protection and deprotection reaction for twice, though synthetic route 1 shortens to some extent relatively, but still seem longer, total recovery 2.3% (referring to, Holy A, Maso jidkova M., CollectCzechChem Commun, 1995,60 (8): 1390～1490; Holy A, Dvorakova H, DeClerq E, et al., US6653296B1,2003-11-25)).
Synthetic route 3
This route uses expensive chiral auxiliary(reagent) (S, S)-SalenCr, be unsuitable for suitability for industrialized production, and productive rate lower (referring to, Jay F.Larrow, Scott E.Schaus, Eric N.Jacobsen, J.Am.Chem.Soc, 1996,118 (31): 7420-7421).
Synthetic route 4
This route is comparatively brief, use trimethyl carbinol lithium to make catalyzer, (7) → (2) → (3) two step yields be 30% left and right (referring to, Schultze LM, Chapman HH, Dubree NJP, et al.Tetrahedron Letters, 1998,39 (14): 1853～1856; Munger J D, Rohloff J C, Schultze L M., US5935946A1,1999-08-10)).Patent (Becker.Mark.W, Chapman.Harlan.H, et al, CN100402539,2001-07-20) take tert-butyl alcohol magnesium as catalyzer, (7) react and make (2) with tolysulfonyl oxygen methyl-phosphorous acid diethyl ester, then by the de-ethyl of TMSBr, two step total recoverys 50.4%.
Therefore, still need the novel method of synthetic tynofovir at present, first need the novel method of the intermediate of developing synthetic tynofovir, to overcome now methodical deficiency.
Summary of the invention
The object of the invention is in order to overcome weak point of the prior art, the method for the sulphonyl oxygen methyl-phosphorous acid diethyl ester compounds shown in a kind of preparation formula (1) be provided,
It is characterized in that, the compound shown in formula (4) is reacted with methylol diethyl phosphoric acid,
Wherein Y is selected from methyl, trifluoromethyl, phenyl, 4-trifluoromethyl or to fluorophenyl.
More preferably, described Y is methyl.
According to the present invention one preferred embodiment, described reaction is take one or more in triethylamine, tripropyl amine, Tributylamine and pyridine as acid binding agent.Preferably, described reaction is take triethylamine as acid binding agent.
According to the present invention one preferred embodiment, described reaction is take one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride as reaction solvent.
According to the present invention one preferred embodiment the temperature of described reaction is-50～25 ℃, preferably 0～10 ℃.
The method tool of the sulphonyl oxygen methyl-phosphorous acid diethyl ester compounds shown in preparation formula of the present invention (1) has the following advantages:
(1) the present invention does not use expensive or special reagent, and raw material is easy to get, and is conducive to scale operation.
(2) the present invention uses magnesium alkoxide for catalyzer, compares sodium hydrogen, trimethyl carbinol lithium and potassium tert.-butoxide, has reduced the generation of amino replacement by product, has improved the security of reaction yield and operation.
(3) the present invention uses sulphonyl oxygen methyl-phosphorous acid diethyl ester to substitute tolysulfonyl oxygen methyl-phosphorous acid diethyl ester, has improved yield.
(4) the present invention uses 1-Methyl-2-Pyrrolidone to make solvent, and the tynofovir reaction solution that makes is not treated can directly drop into next step reaction, and the tynofovir solid of generation is separated out, and this " one kettle way " operation is easy to realize suitability for industrialized production.
Sulphonyl oxygen methyl-phosphorous acid diethyl ester compounds shown in formula of the present invention (1) is as the intermediate of the compound tynofovir of synthetic hepatitis B virus resisting and hiv virus.
Embodiment
Further illustrate the present invention below by concrete intermediate and embodiment, still, should be understood to, these intermediates and embodiment are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the working method that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.Wherein VITAMIN B4 is purchased from Shanghai Hai Qu Chemical Co., Ltd.; R-propylene carbonate, trifluoromethanesulfchloride chloride, to trifluoromethyl benzene sulfonyl chloride, fluorobenzene SULPHURYL CHLORIDE is purchased from Shanghai De Mo Pharmaceutical Technology Co., Ltd; Tert-butyl alcohol magnesium, bromotrimethylsilane, phosphonous acid diethyl ester are purchased from Sa En chemical technology (Shanghai) Co., Ltd.; All the other reagent provide by reagent company of traditional Chinese medicines group.
Embodiment 1
The preparation of hydroxymethyl phosphonic acid diethyl ester
For example, in a reactor that contains inert atmosphere (nitrogen), add diethyl phosphite (81.0g, 0.586mol), triethylamine (63.2g, 0.625mol), paraformaldehyde (22.4g, 0.746mol), stir.At 90 ℃, reflux 8h until reacted, and according to TLC, monitoring shows only have the diethyl phosphite of trace or can't detect diethyl phosphite, and underpressure distillation obtains 59.2g product, yield 60%, ESI-MS (m/z): 169.06 M
+.
Embodiment 2
The preparation of methylsulfonyl oxygen methyl-phosphorous acid diethyl ester
By hydroxymethyl phosphonic acid diethyl ester (59.2g, 0.352mol) be dissolved in 70ml methylene dichloride, solution is cooled to 1 ℃ (typically about-2～4 ℃), slowly drip methylsulfonyl chloride (43.63g, 0.381mol), then slowly add triethylamine (57.6g, 0.540mol) keep temperature to be no more than 10 ℃ simultaneously, at least about 5 hours of stirring at room temperature, has reacted (methylsulfonyl chloride of trace only detected or can't detect methylsulfonyl chloride) until TLC shows.Solids removed by filtration, uses washed with dichloromethane.In filtrate, add 100ml water, add 150ml dichloromethane extraction at least twice.Organic layer anhydrous sodium sulfate drying, steaming desolventizes, and obtains faint yellow oily matter 72.4g.Crude product is directly used in prepares tynofovir.ESI-MS(m/z)：246.98?M
+。
Embodiment 3:
The preparation of fluoroform sulphonyl oxygen methyl-phosphorous acid diethyl ester
By hydroxymethyl phosphonic acid diethyl ester (59.2g, 0.352mol) be dissolved in 70ml methylene dichloride, add trifluoromethanesulfchloride chloride (114.3g, 0.381mol), then slowly add triethylamine (57.6g, 0.540mol) keep temperature to be no more than 10 ℃ simultaneously, the mixture of gained is warming to 22 ℃ and also stirs at least about 5 hours, reacted until TLC shows.Solids removed by filtration, uses washed with dichloromethane.In filtrate, add 100ml water, add 150ml dichloromethane extraction at least twice.Organic layer anhydrous sodium sulfate drying, steaming desolventizes, and obtains faint yellow oily matter 102.4g.Crude product is directly used in prepares tynofovir.ESI-MS(m/z)：300.0?M
+。
Embodiment 4:
To the preparation of trifluoromethyl benzene sulfonyl oxygen methyl-phosphorous acid diethyl ester
By hydroxymethyl phosphonic acid diethyl ester (6.3g, 38.0mmol) be dissolved in 20ml methylene dichloride, add trifluoromethyl benzene sulfonyl chloride (10.0g, 41.0mmol), then slowly add triethylamine 8.5ml to keep temperature to be no more than 10 ℃ simultaneously, the mixture of gained is warming to 22 ℃ and also stirs at least about 5 hours, reacted until TLC shows.Solids removed by filtration, uses washed with dichloromethane.In filtrate, add 50ml water, add 50ml dichloromethane extraction at least twice.Organic layer anhydrous sodium sulfate drying, steaming desolventizes, and obtains faint yellow oily matter 11.7g.Crude product is directly used in prepares tynofovir.ESI-MS(m/z)：399.06[M+Na]
+。
Embodiment 5:
To the preparation of fluorobenzene sulphonyl oxygen methyl-phosphorous acid diethyl ester
By hydroxymethyl phosphonic acid diethyl ester (18.48g, 0.11mol) be dissolved in 40ml methylene dichloride, add fluorobenzene SULPHURYL CHLORIDE (19.4g, 0.10mol), then slowly add triethylamine (11.1g, 0.11mol) keep temperature to be no more than 10 ℃ simultaneously, the mixture of gained is warming to 22 ℃ and also stirs at least about 5 hours, reacted until TLC shows.Solids removed by filtration, uses washed with dichloromethane.In filtrate, add 80ml water, add 100ml dichloromethane extraction at least twice.Organic layer anhydrous sodium sulfate drying, steaming desolventizes, and obtains faint yellow oily matter 20.64g.Crude product is directly used in prepares tynofovir.ESI-MS(m/z)：327.04[M+H]
+。
Claims (7)
1. the method for preparation formula (1) compound,
It is characterized in that, the compound shown in formula (4) is reacted with methylol diethyl phosphoric acid,
Wherein Y is selected from methyl, trifluoromethyl, phenyl, 4-trifluoromethyl or to fluorophenyl.
2. method according to claim 1, is characterized in that, described Y is methyl.
3. method according to claim 1, is characterized in that, described reaction is take one or more in triethylamine, tripropyl amine, Tributylamine and pyridine as acid binding agent.
4. method according to claim 3, is characterized in that, described reaction is take triethylamine as acid binding agent.
5. method according to claim 1, is characterized in that, described reaction is take one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride as reaction solvent.
6. method according to claim 1, is characterized in that, the temperature of described reaction is-50～25 ℃.
7. method according to claim 1, is characterized in that, the temperature of described reaction is 0～10 ℃.
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| CN201210514646.2A CN103848866A (en) | 2012-12-04 | 2012-12-04 | Method for preparing sulfonyl oxymethyl diethyl phosphate compounds |
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| CN201210514646.2A CN103848866A (en) | 2012-12-04 | 2012-12-04 | Method for preparing sulfonyl oxymethyl diethyl phosphate compounds |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112175003A (en) * | 2019-07-01 | 2021-01-05 | 上海医药工业研究院 | Preparation method of phenyl hydrogen phosphonate and intermediate thereof |
| CN115028661A (en) * | 2022-05-19 | 2022-09-09 | 上海应用技术大学 | 4-aminopiperidine-1-methyl phosphate and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1066266A (en) * | 1991-04-29 | 1992-11-18 | 罗姆和哈斯公司 | Phosphosulfonate herbicides |
| US5500405A (en) * | 1992-04-01 | 1996-03-19 | Rohm And Haas Company | Phosphosulfonate herbicides |
| WO1997036909A1 (en) * | 1996-04-03 | 1997-10-09 | Medichem Research, Inc. | WITTIG REAGENTS AND METHOD FOR PREPARING α,β-UNSATURATED PHOSPHONATES |
| CN101020693A (en) * | 2007-02-05 | 2007-08-22 | 安徽师范大学 | Prepn process of Adefovir |
| CN101565433A (en) * | 2008-04-22 | 2009-10-28 | 吴小峰 | New production technology of diethyl (tosyloxy)methylphosphonate |
| CN102108086A (en) * | 2009-12-25 | 2011-06-29 | 中国人民解放军军事医学科学院微生物流行病研究所 | Method for preparing p-tosyloxymethyl diethyl phosphonate |
-
2012
- 2012-12-04 CN CN201210514646.2A patent/CN103848866A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1066266A (en) * | 1991-04-29 | 1992-11-18 | 罗姆和哈斯公司 | Phosphosulfonate herbicides |
| US5500405A (en) * | 1992-04-01 | 1996-03-19 | Rohm And Haas Company | Phosphosulfonate herbicides |
| WO1997036909A1 (en) * | 1996-04-03 | 1997-10-09 | Medichem Research, Inc. | WITTIG REAGENTS AND METHOD FOR PREPARING α,β-UNSATURATED PHOSPHONATES |
| CN101020693A (en) * | 2007-02-05 | 2007-08-22 | 安徽师范大学 | Prepn process of Adefovir |
| CN101565433A (en) * | 2008-04-22 | 2009-10-28 | 吴小峰 | New production technology of diethyl (tosyloxy)methylphosphonate |
| CN102108086A (en) * | 2009-12-25 | 2011-06-29 | 中国人民解放军军事医学科学院微生物流行病研究所 | Method for preparing p-tosyloxymethyl diethyl phosphonate |
Non-Patent Citations (2)
| Title |
|---|
| D P PHILLION ET AL.: "SYNTHESIS AND REACTIVITY OF DIETHYL PHOSPHONOMETHYLTRIFLATE", 《TETRAHEDRON LETTERS》 * |
| Y B XU ET AL.: "Preparation of New Wittig Reagents and Their Application to the Synthesis ofα,β-Unsaturated Phosphonates", 《J. ORG. CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112175003A (en) * | 2019-07-01 | 2021-01-05 | 上海医药工业研究院 | Preparation method of phenyl hydrogen phosphonate and intermediate thereof |
| CN112175003B (en) * | 2019-07-01 | 2022-02-15 | 上海医药工业研究院 | Preparation method of phenyl hydrogen phosphonate and intermediate thereof |
| CN115028661A (en) * | 2022-05-19 | 2022-09-09 | 上海应用技术大学 | 4-aminopiperidine-1-methyl phosphate and preparation method thereof |
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