CN105153231A - Preparation method of phenyl PMPA - Google Patents
Preparation method of phenyl PMPA Download PDFInfo
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- CN105153231A CN105153231A CN201510542176.4A CN201510542176A CN105153231A CN 105153231 A CN105153231 A CN 105153231A CN 201510542176 A CN201510542176 A CN 201510542176A CN 105153231 A CN105153231 A CN 105153231A
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Abstract
The invention relates to a preparation method of phenyl PMPA shown in formula 1. The method includes the steps of A, allowing 9-(2-hydroxypropyl) adenine (HPA) shown in formula 3 and magnesium alkoxide to react with diphenyl p-toluenesulfonyloxy methylphosphonate to obtain a compound 2; B, hydrolyzing the compound to obtain the phenyl PMPA shown in formula 1. Compared with the prior art, the method is short in reaction step and high in reaction yield.
Description
One, technical field
The present invention relates to the preparation method of the phenyl PMPA shown in a kind of formula (1),
Two, background technology
Tynofovir Chinese mugwort draws the chemical name of phenol amine (tenofoviralafenamide) to be: 9-{ (R)-2-[((S)-{ [(S)-1-(isopropoxy carbonyl) ethyl] is amino } phenoxy group phosphinyl) methoxyl group] propyl group } VITAMIN B4, structural formula is as follows:
Tynofovir Chinese mugwort draws phenol amine to be the prodrug of tynofovir, belongs to nucleoside reverse transcriptase inhibitor.In clinical trial, this medicine has been proved to be when lower than lucky moral marketed drug Viread (tenofovir disoproxil fumarate sheet, Viread, TDF) ten/dose, just there is very high antiviral effect, renal function and bone aspect parameter can be improved simultaneously.
The tynofovir Chinese mugwort of current report draws phenol amine synthetic route mainly lucky moral house journal WO2002008241A2, and its synthetic route is as follows:
This route is that raw material synthesizes PMPA through three-step reaction with VITAMIN B4, then synthesize a phenyl PMPA with phenol or triphenyl phosphite, and reactions steps is many, needs to use a large amount of catalyzer DMAP or acylating reagent thionyl chloride etc.
Three, summary of the invention
The object of this invention is to provide the preparation method of the phenyl PMPA shown in formula 1 that a kind of reactions steps is short, yield is high.
For achieving the above object, the technical solution used in the present invention is as follows:
A preparation method of a phenyl PMPA shown in formula 1, comprising:
A, 9-(2-hydroxypropyl) VITAMIN B4 (HPA) shown in formula 3, magnesium alkoxide and tolysulfonyl oxygen methyl acid phosphate diphenyl ester are obtained by reacting compound 2;
The hydrolysis of B, compound 2 obtains the phenyl PMPA shown in formula 1;
Reaction formula is as follows:
Further, the preferred tert-butyl alcohol magnesium of described magnesium alkoxide or magnesium isopropoxide.
Further, in steps A, the molar ratio of 9-(2-hydroxypropyl) VITAMIN B4 (HPA), magnesium alkoxide and tolysulfonyl oxygen methyl acid phosphate diphenyl ester is 1:0.5 ~ 1.0:1.0 ~ 1.2.
Further, react and carry out in a solvent described in steps A, described solvent is selected from DMF or DMSO.
Further, react and carry out at 50 ~ 90 DEG C described in steps A, the reaction times was at 3 ~ 6 hours.
Further, the hydrolysis reaction in step B acid or basic cpd effect under carry out, described basic cpd is preferably sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood; Described acid is preferably hydrochloric acid or Hydrogen bromide.
Further, the hydrolysis reaction of step B carries out at room temperature ~ 100 DEG C, and the reaction times was at 3 ~ 12 hours.
Compared with prior art, beneficial effect of the present invention is: raw material is easy to get, reactions steps is short, quality controllable, improves yield.
Four, embodiment:
With specific embodiment, technical scheme of the present invention is described further below, but protection scope of the present invention is not limited thereto:
Embodiment 1: the synthesis of tolysulfonyl oxygen methyl acid phosphate diphenyl ester:
50.0g (0.214 mole) diphenyl phosphite, formaldehyde 23.0g (0.767 mole), 60ml toluene is dropped in 250ml there-necked flask, stirring is cooled to 10 DEG C, drip 1.5g triethylamine, dropwise rear room temperature reaction 30min, stratification, water layer 200ml chloroform extraction twice, combined chloroform layer, pressure reducing and steaming solvent obtains oily matter 50.6g, purity 98.2%.
Drop in 500ml there-necked flask on 50.0g (0.189 mole) and walk oily matter, 72.1g (0.378 mole) PTSC, 100ml methylene dichloride, triethylamine 38.2g (0.378 mole), backflow 3.5h, be chilled to room temperature, 150ml washes three times, dried over sodium sulfate, concentrate to obtain tolysulfonyl oxygen methyl acid phosphate diphenyl ester 73.5g, purity 98.7%.
Embodiment 2
10.0g (0.052 mole) (R)-9-(2-hydroxypropyl) VITAMIN B4 (HPA) is dropped in 250ml there-necked flask, add 100mlDMF, 7.0g (0.041 mole) tert-butyl alcohol magnesium, tolysulfonyl oxygen methyl acid phosphate diphenyl ester 23.9g (0.057 mole), be warming up to 75 DEG C, insulation reaction 3h.Pressure reducing and steaming solvent, adds 30% sodium hydroxide 100g, and 90 DEG C of stirring reaction 6h, are down to room temperature, and 0.1N hydrochloric acid adjusts pH=2.5 ~ 3.0, and filter, 70 DEG C of air blast dry to obtain 10.8g mono-phenyl PMPA, purity 98.6%.
Embodiment 3
10.0g (0.052 mole) (R)-9-(2-hydroxypropyl) VITAMIN B4 (HPA) is dropped in 250ml there-necked flask, add 100mlDMF, 5.2g (0.037 mole) magnesium isopropoxide, tolysulfonyl oxygen methyl acid phosphate diphenyl ester 23.9g (0.057 mole), be warming up to 75 DEG C, insulation reaction 4h.Pressure reducing and steaming solvent, adds the technical hydrochloric acid 80g of 31%, and 70 DEG C of stirring reaction 7h, are down to room temperature, and 30% sodium hydroxide adjusts pH=2.5 ~ 3.0, and filter, 70 DEG C of air blast dry to obtain 10.6g mono-phenyl PMPA, purity 98.5%.
Embodiment 4
10.0g (0.052 mole) (R)-9-(2-hydroxypropyl) VITAMIN B4 (HPA) is dropped in 250ml there-necked flask, add 100mlDMSO, 5.2g (0.037 mole) magnesium isopropoxide, tolysulfonyl oxygen methyl acid phosphate diphenyl ester 23.9g (0.057 mole), be warming up to 65 DEG C, insulation reaction 6h.Pressure reducing and steaming solvent, adds saturated aqueous sodium carbonate 120g, and 100 DEG C of stirring reaction 12h, are down to room temperature, and 0.1N hydrochloric acid adjusts pH=2.5 ~ 3.0, and filter, 70 DEG C of air blast dry to obtain 10.2g mono-phenyl PMPA, purity 98.9%.
Claims (7)
1. a preparation method of the phenyl PMPA shown in formula 1, comprising:
A, 9-(2-hydroxypropyl) VITAMIN B4 shown in formula 3, magnesium alkoxide and tolysulfonyl oxygen methyl acid phosphate diphenyl ester are obtained by reacting compound 2;
The hydrolysis of B, compound 2 obtains the phenyl PMPA shown in formula 1;
Reaction formula is as follows:
2. the preparation method of a phenyl PMPA as claimed in claim 1, is characterized in that: described magnesium alkoxide is tert-butyl alcohol magnesium or magnesium isopropoxide.
3. the preparation method of a phenyl PMPA as claimed in claim 1 or 2, is characterized in that: in steps A, the molar ratio of 9-(2-hydroxypropyl) VITAMIN B4, magnesium alkoxide and tolysulfonyl oxygen methyl acid phosphate diphenyl ester is 1:0.5 ~ 1.0:1.0 ~ 1.2.
4. the preparation method of a phenyl PMPA as claimed in claim 1 or 2, it is characterized in that: react described in steps A and carry out in a solvent, described solvent is selected from DMF or DMSO.
5. the preparation method of a phenyl PMPA as claimed in claim 4, it is characterized in that: react described in steps A and carry out at 50 ~ 90 DEG C, the reaction times was at 3 ~ 6 hours.
6. the preparation method of a phenyl PMPA as claimed in claim 1 or 2, is characterized in that: the hydrolysis reaction in step B acid or basic cpd effect under carry out, described basic cpd is sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood; Described acid is hydrochloric acid or Hydrogen bromide.
7. the preparation method of a phenyl PMPA as claimed in claim 6, is characterized in that: the hydrolysis reaction of step B carries out at room temperature ~ 100 DEG C, and the reaction times was at 3 ~ 12 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510542176.4A CN105153231A (en) | 2015-08-28 | 2015-08-28 | Preparation method of phenyl PMPA |
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| CN201510542176.4A CN105153231A (en) | 2015-08-28 | 2015-08-28 | Preparation method of phenyl PMPA |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866739A (en) * | 2017-03-10 | 2017-06-20 | 华东师范大学 | It is a kind of（R）‑1‑（The base of 6 amino 9H purine 9）The preparation method of 2 phenyl esters |
| CN110272455A (en) * | 2019-04-15 | 2019-09-24 | 浙江车头制药股份有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws the preparation method of phenol amine key intermediate |
| 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 |
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| CN1786007A (en) * | 2005-08-19 | 2006-06-14 | 浙江车头制药有限公司 | Preparation method of adenine derivative |
| WO2013116730A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections |
| CN103288878A (en) * | 2013-06-09 | 2013-09-11 | 江西师范大学 | Magnesium salt precipitator used for purifying (R)-9-[2-(diethyoxyl phosphorus acyl methoxyl) propyl] adenine and purifying method |
| CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
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2015
- 2015-08-28 CN CN201510542176.4A patent/CN105153231A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1786007A (en) * | 2005-08-19 | 2006-06-14 | 浙江车头制药有限公司 | Preparation method of adenine derivative |
| WO2013116730A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections |
| CN103288878A (en) * | 2013-06-09 | 2013-09-11 | 江西师范大学 | Magnesium salt precipitator used for purifying (R)-9-[2-(diethyoxyl phosphorus acyl methoxyl) propyl] adenine and purifying method |
| CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866739A (en) * | 2017-03-10 | 2017-06-20 | 华东师范大学 | It is a kind of（R）‑1‑（The base of 6 amino 9H purine 9）The preparation method of 2 phenyl esters |
| CN106866739B (en) * | 2017-03-10 | 2018-11-02 | 华东师范大学 | The preparation method of one kind (R) -1- (6- amino -9H- purine -9- bases) 2- phenyl esters |
| CN110272455A (en) * | 2019-04-15 | 2019-09-24 | 浙江车头制药股份有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws the preparation method of phenol amine key intermediate |
| 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 |
| CN114409706A (en) * | 2019-07-01 | 2022-04-29 | 上海医药工业研究院 | Preparation method of phenyl hydrogen phosphonate and intermediate thereof |
| CN114409706B (en) * | 2019-07-01 | 2023-11-28 | 上海医药工业研究院 | Preparation method of phenyl hydrogen phosphonate and intermediate thereof |
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