CN103288878A - Magnesium salt precipitator used for purifying (R)-9-[2-(diethyoxyl phosphorus acyl methoxyl) propyl] adenine and purifying method - Google Patents
Magnesium salt precipitator used for purifying (R)-9-[2-(diethyoxyl phosphorus acyl methoxyl) propyl] adenine and purifying method Download PDFInfo
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- CN103288878A CN103288878A CN2013102298006A CN201310229800A CN103288878A CN 103288878 A CN103288878 A CN 103288878A CN 2013102298006 A CN2013102298006 A CN 2013102298006A CN 201310229800 A CN201310229800 A CN 201310229800A CN 103288878 A CN103288878 A CN 103288878A
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Abstract
The invention discloses a magnesium salt precipitator used for purifying (R)-9-[diethyoxyl phosphorous acyl methoxyl) propyl] adenine and a purifying method. The magnesium salt precipitator comprises water and polar ether. The method for purifying (R)-9-[diethyoxyl phosphorous acyl methoxyl) propyl] adenine comprises the following steps of: adding organic acid into an end reaction liquid for neutralization, then carrying out reduced pressure steaming to remove an organic solvent, wherein the end reaction liquid is obtained by preparing the (R)-9-[diethyoxyl phosphorous acyl methoxyl) propyl] adenine by catalyzing (R)-9-(2-hydroxyl propyl) adenine and p-toluenesulfonyl acyloxy phosphonic acid diethyl ester by virtue of magnesium tert-butoxide; adding the magnesium salt precipitator into the rest mixture and then stirring, separating out magnesium salt crystals, and carrying out leaching; carrying out extraction on filtrate, separating out water, and concentrating an organic phase to obtain a crude product; and recrystallizing the crude product with a polar organic solvent, thus the purified (R)-9-[diethyoxyl phosphorous acyl methoxyl) propyl] adenine is obtained. According to the magnesium salt precipitator used for purifying the (R)-9-[diethyoxyl phosphorous acyl methoxyl) propyl] adenine and the purifying method, the magnesium salt precipitator is simple in component, raw materials are low in price, magnesium salt can be rapidly and efficiently separated out, and extraction of high-purity (R)-9-[diethyoxyl phosphorous acyl methoxyl) propyl] adenine is really realized.
Description
Technical field
The present invention relates to for (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group of purifying] magnesium salts precipitation agent and the method for purification of VITAMIN B4; Belong to fumaric acid tynofovir ester preparation field.
Background technology
(R)-and 9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4,
Molecular formula: C
13H
22N
5O
4P
Molecular weight: 343.1
(R)-and 9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 is an important organic intermediate in the fumaric acid tynofovir ester preparation process, in existing preparation technology, mostly adopt under the anhydrous and oxygen-free condition, (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate condensation reaction preparation (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group under the katalysis of tert-butyl alcohol magnesium] VITAMIN B4.Reaction formula is as follows:
(R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that makes by aforesaid method] there is a large amount of magnesium salts in the VITAMIN B4 product, magnesium salts easily is wrapped in the product, makes product be quite difficulty of thickness state, sharp separation, is difficult to industrial amplification production; Method of purification in the existing technology, or can not solve the problem that product is the thickness state, it is more that magnesium ion is wrapped up in product, is easy to cause final product fumaric acid tynofovir ester impurity and magnesium ion to exceed standard; Having (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 loss is bigger, and productive rate reduces, the defective that the drug manufacture cost increases.
Summary of the invention
The present invention is directed to (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group in the existing technology] method of purification of VITAMIN B4, exist or can not solve the problem that product is the thickness state, it is more that magnesium ion is wrapped up in product, be easy to cause impurity and the magnesium ion of final product fumaric acid tynofovir ester to exceed standard, (R)-and 9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 loss is bigger, productive rate reduces, the defective that the drug manufacture cost increases, purpose is to be to provide a kind of composition simple, cheap, magnesium salts is separated out effective, is easy to separate obtain high purity (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] the magnesium salts precipitation agent of VITAMIN B4.
Another object of the present invention be to provide the above-mentioned magnesium salts precipitation agent of a kind of usefulness fast, high-level efficiency separates out magnesium salts, realizes extracting high purity (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] method of VITAMIN B4.
The invention provides a kind of for (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group of purifying] the magnesium salts precipitation agent of VITAMIN B4, this precipitation agent comprises following component: water 20～28vol%; Polarity ethers 72～80vol%.
Described polarity ethers is one or more in methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, the methyl isopropyl ether.
The present invention also provides a kind of purification (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] method of VITAMIN B4, this method is at tert-butyl alcohol magnesium catalysis (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate preparation (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] add in the end reaction liquid that obtains of VITAMIN B4 in the organic acid and after, remove organic solvent under reduced pressure; Under 30～35 ° of C, stirred 0.5～1 hour after in remaining mixture, adding the magnesium salts precipitation agent, separate out the magnesium salts crystal, suction filtration; Filtrate after the extracting and separating water outlet, is concentrated organic phase, obtain crude product; Gained crude product polar organic solvent recrystallization, namely; The consumption of described magnesium salts precipitation agent is 2～8 times of remaining mixture volume; The magnesium salts precipitation agent comprises following component: water 20～28vol%, polarity ethers 72～80vol%.
Described polarity ethers is one or more in methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, the methyl isopropyl ether.
The consumption of described magnesium salts precipitation agent is preferably 4～6 times of described remaining mixture volume.
Described polar organic solvent is one or more of acetone, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether.
Described thickening temperature is 60～80 ℃.
Described organic acid be in formic acid, acetic acid, the propionic acid one or more; Be preferably acetic acid.
Described organic acid consumption is neutral for making entire reaction liquid.
Described magnesium salts be mainly in the organic acid and after and the magnesium salts that forms of magnesium ion; Be mainly magnesium salts in the described magnesium salts crystal, also comprised impurity such as the magnesium oxide introduced by the catalyzer of tert-butyl alcohol magnesium, MAGNESIUM METAL.
One or more are as extraction agent in described extraction employing methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, the methyl isopropyl ether.
Technical essential of the present invention: (2-hydroxypropyl) VITAMIN B4 of (R)-9-in the prior art and tolysulfonyl oxygen base diethyl phosphonate prepare (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group under the catalysis of tert-butyl alcohol magnesium] VITAMIN B4; Never the method high yield is high-purity preferably extracts for the product of gained, and the inside is wrapped in the middle of the product based on the impurity of magnesium salts, makes product be sticky state, can't remove impurity such as magnesium salts by the simple filtration means, has hindered suitability for industrialized production; The present invention is through repetition test, make composite precipitation agent with the bigger inorganic water of polarity with the asymmetric ethers with certain polarity first, this precipitation agent has strict composite component, when water volume content is lower than 20% or the volume content of asymmetric ethers when being higher than 80%, magnesium salts does not reach the good effect of separating out, when moisture content is higher than 28% or the body burden of asymmetric ethers when being lower than 72%, part (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group being arranged] VITAMIN B4 can enter in the water and be lost; Find further that through experimental study the precipitation process of magnesium salts is a process extremely rambunctious, because precipitation agent consumption, temperature and separate out the factor of time and can cause (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 enters the water loss, perhaps magnesium salts separate out insufficient; Using precipitation agent of the present invention and in conjunction with the preferred consumption of the present invention and temperature with separate out and but can make magnesium salts reach a best in the time range to separate out effect.
Beneficial effect of the present invention: the present invention is through repetition test, it is composite that to go out a kind of composition simple, cost is low, but the magnesium salts precipitation agent that effect is splendid, and (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that is applied to first purify] VITAMIN B4, reached extraction efficiency up to 95%, product purity is not less than 98%, and molar yield is up to 80% good result; Extraction high purity of the present invention (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] method of VITAMIN B4, simple, high-level efficiency can suitability for industrialized production.
Description of drawings
[Fig. 1] is (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that embodiment 4 extracts] the HPLC spectrogram of VITAMIN B4.
Embodiment
Following examples are to further specify of the present invention, rather than restriction the present invention.
Embodiment 1
Be solvent to 5L with the dimethyl formamide by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate, under the catalysis of tert-butyl alcohol magnesium, carry out (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that condensation reaction makes] add 200～350 gram Glacial acetic acid neutralization reaction systems in the reaction product (product muddiness) of VITAMIN B4, steam except dimethyl formamide under the reduced pressure, thickening temperature is 60～80 ℃; Vessel temp to be concentrated is down to 40～50 ℃, guarantee that material does not solidify in the bottle, add 3000 milliliters of composite precipitation agents, wherein water is 600 milliliters, 2400 milliliters of methyl tertiary butyl ethers, naturally cool to 30～35 ℃, the tool of changing planes stirred 30 minutes, had a large amount of white solids to separate out, insulated and stirred 30 minutes, suction filtration is removed solid, obtains 0.6 kilogram of solid (being mainly magnesium acetate); Behind the standing demix, solvent is concentrated into dried, obtains 0.7 kg crude product, golden yellow syrupy shape; Add 500 gram acetone recrystallizations, obtain (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), molar yield 80.2%, it is 98.4% that the HPLC method detects purity.
Comparative Examples 1
Other condition is all identical with embodiment 1, does not exist together: add 3000 milliliters of composite precipitation agents, wherein water is 800 milliliters, 2200 milliliters of methyl tertiary butyl ethers; Finally obtain solid 0.58kg; Obtain crude product 0.5kg, golden yellow syrupy shape; Add 400 gram acetone recrystallizations, obtain (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), molar yield 57.2%; It is 98.0% that the HPLC method detects purity.
Embodiment 2
Be solvent to 10L with the dimethyl formamide by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate, under the catalysis of tert-butyl alcohol magnesium, carry out (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that condensation reaction makes] add 450～6000 gram Glacial acetic acid neutralization reaction systems in the reaction product (product muddiness) of VITAMIN B4, steam except dimethyl formamide under the reduced pressure, thickening temperature is 60～80 ℃; Vessel temp to be concentrated is down to 40～50 ℃, guarantee that material does not solidify in the bottle, add 6500 milliliters of composite precipitation agents, wherein water is 1620 milliliters, and methyl tertiary butyl ether and Ethyl Tertisry Butyl Ether are with 4880 milliliters of 6:1 mixed solutions, naturally cool to 30～35 ℃, the tool of changing planes stirred 28 minutes, had a large amount of white solids to separate out, insulated and stirred 25 minutes, suction filtration is removed solid, obtains 1.25 kilograms of solids (being mainly magnesium acetate); Behind the standing demix, glycol dimethyl ether is concentrated into dried, obtains 1.4 kg crude products, golden yellow syrupy shape; Add 1.2 kilograms of re-crystallizing in ethyl acetate, obtain high purity (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), it is 98.1% that the HPLC method detects purity, molar yield 79.0%.
Embodiment 3:
Be solvent to 5L with the dimethyl formamide by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate, under the catalysis of tert-butyl alcohol magnesium, carry out (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that condensation reaction makes] add 200～350 gram Glacial acetic acid neutralization reaction systems in the reaction product (product muddiness) of VITAMIN B4, steam except dimethyl formamide under the reduced pressure, thickening temperature is 60～80 ℃; Vessel temp to be concentrated is down to 40～50 ℃, guarantee that material does not solidify in the bottle, add 3500 milliliters of composite precipitation agents, wherein, 980 milliliters in water, 2520 milliliters of the mixed solutions of methyl tertiary butyl ether and methyl isopropyl ether 4:1 naturally cool to 30～35 ℃, and the tool of changing planes stirred 30 minutes, there are a large amount of white solids to separate out, insulated and stirred 25 minutes, suction filtration is removed solid, obtains 0.58 kilogram of solid (being mainly magnesium acetate); Behind the standing demix, organic solvent is concentrated into dried, obtains 0.7 kg crude product, golden yellow syrupy shape; Add 550 gram re-crystallizing in ethyl acetate, obtain (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), it is 98.2% that the HPLC method detects purity, molar yield 81.0%.
Embodiment 4:
Be solvent to 5L with the dimethyl formamide by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate, under the catalysis of tert-butyl alcohol magnesium, carry out (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that condensation reaction makes] add 200～350 gram Glacial acetic acid neutralization reaction systems in the reaction product (product muddiness) of VITAMIN B4, steam except dimethyl formamide under the reduced pressure, thickening temperature is 60～80 ℃; Vessel temp to be concentrated is down to 40～50 ℃, guarantee that material does not solidify in the bottle, add 2800 milliliters of composite precipitation agents, wherein water is 700 milliliters, 2100 milliliters of methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether and methyl-isobutyl ether mixed solutions, naturally cool to 30～35 ℃, the tool of changing planes stirred 30 minutes, had a large amount of white solids to separate out, insulated and stirred 28 minutes, suction filtration is removed solid, obtains 0.6 kilogram of solid (being mainly magnesium acetate); Behind the standing demix, organic solvent is concentrated into dried, obtains 0.7 kg crude product, golden yellow syrupy shape; Add 550 gram methyl tertiary butyl ether recrystallizations, obtain high purity (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), it is 98.4% that the HPLC method detects purity, molar yield 80.5%.
(R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group that table 1 embodiment 4 extracts] the HPLC data of VITAMIN B4
| Peak # | Retention time | Area | Highly | Area % | Height % |
| 1 | 0.999 | 5710 | 700 | 0.029 | 0.021 |
| 2 | 1.700 | 19626271 | 3356006 | 98.452 | 98.773 |
| 3 | 2.266 | 7070 | 1608 | 0.035 | 0.047 |
| 4 | 2.376 | 25689 | 5251 | 0.129 | 0.155 |
| 5 | 2.977 | 82745 | 15127 | 0.415 | 0.445 |
| 6 | 13.368 | 7478 | 526 | 0.038 | 0.015 |
| 7 | 23.271 | 8042 | 937 | 0.040 | 0.028 |
| 8 | 23.559 | 5550 | 402 | 0.028 | 0.012 |
| 9 | 23.917 | 5222 | 690 | 0.026 | 0.020 |
| 10 | 27.387 | 90829 | 11206 | 0.456 | 0.330 |
| 11 | 29.133 | 6404 | 264 | 0.032 | 0.008 |
| 12 | 31.687 | 47697 | 3611 | 0.239 | 0.106 |
| 13 | 35.009 | 16212 | 1380 | 0.081 | 0.041 |
| Amount to | ? | 19934921 | 3397708 | 100.000 | 100.000 |
Comparative Examples 2
Other condition all with embodiment 1, do not exist together: add 2800 milliliters of composite precipitation agents, wherein water is 400 milliliters, 2400 milliliters of the mixed solutions of methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether and methyl-isobutyl ether 6:1:1, naturally cool to 30～35 ℃, the tool of changing planes stirred 30 minutes, and no white solid is separated out, and thick substances occurs; Illustrating that magnesium salts is at (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] parcel is more in the VITAMIN B4.
Claims (9)
1. (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group of be used for purifying] the magnesium salts precipitation agent of VITAMIN B4, it is characterized in that, comprise following component: water 20～28vol%; Polarity ethers 72～80vol%.
2. magnesium precipitate agent as claimed in claim 1 is characterized in that, described polarity ethers is one or more in methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, the methyl isopropyl ether.
3. purification (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] method of VITAMIN B4, it is characterized in that, at tert-butyl alcohol magnesium catalysis (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate preparation (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] add in the end reaction liquid that obtains of VITAMIN B4 in the organic acid and after, remove organic solvent under reduced pressure; Under 30～35 ° of C, stirred 0.5～1 hour after in remaining mixture, adding the magnesium salts precipitation agent, separate out the magnesium salts crystal, suction filtration; Filtrate after the extracting and separating water outlet, is concentrated organic phase, obtain crude product; Gained crude product polar organic solvent recrystallization, namely; The consumption of described magnesium salts precipitation agent is 2～8 times of remaining mixture volume; The magnesium salts precipitation agent comprises following component: water 20～28vol%, polarity ethers 72～80vol%.
4. method as claimed in claim 3 is characterized in that, described polarity ethers is one or more in methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, the methyl isopropyl ether.
5. method as claimed in claim 3 is characterized in that, the consumption of described magnesium salts precipitation agent is 4～6 times of described remaining mixture volume.
6. method as claimed in claim 3 is characterized in that, described polar organic solvent is one or more of acetone, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether.
7. method as claimed in claim 3 is characterized in that, described thickening temperature is 60～80 ℃.
8. method as claimed in claim 3 is characterized in that, described organic acid be in formic acid, acetic acid, the propionic acid one or more.
9. as each described method of claim 3～8, it is characterized in that one or more are as extraction agent in described extraction employing methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, the methyl isopropyl ether.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153231A (en) * | 2015-08-28 | 2015-12-16 | 浙江车头制药股份有限公司 | Preparation method of phenyl PMPA |
| CN106687467A (en) * | 2014-09-30 | 2017-05-17 | 韩美精密化学株式会社 | Method for preparing high-purity (r)-9-[2-(phosphonomethoxy)propyl]adenine |
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| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
| CN102219805A (en) * | 2011-03-10 | 2011-10-19 | 苏州腾龙生物医药技术有限公司 | Novel production process of tenofovir |
| CN102250146A (en) * | 2011-05-27 | 2011-11-23 | 扬州三友合成化工有限公司 | Method for synthesizing adefovir serving as anti-hepatitis B virus medicine |
| CN102295660A (en) * | 2011-07-04 | 2011-12-28 | 常州大学 | Synthetic technology of PMPA |
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2013
- 2013-06-09 CN CN201310229800.6A patent/CN103288878B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
| CN102219805A (en) * | 2011-03-10 | 2011-10-19 | 苏州腾龙生物医药技术有限公司 | Novel production process of tenofovir |
| CN102250146A (en) * | 2011-05-27 | 2011-11-23 | 扬州三友合成化工有限公司 | Method for synthesizing adefovir serving as anti-hepatitis B virus medicine |
| CN102295660A (en) * | 2011-07-04 | 2011-12-28 | 常州大学 | Synthetic technology of PMPA |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106687467A (en) * | 2014-09-30 | 2017-05-17 | 韩美精密化学株式会社 | Method for preparing high-purity (r)-9-[2-(phosphonomethoxy)propyl]adenine |
| CN105153231A (en) * | 2015-08-28 | 2015-12-16 | 浙江车头制药股份有限公司 | Preparation method of phenyl PMPA |
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