CN103288878B - For magnesium salts precipitation agent and the method for purification of (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying - Google Patents
For magnesium salts precipitation agent and the method for purification of (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying Download PDFInfo
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- CN103288878B CN103288878B CN201310229800.6A CN201310229800A CN103288878B CN 103288878 B CN103288878 B CN 103288878B CN 201310229800 A CN201310229800 A CN 201310229800A CN 103288878 B CN103288878 B CN 103288878B
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- vitamin
- magnesium salts
- diethoxy
- propyl group
- precipitation agent
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- 239000011782 vitamin Substances 0.000 title claims abstract description 45
- 229940088594 vitamin Drugs 0.000 title claims abstract description 45
- 229930003231 vitamin Natural products 0.000 title claims abstract description 45
- 235000013343 vitamin Nutrition 0.000 title claims abstract description 45
- 150000003722 vitamin derivatives Chemical class 0.000 title claims abstract description 45
- 159000000003 magnesium salts Chemical class 0.000 title claims abstract description 38
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 title claims abstract description 38
- 238000001556 precipitation Methods 0.000 title claims abstract description 35
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000000746 purification Methods 0.000 title claims abstract description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 150000002170 ethers Chemical class 0.000 claims abstract description 10
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 10
- 239000011777 magnesium Substances 0.000 claims abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- 238000000967 suction filtration Methods 0.000 claims abstract description 7
- 238000001953 recrystallisation Methods 0.000 claims abstract description 6
- 239000012467 final product Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims abstract description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- 239000000706 filtrate Substances 0.000 claims abstract description 3
- 239000012074 organic phase Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 claims description 7
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical compound COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 230000008719 thickening Effects 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 1
- 239000000284 extract Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 15
- 239000002131 composite material Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 6
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 5
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 5
- 238000006482 condensation reaction Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229910001425 magnesium ion Inorganic materials 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000010907 mechanical stirring Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 4
- 239000011654 magnesium acetate Substances 0.000 description 4
- 229940069446 magnesium acetate Drugs 0.000 description 4
- 235000011285 magnesium acetate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000013517 stratification Methods 0.000 description 4
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 4
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 4
- 235000011837 pasties Nutrition 0.000 description 3
- 229930024421 Adenine Natural products 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of magnesium salts precipitation agent for (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying and method of purification; This magnesium salts precipitation agent comprises water, polarity ethers; (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 method of purifying be tert-butyl alcohol magnesium catalysis (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate prepare in the end reaction liquid that (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 obtains add in organic acid with after, remove organic solvent under reduced pressure; Stir add magnesium salts precipitation agent in remaining mixture after, separate out magnesium salts crystal, suction filtration; By filtrate after extracting and separating water outlet, concentrated organic phase, obtains crude product; Gained crude product polar organic solvent recrystallization, to obtain final product; The component of magnesium salts precipitation agent is simple, cheaper starting materials, separates out magnesium salts, really achieve and extract highly purified (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 for quick, high-level efficiency.
Description
Technical field
The present invention relates to the magnesium salts precipitation agent for (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying and method of purification; Belong to tenofovir disoproxil fumarate preparation field.
Background technology
(R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4,
Molecular formula: C
13h
22n
5o
4p
Molecular weight: 343.1
(R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 is an important organic intermediate in tenofovir disoproxil fumarate preparation process, in existing preparation technology, mostly adopt under anhydrous and oxygen-free condition, (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 is prepared in (R)-9-(2-hydroxypropyl) VITAMIN B4 and the condensation reaction under the katalysis of tert-butyl alcohol magnesium of tolysulfonyl oxygen base diethyl phosphonate.Reaction formula is as follows:
A large amount of magnesium salts is there is by (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] the VITAMIN B4 product that aforesaid method is obtained, magnesium salts is easily wrapped in product, make product be that viscous pasty state, sharp separation are quite difficult, be difficult to industrial amplification production; Method of purification in existing technique, or the problem that can not solve that product is viscous pasty state, make magnesium ion wrap up in the product more, is easy to cause final product tenofovir disoproxil fumarate impurity and magnesium ion to exceed standard; There is (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] adenine lost comparatively large, productive rate reduces, the defect that drug manufacture cost increases.
Summary of the invention
The present invention is directed to the method for purification of (R)-9-in existing technique [2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4, exist or the problem that product is viscous pasty state can not be solved, magnesium ion is wrapped up in the product more, be easy to cause the impurity of final product tenofovir disoproxil fumarate and magnesium ion to exceed standard, (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] adenine lost is larger, productive rate reduces, the defect that drug manufacture cost increases, object is that to be to provide a kind of composition simple, cheap, magnesium salts is separated out effective, be easy to be separated the magnesium salts precipitation agent obtaining high purity (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4.
Another object of the present invention be to provide a kind of above-mentioned magnesium salts precipitation agent fast, high-level efficiency separates out magnesium salts, realizes the method extracting high purity (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4.
The invention provides a kind of magnesium salts precipitation agent for (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying, 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, methyl isopropyl ether.
Present invention also offers a kind of method of (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying, the method be tert-butyl alcohol magnesium catalysis (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate prepare in the end reaction liquid that (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 obtains add in organic acid and after, remove organic solvent under reduced pressure; Stir 0.5 ~ 1 hour under 30 ~ 35 ° of C add magnesium salts precipitation agent in remaining mixture after, separate out magnesium salts crystal, suction filtration; By filtrate after extracting and separating water outlet, concentrated organic phase, obtains crude product; Gained crude product polar organic solvent recrystallization, to obtain final product; The consumption of described magnesium salts precipitation agent is 2 ~ 8 times of remaining mixture volume; 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, 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 be acetone, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether one or more.
Described thickening temperature is 60 ~ 80 DEG C.
Described organic acid is one or more in formic acid, acetic acid, propionic acid; Be preferably acetic acid.
Described organic acid consumption is for making whole reaction solution in neutral.
Described magnesium salts to be mainly in organic acid and after, and the magnesium salts that magnesium ion is formed; Be mainly magnesium salts in described magnesium salts crystal, further comprises the impurity such as magnesium oxide, MAGNESIUM METAL introduced by the catalyzer of tert-butyl alcohol magnesium.
Described extraction to adopt in methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, methyl isopropyl ether one or more as extraction agent.
Technical essential of the present invention: in prior art, (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate are under the catalysis of tert-butyl alcohol magnesium, preparation (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4; Never good method high yield is high-purity extracts for the product of gained, and the impurity of the inside based on magnesium salts is wrapped in the middle of product, makes product be sticky state, cannot remove the impurity such as magnesium salts, hinder suitability for industrialized production by simple filtration means; The present invention is through repetition test, composite precipitation agent is made with the asymmetric ethers with certain polarity first with the inorganic water that polarity is larger, this precipitation agent has stricter composite component, when moisture volume content lower than 20% or asymmetric ethers volume content higher than 80% time, magnesium salts does not reach good precipitation effect, when moisture content higher than 28% or asymmetric ethers body burden lower than 72% time, have part (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 can enter in water and be lost; Find that the precipitation process of magnesium salts is a process extremely rambunctious further through experimental study, because precipitation agent consumption, temperature and the factor of precipitation time can cause (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 to enter aqueous phase loss, or the precipitation of magnesium salts is insufficient; Employing precipitation agent of the present invention and best separate out effect in conjunction with magnesium salts but can be made in the preferred consumption of the present invention and temperature and precipitation time range to reach one.
Beneficial effect of the present invention: the present invention is through repetition test, composite go out a kind of composition simple, cost is low, but the magnesium salts precipitation agent of excellent, and be applied to (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying first, reach extraction efficiency up to 95%, product purity is not less than 98%, molar yield up to 80% good result; The method of extraction high purity (R)-9-of the present invention [2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4, simple, high-level efficiency, can suitability for industrialized production.
Accompanying drawing explanation
The HPLC spectrogram of (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 that [Fig. 1] extracts for embodiment 4.
Embodiment
Following examples further illustrate of the present invention, instead of restriction the present invention.
Embodiment 1
Be solvent by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate with dimethyl formamide to 5L, under the catalysis of tert-butyl alcohol magnesium, carry out adding 200 ~ 350 grams of Glacial acetic acid neutralization reaction systems in the reaction product (product is muddy) of obtained (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of condensation reaction, steam except dimethyl formamide under reduced pressure, thickening temperature is 60 ~ 80 DEG C; Vessel temp to be concentrated is down to 40 ~ 50 DEG C, ensure that in bottle, material does not solidify, add 3000 milliliters of composite precipitation agents, wherein 600 milliliters, water, methyl tertiary butyl ether 2400 milliliters, naturally cool to 30 ~ 35 DEG C, change mechanical stirring 30 minutes, have a large amount of white solid to separate out, insulated and stirred 30 minutes, suction filtration removes solid, obtains solid 0.6 kilogram (being mainly magnesium acetate); After stratification, by solvent concentration to dry, obtain 0.7 kg crude product, golden yellow syrupy shape; Add 500 grams of acetone recrystallizations, obtain (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), it is 98.4% that molar yield 80.2%, HPLC method detects purity.
Comparative example 1
Other condition is all identical with embodiment 1, does not exist together: add 3000 milliliters of composite precipitation agents, wherein 800 milliliters, water, methyl tertiary butyl ether 2200 milliliters; Finally obtain solid 0.58kg; Obtain crude product 0.5kg, golden yellow syrupy shape; Add 400 grams of acetone recrystallizations, obtain (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), molar yield 57.2%; It is 98.0% that HPLC method detects purity.
Embodiment 2
Be solvent by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate with dimethyl formamide to 10L, under the catalysis of tert-butyl alcohol magnesium, carry out adding 450 ~ 6000 grams of Glacial acetic acid neutralization reaction systems in the reaction product (product is muddy) of obtained (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of condensation reaction, steam except dimethyl formamide under reduced pressure, thickening temperature is 60 ~ 80 DEG C; Vessel temp to be concentrated is down to 40 ~ 50 DEG C, ensure that in bottle, material does not solidify, add 6500 milliliters of composite precipitation agents, wherein 1620 milliliters, water, methyl tertiary butyl ether and Ethyl Tertisry Butyl Ether are with 6:1 mixed solution 4880 milliliters, naturally cool to 30 ~ 35 DEG C, change mechanical stirring 28 minutes, have a large amount of white solid to separate out, insulated and stirred 25 minutes, suction filtration removes solid, obtains solid 1.25 kilograms (being mainly magnesium acetate); After stratification, glycol dimethyl ether is concentrated into dry, 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 HPLC method detects purity, molar yield 79.0%.
Embodiment 3:
Be solvent by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate with dimethyl formamide to 5L, under the catalysis of tert-butyl alcohol magnesium, carry out adding 200 ~ 350 grams of Glacial acetic acid neutralization reaction systems in the reaction product (product is muddy) of obtained (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of condensation reaction, steam except dimethyl formamide under reduced pressure, thickening temperature is 60 ~ 80 DEG C; Vessel temp to be concentrated is down to 40 ~ 50 DEG C, ensure that in bottle, material does not solidify, and adds 3500 milliliters of composite precipitation agents, wherein, 980 milliliters, water, the mixed solution of methyl tertiary butyl ether and methyl isopropyl ether 4:1 2520 milliliters, naturally cools to 30 ~ 35 DEG C, changes mechanical stirring 30 minutes, a large amount of white solid is had to separate out, insulated and stirred 25 minutes, suction filtration removes solid, obtains solid 0.58 kilogram (being mainly magnesium acetate); After stratification, organic solvent is concentrated into dry, obtains 0.7 kg crude product, golden yellow syrupy shape; Add 550 grams of re-crystallizing in ethyl acetate, obtain (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 (white solid), it is 98.2% that HPLC method detects purity, molar yield 81.0%.
Embodiment 4:
Be solvent by (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate with dimethyl formamide to 5L, under the catalysis of tert-butyl alcohol magnesium, carry out adding 200 ~ 350 grams of Glacial acetic acid neutralization reaction systems in the reaction product (product is muddy) of obtained (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of condensation reaction, steam except dimethyl formamide under reduced pressure, thickening temperature is 60 ~ 80 DEG C; Vessel temp to be concentrated is down to 40 ~ 50 DEG C, ensure that in bottle, material does not solidify, add 2800 milliliters of composite precipitation agents, wherein 700 milliliters, water, methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether and methyl-isobutyl ether mixed solution 2100 milliliters, naturally cool to 30 ~ 35 DEG C, change mechanical stirring 30 minutes, have a large amount of white solid to separate out, insulated and stirred 28 minutes, suction filtration removes solid, obtains solid 0.6 kilogram (being mainly magnesium acetate); After stratification, organic solvent is concentrated into dry, obtains 0.7 kg crude product, golden yellow syrupy shape; Add 550 grams of 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 HPLC method detects purity, molar yield 80.5%.
The HPLC data of (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 that table 1 embodiment 4 is extracted
| 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 example 2
Other condition all with embodiment 1, do not exist together: add 2800 milliliters of composite precipitation agents, wherein 400 milliliters, water, the mixed solution 2400 milliliters of methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether and methyl-isobutyl ether 6:1:1, naturally cool to 30 ~ 35 DEG C, change mechanical stirring 30 minutes, separate out without white solid, occur thick substances; Illustrate that magnesium salts wraps up in (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 more.
Claims (6)
1. the method for purification (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4, it is characterized in that, tert-butyl alcohol magnesium catalysis (R)-9-(2-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen base diethyl phosphonate prepare in the end reaction liquid that (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 obtains add in organic acid and after, remove organic solvent under reduced pressure; Stir 0.5 ~ 1 hour at 30 ~ 35 DEG C add magnesium salts precipitation agent in remaining mixture after, separate out magnesium salts crystal, suction filtration; By filtrate after extracting and separating water outlet, concentrated organic phase, obtains crude product; Gained crude product polar organic solvent recrystallization, to obtain final product; The consumption of described magnesium salts precipitation agent is 2 ~ 8 times of remaining mixture volume; 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, methyl isopropyl ether.
2. the method for claim 1, is characterized in that, the consumption of described magnesium salts precipitation agent is 4 ~ 6 times of described remaining mixture volume.
3. the method for claim 1, is characterized in that, described polar organic solvent be acetone, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether one or more.
4. the method for claim 1, is characterized in that, described thickening temperature is 60 ~ 80 DEG C.
5. the method for claim 1, is characterized in that, described organic acid is one or more in formic acid, acetic acid, propionic acid.
6. the method as described in any one of Claims 1 to 5, is characterized in that, in described extraction employing methyl tertiary butyl ether, Ethyl Tertisry Butyl Ether, methyl-isobutyl ether, methyl isopropyl ether, one or more are as extraction agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310229800.6A CN103288878B (en) | 2013-06-09 | 2013-06-09 | For magnesium salts precipitation agent and the method for purification of (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying |
Applications Claiming Priority (1)
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| 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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| 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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| 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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