CN102766673A - Synthetic method of (R)-4-benzyloxy-2-methyl-1-butyl alcohol in dolichol biological chain - Google Patents
Synthetic method of (R)-4-benzyloxy-2-methyl-1-butyl alcohol in dolichol biological chain Download PDFInfo
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- CN102766673A CN102766673A CN2012102658577A CN201210265857A CN102766673A CN 102766673 A CN102766673 A CN 102766673A CN 2012102658577 A CN2012102658577 A CN 2012102658577A CN 201210265857 A CN201210265857 A CN 201210265857A CN 102766673 A CN102766673 A CN 102766673A
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Abstract
The invention discloses a synthetic method of (R)-4-benzyloxy-2-methyl-1-butyl alcohol in dolichol biological chain, comprising the following steps: adding raw materials consisting of X1mol of (R,S)-4-benzyloxy-2-methyl-1-butyl alcohol and X2ml of anhydrous chloroform in X3U of pseudomonas fluorescens lipase, dropping X4mol of vinyl acetate at the temperature A while stirring, and reacting at the temperature A under stirring for T hour, wherein the molar ratio range of each reaction raw material is as follows: X1mol: X2mol: X3U: X4mol is equal to 1: (5-100): (100-1000): (1-15), the related temperature A is ranged from 25 DEG C to 65 DEG C, and the related time T is ranged from 0.2h to 4h.
Description
Technical field
The present invention relates to the compound method of (R)-4-benzyloxy in a kind of dolichol biologic chain-2-methyl-1-butene alcohol.
Background technology
Natural dolichol is by a series of and have the natural quasi-ester compound that the isopentene group unit that necessarily puts in order is formed, and the terminal is the primary isoamyl alcohol unit, contains a chiral carbon atom, is the S configuration, has optical activity.The Ginkgo Leaf polyprenol also is to be made up of a series of isopentene groups unit, and isopentene group unit number and S-dolichol are basic identical, and just terminal unit is undersaturated isopentene group unit.Therefore, can be raw material with the Ginkgo Leaf polyprenol, through the synthetic S-dolichol of semisynthetic way.
(R)-and 4-benzyloxy-1-bromo-2-methylbutane (chirality C5 synthon) is the important intermediate of synthetic S-dolichol, its study on the synthesis also is the main difficult problem of synthetic S-dolichol.
(R)-4-benzyloxy-2-methyl-1-butene alcohol is synthetic (R)-4-benzyloxy-1-bromo-2-methylbutane (chirality C5 synthon) three-step reaction product; Be enzymatic stereoselectivity acetylization reaction, obtain (the R)-4-benzyloxy-2-methyl-1-butene alcohol of single configuration.
Summary of the invention
The objective of the invention is to 4-benzyloxy-2-methyl-1-butene alkene is raw material, and the compound method of a kind of (R)-4-benzyloxy-2-methyl-1-butene alcohol is provided, and the problem of midbody (chirality C5 synthon) raw material is provided with the synthetic S-dolichol of further solution.
For realizing above purpose, the present invention adopts concrete steps to be:
The first step: building-up reactions
Add in the reaction vessel raw material (R, S)-the 4-benzyloxy-2-methyl-1-butene alcohol X
1Mol, anhydrous chloroform X
2Mol adds Pseudomonas fluorescens lypase X
3U, the A temperature splashes into vinyl-acetic ester X under stirring
4Mol, this system stirring reaction time under the A temperature is T hour.
Wherein, each reaction raw materials molar ratio range is X
1Mol: X
2Mol: X
3U: X
4Mol=1: 5～100: 100～1000: 1～15.Wherein, the TR A that relates to is 25～65 ℃.The time range T that relates to does.0.2～4 hours.
Second step: aftertreatment
Reaction mixture filters, and filtrating volatilizes solvent through the decompression rotary evaporation, obtains crude product.With thin-layer chromatography (TLC) detection reaction process: with kapillary draw a little crude product and reactant (R, S)-4-benzyloxy-2-methyl-1-butene alcohol point sample on silica-gel plate, developping agent is the ethyl acetate petroleum ether mixing system, iodine vapor develops the color.
Wherein, developping agent ETHYLE ACETATE and sherwood oil mixing system volume ratio scope are 1: 3～10.
The 3rd step: the purifying of title product
Obtain title product through silica gel column chromatography separating purification.Silicagel column is used the ethyl acetate petroleum ether mixing system, and polarity, is collected each component of merging and adopted TLC to detect to high wash-out by low, the iodine vapor colour developing, and wash-out partly was title product when the ethyl acetate petroleum ether gradient was M.
Wherein, silicagel column mixing system wash-out scope is an ETHYLE ACETATE: sherwood oil=1: 99～3, gradient M is an ETHYLE ACETATE: sherwood oil=1: 10～3.
The 4th step: the structure of title product is identified
Through IR, GC-MS,
1H-NMR,
13C-NMR carries out structure to title product to be identified.
1. ir spectra (IR)
(R)-and the main absorption peak of ir spectra (seeing accompanying drawing 1 for details) of 4-benzyloxy-2-methyl-1-butene alcohol has: 1027.22,1092.63 and 3384.22cm
-1Deng, 1027.22cm wherein
-1Be the absorption of the C-OH key of alcohol, 1092.63cm
-1The stretching vibration that is ehter bond C-O-C causes, 3384.22cm
-1Absorption is the stretching vibration of alcoholic extract hydroxyl group O-H.
2. mass spectrum (MS)
Mass spectrum (seeing accompanying drawing 2 for details) analysis revealed, m/z=194.1 (M), 108 (PhCH
2O+H), 107.1 (PhCH
2O), 105 (PhCO), 92 (PhCH
2+ H), 91 (PhCH
2), 89 (PhC), 85 (C
4H
9CO), 79 (C
6H
5+ 2H), 77 (C
6H
5), 69 (C
5H
9), 65 (C
5H
5) and 57 (C
4H
9).
Hydrogen spectrum (
1H-NMR)
Hydrogen spectrum (CDCl
3, see accompanying drawing 3 for details) and analysis revealed, δ: 0.90-0.92 (d, 3H; CH
3), 1.57-1.81 (2m, 3H; CH
2CH), 2.60 (bs, 1H; OH), 3.41-3.59 (2m, 4H; CH
2O), 4.51 (s, 2H; CH
2-Ph) and 7.25-7.34ppm (m, 5H; Ph-H).
Carbon spectrum (
13C-NMR)
Carbon spectrum (CDCl
3, see accompanying drawing 4 for details) and analysis revealed, δ: 17.17 (CH
3), 34.01 (CH), 34.09 (CH
2), 68.07 (CH
2O), 68.68 (CH
2OH), 77.05 (CH
2-Ph), 127.71 (Ph:C4), 127.75 (Ph:C2, C6), 128.44 (Ph:C3, C5) and 138.03ppm (Ph:C1).
Description of drawings:
Ir spectra (IR) figure of accompanying drawing 1 (R)-4-benzyloxy-2-methyl-1-butene alcohol
Mass spectrum (MS) figure of accompanying drawing 2 (R)-4-benzyloxy-2-methyl-1-butene alcohol
The hydrogen spectrum of accompanying drawing 3 (R)-4-benzyloxy-2-methyl-1-butene alcohol (
1H-NMR) figure
The carbon spectrum of accompanying drawing 4 (R)-4-benzyloxy-2-methyl-1-butene alcohol (
13C-NMR) figure
Embodiment
Following examples are more of the present invention giving an example, and should not regarded as qualification of the present invention.
Synthesizing of embodiment 1 (R)-4-benzyloxy-2-methyl-1-butene alcohol
The first step: building-up reactions
Add (R in the there-necked flask; S)-and 4-benzyloxy-2-methyl-1-butene alcohol 1.06g (purity 94%, 5.16mmol), anhydrous chloroform 10.4mL; Add Pseudomonas fluorescens lypase 120.6mg (20U/mg), splash into vinyl-acetic ester 1.9mL (21.3mmol) under 55 ℃ of stirrings.After dropwising, 55 ℃ of following stirring reaction 2h.
Second step: aftertreatment
Reaction mixture filters, and filtrating volatilizes solvent through the decompression rotary evaporation, obtains crude product.With thin-layer chromatography (TLC) detection reaction process: (R, S)-4-benzyloxy-2-methyl-1-butene alcohol point sample on silica-gel plate, developping agent is an ETHYLE ACETATE: sherwood oil=17: 83 (V/V), iodine vapor develops the color to draw a little crude product and reactant with kapillary.
The 3rd step: the purifying of title product
Obtain title product through silica gel column chromatography separating purification.Use successively 10% ethyl acetate/petroleum ether (V/V, 400mL), 12% ethyl acetate/petroleum ether (V/V, 400mL), 15% ethyl acetate/petroleum ether wash-out (V/V, 400mL), 17% ethyl acetate/petroleum ether wash-out (V/V, 400mL).Each component that receives adopts TLC to detect, the iodine vapor colour developing.
The 4th step: the structure of title product is identified
Through FT-IR, GC-MS,
1H-NMR,
13C-NMR carries out structure to title product to be identified.
Synthesizing of embodiment 2 (R)-4-benzyloxy-2-methyl-1-butene alcohol
The first step: building-up reactions
Add in the there-necked flask (R, S)-(purity 94%, 2.58mmol), anhydrous chloroform 5.5mL adds Pseudomonas fluorescens lypase 60.5mg (20U/mg) to 4-benzyloxy-2-methyl-1-butene alcohol 0.53g, splashes into vinyl-acetic ester 1mL (11.2mmol) under 50 ℃ of stirrings.After dropwising, 50 ℃ of following stirring reaction 1.5h.
Second step: aftertreatment
Reaction mixture filters, and filtrating volatilizes solvent through the decompression rotary evaporation, obtains crude product.With thin-layer chromatography (TLC) detection reaction process: (R, S)-4-benzyloxy-2-methyl-1-butene alcohol point sample on silica-gel plate, developping agent is an ETHYLE ACETATE: sherwood oil=17: 83 (V/V), iodine vapor develops the color to draw a little crude product and reactant with kapillary.
The 3rd step: the purifying of title product
Obtain title product through silica gel column chromatography separating purification.Use successively 10% ethyl acetate/petroleum ether (V/V, 200mL), 12% ethyl acetate/petroleum ether (V/V, 200mL), 15% ethyl acetate/petroleum ether wash-out (V/V, 200mL), 17% ethyl acetate/petroleum ether wash-out (V/V, 200mL).Each component that receives adopts TLC to detect, the iodine vapor colour developing.
The 4th step: the structure of title product is identified
Through FT-IR, GC-MS,
1H-NMR,
13C-NMR carries out structure to title product to be identified.
(R)-pure the synthesizing of 4-benzyloxy-2-methyl-1-butene
The first step: building-up reactions
Add in the there-necked flask (R, S)-(purity 94%, 25.8mmol), anhydrous chloroform 50mL adds Pseudomonas fluorescens lypase 603mg (20U/mg) to 4-benzyloxy-2-methyl-1-butene alcohol 5.3g, splashes into vinyl-acetic ester 10mL (112mmol) under 55 ℃ of stirrings.After dropwising, 55 ℃ of following stirring reaction 2.5h.
Second step: aftertreatment
Reaction mixture filters, and filtrating volatilizes solvent through the decompression rotary evaporation, obtains crude product.With thin-layer chromatography (TLC) detection reaction process: (R, S)-4-benzyloxy-2-methyl-1-butene alcohol point sample on silica-gel plate, developping agent is an ETHYLE ACETATE: sherwood oil=17: 83 (V/V), iodine vapor develops the color to draw a little crude product and reactant with kapillary.
The 3rd step: the purifying of title product
Obtain title product through silica gel column chromatography separating purification.Use successively 10% ethyl acetate/petroleum ether (V/V, 2000mL), 12% ethyl acetate/petroleum ether (V/V, 2000mL), 15% ethyl acetate/petroleum ether wash-out (V/V, 2000mL), 17% ethyl acetate/petroleum ether wash-out (V/V, 2000mL).Each component that receives adopts TLC to detect, the iodine vapor colour developing.
The 4th step: the structure of title product is identified
Through FT-IR, GC-MS,
1H-NMR,
13C-NMR carries out structure to title product to be identified.
Claims (4)
1. the compound method of (R)-4-benzyloxy in the dolichol biologic chain-2-methyl-1-butene alcohol is characterized in that being made up of following steps:
The first step: building-up reactions
Add in the reaction vessel raw material (R, S)-the 4-benzyloxy-2-methyl-1-butene alcohol X
1Mol, anhydrous chloroform X
2Mol adds Pseudomonas fluorescens lypase X
3U, the A temperature splashes into vinyl-acetic ester X under stirring
4Mol, this system stirring reaction time under the A temperature is T hour.
Second step: aftertreatment
Reaction mixture filters, and filtrating volatilizes solvent through the decompression rotary evaporation, obtains crude product.With thin-layer chromatography (TLC) detection reaction process: with kapillary draw a little crude product and reactant (R, S)-4-benzyloxy-2-methyl-1-butene alcohol point sample on silica-gel plate, developping agent is the ethyl acetate petroleum ether mixing system, iodine vapor develops the color.
The 3rd step: the purifying of title product
Obtain title product through silica gel column chromatography separating purification.Silicagel column is used the ethyl acetate petroleum ether mixing system, and polarity, is collected each component of merging and adopted TLC to detect to high wash-out by low, the iodine vapor colour developing, and wash-out partly was title product when the ethyl acetate petroleum ether gradient was M.
The 4th step: the structure of title product is identified
Through IR, GC-MS,
1H-NMR,
13C-NMR carries out structure to title product to be identified.
2. according to the compound method of said a kind of (the R)-4-benzyloxy of claim 1-2-methyl-1-butene alcohol, it is characterized in that, use the molar ratio scope of reaction raw materials to be X in the first step
1Mol: X
2Mol: X
3U: X
4Mol=1: 5～100: 100～1000: 1～15.Wherein, the TR A that relates to is 25～65 ℃.The time range T that relates to does.0.2～4 hours.
3. used developping agent ETHYLE ACETATE of thin-layer chromatography and sherwood oil mixing system volume ratio scope are 1: 3～10 in second step.
4. the 3rd silicagel column mixing system wash-out scope mentioned of step is an ETHYLE ACETATE: sherwood oil=1: 99～3, gradient M is an ETHYLE ACETATE: sherwood oil=1: 10～3.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115403500A (en) * | 2022-10-08 | 2022-11-29 | 上海壮铭生物医药有限公司 | Preparation method of levetiracetam |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1204636A (en) * | 1997-04-25 | 1999-01-13 | 可乐丽股份有限公司 | Process for preparing polyprenols |
| WO2002074081A1 (en) * | 2001-03-14 | 2002-09-26 | Seong-Ryong Kwon | Plant growth regulator for increasing crop yield comprising polyprenol and extraction method thereof |
| CN101709030A (en) * | 2009-11-23 | 2010-05-19 | 江苏同源堂生物工程有限公司 | Method for extracting and separating ginkgo leaf polyprenol acetic ester from ginkgo leaf by supercritical carbon oxide |
-
2012
- 2012-07-26 CN CN2012102658577A patent/CN102766673A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1204636A (en) * | 1997-04-25 | 1999-01-13 | 可乐丽股份有限公司 | Process for preparing polyprenols |
| WO2002074081A1 (en) * | 2001-03-14 | 2002-09-26 | Seong-Ryong Kwon | Plant growth regulator for increasing crop yield comprising polyprenol and extraction method thereof |
| CN101709030A (en) * | 2009-11-23 | 2010-05-19 | 江苏同源堂生物工程有限公司 | Method for extracting and separating ginkgo leaf polyprenol acetic ester from ginkgo leaf by supercritical carbon oxide |
Non-Patent Citations (1)
| Title |
|---|
| 杨兰: "银杏叶聚戊烯醇的精制及合成S_多萜醇的研究", 《中国优秀硕士学位论文全文数据库，医药卫生科技辑》, 30 April 2012 (2012-04-30) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115403500A (en) * | 2022-10-08 | 2022-11-29 | 上海壮铭生物医药有限公司 | Preparation method of levetiracetam |
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Application publication date: 20121107 |