CN101665461A - Method for preparing (4S, 5R)-half-ester - Google Patents
Method for preparing (4S, 5R)-half-ester Download PDFInfo
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- CN101665461A CN101665461A CN200810042506A CN200810042506A CN101665461A CN 101665461 A CN101665461 A CN 101665461A CN 200810042506 A CN200810042506 A CN 200810042506A CN 200810042506 A CN200810042506 A CN 200810042506A CN 101665461 A CN101665461 A CN 101665461A
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- cycloalkyl
- acid anhydride
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Abstract
The invention belongs to the technical field of organic chemistry, and particularly provides a method for preparing (4S, 5R)-half-esters. The method is characterized by performing enantioselective ring opening on ring anhydride and alcohol in the presence of a 9-epiquinine urea catalyst to prepare the (4S, 5R)-half-ester. The method ensures that the preparation of the (4S, 5R)-half-esters under the condition of room temperature can obtain high yield and high stereoselectivity; and reactive raw materials have low price and are accessible, and the catalyst can be recovered quantitatively, so themethod is suitable for industrial production.
Description
Technical field:
The invention belongs to organic chemistry filed, be a kind of (4S, 5R)-preparation method of half ester (I).
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, p-methylphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, Ar is phenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, thienyl phenyl, furyl or naphthyl; R
2Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, aralkyl or arylalkenyl.
Background technology
(4S, 5R)-half ester (I) is the important intermediate of synthetic (+)-vitamin H ((+)-Biotin, vitamin H).The preparation of this compound at present mainly contains chiral separation method, chiral adjuvant method and asymmetry catalysis method.Split Method is the earliest by (Helv Chim Acta such as Gerecke, 1970,53,991) report, with cyclic acid anhydride (II) and hexalin mono-esterification make racemize naphthenic acid monocycle hexanol ester again with pseudoephedrine carry out diastereomer crystallization (direct enantiomorphouscrystallization) split preparation needed (4S, 5R)-half ester (I); (SCIs such as German Patent 2058234, Chinese patent 106365, European patent 92194 and Chen Fener; 2001; 12; 1141) reported chiral benzhydryl base ethamine and the paraxin by product (1S that uses dehydroabietylamine, replacement respectively; 2S)-Su Shi-1-(p-nitrophenyl)-1; ammediol be resolving agent method preparation (4S, 5R)-half ester (I).But above method for splitting all exists and costs an arm and a leg, the raw material sources deficiency, split defectives such as efficient difference and inconvenience recovery.
Gerecke etc. (Helv Chim Acta, 1970,53,991) have reported with the cholesterol to be chiral adjuvant and cyclic acid anhydride (II) reaction forming diastereomer naphthenic acid half ester, through recrystallization separate (4S, 5R)-half ester (I); European patent 92194 with optical activity substituted chiral secondary alcohol and the trimethyl carbinol as the chiral adjuvant preparation (4S, 5R)-half ester (I); But there is defectives such as costing an arm and a leg, prepare difficulty and inconvenience recovery in the chiral adjuvant that these methods are used.
(Advanced Synthesis such as European patent 84892, Chen Fener; Catalysis, 2005,347,549) reported respectively with Pig Liver Esterase and polymerization Pig Liver Esterase be catalyzer internally disappear the stereo selective hydrolysis that selects diester the method preparation (4S, 5R)-half ester (I); Chinese patent 1473832,101157655 has been described respectively with Chiral Amine (1S, 2S)-1-(4-nitrophenyl)-2-N, N-dimethylamino-3-three benzyloxies-1-propyl alcohol and 9-propargyl quinine are that catalyzer carries out asymmetric alcoholysis preparation (4S to cyclic acid anhydride (II), 5R)-method of half ester (I), but these methods all exist defectives such as industrial scale is little, complicated operation, temperature of reaction harshness.
Summary of the invention
The object of the invention is to overcome the prior art deficiency, provide the preparation of a kind of reaction conditions gentleness, high yield and highly-solid selectively (4S, 5R)-method of half ester (I).
The present invention with cyclic acid anhydride (II) under the catalysis of 9-epiquinine urea catalyzer (A) with alcohol carry out the enantioselectivity open loop make (4S, 5R)-half ester (I), yield＞95%, ee＞98%.Its synthetic route is as follows:
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, p-methylphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, Ar is phenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, thienyl phenyl, furyl or naphthyl; R
2Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, aralkyl or arylalkenyl.
In asymmetric mono-esterification of the present invention, catalyzer is the 9-epiquinine carbamide compound of structure shown in (A), and it can make under the condition that is reflected at room temperature, and the preparation of high yield and highly-solid selectively (4S, 5R)-half ester (I).This chiral catalyst is synthetic convenient simultaneously, and raw material sources are extensive, but and quantitative recovery, be suitable for industrialization production.
R in the formula
3Be hydrogen, C
1～C
6Alkyl, C
2～C
6Thiazolinyl or C
2～C
6Alkynyl; R
4Be hydrogen, C
1～C
6Alkyl, C
2～C
6Thiazolinyl, C
2～C
6Alkynyl, C
3～C
6The substitutive derivative of cycloalkyl, aryl or any above-mentioned base; R
5For-H or-OR
6, R
6Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, C
2～C
6The substitutive derivative of acyl group, benzyl, benzoyl, cinnamyl or any above-mentioned base; Z is O, S or Se.
The used alcohol of the present invention is C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), C
3～C
6Cycloalkyl alcohol, C
2～C
6The optional substitutive derivative of enol, aralkyl alcohol, aryl enol or above-mentioned alcohol, as: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, hexalin, vinyl carbinol, benzylalcohol, styryl carbinol etc. all can be used for asymmetric single-esterification.These alcohol are cheap and easy to get, wide material sources.Used organic solvent has halohydrocarbon (as methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin etc.); Aliphatic hydrocarbon (as hexane, heptane, octane, nonane, acetonitrile, ethyl acetate etc.); Aromatic hydrocarbon (as benzene,toluene,xylene, oil of mirbane etc.); Various halogenated aromatics (as chlorobenzene etc.); Ether solvent (as ether, methyl tertiary butyl ether, tetrahydrofuran (THF) or 1,4-dioxane etc.).These solvent wide material sources, cheap and easy to get, be convenient to reclaim.The mol ratio of cyclic acid anhydride (II)/alcohol/chiral catalyst is 1: 1～10: 0.01～2.2, and reaction can be finished smoothly.Temperature of reaction is controlled at-15 ℃～50 ℃, and the reaction times was controlled between 4～80 hours, and reaction can be finished.
Among the present invention, R in the 9-epiquinine urea catalyzer (A)
3Be ethyl, vinyl; R
4Be cycloalkyl, aryl and the derivative of the two; R
5For-OR
6, R
6Be methyl, Z is that the 9-epiquinine thiourea catalyst of sulphur atom is preferred chiral catalyst, and this catalyzer has synthetic convenient, and raw material sources are extensive, are easy to advantages such as recovery.
Among the present invention, used alcohol is methyl alcohol, wide material sources, cheap.
Among the present invention, the mol ratio of cyclic acid anhydride (II)/alcohol/chiral catalyst is preferably 1: 3～and 10: 0.01～1.1.
Among the present invention, temperature of reaction is preferably 0～25 ℃ of scope.
Among the present invention, the reaction times is preferably at 10～36 hours.
Among the present invention, used organic solvent is preferably methyl tertiary butyl ether (MTBE), environmental friendliness, wide material sources, cheap.
The present invention has the reaction conditions gentleness, and is easy and simple to handle, and raw material is cheap and easy to get, and products therefrom has high yield and highly-solid selectively, but and the catalyzer quantitative recovery apply mechanically, cost is low, is suitable for industrialization production.
Embodiment
Following embodiment illustrates content of the present invention better.But the invention is not restricted to following embodiment.
Embodiment 1 is suitable-1,3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, 0.10mol), catalyst A (R
3=-CH=CH
2R
4=3,5-(CF
3)
2C
6H
3R
5=-OR
6, R
6=CH
3, Z=S) (5.94g, 0.01mol), methyl tertiary butyl ether (4L) places a dry reaction bottle, (40.4mL, 1mol) back continues to stir 24 hours to drip anhydrous methanols in 25 ℃.Reaction is finished, and adds 2M hydrochloric acid (400mL) and stir 10min in residuum, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent and obtains white crystalline powder I (R
1=-H, Ar=-Ph, R
2=-CH
3, 36g, 98%), mp149～150 ℃, [α]
D 22=+2.74 ° (c 0.20, CHCl
3) IR (KBr): v=2979,2384,2281,1742,1463,1229,1169,767cm
-1.
1H NMR (CDCl
3): δ=3.54 (s, 1H, OCH
3), 4.00～4.04 (m, 2H, C
6a-H, C
3a-H), 4.16～4.80 (dddd, 4H, 2 * CH
2C
6H
5), 7.19～7.53 (m, 10H, 2 * ArH) ppm.EI-MS:(m/z, %)=368 (M
+, 37), 323 (46), 309 (59), 265 (44), 154 (8), 136 (18), 91 (100).
The recovery of catalyzer: the aqueous hydrochloric acid layer of telling is regulated PH to 14 with 20%NaOH solution, the white solid of separating out is filtered, the dry quantitative recovery catalyzer that gets final product.
Embodiment 2 is suitable-1,3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, 0.10mol), catalyst A (R
3=-CH=CH
2R
4=3,5-(NO
2)
2C
6H
3R
5=-OR
6, R
6=CH
3, Z=S) (5.5g, 0.01mol), 1,4-dioxane (4L) places a dry reaction bottle, and (58.2mL, 1mol) back continues to stir 24 hours to drip propiolic alcohols in 25 ℃.Reaction is finished, and adds 2M hydrochloric acid (40mL) and stir 10min in residuum, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, gets white crystalline powder I (R
1=-H, Ar=-Ph, R
2=propargyl, 37.2g, 95%), mp132.7～135.8 ℃, [α]
D 25=+14.3 ° (c 1.0, CHCl
3).
Embodiment 3 is suitable-1,3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, 0.10mol), catalyst A (R
3=-CH=CH
2R
4=2-NO
2C
6H
4R
5=-OR
6, R
6=CH
3, Z=S) (5.0g, 0.01mol), 1,4-dioxane (4L) places a dry reaction bottle, and (40.4mL, 1.0mol) back continues to stir 24 hours to drip anhydrous methanols in 25 ℃.Reaction is finished, and adds 2M hydrochloric acid (400mL) and stir 10min in residuum, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, gets white crystalline powder I (R
1=-H, Ar=-Ph, R
2=-CH
3, 35.2g, 96%), mp148～150 ℃, [α]
D 22=+2.70 ° (c 0.20, CHCl
3).
Embodiment 4 is suitable-1,3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, 0.10mol), catalyst A (R
3=-CH=CH
2R
4=4-FC
6H
4R
5=-OR
6, R
6=CH
3, Z=S) (4.8g, 0.01mol), tetrahydrofuran (THF) (4L) places a dry reaction bottle, (40.4mL, 1.0mol) back continues to stir 24 hours to drip anhydrous methanol down in 25 ℃.Reaction is finished, and adds 2M hydrochloric acid (400mL) and stir 10min in residuum, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, gets white crystalline powder I (R
1=-H, Ar=-Ph, R
2=-CH
3, 35g, 95%), mp147～150 ℃, [α]
D 22=+2.70 ° (c 0.20, CHCl
3).
Embodiment 5 is suitable-1,3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, 0.10mol), catalyst A (R
3=-CH=CH
2R
4=2-(MeO) C
6H
4R
5=-OR
6, R
6=CH
3, Z=S) (4.9g, 0.01mol), methyl tertiary butyl ether (4L) places a dry reaction bottle, (40.4mL, 1.0mol) back continues to stir 24 hours to drip anhydrous methanol down in 25 ℃.Reaction is finished, and adds 2M hydrochloric acid (400mL) and stir 10min in residuum, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, gets white crystalline powder I (R
1=-H, Ar=-Ph, R
2=-CH
3, 35.3g, 96%), mp147～150 ℃, [α]
D 22=+2.70 ° (c 0.20, CHCl
3).
Embodiment 6 is suitable-1,3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, 0.10mol), catalyst A (R
3=-CH=CH
2R
4=3,5-[3 ', 5 '-(CF
3)
2C
6H
3]
2C
6H
3R
5=-OR
6, R
6=CH
3, Z=S) (8.82g, 0.01mol), methyl tertiary butyl ether (4L) places a dry reaction bottle, (40.4mL, 1.0mol) back continues to stir 24 hours to drip anhydrous methanol down in 25 ℃.Reaction is finished, and adds 2M hydrochloric acid (400mL) and stir 10min in residuum, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, gets white crystalline powder I (R
1=-H, Ar=-Ph, R
2=-CH
3, 35.4g, 96%), mp147～150 ℃, [α]
D 22=+2.70 ° (c 0.20, CHCl
3).
Embodiment 7 is suitable-1,3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, O.10mol), catalyst A (R
3=-CH=CH
2R
4=cyclohexyl; R
5=-OR
6, R
6=CH
3, Z=S) (4.6g, 0.01mol), methyl tertiary butyl ether (4L) places a dry reaction bottle, (40.4mL, 1.0mol) back continues to stir 24 hours to drip anhydrous methanol down in 25 ℃.Reaction is finished, and adds 2M hydrochloric acid (400mL) and stir 10min in residuum, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, gets white crystalline powder I (R
1=-H, Ar=-Ph, R
2=-CH
3, 36.0g, 98%), mp148～150 ℃, [α]
D 22=+2.70 ° (c 0.20, CHCl
3).
Claims (8)
1, a kind of (4S, 5R)-preparation method of half ester (I);
It is characterized in that cyclic acid anhydride (II) in the presence of 9-epiquinine urea catalyzer (A) with alcohol carry out the enantioselectivity open loop make (4S, 5R)-half ester (I); This is reflected in the organic solvent in normal temperature, carries out under the state of normal pressure, pressurization or decompression:
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, p-methylphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, Ar is phenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, thienyl phenyl, furyl or naphthyl; R
2Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, aralkyl or arylalkenyl;
Described 9-epiquinine urea catalyst structure is shown in A:
R in the formula
3Be hydrogen, C
1～C
6Alkyl, C
2～C
6Thiazolinyl or C
2～C
6Alkynyl; R
4Be hydrogen, C
1～C
6Alkyl, C
2～C
6Thiazolinyl, C
2～C
6Alkynyl, C
3～C
6The substitutive derivative of cycloalkyl, aryl or any above-mentioned base; R
5For-H or-OR
6, R
6Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, C
2～C
6The substitutive derivative of acyl group, benzyl, benzoyl, cinnamyl or any above-mentioned base; Z is O, S or Se;
Described alcohol is C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), C
3～C
6Cycloalkyl alcohol, C
2～C
6The optional substitutive derivative of enol, aralkyl alcohol, aryl enol or above-mentioned alcohol;
The molar ratio of cyclic acid anhydride (II)/alcohol/chiral catalyst is 1: 1～10: 0.01～2.2; Temperature of reaction is-15 ℃～50 ℃; Reaction times is 4～80h.
2, the method for claim 1 is characterized in that used alcohol is methyl alcohol, vinyl carbinol, hexalin, benzylalcohol or styryl carbinol.
3, the method for claim 1 is characterized in that described organic solvent is one or more in halohydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon or the ether solvent.
4, method as claimed in claim 3 is characterized in that described organic solvent is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 1, the 4-dioxane.
5, the method for claim 1, the mol ratio that it is characterized in that cyclic acid anhydride (II)/alcohol/chiral catalyst is 1: 3～10: 0.01～1.1.
6, the method for claim 1, the temperature of reaction when it is characterized in that by cyclic acid anhydride (II) preparation half ester (I) is 0 ℃～25 ℃.
7, the method for claim 1, the reaction times when it is characterized in that by cyclic acid anhydride (II) preparation half ester (I) is 10～72 hours.
8, the method for claim 1 is characterized in that R in the used 9-epiquinine urea catalyzer (A)
3Be ethyl, vinyl; R
4Be cycloalkyl, aryl and the derivative of the two; R
5For-OR
6, R
6Be methyl, Z is a sulphur atom.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810042506A CN101665461A (en) | 2008-09-04 | 2008-09-04 | Method for preparing (4S, 5R)-half-ester |
| CN2009801207800A CN102282135A (en) | 2008-06-05 | 2009-06-05 | A preparation method of (4s,5r)-semiester |
| JP2011511956A JP2011523654A (en) | 2008-06-05 | 2009-06-05 | Method for preparing (4S, 5R) -half ester |
| EP09757041A EP2294054A4 (en) | 2008-06-05 | 2009-06-05 | A preparation method of (4s,5r)-semiester |
| KR1020107027236A KR20110017378A (en) | 2008-06-05 | 2009-06-05 | (4S, 5R) -Method for producing half ester |
| PCT/CN2009/000627 WO2009146607A1 (en) | 2008-06-05 | 2009-06-05 | A preparation method of (4s,5r)-semiester |
| US12/996,078 US20110137046A1 (en) | 2008-06-05 | 2009-06-05 | Preparation method of (4s,5r)-semiester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810042506A CN101665461A (en) | 2008-09-04 | 2008-09-04 | Method for preparing (4S, 5R)-half-ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101665461A true CN101665461A (en) | 2010-03-10 |
Family
ID=41802265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810042506A Pending CN101665461A (en) | 2008-06-05 | 2008-09-04 | Method for preparing (4S, 5R)-half-ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101665461A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102120977A (en) * | 2010-12-24 | 2011-07-13 | 上海应用技术学院 | Microbacterium chocolatum and method for preparing (4S,5R)-half ester by using same |
| CN106905239A (en) * | 2017-03-15 | 2017-06-30 | 安徽泰格维生素实业有限公司 | A kind of pair of process for purification of benzyl dicarboxylic acids |
-
2008
- 2008-09-04 CN CN200810042506A patent/CN101665461A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102120977A (en) * | 2010-12-24 | 2011-07-13 | 上海应用技术学院 | Microbacterium chocolatum and method for preparing (4S,5R)-half ester by using same |
| CN102120977B (en) * | 2010-12-24 | 2012-08-22 | 上海应用技术学院 | Microbacterium chocolatum and method for preparing (4S,5R)-half ester by using same |
| CN106905239A (en) * | 2017-03-15 | 2017-06-30 | 安徽泰格维生素实业有限公司 | A kind of pair of process for purification of benzyl dicarboxylic acids |
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Open date: 20100310 |