CN101284832A - Preparation method of (4S, 5R)- half-ester - Google Patents
Preparation method of (4S, 5R)- half-ester Download PDFInfo
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- CN101284832A CN101284832A CNA2008100385846A CN200810038584A CN101284832A CN 101284832 A CN101284832 A CN 101284832A CN A2008100385846 A CNA2008100385846 A CN A2008100385846A CN 200810038584 A CN200810038584 A CN 200810038584A CN 101284832 A CN101284832 A CN 101284832A
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- alcohol
- reaction
- alkyl
- half ester
- chiral catalyst
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Abstract
The invention belongs to the organic chemistry technical field, in particular to a preparation method for (4S, 5R)-half ester. The invention is characterized in that preparing (4S, 5R)-half ester under the presence of 9-epiquinine urea catalyst by enantioselective ring opening cyclic polyanhyride and alcohol. The preparation method enables (4S, 5R)-half ester to obtain high yields and high stereo selectivity under room temperature conditions, and the reactive raw material is cheap and available, the catalyst can be recovered quantitatively and is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of organic chemistry, be specifically related to a kind of (4S, 5R)-preparation method of half ester.
Background technology
Compound (4S, 5R)-structural formula of half ester is shown in (I) formula:
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, alkyl-substituted phenyl or alkoxy substituted phenyl, Ar are phenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, nitro substituted-phenyl, halogenophenyl, thienyl, furyl or naphthyl; R
2Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, aralkyl or arylalkenyl.
(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 ChimActa, 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 be to provide a kind of reaction conditions gentleness, high yield and highly-solid selectively preparation (4S, 5R)-method of half ester (I).
The present invention with cyclic acid anhydride (structural formula is seen (II) formula) under the catalysis of 9-epiquinine urea catalyzer (structural formula is seen (A) formula) with alcohol carry out the enantioselectivity open loop make (4S, 5R)-half ester (structural formula is seen (I) formula), yield＞95%, ee＞98%.Its synthetic route is as follows:
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, alkyl-substituted phenyl or alkoxy substituted phenyl, Ar are phenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, nitro substituted-phenyl, halogenophenyl, thienyl, 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 alkyl, alkenyl or alkynyl; R
4For-H or-OR
5, R
5Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, C
2～C
6Acyl group, benzyl, benzoyl or cinnamyl, or the substitutive derivative of 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
6Enol, aralkyl alcohol or aryl enol, or the optional substitutive derivative of 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 vinyl, R
4For-OR
5, R
5Be 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
2, R
4=-OR
5, R
5=CH
3, Z=S) (65.34g, 0.11mol), 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.
1HNMR(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
2, R
4=-OR
5, R
5=CH
3, Z=S) (5.94g, 0.01mol), 1,4-dioxane (8L) 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
2, R
4=-OR
5, R
5=CH
3, Z=S) (65.34g, 0.11mol), 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
2CH
3, R
4=-OR
5, R
5=CH
3, Z=S) (65.34g, 0.11mol), 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).
Claims (8)
1, a kind of (4S, 5R)-preparation method of half ester, should (4S, structural formula 5R) is as follows:
It is characterized in that, in the presence of 9-epiquinine urea chiral catalyst, carry out the enantioselectivity ring-opening reaction with alcohol by cyclic acid anhydride, make (4S, 5R)-half ester; This reaction is at room temperature carried out under the state of normal pressure, pressurization or decompression in organic solvent, and the structural formula of described cyclic acid anhydride is shown in (II) formula:
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, p-methylphenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl or 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 chiral catalyst structure is shown in A:
R in the formula
3Be alkyl, alkenyl or alkynyl; R
4For-H or-OR
5, R
5Be C
1～C
6Alkyl, C
3～C
6Cycloalkyl, C
2～C
6Thiazolinyl, C
2～C
6Acyl group, benzyl, benzoyl or cinnamyl, or be the substitutive derivative of 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
6Enol, aralkyl alcohol or aryl enol perhaps are the optional substitutive derivative of above-mentioned alcohol;
The molar ratio of cyclic acid anhydride/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) or 1, the 4-dioxane.
5, the method for claim 1, the mol ratio that it is characterized in that cyclic acid anhydride/alcohol/chiral catalyst is 1: 3～10: 0.01～1.1.
6, the method for claim 1 is characterized in that temperature of reaction is 0 ℃～25 ℃.
7, the method for claim 1 is characterized in that the reaction times is 10～72 hours.
8, the method for claim 1 is characterized in that in the used 9-epiquinine urea chiral catalyst R
3Be vinyl, R
4For-OR
5, R
5Be methyl, Z is a sulphur atom.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100385846A CN101284832A (en) | 2008-06-05 | 2008-06-05 | Preparation method of (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 |
| KR1020107027236A KR20110017378A (en) | 2008-06-05 | 2009-06-05 | A preparation method of (4s,5r)-semiester |
| PCT/CN2009/000627 WO2009146607A1 (en) | 2008-06-05 | 2009-06-05 | A preparation method of (4s,5r)-semiester |
| EP09757041A EP2294054A4 (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 |
|---|---|---|---|
| CNA2008100385846A CN101284832A (en) | 2008-06-05 | 2008-06-05 | Preparation method of (4S, 5R)- half-ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101284832A true CN101284832A (en) | 2008-10-15 |
Family
ID=40057259
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100385846A Pending CN101284832A (en) | 2008-06-05 | 2008-06-05 | Preparation method of (4S, 5R)- half-ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101284832A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009146607A1 (en) * | 2008-06-05 | 2009-12-10 | Dsm Ip Assets B.V. | A preparation method of (4s,5r)-semiester |
| WO2010094210A1 (en) * | 2009-02-18 | 2010-08-26 | 帝斯曼知识产权资产管理有限公司 | Preparation method of (4s,5r)-half-ester |
| CN109748924A (en) * | 2019-01-31 | 2019-05-14 | 浙江圣达生物药业股份有限公司 | A kind of asymmetric syntheses new method of biotin chiral lactone |
| CN114560865A (en) * | 2022-02-25 | 2022-05-31 | 复旦大学 | Continuous flow synthesis method of (3aS,6aR) -lactone |
-
2008
- 2008-06-05 CN CNA2008100385846A patent/CN101284832A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009146607A1 (en) * | 2008-06-05 | 2009-12-10 | Dsm Ip Assets B.V. | A preparation method of (4s,5r)-semiester |
| EP2294054A1 (en) * | 2008-06-05 | 2011-03-16 | DSM IP Assets B.V. | A preparation method of (4s,5r)-semiester |
| EP2294054A4 (en) * | 2008-06-05 | 2012-04-18 | Dsm Ip Assets Bv | A preparation method of (4s,5r)-semiester |
| WO2010094210A1 (en) * | 2009-02-18 | 2010-08-26 | 帝斯曼知识产权资产管理有限公司 | Preparation method of (4s,5r)-half-ester |
| CN102325779A (en) * | 2009-02-18 | 2012-01-18 | 帝斯曼知识产权资产管理有限公司 | (4S, 5R)-preparation method of half ester |
| CN109748924A (en) * | 2019-01-31 | 2019-05-14 | 浙江圣达生物药业股份有限公司 | A kind of asymmetric syntheses new method of biotin chiral lactone |
| CN114560865A (en) * | 2022-02-25 | 2022-05-31 | 复旦大学 | Continuous flow synthesis method of (3aS,6aR) -lactone |
| CN114560865B (en) * | 2022-02-25 | 2024-02-02 | 复旦大学 | Continuous flow synthesis method of (3 aS,6 aR) -lactone |
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Application publication date: 20081015 |