CN1183137C - Synthesis method of [3aS, 6aR]-1,3-dibenzyl-tetrahydro-4H-fruo [3,4-d]-imidazolyl-2,4 [1H]-diketone [I] - Google Patents
Synthesis method of [3aS, 6aR]-1,3-dibenzyl-tetrahydro-4H-fruo [3,4-d]-imidazolyl-2,4 [1H]-diketone [I] Download PDFInfo
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Abstract
The present invention provides a method for synthesizing (3aS, 6aR)-1, 3-dibenzyl-tetrahydro-4H-fruo [3, 4-d]-imidazolyl-2, 4 [1H]-diketone, which comprises the steps: preparing (4S, 5R)-1, 3-dibenzyl-5-alkoxy carbonyl-2-oxoimidazoline-4-carboxylic acid (III) from cis-1.3-dibenzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazole-2, 4, 6-trione (II), fatty alcohol and aralkyl alcohol under the catalysis of chiral amine through enantioselectivity ring-opening reaction; preparing (3aS, 6aR)-1, 3-dibenzyl-tetrahydro-4H-furo [3, 4-d] imidazole-2, 4 (1H)-dione [(3aS, 6aR)-lactone, I] from borohydride in organic solvents under lewis acid through the reactions of reduction and ring-closing reaction by acid catalysis, wherein the total yield is more than 88 %. With the advantages of easy obtainment of raw material, and milden reaction condition, the method is suitable for industrial production.
Description
Technical field
The invention belongs to organic chemistry filed, be (3aS, 6aR)-1, the synthetic method of 3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone (I).
Background technology
(3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone (I) is the key intermediate of synthetic d-vitamin H (d-Biotin, vitamin H, vitamin H).
(Helv Chim Acta such as Gerecke, 1970,53,991) report is with suitable-1.3-dibenzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2,4, the 6-triketone (II) make racemize naphthenic acid monocycle hexanol ester and pseudo-numb sulphur alkali with the hexalin mono-esterification and carry out diastereomer crystallization (direct enantiomorphous crystallization) and split into needed (4S by cyclic acid anhydride, 5R)-naphthenic acid monocycle hexanol ester, and then reduce, close ring through lithium borohydride and promptly get I; This method is that Switzerland Roche produces d-vitamin H production technique the earliest; German Patent 2058234, Chinese patent 106365 has been narrated with II and primary alconol mono-esterification and has been made racemize naphthenic acid monoesters, generate naphthenic acid monoesters and dehydroabietylamine diastereomeric salt with the dehydroabietylamine reaction, then become (4S through acidolysis, 5R)-and the naphthenic acid monoesters, through sodium borohydride reduction, close ring and promptly get (4S then, 5R)-the naphthenic acid monoesters, and then reduce, close ring through hydroborate and promptly get I; European patent 92194 described with optical activity substituted diphenylamine base ethamine replace dehydroabietylamine as resolving agent split through (4S, 5R)-the naphthenic acid monoesters prepares the method for I; (SCI such as Chen Fener; 2001; 12; 1141) report paraxin by product (1S; 2S)-and Su Shi-1-(p-nitrophenyl)-1, ammediol is the technology that resolving agent resolution of racemic naphthenic acid monoesters prepares I, though this resolving agent is cheap and easy to get; wide material sources, but single fractionation rate only is 37%.It is low that these methods all exist single fractionation rate, complex operation, the higher common fault that waits fractionation of cost, in addition, also have cyclic acid anhydride and optical activity substituted chiral secondary alcohol and the trimethyl carbinol (EP, 92194) and cholesterol (Helv Chim Acta, 1970,53,991) form diastereomer naphthenic acid half ester, separate promptly getting (4S through recrystallization, 5R)-the naphthenic acid monoesters, through reduction, close the report of ring preparation I again, but these methods are used the optical activity substituted chiral secondary alcohol and the trimethyl carbinol and cholesterol to have the preparation difficulty or are cost an arm and a leg or reclaim drawback such as inconvenience.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provides a kind of easy, and efficiently with cheaply (3aS, 6aR)-1, the asymmetric industrial preparative method of 3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone (I).
The invention provides a kind of (3aS, 6aR)-1, the synthetic method of 3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone.This method is with suitable-1.3-dibenzyl imidazoline-2-ketone-2H-furo [3,4-d] imidazoles-2,4,6-triketone (II) under the catalysis of Chiral Amine with Fatty Alcohol(C12-C14 and C12-C18) and or aralkyl alcohol carry out the enantioselectivity open loop and make (4S, 5R)-1,3-dibenzyl-5-alkoxy carbonyl-2-oxoimidazolinium-4-carboxylic acid (III), if alcohol mixture, both ratios are 1: the 0.1-0.9 scope.Again in the presence of lewis acidic with hydroborate in organic solvent, reduce, acid catalysis close ring make (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone [(3aS, 6aR)-lactone, I], total recovery＞88%, ee＞98.5%.Its synthetic route is as follows:
In asymmetric mono-esterification of the present invention, the Chiral Amine catalyzer be (1S, 2S)-any of amine alcohols (A) all have very high enantioselectivity catalytic effect, the reaction conditions gentleness, easy and simple to handle, the yield height.Chemical yield and optical purity height.
R in the formula
1Be nitro.R
2, R
3Be identical or different C
1-C
12Alkyl or aralkyl.R
4Be trityl.
Used C
1-C
6Fatty Alcohol(C12-C14 and C12-C18) or aralkyl are pure as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, hexalin, phenylcarbinol or various C
1～C
5Alkyl substituted benzene methyl alcohol all can be used for asymmetric single-esterification.These alcohol are cheap and easy to get, wide material sources.The mol ratio of compound (II)/alcohol/Chiral Amine catalyzer is 1: 1～5: 0.1～1.5, and reaction can be finished smoothly.Used organic solvent such as benzene, toluene, tetracol phenixin, ether, tetrahydrofuran (THF), dioxane, chloroform, ethyl acetate can be a single solvent, also can be mixed solvent, the mixed solvent volume ratio is in 1: 0.1～0.9 scope.These solvent wide material sources, cheap and easy to get, it is convenient to reclaim.Temperature of reaction is controlled at-50 ℃～25 ℃.Reaction times is controlled between 10～50h, and reaction is promptly accused fully.
In reduction reaction of the present invention, hydroborate is that any of POTASSIUM BOROHYDRIDE or sodium borohydride all has good reduction effect.Lewis acid such as Lithium chloride (anhydrous), Calcium Chloride Powder Anhydrous, Zinc Chloride Anhydrous, aluminum trichloride (anhydrous), any of the diethyl ether solution of waterless cobaltous chloride and boron trifluoride.These Lewis acids are cheap and easy to get, all catalytic reduction reaction effect well.Compound (III)/hydroborate/lewis acidic mol ratio is 1: 1.5～4: 1～3 material ratio, and reaction is carried out smoothly.Anticaustic solvent such as tetrahydrofuran (THF), ether, 1, the 2-ethylene dichloride, chloroform, dehydrated alcohol can be a single solvent, also can be mixed solvent, the mixed solvent proportion of composing is volume ratio 1: 0.1～0.9.These solvent wide material sources, cheap and easy to get, it is convenient to reclaim.Suitable reaction temperature and reaction times are respectively the scope of 0～50 ℃ and 2～50h.
In the asymmetric mono-esterification of the present invention, (1S, 2S)-1-(4-nitrophenyl)-2-N, N-dimethylamino-3-three benzyloxies-1-propyl alcohol is best Chiral Amine catalyzer, preparation is reclaimed conveniently economical rationality easily.
In the asymmetric mono-esterification of the present invention, used alcohol is methyl alcohol, effect optimum and wide material sources, inexpensive.
In the asymmetric mono-esterification of the present invention, the mol ratio of compound (II)/alcohol/Chiral Amine catalyzer is the 1: 2～3: 0.2～the 0.4th, best material ratio, and reaction can be finished smoothly.
In the asymmetric mono-esterification of the present invention, temperature of reaction preferably is controlled at-15～-10 ℃ of scopes.
In the asymmetric mono-esterification of the present invention, the reaction times is 34～36h, the effect optimum.
In the asymmetric mono-esterification of the present invention, used organic solvent tetrahydrofuran is better, wide material sources.
In reduction of the present invention, the ring closure reaction, used hydroborate is preferably POTASSIUM BOROHYDRIDE, and this reductive agent chemical property is stable, and is cheap and easy to get.
When preparing Compound I by compound III among the present invention, compound (III)/hydroborate/lewis acidic mol ratio served as better with 1: 2.6: 2.6.In reduction/ring closure reaction of the present invention, used Lewis acid is Calcium Chloride Powder Anhydrous or Lithium chloride (anhydrous), these two kinds of Louis acid catalysis best results.
In reduction/ring closure reaction of the present invention, used solvent is optimum with dehydrated alcohol, this solvent low price, and it is convenient to reclaim.
In reduction of the present invention, the ring closure reaction, optimum temperature of reaction and reaction times are 23～25 ℃, 18～20h.
The present invention has raw material and is easy to get, and the reaction conditions gentleness is easy and simple to handle, chemical yield and optical purity height, and 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:
One, (4S, 5R)-1, the preparation of 3-dibenzyl-5-alkoxy carbonyl-2-oxoimidazolinium-4-carboxylic acid (III)
Example 1 is with suitable-1,3-dibenzyl-tetrahydrochysene-2H-furo [3,4-d] imidazoles-2,4,6-triketone (33.6g, 0.10mol), methyl alcohol (8.1mL, 0.20mol), (1S, 2S)-1-(4-nitrophenyl)-2-(N, N dimethylamine base)-3-three benzyloxies-1-propyl alcohol (6.7g, 0.03mol) and tetrahydrofuran (THF) (200mL) drying put in the reaction flask, stir 36h in-15 ~-10 ℃.Reaction is finished, and decompression and solvent recovery is cooled to room temperature, adds ethyl acetate (140mL) and stir 15min in residuum, adds 5% hydrochloric acid (400mL) again in 10 ~ 15 ℃ of stirring 10min, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, adds toluene (35mol), stirs 15min, separates out solid, and drying gets white powder III (R=CH
3, 35g, 95%), mp148 ~ 150 ℃, [α]
D 22=+2.73 ° of (c0.20, CHCl
3)
IR(KBr)：ν＝2979，2384，2280，1742，1462，1229，1169，768cm
-1.
1H?NMR(CDCl
3)：δ＝3.54(s，1H，OCH3)，4.00~4.04(m，2H，C
6a-H，G
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).
Embodiment 2, with suitable-1,3-dibenzyl-tetrahydrochysene-2H-furo [3,4-d] imidazoles-2,4, the 6-triketone (33.6g, 0.10mol), hexalin (39.5mL, 0.38mol), (1S, 2S)-1-(4-nitrophenyl)-2-(N, the N diethylin)-and 3-three benzyloxies-1-propyl alcohol (25.5g, 0.05mol), tetrahydrofuran (THF) (300mL) and toluene (200mL) puts in the dry reaction bottle, stirs 45h in-10 ~-5 ℃.Reaction is finished, and decompression and solvent recovery is cooled to room temperature, adds ethyl acetate (150mL) in residuum, stirs 10min, adds 20% acetate (300mL) again, in 10 ~ 15 ℃ of stirring 5min, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, adds toluene (350mL), stirs 20min, separates out solid, drying, white powder III (R=cyclohexyl, 36.5g, 85%), mp172 ~ 175 ℃, [α]
D 22=+2.70 ° (c0.20, CHCl3).[α]
D 25＝+10.8°(c1.0，DMF)。
Embodiment 3, with suitable-1,3-dibenzyl-tetrahydrochysene-2H-furo [3,4-d] imidazoles-2,4,6-triketone (33.6g, 0.10mol), methyl alcohol (14.2mL, 0.35mol), (1S, 2S)-1-(4-nitrophenyl)-2-(N-methyl-N-benzyl)-3-three benzyloxies-1-propyl alcohol (55.8g, 0.01mol), tetracol phenixin (300mL) and toluene (200mL) puts in the dry reaction bottle, stirs 50h in-25 ~-20 ℃.Reaction is finished, and decompression and solvent recovery is cooled to room temperature, adds ethyl acetate (250mL) in residuum, stirs 5min, adds 20% sulfuric acid (300mL) again, in 15 ℃ of stirring 10min, leaves standstill, and tells organic layer, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, adds toluene (350mL), stirs 5min, separates out solid, and drying gets white powder III (R=CH
3, 29g, 90%), mp147 ~ 150 ℃, [α]
D 22=+2.70 ° of (c0.20, CHCl
3).
Two (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] tetrahydroglyoxaline-2, the preparation of 4-(1H)-diketone (I)
Embodiment 1, with POTASSIUM BOROHYDRIDE (7.83g, 0.145mol) and dehydrated alcohol (55mL) put in the dry reaction bottle, in 0 ~ 5 ℃, stir and drip III (20g down successively, 0.054mol) (6.0g 0.054mol) is dissolved in the solution of dehydrated alcohol (50mL), in stirring at room 18h to be dissolved in the solution of dehydrated alcohol (175mL) and Calcium Chloride Powder Anhydrous.Reaction is finished, reclaim under reduced pressure dehydrated alcohol (about 240mL), slowly Dropwise 5 % hydrochloric acid (200mL) in 45 ~ 50 ℃ of stirring 0.5h, is cooled to room temperature, extract with chloroform (40mL * 3), merge organic layer, use 5% sodium hydrogen carbonate solution and water washing successively, decompression and solvent recovery, be cooled to room temperature, separate out solid.Use 95% ethyl alcohol recrystallization, white crystalline powder I (15.7g, 90%), mp118 ~ 120 ℃, [α]
D 20=+61.7 ° of (c1.0, CHCl
3).
IR(KBr)：ν＝1776，1700，1416，1210cm
-1.
1H?NMR(CDCl
3)：δ＝3.92(d，1H，J＝8.51Hz，C
3a-H)，4.13(m，3H，C
6a-H，C
6α-H?and?C
6β-H)，4.36，4.38，4.64，5.05(dddd，4H，J＝14.80，15.17Hz，2×CH
2C
6H
5)，7.25~7.40(m，10H，2×ArH)ppm.
EI-MS：(m/z，％)＝322(M
+，16.6)，264(5.43)，187(14.2)，91(100).
Embodiment 2, with sodium borohydride (4.54g, 0.12mol) and anhydrous tetrahydro furan (70mL) put in the dry reaction bottle, in 5 ℃, stir and drip III (20g down successively, 0.054mol) (7.4g 0.054mol) is dissolved in the solution of anhydrous tetrahydro furan (70mL), in stirring at room 6h to be dissolved in the solution of anhydrous tetrahydro furan (175mL) and Zinc Chloride Anhydrous.Reaction is finished, reclaim under reduced pressure tetrahydrofuran (THF) (about 250mL), slowly Dropwise 5 % hydrochloric acid (250mL) in 45 ℃ of stirring 20min, is cooled to room temperature, extract with chloroform (45mL * 3), merge organic layer, use 5% sodium hydrogen carbonate solution and water washing successively, decompression and solvent recovery, be cooled to room temperature, separate out solid.Use 95% ethyl alcohol recrystallization, white crystalline powder I (8.3g, 88%), mp119 ~ 121 ℃, [α]
D 20=+61.9 ° of (c1.0, CHCl
3).
Claims (13)
1, a kind of (3aS, 6aR)-1, the synthetic method of 3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone (I)
It is characterized in that suitable-1.3-dibenzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2,4,6-triketone (II) in the presence of the Chiral Amine catalyzer with Fatty Alcohol(C12-C14 and C12-C18) and, or aralkyl alcohol carries out the enantioselectivity open loop and makes (4S in organic solvent, 5R)-1,3-dibenzyl-5-alkoxy carbonyl-2-oxoimidazolinium-4-carboxylic acid (III), in the presence of lewis acidic, in organic solvent, reduce again with hydroborate, acid catalysis is closed ring and is made (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone
Concrete preparation condition is:
(1) during compound (II) preparation compound (III) used Chiral Amine catalyzer be (1S, 2S)-amine alcohols (A):
R in the formula
1Be nitro, R
2, R
3Be identical or different C
1-C
12Alkyl or aralkyl, R
4Be trityl;
Used alcohol is the C1-C6 Fatty Alcohol(C12-C14 and C12-C18) during (2) by compound (II) preparation compound (III), or C
1～C
5Alkyl substituted benzene methyl alcohol;
The mol ratio of compound (II)/alcohol/Chiral Amine catalyzer is 1: 1～5: 0.1～1.5 during (3) by compound (II) preparation compound (III);
Used organic solvent can be a single solvent during (4) by compound (II) preparation compound (III), also can be mixed solvent;
Temperature of reaction is-50 ℃～25 ℃ during (5) by compound (II) preparation compound (III);
(6) it is 10～50 hours by compound (II) preparation compound (III) the reaction time;
Used hydroborate is POTASSIUM BOROHYDRIDE or sodium borohydride during (7) by compound (III) preparation compound (I);
Compound (III)/hydroborate/lewis acidic mol ratio is 1: 1.5～4: 1～3 during (8) by compound (III) preparation compound (I);
Used solvent can be a single solvent during (9) by compound (III) preparation compound (I), also can be mixed solvent;
Temperature of reaction is 0～50 ℃ during (10) by compound (III) preparation compound (I);
(11) it is 2～50 hours by compound (III) preparation compound (I) the reaction time.
2, the method for claim 1, it is characterized in that used Chiral Amine catalyzer for (1S, 2S)-1-(4-nitrophenyl)-2-(N, N dimethylamine base)-3-three benzyloxies-1-propyl alcohol.
3, the method for claim 1, when it is characterized in that by compound (II) preparation compound (III), used alcohol is methyl alcohol.
4, the method for claim 1, when it is characterized in that compound (II) preparation compound (III), the mol ratio of compound (II)/alcohol/Chiral Amine catalyzer is 1: 2～3: 0.2～0.4.
5, the method for claim 1, when it is characterized in that compound (II) preparation compound (III), used organic solvent is a tetrahydrofuran (THF).
6, the method for claim 1, when it is characterized in that compound (II) preparation compound (III), temperature of reaction is-15～-10 ℃.
7, the method for claim 1, when it is characterized in that compound (II) preparation compound (III), the reaction times is 34～36 hours.
8, the method for claim 1 is characterized in that hydroborate is a POTASSIUM BOROHYDRIDE.
9, the method for claim 1 is characterized in that Lewis acid is Calcium Chloride Powder Anhydrous or Lithium chloride (anhydrous).
10, the method for claim 1 is characterized in that compound (III)/hydroborate/lewis acidic mol ratio is 1: 2.6: 2.6.
11, the method for claim 1, when it is characterized in that compound (III) preparation compound (I), used solvent is a dehydrated alcohol.
12, the method for claim 1, when it is characterized in that compound (III) preparation compound (I), temperature of reaction is 23～25 ℃.
13, the method for claim 1, when it is characterized in that compound (III) preparation compound (I), the reaction times is 18～20 hours.
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| CN101175565B (en) * | 2005-04-08 | 2011-11-09 | 帝斯曼知识产权资产管理有限公司 | Manufacture of lactones |
| CN101284837B (en) * | 2008-06-05 | 2011-07-20 | 复旦大学 | Stereoselective total synthesis method of (+)-biotin |
| CN102282149A (en) * | 2007-09-20 | 2011-12-14 | 帝斯曼知识产权资产管理有限公司 | Process for the manufacture of (+)-biotin |
| CN101279947B (en) * | 2008-05-22 | 2011-05-04 | 复旦大学 | Synthetic method of (4S,5R)-half-ester |
| KR20110017378A (en) * | 2008-06-05 | 2011-02-21 | 디에스엠 아이피 어셋츠 비.브이. | 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 |
| CN103073443B (en) * | 2013-02-04 | 2015-03-04 | 复旦大学 | Preparation method of pregabalin |
| CN103524514B (en) * | 2013-10-25 | 2016-03-02 | 东北制药集团股份有限公司 | The preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones |
| CN110804062B (en) * | 2019-11-06 | 2021-03-30 | 浙江工业大学 | Synthesis method of (3S,6R) -1, 3-dibenzyl tetrahydrofuran imidazole-2, 4-diketone |
| CN114634515A (en) * | 2022-02-25 | 2022-06-17 | 复旦大学 | Stereoselective 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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