CN103524514B - The preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones - Google Patents

The preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones Download PDF

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CN103524514B
CN103524514B CN201310518586.6A CN201310518586A CN103524514B CN 103524514 B CN103524514 B CN 103524514B CN 201310518586 A CN201310518586 A CN 201310518586A CN 103524514 B CN103524514 B CN 103524514B
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alkali metal
diphenyl
methyl
furo
tetrahydrochysene
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CN103524514A (en
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刘永明
郎福山
俎云龙
刘艳
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NORTHEAST PHARMACEUTICAL GROUP CO Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

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Abstract

A kind of (3aS be applied in biotin intermediate preparation field, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone, described method comprises step, in the presence of an organic, (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester and alkali metal hydroxide hydrate reaction obtain dicarboxylic acid monoesters an alkali metal salt; Described dicarboxylic acid monoesters an alkali metal salt and complexing hydroborate carry out reduction reaction and obtain hydroxycarboxylic acid an alkali metal salt; Described hydroxycarboxylic acid an alkali metal salt carries out cyclization and obtains (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones in sour environment; Described alkali metal hydroxide hydrate is alkali metal hydroxide monohydrate, alkali metal hydroxide dihydrate.This invention raw material be easy to get and store convenient, reaction process is easy and simple to handle, security is high, cost is low, products obtained therefrom yield is high, quality good, be suitable for suitability for industrialized production.

Description

The preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones
Technical field
The present invention relates to the preparation method of one (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3, the 4-d] imidazole-2,4-diones in biotin intermediate preparation field.
Background technology
(3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2,4-diketone, English name (3aS, 6aR)-1,3-dibenzyltetrahydro-1H-furo [3,4-d] imidazole-2,4-dione, be called for short d-lactone, structural formula is shown in accompanying drawing 1, molecular formula C 19h 18n 2o 3, molecular weight 332.37, CAS 28092-62-8 is the key intermediate needed for D-biotin (vitamin H, vitamin H) industry preparation.
Well known in the art by means of chiral alcohol by ring-type meso carboxylic acid anhydride asymmetric synthesis d-lactone.Han Weihua etc. mention in " Biotin intermediate lactone synthesis progress " (" chemistry circular " 08 phase in 2004), chloramphenicol base dextrorotation aminodiol is utilized to carry out asymmetric synthesis for cyclin imide as chiral reagent, through reduction, open loop, then acid treatment, obtain the d-lactone needed, yield 65% after recrystallization.This route is the route that current domestic manufacturer mainly adopts, the shortcoming that although this chiral resolving agent is cheap and easy to get, the method exists that product yield is low, of poor quality, complex operation man-hour is long, thus causes the finished product high expensive.
Chinese patent CN1768063A discloses a kind of method of stereoselective syntheses d-lactone, in disclosed method, alkali metal hydroxide needs to add as an aqueous solution, operation more complicated, in the process of preparation alkali metal hydroxide aqueous solution, also there is potential safety hazard, be unfavorable for suitability for industrialized production.Therefore, the preparation method of a kind of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones of research and development is current assistant officer new problem to be solved.
Summary of the invention
The object of the present invention is to provide the preparation method of one (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, the method is easy and simple to handle, security is high, yield is high, good product quality, cost are low.
The object of the present invention is achieved like this: the preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, and described method comprises step,
(1) in the presence of an organic, (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester and alkali metal hydroxide hydrate reaction obtain dicarboxylic acid monoesters an alkali metal salt;
(2) described dicarboxylic acid monoesters an alkali metal salt and complexing hydroborate carry out reduction reaction and obtain hydroxycarboxylic acid an alkali metal salt;
(3) described hydroxycarboxylic acid an alkali metal salt carries out cyclization and obtains (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones in sour environment;
Described alkali metal hydroxide hydrate is alkali metal hydroxide monohydrate, alkali metal hydroxide dihydrate; Described alkali metal hydroxide monohydrate is selected from the one in lithium hydroxide monohydrate, sodium hydroxide monohydrate, potassium hydroxide monohydrate, rubidium hydroxide monohydrate, cesium hydroxide monohydrate; Described alkali metal hydroxide dihydrate is selected from the one in lithium hydroxide dihydrate, sodium hydroxide dihydrate, potassium hydroxide dihydrate, rubidium hydroxide dihydrate, cesium hydroxide dihydrate; In step (1), described organic solvent is anhydrous organic solvent, and described organic solvent is selected from ether solvent, and described ether solvent is selected from one or more in ether, butyl ether, amyl ether, tetrahydrofuran (THF), dioxane; In step (2), described complexing hydroborate is alkali metal borohydride, and described alkali metal borohydride is selected from the one in lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE; In step (2), described lithium borohydride is lithium borohydride solution, described lithium borohydride solution is prepared by lithium borohydride and ether solvent and is obtained, and described ether solvent is selected from one or more in ether, butyl ether, amyl ether, tetrahydrofuran (THF), dioxane; Described (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid 5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester, alkali metal hydroxide hydrate, complexing hydroborate mol ratio be: (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid 5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester: alkali metal hydroxide hydrate: complexing hydroborate=1:1.0-1.5:1.0-5.0; In step (1), the temperature of described reaction is-10 DEG C-40 DEG C; In step (2), described reaction is reacted for being dropped in dicarboxylic acid monoesters alkali metal salt soln by lithium borohydride solution, the described time being added dropwise to complete rear continuation reaction is 2-6 hour, the temperature of described reaction is 40 DEG C-80 DEG C, also comprises the step steaming organic solvent to reaction solution, be dissolved in water and extract with toluene after described reaction completes; In step (3), the temperature of described cyclization is 60 DEG C-95 DEG C, and the time of described reaction is 3-7 hour, and the pH value of described sour environment is 1-5.
Main points of the present invention are the preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones.Its pharmacy principle is: (1) in the presence of an organic, especially under anhydrous organic solvent exists, by adopting alkali metal hydroxide hydrate and (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester is obtained by reacting dicarboxylic acid monoesters an alkali metal salt, can obtain extraordinary reaction effect, the yield of the d-lactone of gained is high, and easy and simple to handle, security is high.If with the oxyhydroxide salify described in Chinese patent CN1768063A, then need to carry out when adding 0.5-1.5 molar equivalent water, there is potential safety hazard in this operation, complex operation and wayward.(2) pass through (4S in reaction, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid 5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] mol ratio of ester, alkali metal hydroxide hydrate and complexing hydroborate selects, and can better improve product yield and quality.(3) good reaction effect can be obtained after the reaction conditions such as reaction times, temperature of reaction is optimized.(4) described ethers is particularly preferably tetrahydrofuran (THF) or dioxane, to reach the object reduced costs.
(3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone compared with prior art, have raw material be easy to get and store convenient, reaction process is easy and simple to handle, security is high, cost is low, products obtained therefrom yield is high, quality good, be suitable for the advantages such as suitability for industrialized production, will be widely used in biotin intermediate preparation field.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the present invention is described in detail.
Fig. 1 is the structural formula figure of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones.
Fig. 2 is (4S, 5R)-1,3-structural formula figure of diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester.
Fig. 3 is the structural formula figure of dicarboxylic acid monoesters an alkali metal salt;
Fig. 4 is the structural formula figure of hydroxycarboxylic acid an alkali metal salt;
Fig. 5 is the synthetic route schematic diagram that the present invention prepares (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones.
Embodiment
Following examples will contribute to understanding of the present invention, but these embodiments are only in order to be illustrated the present invention, and the present invention is not limited to these contents.
Term illustrates:
Dicarboxylic acid monoesters, structural formula is shown in accompanying drawing 2, its Chinese name is called: (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester, English language Chemical is called: (4S, 5R)-1,3-dibenzyl-5-(((S)-1-hydroxy-1,1-diphenylpropan-2-yloxy) carbonyl)-2-oxoimidazolidine-4-carboxylicacid;
Dicarboxylic acid monoesters an alkali metal salt, structural formula is shown in accompanying drawing 3, its Chinese name is called: (4S, 5R)-1,3-diphenyl-methyl-2-oxo-5-imidazolidine carboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester-4-alkali metal carboxylates, English language Chemical is called alkalimetal (4S, 5R)-1,3-dibenzyl-5-(((S)-1-hydroxy-1,1-diphenylpropan-2-yloxy) carbonyl)-2-oxoimidazolidine-4-carboxylate;
Hydroxycarboxylic acid an alkali metal salt, structural formula is shown in accompanying drawing 4, its Chinese name is called: (4S, 5R)-1,3-dibenzyl-5-hydroxymethyl-2-oxo-imidazole alkane-4-alkali metal carboxylates, English language Chemical is called alkalimetal (4S, 5R)-1,3-dibenzyl-5-(hydroxymethyl)-2-oxoimidazolidine-4-carboxylate.
Embodiment one
Adopt different alkali metal hydroxide hydrates on the impact of reaction yield:
(1) in there-necked flask, dicarboxylic acid monoesters 20g(35.4mmol is added), add 300ml anhydrous tetrahydro furan, stir molten clear after add alkali metal hydroxide hydrate 40.5mmol, the selection situation of described alkali metal hydroxide hydrate is in table 1, and 20 DEG C have been stirred to a large amount of dicarboxylic acid monoesters an alkali metal salt solid and have separated out.
(2) be warming up to 50-60 DEG C, slowly drip borane reducing agent lithium hydride tetrahydrofuran solution 40ml (wherein containing lithium borohydride 55.1mmol).Dropwise and continue reaction 4h, normal pressure steams tetrahydrofuran (THF).Be down to room temperature, add water 300ml, uses 120ml toluene aqueous layer extracted twice respectively.Stay aqueous phase, wherein containing hydroxycarboxylic acid an alkali metal salt.
(3) aqueous phase is placed in reaction flask, being acidified to pH value with dilute hydrochloric acid is 3, is then warming up to 80 DEG C of reactions 5 hours.Reaction terminates, cooling, and filter, filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid, yield situation is in table 1.
Table 1: the selection situation of alkali metal hydroxide hydrate and the yield of d-lactone
Sequence number Alkali metal hydroxide hydrate Yield %
1 Lithium hydroxide monohydrate 90.2
2 Sodium hydroxide monohydrate 86.7
3 Potassium hydroxide monohydrate 87.6
4 Lithium hydroxide dihydrate 85.8
5 Sodium hydroxide dihydrate 82.8
6 Potassium hydroxide dihydrate 83.6
Embodiment two
Adopt the aqueous solution that different alkali metal hydroxides is mixed with on the impact of reaction yield:
(1) in there-necked flask, dicarboxylic acid monoesters 20g(35.4mmol is added), add 300ml anhydrous tetrahydro furan, stir molten clear after add the alkali metal hydroxide aqueous solution be mixed with by alkali metal hydroxide and water, the selection situation of described alkali metal hydroxide and water is in table 2, and 20 DEG C have been stirred to a large amount of dicarboxylic acid monoesters an alkali metal salt solid and have separated out.
(2) be warming up to 50-60 DEG C, slowly drip borane reducing agent lithium hydride tetrahydrofuran solution 40ml (wherein containing lithium borohydride 55.1mmol).Dropwise and continue reaction 4h, normal pressure steams tetrahydrofuran (THF).Be down to room temperature, add water 300ml, uses 120ml toluene aqueous layer extracted twice respectively.Stay aqueous phase, wherein containing hydroxycarboxylic acid an alkali metal salt.
(3) aqueous phase is placed in reaction flask, being acidified to pH value with dilute hydrochloric acid is 3, is then warming up to 80 DEG C of reactions 5 hours.Reaction terminates, cooling, and filter, filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid, yield situation is in table 2.
Table 2: the selection situation of alkali metal hydroxide and water and the yield of d-lactone
Sequence number Alkali metal hydroxide and water Yield %
1 40.5mmol lithium hydroxide+40.5mmol water 82.3
2 40.5mmol sodium hydroxide+40.5mmol water 79.7
3 40.5mmol potassium hydroxide+40.5mmol water 81.4
4 40.5mmol lithium hydroxide+81mmol water 80.5
5 40.5mmol sodium hydroxide+81mmol water 77.4
6 40.5mmol potassium hydroxide+81mmol water 79.8
Embodiment three
The different add-on of alkali metal hydroxide hydrate is on the impact of reaction yield:
(1) in there-necked flask, dicarboxylic acid monoesters 20g(35.4mmol is added), add 300ml anhydrous tetrahydro furan, stir molten clear after add alkali metal hydroxide hydrate, the selection situation of the different add-on of described alkali metal hydroxide hydrate is in table 3, and 20 DEG C have been stirred to a large amount of dicarboxylic acid monoesters an alkali metal salt solid and have separated out.
(2) be warming up to 50-60 DEG C, slowly drip borane reducing agent lithium hydride tetrahydrofuran solution 40ml (wherein containing lithium borohydride 55.1mmol).Dropwise and continue reaction 4h, normal pressure steams tetrahydrofuran (THF).Be down to room temperature, add water 300ml, uses 120ml toluene aqueous layer extracted twice respectively.Stay aqueous phase, wherein containing hydroxycarboxylic acid an alkali metal salt.
(3) aqueous phase is placed in reaction flask, being acidified to pH value with dilute hydrochloric acid is 3, is then warming up to 80 DEG C of reactions 5 hours.Reaction terminates, cooling, and filter, filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid, yield situation is in table 3.
Table 3: the different selection situation of add-on of alkali metal hydroxide hydrate and the yield of d-lactone
Sequence number Alkali metal hydroxide hydrate and add-on Yield %
1 Lithium hydroxide monohydrate 1.5g (35.7mmol) 87.6
2 Lithium hydroxide monohydrate 1.7g (40.5mmol) 90.2
3 Lithium hydroxide monohydrate 2.1g (50.0mmol) 91.1
4 Potassium hydroxide monohydrate 2.1g (35.7mmol) 83.2
5 Potassium hydroxide monohydrate 2.3g (40.5mmol) 87.6
6 Potassium hydroxide monohydrate 2.9g (50.0mmol) 88.5
Embodiment four
The different add-on of reductive agent is on the impact of reaction yield:
(1) in there-necked flask, dicarboxylic acid monoesters 20g(35.4mmol is added), add 300ml anhydrous tetrahydro furan, stir molten clear after add lithium hydroxide monohydrate 2.1g (50.0mmol), 20 DEG C have been stirred to a large amount of dicarboxylic acid monoesters lithium salts solid and have separated out.
(2) be warming up to 50-60 DEG C, slowly drip borane reducing agent lithium hydride tetrahydrofuran solution, the add-on of described lithium borohydride tetrahydrofuran solution is in table 4.Dropwise and continue reaction 4h, normal pressure steams tetrahydrofuran (THF).Be down to room temperature, add water 300ml, uses 120ml toluene aqueous layer extracted twice respectively.Stay aqueous phase, wherein containing hydroxycarboxylic acid lithium salts.
(3) aqueous phase is placed in reaction flask, being acidified to pH value with dilute hydrochloric acid is 3, is then warming up to 80 DEG C of reactions 5 hours.Reaction terminates, cooling, and filter, filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid, yield situation is in table 4.
Table 4: the add-on of borane reducing agent lithium hydride tetrahydrofuran solution and the yield of d-lactone
Sequence number The add-on of lithium borohydride tetrahydrofuran solution Yield
1 40ml (containing lithium borohydride 55.1mmol) 91.1%
2 60ml (containing lithium borohydride 82.65mmol) 94.6%
3 90ml (containing lithium borohydride 123.98mmol) 95.2%
Embodiment five
(1) in there-necked flask, dicarboxylic acid monoesters 20g(35.4mmol is added), add 300ml tetrahydrofuran (THF), stir molten clear after add a hydronium(ion) Lithium Oxide 98min 1.49g (35.4mmol) ,-10 DEG C have been stirred to a large amount of white dicarboxylic acid monoesters lithium salts solid and have separated out.
(2) be warming up to 40-50 DEG C, slowly drip borane reducing agent lithium hydride tetrahydrofuran solution 25.7ml (wherein containing lithium borohydride 35.4mmol).Dropwise and continue reaction 2h, normal pressure steams tetrahydrofuran (THF).Be down to room temperature, add water 300ml, uses 120ml toluene aqueous layer extracted twice respectively.Stay aqueous phase, wherein containing hydroxycarboxylic acid lithium salts.
(3) aqueous phase is placed in reaction flask, being acidified to pH value with dilute hydrochloric acid is 1, is then warming up to 60 DEG C of reactions 3 hours.Reaction terminates, cooling, and filter, filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid 8.9g, yield 78.0%, mp118-120 DEG C, [α] d 20=+63.0 ° of (C=2.0.CHCl 3).
Embodiment six
(1) in there-necked flask, dicarboxylic acid monoesters 20g(35.4mmol is added), add 300ml tetrahydrofuran (THF), stir molten clear after add a hydronium(ion) Lithium Oxide 98min 2.24g (53.1mmol), 40 DEG C have been stirred to a large amount of white dicarboxylic acid monoesters lithium salts solid and have separated out.
(2) be warming up to 70-80 DEG C, slowly drip borane reducing agent lithium hydride tetrahydrofuran solution 128.5ml (wherein containing lithium borohydride 177mmol).Dropwise and continue reaction 6h, normal pressure steams tetrahydrofuran (THF).Be down to room temperature, add water 300ml, uses 120ml toluene aqueous layer extracted twice respectively.Stay aqueous phase, wherein containing hydroxycarboxylic acid lithium salts.
(3) aqueous phase is placed in reaction flask, being acidified to pH value with dilute hydrochloric acid is 5, is then warming up to 95 DEG C of reactions 7 hours.Reaction terminates, cooling, and filter, filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid 10.9g, yield 95.6%, mp118-120 DEG C, [α] d 20=+62.9 ° of (C=2.0.CHCl 3).
Wherein, the R in Fig. 3, Fig. 4 and Fig. 5 is lithium, sodium, potassium, rubidium or caesium.

Claims (7)

1. the preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, is characterized in that: described method comprises step,
(1) in the presence of an organic, (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester and alkali metal hydroxide hydrate reaction obtain dicarboxylic acid monoesters an alkali metal salt;
(2) described dicarboxylic acid monoesters an alkali metal salt and complexing hydroborate carry out reduction reaction and obtain hydroxycarboxylic acid an alkali metal salt;
(3) described hydroxycarboxylic acid an alkali metal salt carries out cyclization and obtains (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones in sour environment;
Described alkali metal hydroxide hydrate is alkali metal hydroxide monohydrate, alkali metal hydroxide dihydrate;
Described alkali metal hydroxide monohydrate is selected from the one in lithium hydroxide monohydrate, sodium hydroxide monohydrate, potassium hydroxide monohydrate; Described alkali metal hydroxide dihydrate is selected from the one in lithium hydroxide dihydrate, sodium hydroxide dihydrate, potassium hydroxide dihydrate;
In step (1), described organic solvent is selected from ether solvent, and described ether solvent is selected from tetrahydrofuran (THF);
In step (2), described complexing hydroborate is alkali metal borohydride, and described alkali metal borohydride is selected from lithium borohydride.
2. (3aS, 6aR)-1,3-diphenyl-methyl according to claim 1-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone, is characterized in that: in step (1), and described organic solvent is anhydrous organic solvent.
3. (3aS according to claim 1,6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone, is characterized in that: in step (2), and described lithium borohydride is lithium borohydride solution, described lithium borohydride solution is prepared by lithium borohydride and ether solvent and is obtained, and described ether solvent is selected from one or more in ether, butyl ether, amyl ether, tetrahydrofuran (THF), dioxane.
4. (3aS according to claim 1, 6aR)-1, 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3, 4-d] imidazoles-2, the preparation method of 4-diketone, it is characterized in that: described (4S, 5R)-1, 3-diphenyl-methyl-2-oxo-4, 5-imidazole alkane dicarboxylic acid 5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester, alkali metal hydroxide hydrate, the mol ratio of complexing hydroborate is: (4S, 5R)-1, 3-diphenyl-methyl-2-oxo-4, 5-imidazole alkane dicarboxylic acid 5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-Diphenethyl] ester: alkali metal hydroxide hydrate: complexing hydroborate=1:1.0-1.5:1.0-5.0.
5. (3aS, 6aR)-1,3-diphenyl-methyl according to claim 1-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone, is characterized in that: in step (1), and the temperature of described reaction is-10 DEG C-40 DEG C.
6. (3aS according to claim 3,6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone, it is characterized in that: in step (2), described reaction is reacted for being dropped in dicarboxylic acid monoesters alkali metal salt soln by lithium borohydride solution, the described time being added dropwise to complete rear continuation reaction is 2-6 hour, the temperature of described reaction is 40 DEG C-80 DEG C, also comprises the step steaming organic solvent to reaction solution, be dissolved in water and extract with toluene after described reaction completes.
7. (3aS according to claim 1,6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone, is characterized in that: in step (3), and the temperature of described cyclization is 60 DEG C-95 DEG C, the time of described reaction is 3-7 hour, and the pH value of described sour environment is 1-5.
CN201310518586.6A 2013-10-25 2013-10-25 The preparation method of (3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones Active CN103524514B (en)

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