CN103524514A - Preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione - Google Patents
Preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione Download PDFInfo
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- CN103524514A CN103524514A CN201310518586.6A CN201310518586A CN103524514A CN 103524514 A CN103524514 A CN 103524514A CN 201310518586 A CN201310518586 A CN 201310518586A CN 103524514 A CN103524514 A CN 103524514A
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Abstract
The invention provides a preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione, which is applied to the field of preparation of biotin intermediates. The method comprises the following steps: in the presence of an organic solvent, reacting (4S,5R)-1,3-dibenzyl-2-oxo-4,5-imidazolidinedicarboxylic acid-5-[(s)-2-hydroxy-1-toluene-2,2-diphenethyl]ester with alkali metal hydroxide hydrate to produce dicarboxylic acid monoester alkali metal salt; subjecting the dicarboxylic acid monoester alkali metal salt and complex borohydride to a reduction reaction so as to produce hydroxycarboxylic acid alkali metal salt; and subjecting the hydroxycarboxylic acid alkali metal salt to a cyclization reaction in an acidic environment so as to produce (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione; wherein the alkali metal hydroxide hydrate comprises alkali metal hydroxide monohydrate and alkali metal hydroxide dihydrate. The invention has the following advantages: raw materials are easily available and convenient to store, operation in the reaction process is easy and convenient, has high security and is low in cost, the yield of the produced product is high, and the method is applicable to industrial production.
Description
Technical field
The present invention relates to a kind of (3aS, 6aR)-1 in biotin intermediate preparation field, the preparation method of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones.
Background technology
(3aS, 6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, English name (3aS, 6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d] imidazole-2,4-dione, is called for short d-lactone, and 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 required key intermediate of D-biotin (vitamin H, vitamin H) industry preparation.
By means of chiral alcohol, by ring-type meso carboxylic acid anhydride asymmetric synthesis d-lactone, be well known in the art.Han Weihua etc. mention in " Biotin intermediate lactone synthesis progress " (" chemistry circular " 08 phase in 2004), utilize chloramphenicol base dextrorotation aminodiol to carry out asymmetric synthesis for cyclin imide as chiral reagent, through reduction, open loop, then acid treatment, obtain the d-lactone needing, after recrystallization, yield 65%.This route is the route that current domestic manufacturer mainly adopts, although this chiral resolving agent is cheap and easy to get, the method exists that product yield is low, of poor quality, complex operation long shortcoming in man-hour, thereby causes the finished product high expensive.
Chinese patent CN1768063A has announced the method for the synthetic d-lactone of a kind of stereoselectivity, in disclosed method, alkali metal hydroxide need to add with aqueous solution form, 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, research and develop a kind of (3aS, 6aR)-1, the preparation method of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones is current assistant officer new problem to be solved.
Summary of the invention
The object of the present invention is to provide a kind of (3aS, 6aR)-1, the preparation method of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, the method is easy and simple to handle, safe, yield is high, good product quality, cost are low.
The object of the present invention is achieved like this: (3aS, 6aR)-1, and the preparation method of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, described method comprises step,
(1) under organic solvent exists, (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-bis-styroyls] 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 a kind of in lithium hydroxide monohydrate, sodium hydroxide monohydrate, potassium hydroxide monohydrate, rubidium hydroxide monohydrate, cesium hydroxide monohydrate; Described alkali metal hydroxide dihydrate is selected from a kind of 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 a kind of in lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE; In step (2), described lithium borohydride is lithium borohydride solution, described lithium borohydride solution is prepared and is obtained by lithium borohydride and ether solvent, 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-bis-styroyls] mol ratio of ester, alkali metal hydroxide hydrate, 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-bis-styroyls] 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 ℃-40 ℃; In step (2), described reaction is reacted for lithium borohydride solution is dropped in dicarboxylic acid monoesters alkali metal salt soln, the described time that is added dropwise to complete rear continuation reaction is 2-6 hour, the temperature of described reaction is 40 ℃-80 ℃, after described reaction completes, also comprises the step that reaction solution is steamed organic solvent, is dissolved in water and extracted with toluene; In step (3), the temperature of described cyclization is 60 ℃-95 ℃, 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 (3aS, 6aR)-1, the preparation method of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones.Its pharmacy principle is: (1) is under organic solvent exists, 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-bis-styroyls] ester reaction obtains 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, safe.If with the oxyhydroxide salify described in Chinese patent CN1768063A, need in the situation that adding 0.5-1.5 molar equivalent water, carry out, 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-bis-styroyls] mol ratio of ester, alkali metal hydroxide hydrate and complexing hydroborate selects, and can better improve product yield and quality.(3) after being optimized, the reaction conditionss such as reaction times, temperature of reaction can obtain good reaction effect.(4) described ethers is particularly preferably tetrahydrofuran (THF) or dioxane, to reach the object reducing 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 conveniently, reaction process is easy and simple to handle, safe, 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 (3aS, 6aR)-1, the structural formula figure of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones.
Fig. 2 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-bis-styroyls] the structural formula figure of 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 that the present invention prepares (3aS, 6aR)-1, the synthetic route schematic diagram of 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 embodiment are only for the present invention is illustrated, and the present invention is not limited to these contents.
Term explanation:
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-bis-styroyls] ester, English chemistry is by name: (4S, 5R)-1,3-dibenzyl-5-(((S)-1-hydroxy-1,1-diphenylpropan-2-yloxy) carbonyl)-2-ox oimidazolidine-4-carboxylic acid;
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-bis-styroyls] ester-4-carboxy acid alkali metal-salt, English chemistry alkali metal (4S by name, 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-carboxy acid alkali metal-salt, English chemistry alkali metal (4S, 5R)-1 by name, 3-dibenzyl-5-(hydroxymethyl)-2-oxoimidazolidine-4-carboxylate.
Embodiment mono-
Adopt the impact of different alkali metal hydroxide hydrates on reaction yield:
(1) in there-necked flask, add dicarboxylic acid monoesters 20g(35.4mmol), add 300ml anhydrous tetrahydro furan, stir and moltenly add alkali metal hydroxide hydrate 40.5mmol after clear, the selection situation of described alkali metal hydroxide hydrate has been stirred to a large amount of dicarboxylic acid monoesters an alkali metal salt solids in Table 1,20 ℃ and has separated out.
(2) be warming up to 50-60 ℃, 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, use respectively twice of 120ml toluene aqueous layer extracted.Stay water, wherein contain hydroxycarboxylic acid an alkali metal salt.
(3) water is placed in to reaction flask, with dilute hydrochloric acid, being acidified to pH value is 3, is then warming up to 80 ℃ of reactions 5 hours.Reaction finishes, and cooling is filtered, and 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 bis-
Adopt the impact on reaction yield of the aqueous solution that different alkali metal hydroxides is mixed with:
(1) in there-necked flask, add dicarboxylic acid monoesters 20g(35.4mmol), add 300ml anhydrous tetrahydro furan, stir and moltenly add the alkali metal hydroxide aqueous solution being mixed with by alkali metal hydroxide and water after clear, the selection situation of described alkali metal hydroxide and water has been stirred to a large amount of dicarboxylic acid monoesters an alkali metal salt solids in Table 2,20 ℃ and has separated out.
(2) be warming up to 50-60 ℃, 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, use respectively twice of 120ml toluene aqueous layer extracted.Stay water, wherein contain hydroxycarboxylic acid an alkali metal salt.
(3) water is placed in to reaction flask, with dilute hydrochloric acid, being acidified to pH value is 3, is then warming up to 80 ℃ of reactions 5 hours.Reaction finishes, and cooling is filtered, and 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 tri-
The impact of the different add-on of alkali metal hydroxide hydrate on reaction yield:
(1) in there-necked flask, add dicarboxylic acid monoesters 20g(35.4mmol), add 300ml anhydrous tetrahydro furan, stir and moltenly add alkali metal hydroxide hydrate after clear, the selection situation of the different add-ons of described alkali metal hydroxide hydrate has been stirred to a large amount of dicarboxylic acid monoesters an alkali metal salt solids in Table 3,20 ℃ and has separated out.
(2) be warming up to 50-60 ℃, 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, use respectively twice of 120ml toluene aqueous layer extracted.Stay water, wherein contain hydroxycarboxylic acid an alkali metal salt.
(3) water is placed in to reaction flask, with dilute hydrochloric acid, being acidified to pH value is 3, is then warming up to 80 ℃ of reactions 5 hours.Reaction finishes, and cooling is filtered, and filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid, yield situation is in Table 3.
Table 3: the different selection situations 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 tetra-
The impact of the different add-on of reductive agent on reaction yield:
(1) in there-necked flask, add dicarboxylic acid monoesters 20g(35.4mmol), add 300ml anhydrous tetrahydro furan, stir and moltenly add lithium hydroxide monohydrate 2.1g (50.0mmol) after clear, 20 ℃ have been stirred to a large amount of dicarboxylic acid monoesters lithium salts solids and have separated out.
(2) be warming up to 50-60 ℃, 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, use respectively twice of 120ml toluene aqueous layer extracted.Stay water, wherein contain hydroxycarboxylic acid lithium salts.
(3) water is placed in to reaction flask, with dilute hydrochloric acid, being acidified to pH value is 3, is then warming up to 80 ℃ of reactions 5 hours.Reaction finishes, and cooling is filtered, and 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, add dicarboxylic acid monoesters 20g(35.4mmol), add 300ml tetrahydrofuran (THF), stir and moltenly add a hydronium(ion) oxidation lithium 1.49g (35.4mmol) after clear ,-10 ℃ have been stirred to a large amount of white dicarboxylic acid monoesters lithium salts solids and have separated out.
(2) be warming up to 40-50 ℃, 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, use respectively twice of 120ml toluene aqueous layer extracted.Stay water, wherein contain hydroxycarboxylic acid lithium salts.
(3) water is placed in to reaction flask, with dilute hydrochloric acid, being acidified to pH value is 1, is then warming up to 60 ℃ of reactions 3 hours.Reaction finishes, and cooling is filtered, and filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid 8.9g, yield 78.0%, mp118-120 ℃, [α]
d 20=+63.0 ° of (C=2.0.CHCl
3).
Embodiment six
(1) in there-necked flask, add dicarboxylic acid monoesters 20g(35.4mmol), add 300ml tetrahydrofuran (THF), stir and moltenly add a hydronium(ion) oxidation lithium 2.24g (53.1mmol) after clear, 40 ℃ have been stirred to a large amount of white dicarboxylic acid monoesters lithium salts solids and have separated out.
(2) be warming up to 70-80 ℃, 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, use respectively twice of 120ml toluene aqueous layer extracted.Stay water, wherein contain hydroxycarboxylic acid lithium salts.
(3) water is placed in to reaction flask, with dilute hydrochloric acid, being acidified to pH value is 5, is then warming up to 95 ℃ of reactions 7 hours.Reaction finishes, and cooling is filtered, and filter cake is washed to neutrality, dry cake.Obtain white d-lactone solid 10.9g, yield 95.6%, mp118-120 ℃, [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 (9)
1. one kind (3aS, 6aR)-1, the preparation method of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, is characterized in that: described method comprises step,
(1) under organic solvent exists, (4S, 5R)-1,3-diphenyl-methyl-2-oxo-4,5-imidazole alkane dicarboxylic acid-5-[(s)-2-hydroxyl-1-Toluene-2,4-diisocyanate, 2-bis-styroyls] 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.
2. (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: described alkali metal hydroxide hydrate is alkali metal hydroxide monohydrate, alkali metal hydroxide dihydrate.
3. (3aS according to claim 2,6aR)-1,3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazoles-2, the preparation method of 4-diketone, is characterized in that: described alkali metal hydroxide monohydrate is selected from a kind of in lithium hydroxide monohydrate, sodium hydroxide monohydrate, potassium hydroxide monohydrate, rubidium hydroxide monohydrate, cesium hydroxide monohydrate; Described alkali metal hydroxide dihydrate is selected from a kind of in lithium hydroxide dihydrate, sodium hydroxide dihydrate, potassium hydroxide dihydrate, rubidium hydroxide dihydrate, cesium hydroxide dihydrate.
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, is characterized in that: in step (1), described organic solvent is anhydrous organic solvent, 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 a kind of in lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE.
5. according to the (3aS described in claim 1 or 4,6aR)-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), described lithium borohydride is lithium borohydride solution, described lithium borohydride solution is prepared and is obtained by lithium borohydride and ether solvent, and described ether solvent is selected from one or more in ether, butyl ether, amyl ether, tetrahydrofuran (THF), dioxane.
6. (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-bis-styroyls] 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-bis-styroyls] ester: alkali metal hydroxide hydrate: complexing hydroborate=1:1.0-1.5:1.0-5.0.
7. (3aS, 6aR) according to claim 1-1, the preparation method of 3-diphenyl-methyl-tetrahydrochysene-1H-furo [3,4-d] imidazole-2,4-diones, is characterized in that: in step (1), the temperature of described reaction is-10 ℃-40 ℃.
8. (3aS according to claim 1 or 5,6aR)-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 lithium borohydride solution is dropped in dicarboxylic acid monoesters alkali metal salt soln, the described time that is added dropwise to complete rear continuation reaction is 2-6 hour, the temperature of described reaction is 40 ℃-80 ℃, after described reaction completes, also comprises the step that reaction solution is steamed organic solvent, is dissolved in water and extracted with toluene.
9. (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), the temperature of described cyclization is 60 ℃-95 ℃, the time of described reaction is 3-7 hour, and the pH value of described sour environment is 1-5.
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| CN201310518586.6A CN103524514B (en) | 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 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107686488A (en) * | 2016-08-05 | 2018-02-13 | 浙江医药股份有限公司新昌制药厂 | A kind of synthetic method of biotin intermediate |
| CN109251207A (en) * | 2018-09-29 | 2019-01-22 | 江西天新药业股份有限公司 | The method of stereoselective syntheses asymmetric lactone |
| CN113549084A (en) * | 2020-04-24 | 2021-10-26 | 杭州科兴生物化工有限公司 | Method for stereoselectively synthesizing chiral lactone |
| CN114634515A (en) * | 2022-02-25 | 2022-06-17 | 复旦大学 | Stereoselective synthesis method of (3aS,6aR) -lactone |
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| CN1768063A (en) * | 2003-04-22 | 2006-05-03 | 帝斯曼知识产权资产管理有限公司 | The Stereoselective synthesizing process of lactone |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107686488A (en) * | 2016-08-05 | 2018-02-13 | 浙江医药股份有限公司新昌制药厂 | A kind of synthetic method of biotin intermediate |
| CN109251207A (en) * | 2018-09-29 | 2019-01-22 | 江西天新药业股份有限公司 | The method of stereoselective syntheses asymmetric lactone |
| CN113549084A (en) * | 2020-04-24 | 2021-10-26 | 杭州科兴生物化工有限公司 | Method for stereoselectively synthesizing chiral lactone |
| CN113549084B (en) * | 2020-04-24 | 2023-02-28 | 杭州科兴生物化工有限公司 | Method for stereoselectively synthesizing chiral lactone |
| CN114634515A (en) * | 2022-02-25 | 2022-06-17 | 复旦大学 | Stereoselective synthesis method of (3aS,6aR) -lactone |
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| CN103524514B (en) | 2016-03-02 |
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