CN103554129B - A kind of preparation method of biotin intermediate thioketone - Google Patents
A kind of preparation method of biotin intermediate thioketone Download PDFInfo
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- CN103554129B CN103554129B CN201310470107.8A CN201310470107A CN103554129B CN 103554129 B CN103554129 B CN 103554129B CN 201310470107 A CN201310470107 A CN 201310470107A CN 103554129 B CN103554129 B CN 103554129B
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- tetrahydrochysene
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of preparation method of biotin intermediate thioketone, using thioacetic acid potassium and thiacetic mixing solutions as thio reagents, with (3aS; 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2; 4(1H)-diketone mixing, reclaims benzene, after dehydration to mixed system; under nitrogen protection, carry out vulcanization reaction, obtain (3aS; 6aR)-1; 3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H)-diketone.The present invention uses thioacetic acid and potassium hydroxide to prepare thioacetic acid potassium and thiacetic mixing solutions as thio reagents, add (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone, utilizes benzene low temperature reflux and fraction water device water-dividing to remove water in system, obtains high purity product.The present invention substantially avoid the perishable decomposition of thio reagents, and vulcanization reaction affects the shortcomings such as large by water in system, and improve curing efficiency, good product quality, yield is high.
Description
Technical field
The invention belongs to organic chemistry filed, relate to a kind of biotin key intermediate thioketones (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H) preparation method of-diketone.
Background technology
(3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H)-diketone (I) be synthesis D-biotin key intermediate.This intermediate adds after side chain, hydrogenation, de-benzyl, hydrolysis can generate D-biotin through form.Synthesis (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H) main raw material of-diketone is thio reagents and (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone (interior ketone, II), its chemical formula is as follows:
Wherein use thioacetic acid potassium to be use more thioketones synthetic method at present as thio reagents and interior reactive ketone, initiate for Roche Holding Ag of Switzerland and use till today.The clear 50-014692 of patent documentation TOHKEMY uses 70% Sodium sulfhydrate, dithiocarbonic anhydride as thio reagents, clear 62-7196 uses thioacetamide as thio reagents, patent CN1548440A uses sodium sulphite and thioacetic acid as thio reagents, and patent CN1285595C uses homemade potassium bisulfide solution as thio reagents.In these methods, thio reagents instability is oxidizable at present, and in reaction process, thio reagents affects greatly by water and oxygen, and sulfo-efficiency is low, causes thioketones yield on the low side.
Summary of the invention
The object of this invention is to provide a kind of preparation method of biotin intermediate thioketone.
In order to realize object of the present invention, the present invention adopts following technique means.
A preparation method for biotin intermediate thioketone, using thioacetic acid potassium and thiacetic mixing solutions as thio reagents, with (3aS; 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2; 4(1H)-diketone mixing, reclaims benzene, after dehydration to mixed system; under nitrogen protection, carry out vulcanization reaction, obtain (3aS; 6aR)-1; 3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H)-diketone.
The preparation method of above-mentioned biotin intermediate thioketone specifically comprises the steps:
1) thio reagents preparation
Under cold condition, thioacetic acid and potassium hydroxide react in the mixed solvent of DMF and benzene, generate thioacetic acid potassium;
2) processed
Contain in thioacetic acid potassium, unreacted thiacetic mixed solution to step 1) and add (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone, temperature rising reflux, then the moisture in profit water trap separation system;
3) vulcanization reaction
Under nitrogen protection, by step 2) dehydration after mixed solution be heated to certain temperature, thioacetic acid and thioacetic acid potassium respectively with (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone generation vulcanization reaction, benzene is reclaimed in cooling, then rising temperature reclamation N, dinethylformamide, obtain incarnadine (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H)-diketone crude product;
4) extractive crystallization
With methylene dichloride dissolving step 3) incarnadine (3aS, 6aR)-1, the 3-dibenzyl-tetrahydrochysene-4H-thieno-[3 of gained, 4-d] imidazoles-2,4(1H)-diketone crude product, water extracts, add ethyl acetate, cooling, crystallization, suction filtration, obtain white (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H)-diketone.
Wherein, in step 1), described low temperature control at 0 ~-20 DEG C, preferably-10 DEG C; Reaction times 1 ~ 4H, preferred 2H;
In step 1), the mol ratio of described thioacetic acid and potassium hydroxide is 1:0.25 ~ 1, preferred 1:0.7; Thus guarantee that thioacetic acid both can directly as thio reagents and (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-two reactive ketones, the thioacetic acid potassium hydrolysis generated can be suppressed again.
In step 1), described DMF and thiacetic mol ratio are 1:1 ~ 2; Described DMF and benzene volume ratio are 1:0.25 ~ 1, preferred 1:0.5;
In step 2) in, described reflux temperature 60 DEG C ~ 80 DEG C, preferably 70 DEG C; Return time 1 ~ 4H, preferred 2H;
In step 2) in, described (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H) thiacetic mol ratio is in-diketone and step 1): 1:1 ~ 2, preferred 1:1.1;
In step 3), described vulcanization reaction temperature 140 DEG C ~ 170 DEG C, preferably 150 DEG C, vulcanization reaction time 0.5 ~ 5H, preferred 1H;
In step 3), benzene recovered temperature is 20-40 DEG C, preferably 30 DEG C; DMF recovered temperature is 80 DEG C ~ 100 DEG C, preferably 90 DEG C;
In step 4), in order to obtain better effect of extracting, usually with water extraction 2-4 time; Described Tc is 0 DEG C ~-10 DEG C, preferably-5 DEG C;
The mol ratio of described methylene dichloride and water is 1:3 ~ 6; Described (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone and methylene dichloride, pure water consumption be 1g:5ml:5ml.
Method of the present invention and existing Measures compare have following advantages:
1, the present invention utilizes excessive thioacetic acid and potassium hydroxide to prepare thioacetic acid potassium, and the thioacetic acid of surplus participates in vulcanization reaction as thio reagents jointly with thioacetic acid potassium again; Excessive thiacetic existence effectively can overcome thioacetic acid potassium instability, very easily rotten, is difficult to the defect of preserving, and effectively suppresses generation of its hydrolysis, sulfo-efficiency is significantly improved.
2, before vulcanization reaction of the present invention occurs, increase benzene backflow, fraction water device water-dividing step, guarantee that the water in whole system is fully removed, improve product yield.
3, products obtained therefrom quality of the present invention is higher, specific rotation 90.9., fusing point 125-126 DEG C, product purity reaches 99% through liquid phase analysis, and yield is comparatively up to 94%.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Potassium hydroxide (4.31g, 0.077mol) is dissolved in 32 milliliters of DMFs and 16 milliliters of benzene, is cooled to-10 DEG C, stirring reaction 2H after dropping thioacetic acid (8.36g, 0.11mol).
Continue to add (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone (32.2g, 0.1mol), be warming up to 70 DEG C of backflow 2H, after reclaiming benzene, then the water in profit water trap separation system.
Pass into nitrogen protection; and system is warming up to 150 DEG C; stirring and refluxing reaction 1H, is quickly cooled to 30 DEG C of reclaim under reduced pressure benzene, then is warming up to 90 DEG C of reclaim under reduced pressure N; after dinethylformamide (DMF); obtain incarnadine (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3; 4-d] imidazoles-2,4(1H)-diketone crude product.
In crude product, add 160 milliliters of methylene dichloride, dissolve, then extract three times with 160 ml pure waters, reclaim methylene dichloride, then add 32 milliliters of ethyl acetate, be cooled to-5 DEG C, crystallization, suction filtration, a small amount of ethyl acetate drip washing, obtain white crystal (31.7g, 94.0%).After testing, Mp:125-126 DEG C, [α] D
25=+90.9 ° of (c1.0, CHCl
3).
Embodiment 2
Potassium hydroxide (6.16g, 0.11mol) is dissolved in 32 milliliters of DMFs and 16 milliliters of benzene, is cooled to-10 DEG C, stirring reaction 2H after dropping thioacetic acid (8.36g, 0.11mol).
Continue to add (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone (32.2g, 0.1mol), be warming up to 70 DEG C of backflow 2H, after reclaiming benzene, then the water in profit water trap separation system.
Pass into nitrogen protection, and system is warming up to 150 DEG C, stirring and refluxing reaction 1H.Be quickly cooled to 30 DEG C of reclaim under reduced pressure benzene, then after being warming up to 90 DEG C of reclaim under reduced pressure DMF, obtain incarnadine (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H)-diketone crude product.
In crude product, add 160 milliliters of methylene dichloride, dissolve, then extract three times with 160 ml pure waters, reclaim methylene dichloride, then add 32 milliliters of ethyl acetate, be cooled to-5 DEG C, crystallization, suction filtration, a small amount of ethyl acetate drip washing, obtain white crystal (30.1g, 89.1%).Mp:124-126 DEG C after testing, [α] D
25=+90.2 ° of (c1.0, CHCl
3).
Embodiment 3
Potassium hydroxide (4.31g, 0.077mol) is dissolved in 32 milliliters of DMFs and 8 milliliters of benzene, is cooled to-10 DEG C, stirring reaction 1H after dropping thioacetic acid (8.36g, 0.11mol).
Continue to add (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone (32.2g, 0.1mol), be warming up to 70 DEG C of backflow 1H, after reclaiming benzene, then the water in profit water trap separation system.
Pass into nitrogen protection, and system is warming up to 150 DEG C, stirring and refluxing reaction 1H.Be quickly cooled to 30 DEG C of reclaim under reduced pressure benzene, then be warming up to 90 DEG C of reclaim under reduced pressure DMF, obtain incarnadine (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4(1H)-diketone crude product.
In crude product, add 160 milliliters of methylene dichloride, dissolve, then extract three times with 160 ml pure waters, reclaim methylene dichloride, then add 32 milliliters of ethyl acetate, be cooled to-5 DEG C, crystallization, suction filtration, a small amount of ethyl acetate drip washing, obtain white crystal (28.4g, 84.2%).Mp:123-125 DEG C after testing, [α] D
25=+89.9 ° of (c1.0, CHCl
3).
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (4)
1. the preparation method of a biotin intermediate thioketone, it is characterized in that, using thioacetic acid potassium and thiacetic mixing solutions as thio reagents, with (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone mixing, benzene is reclaimed to mixed system, after dehydration, under nitrogen protection, carry out vulcanization reaction, obtain (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4 (1H)-diketone;
Described preparation method comprises the steps:
1) thio reagents preparation
Under cold condition, thioacetic acid and potassium hydroxide react in the mixed solvent of DMF and benzene, generate thioacetic acid potassium;
2) processed
To step 1) add (3aS containing in thioacetic acid potassium, unreacted thiacetic mixed solution, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone, temperature rising reflux, then the moisture in profit water trap separation system;
3) vulcanization reaction
Under nitrogen protection, by step 2) dehydration after mixed solution be heated to certain temperature, thioacetic acid and thioacetic acid potassium respectively with (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone generation vulcanization reactions, benzene is reclaimed in cooling, then rising temperature reclamation N, dinethylformamide, obtain incarnadine (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4 (1H)-diketone crude product;
4) extractive crystallization
With methylene dichloride dissolving step 3) incarnadine (3aS, 6aR)-1, the 3-dibenzyl-tetrahydrochysene-4H-thieno-[3 of gained, 4-d] imidazoles-2,4 (1H)-diketone crude product, water extracts, add ethyl acetate, cooling, crystallization, suction filtration, obtain white (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-thieno-[3,4-d] imidazoles-2,4 (1H)-diketone;
In step 1) in, described low temperature control is at 0 ~-20 DEG C; Reaction times 1 ~ 4H;
In step 1) in, the mol ratio of described thioacetic acid and potassium hydroxide is 1:0.25 ~ 1; Described DMF and thiacetic mol ratio are 1:1 ~ 2; Described DMF and benzene volume ratio are 1:0.25 ~ 1;
In step 2) in, described reflux temperature 60 DEG C ~ 80 DEG C; Return time 1 ~ 4H;
In step 2) in, described (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone and step 1) in thiacetic mol ratio be: 1:1 ~ 2.
2. preparation method according to claim 1, is characterized in that, in step 3) in, described vulcanization reaction temperature 140 DEG C ~ 170 DEG C; Vulcanization reaction time 0.5 ~ 5H; Benzene recovered temperature is 20-40 DEG C; DMF recovered temperature is 80 DEG C ~ 100 DEG C.
3. preparation method according to claim 1, is characterized in that, in step 4) in, described Tc is 0 DEG C ~-10 DEG C.
4. preparation method according to claim 1, is characterized in that, in step 4) in, the mol ratio of described methylene dichloride and water is 1:3 ~ 6; Described (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone and methylene dichloride, water consumption are 1g:5ml:5ml.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104530076B (en) * | 2014-12-17 | 2016-08-17 | 新发药业有限公司 | (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-thieno [3,4-d] imidazoles-2,4-(1H) synthetic method of-diketone |
| CN107955018B (en) * | 2016-10-14 | 2022-03-11 | 大丰海嘉诺药业有限公司 | Method for preparing D-biotin thiolactone intermediate |
| WO2020110831A1 (en) * | 2018-11-28 | 2020-06-04 | 株式会社トクヤマ | Method for producing thiolactone derivative |
| CN111960979A (en) * | 2020-08-14 | 2020-11-20 | 江西天新药业股份有限公司 | Preparation method of sodium thioacetate and method for preparing thiolactone by using sodium thioacetate |
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| CN101096372A (en) * | 2007-01-24 | 2008-01-02 | 绍兴文理学院 | Process for synthesizing thiolactone |
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| CN101096372A (en) * | 2007-01-24 | 2008-01-02 | 绍兴文理学院 | Process for synthesizing thiolactone |
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