CN1142166C - Syhnthesis of d-biotin - Google Patents

Syhnthesis of d-biotin Download PDF

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CN1142166C
CN1142166C CNB021111731A CN02111173A CN1142166C CN 1142166 C CN1142166 C CN 1142166C CN B021111731 A CNB021111731 A CN B021111731A CN 02111173 A CN02111173 A CN 02111173A CN 1142166 C CN1142166 C CN 1142166C
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ring
reaction
benzyl
organic solvent
acid
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CN1374312A (en
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陈芬儿
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Fudan University
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Fudan University
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Abstract

The present invention provides a synthesizing method of d-biotin. The existing preparing method has the disadvantages of low debenzylation yield, poor product purity, complicated operation, etc. The present invention can obtain d-biotin by using 5-[(1R, 3aS, 6aR)-4, 6-dibenzyl-5-oxyhexahydro-1H-thieno [3, 4-d] iminazole-1-group] valeric acid by a two-step reaction which comprises a debenzylation/ring-opening step and a ring-closing step. Total yield can reach 90%. The present invention has the advantages of mild reaction conditions, easy operation, high total yield, good quality and easy industrial production.

Description

The synthetic method of d-vitamin H
Technical field
The invention belongs to field of medicaments, is d-vitamin H (vitamin H, synthetic method I).
Background technology
The d-vitamin H (d-Biotin I), has another name called vitamin H or vitamin H, belongs to the solubility vitamin B group, in medical treatment, and domestic animal, aspect widespread uses such as Poultry farming industry and biotechnology.United States Patent (USP) 2489235,2489238,4877882, European patent 273270, English Patent 3740416 grades have all been narrated 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] valeric acid II (dibenzylbiotin) and the 48% Hydrogen bromide azeotropic preparation method that takes off the d-vitamin H I of benzyl.This method is except that only obtaining 33～40% I; still have single benzyl vitamin H about 30% and 25～30% open-loop products (2S; 3S, 4S)-generation of 5-(3,4-diamino-tetramethylene sulfide-2-yl) valeric acid III by product; the former must go again and take off the benzyl processing; so 48% Hydrogen bromide unit consumption height, complex operation, the latter must carry out cyclization with hypertoxic phosgene and form I in alkaline dissolubility; labour protection conditional request harshness and phosgene transportation and storage are restricted, and make troubles to suitability for industrialized production.United States Patent (USP) 4537973, European patent 36030, Japanese Patent 45077 have been narrated with methylsulphonic acid and have been replaced 48% Hydrogen bromide to make dibenzylbiotin at high temperature take off the improved method of benzyl, there is reaction conditions requirement height in this method, side reaction is many, product separation difficulty, shortcomings such as production cost height.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, and easy, a high yield and the feasible preparation method of highly purified d-vitamin H I industrialization are provided.
The present invention is with 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] valeric acid II and mineral acid take off benzyl/ring closure reaction and change into (2S, 3S in organic solvent, 4S)-5-(3,4-diamino-tetramethylene sulfide-2-yl) valeric acid halogen acid salt III, and then in basic solvent and organic solvent, carry out ring closure reaction with cyclization reagent, make d-vitamin H I without separating direct acidifying.Total recovery 85～90%, compound III are without separation, and direct and cyclization reagent carries out ring closure reaction, and acidifying also can make I again.Quality product reaches 23 editions standards of American Pharmacopeia.
Above-mentioned reaction conditions mineral acid can be hydrochloric acid, Hydrogen bromide etc., and organic solvent generally is an arene, takes off benzyl/ring-opening reaction reaction and can finish under the condition of heating; Such cyclization reagent of ring closure reaction generally is trichloromethylchloroformate or triphosgene, and ring closure reaction alkali can be used sodium hydroxide or potassium hydroxide commonly used, and temperature can be carried out a little in soluble solvent.
Building-up reactions formula of the present invention is as follows:
Take off in benzyl/ring-opening reaction of the present invention, following reaction conditions can obtain better effects: any of hydroiodic acid HI that mineral acid can be 47～48% Hydrogen bromides or 35～37% hydrochloric acid or 52～57% all has good result.The material ratio of Compound I I and mineral acid is 1: 4～15 (w/v), and reaction can attain the results expected.Boiling points such as organic solvent dimethylbenzene, isopropyl benzene all are suitable as the solvent that takes off benzyl/ring-opening reaction at aromatic hydrocarbon solvent more than 130 ℃, this kind solvent have be easy to get, low price and easily reclaim advantages such as easy control of reaction system.Take off benzyl/ring-opening reaction temperature 120～140 ℃ of scopes, the reaction times is 1～60h.
In cyclization of the present invention, cyclization reagent is any of superpalite (trichloromethylchloroformate) or two (trichloromethyl) carbonic ether (triphosgene), reaction conditions gentleness, reaction yield height.The mol ratio of compound III and cyclization reagent is 1: 1.1～8, and reaction can be finished.Inorganic alkali solution is suitable with the sodium hydroxide of 5～30% (Wt%) or the potassium hydroxide solution of this concentration, and this type of alkali is cheap and easy to get, reaction soln pH8～13.Appropriate organic solvent Wei diox, tetrahydrofuran (THF), methyl-phenoxide.
Closing the ring solvent can be single solvent, also can be mixed solvent, and its proportion of composing not specially provided for, temperature of reaction are 5～50 ℃.
The mineral acid that takes off benzyl/ring-opening reaction of the present invention is 47～48% Hydrogen bromide better effects if.
Of the present inventionly take off the Compound I I of benzyl/ring-opening reaction and the material ratio of mineral acid is that 1: 6～8 (w/v) are optimum ranges, can the most effective mineral acid that utilizes, can make again to react completely.
It is better to take off the used organic solvent dimethylbenzene of benzyl/ring-opening reaction, its convenient sources, and the charge is small, easily aftertreatment.
Above-mentioned temperature of reaction preferably is controlled at 125～135 ℃ of reaction 40～50h down.
Better condition is during cyclisation:
The mol ratio of compound III and cyclization reagent is 1: 1.1～2.5;
Inorganic alkali solution is the sodium hydroxide solution of 10～15% (Wt%), the pH8 of reaction soln～10;
The organic solvent Shi diox of ring closure reaction;
Be reflected at and carry out 2～10h under 20～30 ℃.
Two step method of the present invention can obtain product d-vitamin H, and the reaction conditions gentleness is easy; Product yield height, cost are low; The not high and easy acquisition of reaction agents useful for same price; The product purity height.The above-mentioned effect of the inventive method provides good prospect for industrial production.
Specific implementation method
Embodiment:
One, (2S, 3S, 4S)-preparation of 5-(3,4-diamino-tetramethylene sulfide-2-yl) valeric acid halogen acid salt III
Example 1 is 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] and valeric acid (160g, 0.38mol), 47% Hydrogen bromide (1.2L) and dimethylbenzene (1.0mL) puts in the reaction flask, stirs 45h in 130 ℃.Reaction is finished, and is cooled to room temperature, leaves standstill, and tells organic layer, the water layer concentrating under reduced pressure, solid is separated out in cooling, vacuum-drying, light yellow crystalline powder III (137.2g, 95%), mp238～240 ℃.
Example 2 is 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] and valeric acid (160g, 0.38mol), 47% Hydrogen bromide (720mL), isopropyl benzene (500mL) put in the reaction flask, stirs 30h in 135 ℃.Reaction is finished, and is cooled to room temperature, leaves standstill, and tells organic layer, and water layer uses isopropyl benzene (100mL * 2) to extract again.The water layer concentrating under reduced pressure, solid is separated out in cooling, vacuum-drying, pale yellow powder III (132.8g, 92%), mp236～239 ℃.
Example 3 is 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] and valeric acid (160g, 0.38mol), 48% Hydrogen bromide (640mL) and dimethylbenzene (450mL) puts in the reaction flask, stirs 12h in 125 ℃.Reaction is finished, and is cooled to room temperature, leaves standstill, and tells organic layer, the water layer concentrating under reduced pressure, solid is separated out in cooling, vacuum-drying, pale yellow powder III (126.4g, 87.5%), mp236～249 ℃.
Embodiment 4 is 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] and valeric acid (160g, 0.38mol), 48% Hydrogen bromide (2.4L) and isopropyl benzene (1.5L) put in the reaction flask, stirs 60h in 140 ℃.Reaction is finished, and is cooled to room temperature, leaves standstill, and tells organic layer, the water layer concentrating under reduced pressure, solid is separated out in cooling, vacuum-drying, pale yellow powder III (130g, 90%), mp239～240 ℃.
Two, d-vitamin H I's is synthetic
Embodiment 5 with 10% sodium hydroxide solution [by sodium hydroxide (40g, 1.0mol) formulated with distilled water (360mL)] and (2S, 3S, 4S)-(37.8g 0.1mol) puts in the reaction flask valeric acid hydrobromate III 5-(3,4-diamino-tetramethylene sulfide 2-yl), after the stirring at room dissolving, (44.6g 0.15mol) is dissolved in the solution (controlling reaction solution pH8～10 with 10% sodium hydroxide solution in case of necessity) of diox (270mL), in stirring at room 10h to drip triphosgene.Reaction is finished, the reclaim under reduced pressure diox, and water layer transfers to pH1～2 with active decolouring 30min with concentrated hydrochloric acid, separates out white solid, filters, and is washed to pH7, use the distilled water recrystallization, gets white crystalline powder I23.2g, and 90%, mp230～231 ℃, [α] D 20=+90.8 (c, 1.0,0.1N NaOH).
IR(KBr)：v＝3300，2935，1705，1668cm -1.
1H NMR (DMSO-d 6): δ=1.29～1.60[m, 6H, (CH 2) 3], 2.17 (t, 2H, J=7.3H 2, CH 2CO 2H), 2.57 (d, 1H, J=12.4Hz, C 6a-H), 2.80 (dd, 1H, J=12.4Hz, C 6 β-H), 3.15 (m, 1H, C 4 β-H), 4.18 (m, 1H, C 6a-H), 4.35 (m, 1H, C 6a-H), 6.47 (s, 1H, N-H), 6.48 (s, 1H, N-H), 11.98 (br s, 1H, COOH, D 2O exchanges disappearance).
EI-MS：(m/z，％)＝245(M +，14.6)，227(8，12)，199(0.58)，84(25)，112(25)，97(100)，85(67).
Embodiment 6 with 10% potassium hydroxide solution [by potassium hydroxide (56g, 1.0mol) formulated with aquae destillata (1.064L)] and (2S, 3S, 4S)-(37.8g 0.1mol) puts in the reaction flask valeric acid hydrobromate III 5-(3,4-diamino-tetramethylene sulfide-2-yl), after the stirring at room dissolving, (32g 0.16mol) is dissolved in tetrahydrofuran (THF) (200mL) solution (reacting to pH8～10 with the control of 10% potassium hydroxide in case of necessity), in stirring at room 3h to drip trichloromethylchloroformate.Reaction is complete, reclaim under reduced pressure, and water layer transfers to pH1～2 with active decolouring 30min with concentrated hydrochloric acid, separates out white solid, filters, and is washed to pH7, uses the distilled water recrystallization, gets white crystalline powder I22.5g, yield 92%.mp231～133℃，[α] D 20＝+90.9(c，1.0，0.1N?NaOH)。IR, 1H NMR is consistent with embodiment 3 with MS.
Embodiment 7 with 5% potassium hydroxide solution [by potassium hydroxide (56g, 1.0mol) formulated with distilled water (1.064L)] and (2S, 3S, 4S)-(37.8g 0.1mol) puts in the reaction flask valeric acid hydrobromate III 5-(3,4-diamino-tetramethylene sulfide-2-yl), after the stirring at room dissolving, (89.1g 0.3mol) is dissolved in the solution (in case of necessity with 5% potassium hydroxide solution control pH10～12) of tetrahydrofuran (THF) (800mL), in 30～35 ℃ of stirring 5h to drip triphosgene.Reaction is finished, and reclaims tetrahydrofuran (THF), and water layer transfers to pH1～2 with active decolouring 30min with concentrated hydrochloric acid, separates out white solid, filters, and is washed to pH7, use the distilled water recrystallization, gets white crystalline powder I, mp229～231 ℃, [α] D 20=+90.5 (c, 1.0,0.1N NaOH).IR, 1H NMR is consistent with embodiment 3 with MS.
Embodiment 8 is 5-[(1R, 3aS, 6aR)-4, and 6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] valeric acid (160g, 0.38mol), put in the reaction flask, stirs 45h in 127～128 ℃ by 36% hydrochloric acid (1.25L) and dimethylbenzene (1.1L).Reaction is finished, and is cooled to room temperature; Leave standstill, tell organic layer, behind the water layer concentrating under reduced pressure water (400mL), be cooled to room temperature, in reaction solution, add 10% sodium hydroxide solution [by sodium hydroxide (100g, 0.25mol) formulated with water (900mL)], behind stirring at room 15min, (74.3g 0.25mol) is dissolved in the solution (controlling pH9～10 with 10% sodium hydroxide solution in case of necessity) of methyl-phenoxide (450mL), in stirring at room 8h to drip triphosgene.Reaction is finished, the reclaim under reduced pressure methyl-phenoxide, and water layer transfers to pH1～2 with active decolouring 30min with concentrated hydrochloric acid, separates out white solid, filters, and is washed to pH7, use the distilled water recrystallization, gets white crystalline powder I (80.1g, 86%), mp230.5～231.5 ℃, [α] D 20=+91 (c, 1.0,0.1N NaOH).IR, 1H NMR is consistent with embodiment 3 with MS.
The invention is not restricted to above-mentioned example.

Claims (10)

1, the synthetic method of a kind of d-vitamin H I
It is characterized in that 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxo six hydrogen-1H-thieno-[3,4-d] imidazoles-1-yl] valeric acid II and mineral acid take off benzyl/ring-opening reaction and change into (2S in organic solvent, 3S, 4S)-5-(3,4-diamino-tetramethylene sulfide-2-yl) valeric acid hydrohalogenic acid salt III, and then with cyclization reagent in inorganic alkali solution and organic solvent, close the ring get final product, compound III is directly carried out ring closure reaction without separation and is promptly got I, and concrete preparation condition is:
(1) mineral acid that takes off benzyl/ring-opening reaction is 47～48% Hydrogen bromides or 35～37% hydrochloric acid or 52～57% hydroiodic acid HIs;
(2) material ratio of Compound I I and mineral acid is 1: 4～15 (w/v);
(3) organic solvent that takes off benzyl/ring-opening reaction is an arene;
(4) temperature of taking off benzyl/ring-opening reaction is 120～140 ℃, and the reaction times is 10～60h;
(5) closing the cyclization reagent that encircles is superpalite (trichloromethylchloroformate) or two three chloromethyl ester carbonic ethers (triphosgene);
(6) mol ratio of compound III and cyclization reagent is 1: 1.1～8;
(7) mineral alkali of ring closure reaction is the sodium hydroxide or the potassium hydroxide of 5～30 (Wt%);
(8) the organic solvent Shi diox of ring closure reaction or tetrahydrofuran (THF) or methyl-phenoxide;
(9) the ring closure reaction temperature is 5～50 ℃;
2, the method for claim 1, the organic solvent that it is characterized in that ring closure reaction are single solvent or mixed solvent.
3, the method for claim 1, the mineral acid that it is characterized in that taking off benzyl/ring-opening reaction is 47～48% Hydrogen bromide.
4, the method for claim 1, the material ratio that it is characterized in that taking off benzyl/ring-opening reaction Compound I I and mineral acid is 1: 6～8 (w/v).
5, the method for claim 1, the organic solvent that it is characterized in that taking off benzyl/ring-opening reaction is a dimethylbenzene.
6, the method for claim 1, the temperature that it is characterized in that taking off benzyl/ring-opening reaction is 125～135 ℃.
7, the method for claim 1, the mol ratio that it is characterized in that compound III and cyclization reagent are 1: 1.1～2.5.
8, the method for claim 1, the mineral alkali that it is characterized in that ring closure reaction are 10～15% sodium hydroxide solutions.
9, the method for claim 1 is characterized in that the organic solvent Shi diox of ring closure reaction.
10, the method for claim 1 is characterized in that the ring closure reaction temperature is 20～30 ℃.
CNB021111731A 2002-03-27 2002-03-27 Syhnthesis of d-biotin Expired - Fee Related CN1142166C (en)

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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003276510A1 (en) * 2002-11-07 2004-06-07 Orchid Chemicals And Pharmaceuticals Ltd An improved process for the preparation of biotin
CN101215291B (en) * 2008-01-10 2010-12-29 复旦大学 Synthesis method of (+)-biotin and its derivatives
CN103788112B (en) * 2012-11-02 2016-03-09 菏泽市方明制药有限公司 A kind of benzyl vitamin H takes off the method that benzyl prepares vitamin H
CN103772410B (en) * 2013-12-31 2016-08-31 浙江新和成股份有限公司 A kind of synthetic method of D-biotin
CN104926828B (en) * 2014-03-22 2019-02-19 上海创诺制药有限公司 A method of D-biotin is prepared by dibenzylbiotin
CN104710437B (en) * 2015-04-04 2017-01-25 富阳科兴生物化工有限公司 Improved method for preparing d-biotin from bisbenzyl biotin by debenzylation
CN104987342B (en) * 2015-06-30 2017-03-15 江西科技师范大学 The total synthesis method of natural product (+) biotin
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
CN113121558B (en) * 2019-12-30 2024-05-31 大丰海嘉诺药业有限公司 Purification method for intermediate for producing pharmaceutical grade vitamin H

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