CN112457327A - Preparation method of D-biotin - Google Patents
Preparation method of D-biotin Download PDFInfo
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- CN112457327A CN112457327A CN202011164996.1A CN202011164996A CN112457327A CN 112457327 A CN112457327 A CN 112457327A CN 202011164996 A CN202011164996 A CN 202011164996A CN 112457327 A CN112457327 A CN 112457327A
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 title claims abstract description 208
- 235000000638 D-biotin Nutrition 0.000 title claims abstract description 101
- 239000011665 D-biotin Substances 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- PGESDSQUYHPLRY-FUDKSRODSA-N 5-[(3as,4s,6ar)-1,3-dibenzyl-2-oxo-3a,4,6,6a-tetrahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid Chemical compound N1([C@H]2[C@@H](N(C1=O)CC=1C=CC=CC=1)CS[C@H]2CCCCC(=O)O)CC1=CC=CC=C1 PGESDSQUYHPLRY-FUDKSRODSA-N 0.000 claims abstract description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 19
- 239000012071 phase Substances 0.000 claims abstract description 19
- 239000012074 organic phase Substances 0.000 claims abstract description 15
- 239000000706 filtrate Substances 0.000 claims abstract description 13
- 238000000926 separation method Methods 0.000 claims abstract description 13
- 238000006264 debenzylation reaction Methods 0.000 claims abstract description 12
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 3
- 208000005156 Dehydration Diseases 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 abstract description 7
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 24
- 238000010812 external standard method Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 238000001514 detection method Methods 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229930003756 Vitamin B7 Natural products 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 235000011912 vitamin B7 Nutrition 0.000 description 3
- 239000011735 vitamin B7 Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LLIANSAISVOLHR-GBCQHVBFSA-N 5-[(3as,4s,6ar)-2-oxidanylidene-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 LLIANSAISVOLHR-GBCQHVBFSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- -1 aluminum ions Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- IXGNPUSUVRTQGW-UHFFFAOYSA-M sodium;perchlorate;hydrate Chemical compound O.[Na+].[O-]Cl(=O)(=O)=O IXGNPUSUVRTQGW-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides a preparation method of D-biotin. The preparation method comprises the following steps: dissolving dibenzyl biotin in an organic solvent to obtain a dibenzyl biotin solution; mixing the dibenzyl biotin solution with anhydrous aluminum trichloride, controlling the temperature to be 75-105 ℃, and carrying out debenzylation reaction; after the reaction is finished, adding water into the reaction system, adjusting the pH to 9-12, carrying out solid-liquid separation, layering the filtrate, and separating an organic phase and a water phase; adjusting the pH value of the obtained water phase to be below 3, and carrying out solid-liquid separation to obtain the D-biotin. Compared with the prior art, the preparation method provided by the invention is simple to operate, has lower reaction temperature, does not use toxic triphosgene, and is more environment-friendly.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of D-biotin.
Background
The chemical name of D-Biotin (D-Biotin) is 5- [ (3aS,4S,6aR) -2-oxo-hexahydro-1H-thieno [3,4-D ] imidazol-4-yl ] pentanoic acid, and the structure of the D-Biotin is shown aS a formula I:
vitamin H, biotin, coenzyme R, vitamin B7, a water-soluble vitamin B group, is a colorless crystalline powder.
Natural D-biotin is widely present in organs such as kidney, liver, pancreas, etc. of animals, as well as milk, egg yolk, yeast. It is an essential substance for the synthesis of vitamin C, an indispensable substance for the normal metabolism of fats and proteins. Has wide application in the fields of medical treatment, feed, biotechnology and the like.
At present, D-biotin is almost produced by a chemical synthesis method, and an industrial production technical route basically takes dibenzyl biotin (with the chemical name of 5- [ (3aS,4S,6aR) -1, 3-dibenzyl-2-oxo-hexahydro-1H-thieno [3,4-D ] imidazole-4-yl ] pentanoic acid and the structure shown in formula II) aS an intermediate, and debenzylation reaction is carried out at the reaction temperature of more than 120 ℃ under the action of hydrobromic acid, concentrated sulfuric acid or other strong acids, but the method can cause carbonyl of the dibenzyl biotin or the D-biotin to fall off and open a ring while debenzylation is carried out, so that a byproduct shown in formula III is formed, and triphosgene is further used for ring closure synthesis of the D-biotin;
the above-mentioned industrial synthesis method has three drawbacks: 1. the reaction is carried out in a strong acid system such as hydrobromic acid, concentrated sulfuric acid and the like at the temperature higher than 120 ℃, so that C-S bonds are broken, and a large amount of byproducts are formed; 2. the byproduct benzyl bromide formed in the reaction has strong irritation and lacrimation, and the production environment is severe; 3. the ring opening of the carbonyl bond needs to be closed by triphosgene, and the triphosgene is easily decomposed into phosgene, which is a highly toxic raw material and has great production danger.
Therefore, a preparation method of D-biotin, which has few side reactions, mild reaction conditions, safety and environmental protection, is to be developed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of D-biotin. The preparation method provided by the invention is simple to operate, low in reaction temperature, high in product yield, free of toxic triphosgene and more environment-friendly.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of D-biotin, which comprises the following steps:
(1) dissolving dibenzyl biotin in an organic solvent to obtain a dibenzyl biotin solution;
(2) mixing the dibenzyl biotin solution with anhydrous aluminum trichloride, and performing debenzylation reaction at 75-105 deg.C (such as 75 deg.C, 78 deg.C, 80 deg.C, 82 deg.C, 85 deg.C, 88 deg.C, 90 deg.C, 92 deg.C, 95 deg.C, 98 deg.C, 100 deg.C, 102 deg.C or 105 deg.C);
(3) after the reaction is finished, adding water into the reaction system, adjusting the pH to 9-12 (for example, 9, 9.2, 9.5, 9.8, 10, 10.2, 10.5, 10.8, 11, 11.2, 11.5, 11.8 or 12 and the like can be adopted), carrying out solid-liquid separation, carrying out layering on the filtrate, and separating out an organic phase and a water phase;
(4) adjusting the pH of the aqueous phase obtained in step (3) to 3 or less (for example, 3, 2.8, 2.5, 2.2, 2, 1.8, 1.5, 1.2, 1, 0.8, 0.5, 0.2 or the like), and performing solid-liquid separation to obtain D-biotin.
In the present invention, the reaction formula for preparing D-biotin is as follows:
the invention prepares the D-biotin by debenzylating dibenzyl biotin by adopting anhydrous aluminum trichloride and matching with specific reaction conditions. Compared with the prior art, the preparation method provided by the invention is simple to operate, has lower reaction temperature, does not use toxic triphosgene, and is more environment-friendly.
In the present invention, since the anhydrous aluminum trichloride is dissolved and an exothermic temperature rise phenomenon occurs, the temperature of the dibenzyl biotin solution is preferably lowered (for example, to 10 to 35 ℃, more preferably to 15 to 25 ℃) in step (2) before the anhydrous aluminum trichloride is added, so as to prevent the temperature of the solution from being too high. The reaction temperature in the step (2) of the invention needs to be controlled at 75-105 ℃ so as to ensure that the debenzylation reaction is fully carried out, and if the reaction temperature is too low, the debenzylation reaction is not sufficient, thus easily causing the yield of D-biotin to be lower; if the reaction temperature is too high, D-biotin tends to be unstable, denaturation may occur, and the yield may be lowered.
In the step (3), the pH value is adjusted to 9-12, on one hand, the formed complex bond is replaced by a nitrogen-hydrogen bond, and on the other hand, excessive anhydrous aluminum trichloride is neutralized and precipitated to facilitate separation. If the pH value in the step (3) is too low, aluminum ions cannot be completely removed; if the pH is too high, D-biotin is unstable, and the yield of D-biotin is lowered.
In step (4) of the present invention, the pH of the aqueous phase is adjusted to 3 or less so that D-biotin is more likely to be crystallized and precipitated and that D-biotin is more stable in the system. If the pH in step (4) is too high, D-biotin is liable to be unstable, denaturation may occur, and the yield may be lowered.
In one embodiment of the present invention, the preparation method further comprises: dehydrating the dibenzyl biotin solution prior to the mixing in step (2).
In one embodiment of the present invention, the dehydration treatment is performed by thermal distillation.
In one embodiment of the present invention, the organic solvent in step (1) is an aromatic hydrocarbon, preferably one or a combination of at least two of benzene, toluene and xylene.
In the present invention, aromatic hydrocarbon is used as an extraction solvent, which enables better removal of water in the reaction system.
In one embodiment of the present invention, the mass-to-volume ratio of the dibenzylbiotin to the organic solvent is 0.1 to 0.2g/mL, and may be, for example, 0.1g/mL, 0.12g/mL, 0.13g/mL, 0.15g/mL, 0.16g/mL, 0.18g/mL, or 0.2 g/mL.
In one embodiment of the present invention, the molar ratio of the dibenzylbiotin to the anhydrous aluminum trichloride is 1:2 to 3.5, and may be, for example, 1:2, 1:2.2, 1:2.3, 1:2.5, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.3, or 1: 3.5; preferably 1: 2-2.5.
In the invention, if the molar ratio of the anhydrous aluminum trichloride to the dibenzyl biotin is lower than 2:1, the benzyl is difficult to completely remove, so that the yield of the D-biotin is low; if the molar ratio of the anhydrous aluminum trichloride to the dibenzyl biotin is higher than 3.5:1, the yield of the D-biotin cannot be further improved, and the raw material waste is caused.
In one embodiment of the present invention, the temperature in step (2) is controlled to 90 to 100 ℃ and may be, for example, 90 ℃, 91 ℃, 92 ℃, 93 ℃, 94 ℃, 95 ℃, 96 ℃, 97 ℃, 98 ℃, 99 ℃ or 100 ℃.
The reaction temperature in the step (2) of the invention is preferably 90-100 ℃, which is beneficial to ensuring that the debenzylation reaction is more complete and further improving the yield of D-biotin.
In one embodiment of the present invention, the reaction is terminated until the amount of dibenzylbiotin remaining in step (2) is less than 1%.
In the invention, the residual amount refers to the percentage of the amount of the residual dibenzyl biotin in the reaction system in the initial addition amount. The method for detecting the residual amount of dibenzylbiotin is not particularly limited, and can be performed by High Performance Liquid Chromatography (HPLC).
In one embodiment of the present invention, the volume ratio of the water in step (3) to the organic solvent in step (1) is 1: 0.5-1; for example, it may be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, or 1: 1.
In one embodiment of the invention, the pH is adjusted to 10-11 in step (3); for example, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, or 11, etc.
In the present invention, the yield of D-biotin can be further improved by controlling the pH in step (3) to 10 to 11.
In one embodiment of the present invention, the method for adjusting the pH in step (3) is to use an inorganic base solution for adjustment.
In one embodiment of the present invention, the preparation method further comprises: after the separation in the step (3), the organic phase is washed with an inorganic base solution, the organic phase and the aqueous phase are separated again, and the aqueous phase is combined.
The number of washing is not particularly limited in the present invention, as long as the D-biotin remaining in the organic phase can be sufficiently washed out, and the washing may be performed 2 to 5 times, as an example.
In one embodiment of the present invention, the inorganic alkali solution is a sodium hydroxide solution or a potassium hydroxide solution.
In one embodiment of the present invention, the concentration of the inorganic alkali solution is 15 to 45 wt%, and may be, for example, 15 wt%, 18 wt%, 20 wt%, 22 wt%, 25 wt%, 28 wt%, 30 wt%, 32 wt%, 35 wt%, 38 wt%, 40 wt%, 42 wt%, or 45 wt%, etc.; preferably 30-35 wt%.
In one embodiment of the present invention, the pH is adjusted to 2 or less, preferably 1 to 2, in step (4).
In the present invention, the stability of D-biotin can be further improved and the yield can be increased by controlling the pH in step (4) to 2 or less. When the pH is less than 1, the yield cannot be further improved, but the acid solution is wasted, and therefore, the pH in the step (4) is most preferably 1 to 2.
In one embodiment of the present invention, the method for adjusting the pH in step (4) is to use an inorganic acid solution for adjustment.
In one embodiment of the invention, the inorganic acid solution is 20 to 40 wt% (e.g., can be 20 wt%, 22 wt%, 25 wt%, 28 wt%, 30 wt%, 32 wt%, 35 wt%, 38 wt%, 40 wt%, etc.) of hydrochloric acid or 5 to 35 wt% (e.g., can be 5 wt%, 8 wt%, 10 wt%, 12 wt%, 15 wt%, 18 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, etc.) of hydrobromic acid.
In one embodiment of the present invention, the preparation method further comprises: after the solid-liquid separation in the step (4), the filter cake is recrystallized.
In an embodiment of the present invention, the recrystallization method comprises: and (4) mixing the filter cake obtained in the step (4), activated carbon and water, heating and refluxing, filtering while hot, cooling the filtrate, standing for crystallization, carrying out solid-liquid separation, and drying the filter cake.
In one embodiment of the present invention, in the recrystallization step, the time of heating reflux is 1 to 2.5 hours; for example, it may be 1h, 1.2h, 1.3h, 1.5h, 1.8h, 2h, 2.2h, 2.5h, etc.
In one embodiment of the present invention, in the recrystallization step, the temperature of the filtrate is reduced to-5 to 25 ℃, for example, to-5 ℃, -3 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃, 5 ℃, 8 ℃, 10 ℃, 12 ℃, 15 ℃, 18 ℃, 20 ℃, 22 ℃ or 25 ℃ and the like; preferably 0-5 deg.C.
In an embodiment of the present invention, in the recrystallization step, the standing crystallization time is 2 to 12 hours, and may be, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours; preferably 6-10 h.
In one embodiment of the present invention, the preparation method comprises the steps of:
(1) dissolving dibenzyl biotin into aromatic hydrocarbon according to the mass-volume ratio of 0.1-0.2g/mL, and heating, distilling and dehydrating to obtain a dibenzyl biotin solution;
(2) cooling the dibenzyl biotin solution to 10-35 ℃, adding anhydrous aluminum trichloride for mixing, controlling the molar ratio of the dibenzyl biotin to the anhydrous aluminum trichloride to be 1:2-2.5, controlling the final temperature to be 90-100 ℃, performing debenzylation reaction, and cooling to 45-55 ℃ until the residual quantity of the dibenzyl biotin is less than 1%, so as to finish the reaction;
(3) after the reaction is finished, adding water into the reaction system, wherein the volume ratio of the added water to the aromatic hydrocarbon in the step (1) is 1:0.5-1, adjusting the pH to 10-11 by using an inorganic alkali solution, performing suction filtration under negative pressure, standing and layering the filtrate, and separating an organic phase and a water phase; washing the obtained organic phase with an inorganic alkali solution, separating the organic phase and the water phase again, and combining the water phases;
(4) and (3) adjusting the pH value of the water phase obtained in the step (3) to 1-2 by using an inorganic acid solution, filtering, mixing the filter cake, activated carbon and water, heating and refluxing for 1-2.5h, filtering while hot, cooling the filtrate to 0-5 ℃, standing for 6-10h for crystallization, filtering, and drying the filter cake to obtain the D-biotin.
In the present invention, the organic solvent in the organic phase can be recovered and utilized by a conventional method in the art, and the present invention is not particularly limited.
Compared with the prior art, the invention has the following beneficial effects:
the method provided by the invention adopts anhydrous aluminum trichloride to perform debenzylation on dibenzyl biotin, and prepares D-biotin by matching with specific reaction conditions. Compared with the prior art, the preparation method provided by the invention is simple to operate, has lower reaction temperature, does not use toxic triphosgene, and is more environment-friendly; and the yield of the D-biotin reaches 85-95%, and the yield of the D-biotin can be further improved to 90-95% by selecting the preferable reaction conditions.
Drawings
FIG. 1 is a high performance liquid chromatogram of the finished product of D-biotin prepared in example 1 of the present invention.
Detailed Description
The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached drawings. It should be understood by those skilled in the art that the specific embodiments are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
The embodiment provides a preparation method of D-biotin, which comprises the following specific steps:
(1) a thermometer and a recovery condenser are arranged on a 500mL three-neck flask, 20.0g (98.3 percent, 0.046mol) of dibenzyl biotin is added, 100mL of toluene is added, the internal temperature is raised to 110 ℃, and the reflux heat preservation is carried out until no moisture is evaporated;
(2) cooling to 25 ℃, adding 13.5g (0.1mol) of anhydrous aluminum trichloride, slowly raising the inner temperature to 95 ℃, keeping the temperature and timing, detecting the residual amount of the dibenzyl biotin by adopting HPLC in the reaction process, and finishing the reaction when the residual amount of the dibenzyl biotin is less than 1%, wherein the reaction time is about 6 hours;
(3) cooling to 50 ℃, adding 50mL of purified water, dropwise adding 30 wt% of sodium hydroxide solution, and adjusting the pH value to 10.5; carrying out suction filtration under negative pressure, washing a filter cake with 10mL of purified water, standing and layering the filtrate, and separating a toluene phase from a water phase; washing the toluene phase with 30 wt% sodium hydroxide solution for 2 times, 10mL each time, and combining the water phases;
(4) adjusting the pH value of the obtained water phase to 1 by using 30 wt% hydrochloric acid, stirring for 30 minutes, and filtering to obtain a filter cake, namely a D-biotin crude product;
adding 1000mL of purified water and 1g of activated carbon into the filter cake, heating and refluxing (the temperature is about 95 ℃), keeping the temperature for 1 hour, filtering while the mixture is hot, cooling the filtrate to 5 ℃, recrystallizing for 8 hours, filtering, and drying the filter cake to obtain 10.6g of the D-biotin finished product.
The purity of the D-biotin finished product detected by an external standard method is 99.2 percent, and the molar yield of the D-biotin is 93.1 percent;
wherein the external standard method is to determine the chromatogram of the D-biotin finished product by high performance liquid chromatography and calculate the content of the D-biotin according to the peak area; the chromatographic conditions in the examples of the present invention were:
a chromatographic column: a C18 column with a length of 150mm, an inner diameter of 4.6mm and a particle size of 5 μm;
mobile phase: acetonitrile 8.5 wt% + buffer solution 91.5 wt%, the buffer solution preparation method is: dissolving 1g of sodium perchlorate monohydrate in 500mL of water, adding 1mL of phosphoric acid, and diluting with water to 1000 mL;
flow rate: 1.2 mL/min;
detection wavelength: 210 nm;
sample introduction amount: 20 μ L.
The high performance liquid chromatogram of the finished D-biotin product prepared in this example is shown in FIG. 1, and the retention time is 16.015 min.
Example 2
This example provides a process for producing D-biotin, which is different from example 1 only in that anhydrous aluminum trichloride is added in an amount of 12.27g (0.092 mol).
The purity of the obtained D-biotin finished product is 99.1 percent and the molar yield of the D-biotin is 91.2 percent through detection of an external standard method.
Example 3
This example provides a process for producing D-biotin, which is different from example 1 only in that anhydrous aluminum trichloride is added in an amount of 18.4g (0.138 mol).
The purity of the D-biotin finished product detected by an external standard method is 99.1 percent, and the molar yield of the D-biotin is 93.0 percent.
Example 4
This example provides a process for producing D-biotin, which is different from example 1 only in that the reaction temperature in step (2) is 90 ℃ and the reaction time is about 12 hours.
The purity of the D-biotin finished product detected by an external standard method is 98.9 percent, and the molar yield of the D-biotin is 90.2 percent.
Example 5
This example provides a process for producing D-biotin, which is different from example 1 only in that the reaction temperature in step (2) is 85 ℃ and the reaction time is about 9 hours.
The purity of the D-biotin finished product detected by an external standard method is 99.0 percent, and the molar yield of the D-biotin is 89.2 percent.
Example 6
This example provides a process for producing D-biotin, which is different from example 1 only in that the reaction temperature in step (2) is 75 ℃ and the reaction time is about 15 hours.
The purity of the D-biotin finished product detected by an external standard method is 99.2 percent, and the molar yield of the D-biotin is 85.9 percent.
Example 7
This example provides a process for producing D-biotin, which is different from example 1 only in that the reaction temperature in step (2) is 100 ℃ and the reaction time is about 8 hours.
The purity of the D-biotin finished product detected by an external standard method is 99.0 percent, and the molar yield of the D-biotin is 91.2 percent.
Example 8
This example provides a process for producing D-biotin, which is different from example 1 only in that the reaction temperature in step (2) is 105 ℃ and the reaction time is about 5 hours.
The purity of the obtained D-biotin finished product is 99.1 percent and the molar yield of the D-biotin is 87.4 percent through detection of an external standard method.
Example 9
This example provides a process for producing D-biotin, differing from example 1 only in that the pH in step (3) is 9.
The purity of the obtained D-biotin finished product is 99.2 percent and the molar yield of the D-biotin is 91.9 percent through detection of an external standard method.
Example 10
This example provides a process for producing D-biotin, differing from example 1 only in that the pH in step (3) is 10.
The purity of the obtained D-biotin finished product is 99.1 percent and the molar yield of the D-biotin is 93.2 percent through detection of an external standard method.
Example 11
This example provides a process for producing D-biotin, differing from example 1 only in that the pH in step (3) is 11.
The purity of the D-biotin finished product detected by an external standard method is 99.2 percent, and the molar yield of the D-biotin is 92.9 percent.
Example 12
This example provides a process for producing D-biotin, differing from example 1 only in that the pH in step (3) is 12.
The purity of the D-biotin finished product detected by an external standard method is 99.3 percent, and the molar yield of the D-biotin is 91.2 percent.
Example 13
This example provides a process for producing D-biotin, differing from example 1 only in that the pH in step (4) is 2.
The purity of the obtained D-biotin finished product is 99.1 percent through detection of an external standard method, and the molar yield of the D-biotin is 93.1 percent.
Example 14
This example provides a process for producing D-biotin, differing from example 1 only in that the pH in step (4) is 3.
The purity of the obtained D-biotin finished product is 99.2 percent and the molar yield of the D-biotin is 91.6 percent through detection of an external standard method.
Comparative example 1
A process for producing D-biotin is provided, which differs from example 1 only in that the reaction temperature in step (2) is 65 ℃ and the reaction time is about 18 hours.
The purity of the obtained D-biotin finished product is 99.2 percent and the molar yield of the D-biotin is 83.2 percent through detection of an external standard method.
Comparative example 2
A process for producing D-biotin is provided, which differs from example 1 only in that the reaction temperature in step (2) is 120 ℃ and the reaction time is about 4.5 hours.
The purity of the D-biotin finished product detected by an external standard method is 98.6 percent, and the molar yield of the D-biotin is 85.6 percent.
Comparative example 3
There is provided a process for producing D-biotin, which is different from example 1 only in that the pH in step (3) is 8.
The purity of the D-biotin finished product detected by an external standard method is 98.8 percent, and the molar yield of the D-biotin is 89.2 percent.
Comparative example 4
There is provided a process for producing D-biotin, which is different from example 1 only in that the pH in step (3) is 13.
The purity of the D-biotin finished product detected by an external standard method is 99.1 percent, and the molar yield of the D-biotin is 86.3 percent.
Comparative example 5
There is provided a process for producing D-biotin, which is different from example 1 only in that the pH in step (4) is 4.
The purity of the D-biotin finished product detected by an external standard method is 99.0 percent, and the molar yield of the D-biotin is 90.2 percent.
Comparing example 1 with comparative examples 1 to 5, it can be seen that when the debenzylation reaction temperature, the basic pH value, and the acidic pH value in steps (2) to (4) are out of the ranges defined in the present invention, the yield of D-biotin is decreased.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A preparation method of D-biotin is characterized by comprising the following steps:
(1) dissolving dibenzyl biotin in an organic solvent to obtain a dibenzyl biotin solution;
(2) mixing the dibenzyl biotin solution with anhydrous aluminum trichloride, controlling the temperature to be 75-105 ℃, and carrying out debenzylation reaction;
(3) after the reaction is finished, adding water into the reaction system, adjusting the pH to 9-12, carrying out solid-liquid separation, layering the filtrate, and separating an organic phase and a water phase;
(4) and (4) adjusting the pH value of the water phase obtained in the step (3) to be below 3, and carrying out solid-liquid separation to obtain the D-biotin.
2. The D-biotin according to claim 1, wherein the preparation method further comprises: dehydrating the dibenzyl biotin solution before the mixing in the step (2);
preferably, the dehydration treatment is carried out by heating distillation.
3. The production method according to claim 1 or 2, wherein the organic solvent in step (1) is an aromatic hydrocarbon, preferably one or a combination of at least two of benzene, toluene and xylene;
and/or the mass-volume ratio of the dibenzyl biotin to the organic solvent is 0.1-0.2 g/mL.
4. The production method according to any one of claims 1 to 3, wherein the molar ratio of the dibenzylbiotin to the anhydrous aluminum trichloride is 1:2 to 3.5, preferably 1:2 to 2.5;
and/or, controlling the temperature in the step (2) to be 90-100 ℃;
and/or, in the step (2), ending the reaction until the residual quantity of the dibenzyl biotin is less than 1%.
5. The production method according to any one of claims 1 to 4, wherein the volume ratio of the water in step (3) to the organic solvent in step (1) is 1:0.5 to 1;
and/or, adjusting the pH value to 10-11 in the step (3);
and/or, the method for adjusting the pH value in the step (3) adopts inorganic alkali solution for adjustment;
and/or, the preparation method further comprises the following steps: after the separation in the step (3), the organic phase is washed with an inorganic base solution, the organic phase and the aqueous phase are separated again, and the aqueous phase is combined.
6. The production method according to claim 5, wherein the inorganic alkali solution is a sodium hydroxide solution or a potassium hydroxide solution;
and/or the concentration of the inorganic base solution is 15 to 45 wt%, preferably 30 to 35 wt%.
7. The process according to any one of claims 1 to 6, wherein the pH is adjusted to 2 or less, preferably 1 to 2 in step (4).
8. The production method according to any one of claims 1 to 7, wherein the method of adjusting the pH in the step (4) is adjusting with an inorganic acid solution;
preferably, the inorganic acid solution is 20 to 40 wt% hydrochloric acid or 5 to 35 wt% hydrobromic acid.
9. The production method according to any one of claims 1 to 8, characterized by further comprising: after the solid-liquid separation in the step (4), recrystallizing the filter cake;
preferably, the recrystallization method is as follows: mixing the filter cake obtained in the step (4), activated carbon and water, heating and refluxing, filtering while hot, cooling the filtrate, standing for crystallization, then carrying out solid-liquid separation, and drying the filter cake;
preferably, in the recrystallization step, the heating reflux time is 1-2.5 h;
and/or in the recrystallization step, cooling the filtrate to-5-25 ℃, preferably 0-5 ℃;
and/or in the recrystallization step, the standing crystallization time is 2-12h, preferably 6-10 h.
10. The production method according to any one of claims 1 to 9, characterized by comprising the steps of:
(1) dissolving dibenzyl biotin into aromatic hydrocarbon according to the mass-volume ratio of 0.1-0.2g/mL, and heating, distilling and dehydrating to obtain a dibenzyl biotin solution;
(2) cooling the dibenzyl biotin solution to 10-35 ℃, adding anhydrous aluminum trichloride for mixing, controlling the molar ratio of the dibenzyl biotin to the anhydrous aluminum trichloride to be 1:2-2.5, controlling the final temperature to be 90-100 ℃, performing debenzylation reaction, and cooling to 45-55 ℃ until the residual quantity of the dibenzyl biotin is less than 1%, so as to finish the reaction;
(3) after the reaction is finished, adding water into the reaction system, wherein the volume ratio of the added water to the aromatic hydrocarbon in the step (1) is 1:0.5-1, adjusting the pH to 10-11 by using an inorganic alkali solution, performing suction filtration under negative pressure, standing and layering the filtrate, and separating an organic phase and a water phase; washing the obtained organic phase with an inorganic alkali solution, separating the organic phase and the water phase again, and combining the water phases;
(4) and (3) adjusting the pH value of the water phase obtained in the step (3) to 1-2 by using an inorganic acid solution, filtering, mixing the filter cake, activated carbon and water, heating and refluxing for 1-2.5h, filtering while hot, cooling the filtrate to 0-5 ℃, standing for 6-10h for crystallization, filtering, and drying the filter cake to obtain the D-biotin.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104710437A (en) * | 2015-04-04 | 2015-06-17 | 富阳科兴生物化工有限公司 | Improved method for preparing d-biotin from bisbenzyl biotin by debenzylation |
| CN105130869A (en) * | 2015-09-07 | 2015-12-09 | 曾伟 | Synthetic method of Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone |
| CN109627254A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | A kind of preparation method of D-biotin |
| CN112390815A (en) * | 2020-11-03 | 2021-02-23 | 浙江医药股份有限公司新昌制药厂 | Preparation method for preparing d-biotin by removing N-benzyl group with Lewis acid |
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| CN104710437A (en) * | 2015-04-04 | 2015-06-17 | 富阳科兴生物化工有限公司 | Improved method for preparing d-biotin from bisbenzyl biotin by debenzylation |
| CN105130869A (en) * | 2015-09-07 | 2015-12-09 | 曾伟 | Synthetic method of Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone |
| CN109627254A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | A kind of preparation method of D-biotin |
| CN112390815A (en) * | 2020-11-03 | 2021-02-23 | 浙江医药股份有限公司新昌制药厂 | Preparation method for preparing d-biotin by removing N-benzyl group with Lewis acid |
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