CN111377940B - Method for desulfurizing vitamin H intermediate - Google Patents
Method for desulfurizing vitamin H intermediate Download PDFInfo
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- CN111377940B CN111377940B CN201811644611.4A CN201811644611A CN111377940B CN 111377940 B CN111377940 B CN 111377940B CN 201811644611 A CN201811644611 A CN 201811644611A CN 111377940 B CN111377940 B CN 111377940B
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- toluene
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- 238000000034 method Methods 0.000 title claims abstract description 57
- 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 17
- 229930003756 Vitamin B7 Natural products 0.000 title claims abstract description 16
- 239000011735 vitamin B7 Substances 0.000 title claims abstract description 16
- 235000011912 vitamin B7 Nutrition 0.000 title claims abstract description 16
- 230000003009 desulfurizing effect Effects 0.000 title claims description 11
- 239000000243 solution Substances 0.000 claims abstract description 39
- 229940046892 lead acetate Drugs 0.000 claims abstract description 35
- 239000000203 mixture Substances 0.000 claims abstract description 35
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 15
- 239000011593 sulfur Substances 0.000 claims abstract description 15
- 239000012535 impurity Substances 0.000 claims abstract description 12
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 105
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000007788 liquid Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 25
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000005406 washing Methods 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000005984 hydrogenation reaction Methods 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000006477 desulfuration reaction Methods 0.000 description 14
- 230000023556 desulfurization Effects 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 239000002994 raw material Substances 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100000572 poisoning Toxicity 0.000 description 3
- 230000000607 poisoning effect Effects 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001502 supplementing effect Effects 0.000 description 3
- -1 2- (5-bromopentanyl) -4, 4-dimethyloxazoline Chemical compound 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000004134 energy conservation Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229940068840 d-biotin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- OOMYACICIIMLQI-UHFFFAOYSA-L lead(2+);diacetate;hydrate Chemical compound O.[Pb+2].CC([O-])=O.CC([O-])=O OOMYACICIIMLQI-UHFFFAOYSA-L 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- RBBWNXJFTBCLKT-UHFFFAOYSA-M sodium;ethanethioate Chemical compound [Na+].CC([S-])=O RBBWNXJFTBCLKT-UHFFFAOYSA-M 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for removing sulfur-containing impurities in a vitamin H intermediate solution by washing and extracting with a lead acetate aqueous solution. The method of the invention comprises the following steps: (1) Providing a mixture of crude intermediate 6 in an aqueous lead acetate solution; wherein the intermediate 6 crude product comprises sulfur-containing impurities; and (2) separating the mixture of step (1) to provide a desulphurised intermediate 6. In the process of obtaining the intermediate 7 by reducing the intermediate 6 by palladium carbon, the palladium carbon can be used for three times without adding new palladium carbon, thereby obviously reducing the production cost of the process.
Description
Technical Field
The invention belongs to the technical field of vitamin H production; more particularly to a method for desulfurizing vitamin H intermediate reaction liquid.
Background
Vitamin H is also called d-biotin and coenzyme R, is water-soluble vitamin, and also belongs to vitamin B group and B7. It is an indispensable substance for normal metabolism of fat and protein, and is also a necessary nutrient for maintaining natural growth and development of human body and normal functional health of human body.
To date, several routes have been developed for the synthesis of vitamin H, but the currently accepted route of greatest industrial application value is still that disclosed in the Hoffmann-La Roche company patent (US 2489238):
in the catalytic hydrogenation step from compound 6 to compound 7 in the route, palladium carbon is now mostly used as the catalyst. The palladium-carbon catalyst adopted in the method has the advantages of small dosage, high activity, short reaction time, high conversion rate and the like; meanwhile, the method has the defects of high price and easy poisoning. Since sulfide is used in the preparation of the compound 5 in the route, the subsequent intermediate inevitably brings sulfide into the process, and a trace amount of sulfide can poison palladium-carbon; the cyclic utilization rate of palladium-carbon is reduced, and the production cost is greatly increased.
At present, the energy conservation and environmental protection are advocated, how to improve the recycling rate of chemical reagents in industrial production, and the energy conservation and the cost reduction are one of main targets of industrial production.
In view of the foregoing, there is a great need in the art to develop a new method that can improve the recycling rate of palladium-carbon and reduce the production cost.
Disclosure of Invention
The invention aims to provide a method for removing sulfur impurities in an intermediate which can cause catalyst poisoning with simple operation.
In a first aspect of the present invention, there is provided a process for the desulfurization of vitamin H intermediate 6, the process comprising the steps of:
(1) Providing a mixture of crude intermediate 6 in an aqueous lead acetate solution; wherein the intermediate 6 crude product comprises sulfur-containing impurities; and
(2) Separating the mixture of step (1) to obtain a desulphurised intermediate 6.
In another preferred embodiment, the crude intermediate 6 product contains 0.9% or less of sulfur impurities.
In another preferred embodiment, the crude intermediate 6 product contains 97.5 to 98.5% of intermediate 6.
In another preferred embodiment, the sulfur-containing impurities include: sodium thioacetate, and/or sodium sulfide.
In another preferred embodiment, in the step (1), the concentration of lead acetate in the lead acetate aqueous solution is 0.8 to 1.2wt%; preferably 1wt%.
In another preferred embodiment, in the step (1), the mass ratio of the lead acetate aqueous solution to the crude intermediate 6 is (1-3): 1; preferably 2:1.
In another preferred embodiment, in step (1), the temperature of the mixture is 25-35 ℃; preferably, 30 ℃.
In another preferred embodiment, step (1) comprises the steps of:
an aqueous lead acetate solution was added to the crude intermediate 6 and stirred, thereby obtaining a mixture of the crude intermediate 6 in the aqueous lead acetate solution.
In another preferred embodiment, in the step (1), the stirring time of the stirring is 0.5 to 1.5 hours.
In another preferred embodiment, in the step (1), the stirring temperature of the stirring is 30 ℃.
In another preferred embodiment, in step (2), the mixture of step (1) is separated by extraction.
In another preferred embodiment, the extractant of the extraction is toluene.
In another preferred embodiment, the mass ratio of the extractant to the crude intermediate 6 product is (4-6): 1; preferably 5:1.
In another preferred embodiment, step (2) includes the steps of:
(2.1) adding toluene to the mixture in the step (1) and stirring;
(2.2) separating the liquid and taking the organic phase, thereby obtaining a mixture containing the desulphurized intermediate 6; and
(2.3) concentrating the mixture containing the desulfurized intermediate 6 obtained in the step (2.2), thereby obtaining the desulfurized intermediate 6.
In another preferred embodiment, in the step (2.1), the stirring time of the stirring is 0.5 to 1.5 hours.
In another preferred embodiment, in step (2.2), the liquid separation also yields an aqueous phase;
and the method further comprises the steps of: extracting the aqueous phase with toluene to obtain an extract; the extracts and the organic phase are combined to obtain a mixture containing desulphurised intermediate 6.
In another preferred embodiment, in the step of extracting the aqueous phase with toluene, the weight ratio of toluene to the aqueous lead acetate solution is 1 (1-3); preferably 1:2.
In another preferred embodiment, in step (2.3), the concentration process is distillation under reduced pressure.
In another preferred embodiment, in the step (2.3), the distillation temperature of the reduced pressure distillation is 85 to 95 ℃ (preferably 90 ℃), and/or the vacuum degree is not more than 0.01MPa.
In another preferred embodiment, step (2.3) further comprises the step of washing the mixture containing the desulphurised intermediate 6 with water before concentrating the mixture containing the desulphurised intermediate 6.
In another preferred embodiment, in the step of washing with water, the amount of water is 8 to 12wt% based on the total amount of toluene; preferably, 10wt% (the total amount of toluene is the total amount of toluene used in step (2.1) and step (2.2)).
In another preferred embodiment, the crude intermediate 6 is obtained by direct concentration of the reaction solution containing intermediate 6.
In another preferred embodiment, the solvent of the reaction solution containing the intermediate 6 is methanol.
In another preferred embodiment, the concentration of intermediate 6 in the reaction liquid containing intermediate 6 is 20 to 24wt%.
In another preferred embodiment, the reaction solution containing the intermediate 6 is obtained by the following method:
intermediate 5 is reacted with 2- (5-bromopentanyl) -4, 4-dimethyloxazoline in an inert solvent to obtain a reaction solution containing intermediate 6.
In another preferred embodiment, the inert solvent is THF.
In a second aspect of the present invention, there is provided a desulphurised intermediate 6, said intermediate 6 being desulphurised by a process as in the first aspect.
In a third aspect of the invention, there is provided the use of an intermediate 6 as described in the second aspect,
for the preparation of intermediate 7, or for the preparation of vitamin H.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventors have conducted extensive and intensive studies. The desulfurization step is added in the synthetic route for preparing the vitamin H for the first time, so that the utilization rate of the palladium-carbon catalyst used in the synthesis is obviously improved. In addition, the inventor screens the desulfurization reagent through a large number of experiments, and finally selects lead acetate which is not easily influenced by moisture existing in a reaction system, cannot damage equipment and has thorough desulfurization as the desulfurization reagent. In addition, the inventors have also confirmed through a number of experiments the optimum concentration of lead acetate at which the intermediate 6 can be thoroughly desulphurized and almost lead-free residue in the subsequent process can be ensured. Based on this, the inventors completed the present invention.
In particular, the inventors have studied a large number of common desulfurizing agents such as iron oxide, activated carbon, molecular sieves, etc., which are susceptible to moisture although they have high yield of elemental sulfur and high desulfurizing efficiency. In addition, the common iron oxide desulfurizing agent can not be used in desulfurizing the intermediate 6 by the invention when meeting water powder. The inventors have also examined metal salts capable of desulfurization and found that desulfurization is not complete when zinc chloride is used for desulfurization and that damage to equipment is caused when copper sulfate is used.
Method for desulfurizing vitamin H intermediate
In order to solve the problem that in the existing vitamin H production process, trace sulfide is introduced into a synthetic route to poison palladium and carbon; the invention provides a novel method for improving the cyclic utilization rate of palladium-carbon and reducing the production cost, which reduces the cyclic utilization rate of palladium-carbon and greatly increases the production cost.
In one embodiment, the invention provides a method for removing sulfides in an intermediate reaction solution by washing and extracting with an aqueous lead acetate solution, namely a method for obtaining an intermediate with sulfur-containing impurities removed by concentrating, washing, extracting, layering, washing and desolventizing the compound 6 reaction solution.
In one embodiment, the method provided by the invention comprises the following steps:
(a) Taking a reaction solution containing the intermediate 6, and concentrating to obtain a mixture 1 (namely a crude product of the intermediate 6);
(b) Adding lead acetate aqueous solution to the mixture 1 to obtain a mixture 2 (i.e. a mixture of crude intermediate 6 in lead acetate aqueous solution)
(c) Toluene was added to the mixture 3 and stirred; separating the liquid and taking the organic phase, thereby obtaining a mixture 3 (namely a mixture containing a desulfurated intermediate 6); concentrating the mixture 3 gives the desulphurised intermediate 6.
In another preferred embodiment, the concentration of the aqueous lead acetate solution in step (b) is 1%.
In another preferred embodiment, the weight ratio of the aqueous lead acetate solution in step (b) to the mixture 1 is 2:1.
In another preferred embodiment, the step (c) further comprises stirring for a period of 0.5 to 1.5 hours before adding toluene.
In another preferred embodiment, the weight ratio of toluene to mixture 1 in step (c) is 5:1.
In another preferred embodiment, the concentration in step (c) is performed by distillation under reduced pressure; preferably, the distillation temperature is 90 ℃, and the vacuum degree is controlled below 0.01MPa.
In another preferred embodiment, the stirring in step (c) is carried out for a period of 0.5 to 1.5 hours.
In another preferred embodiment, the separating step of step (c) further comprises extracting the aqueous phase with toluene to obtain an extract; preferably, the weight ratio of toluene to lead acetate aqueous solution is 1:2, and the extract and organic phase are combined, thereby obtaining the mixture 2.
In another preferred embodiment, the mixture 2 of step (c) further comprises washing with water before concentrating; preferably the amount of water is 10% of the total amount of toluene.
The invention also provides the use of the method for desulphurisation of compound 6 in a method for preparing compound 7.
The method for desulfurizing the compound 6 can be applied to a preparation method of vitamin H.
The invention provides a compound 6 prepared by the compound 6 desulfurization method, wherein the compound 6 can be used for preparing a compound 7 and can be used for preparing vitamin H.
The main advantages of the invention include:
(1) The desulfurization method is suitable for a complex reaction system, and can not affect substances except sulfur-containing impurities, such as an intermediate 6, but introduce new impurities which are difficult to separate; the desulfurizing agent used in the method of the invention does not damage the reaction equipment.
(2) The lead acetate used in the method of the invention is easy to remove, and almost no residue (at most only 1.2ppm of lead remains) exists in the subsequent reaction system.
(3) The lead acetate used in the method of the invention is more thorough in sulfur removal than other metal salts (such as zinc chloride).
(4) The method has good desulfurization effect and remarkably improves the problem of sulfur poisoning of the catalyst.
Compared with the prior art, the compound 6 treated by the method of the invention is catalytically hydrogenated by using new palladium carbon, and the palladium carbon can be continuously used for three times (without adding new palladium carbon), thereby improving the utilization rate of the palladium carbon and obviously reducing the production cost.
(5) The process is simple to operate, has low technical requirements, only needs room temperature, such as 30 ℃, does not generate too much three wastes, has small waste water amount, and is easy to realize industrial production of workshops.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Example 1 preparation of intermediate 6 reaction solution
Activated magnesium chips 9.6g and anhydrous THF100ml are placed in a dry reaction bottle, two drops of 1, 2-dibromoethane are added, after the reaction is initiated, a THF (300 ml) solution of 2- (5-bromopentanyl) -4, 4-dimethyl oxazoline (38 g) is slowly added dropwise, meanwhile, the heating is slowly started, the reaction liquid is controlled to be in a micro-boiling state, and after the dropwise addition is completed, the reflux and the heat preservation are continued for 1h. Cooling to room temperature, and then continuously cooling to-15 ℃; a solution of intermediate 5 (33.8 g) in THF (700 ml) was added dropwise over about 3h, and the reaction was continued at reflux with warming for 3h. After the reaction is finished, 300g of 5% dilute hydrochloric acid is added, and the temperature is raised, the reflux and the heat preservation are carried out for 2 hours; standing for layering, separating organic phase, extracting aqueous phase with 200ml toluene for 3 times; the toluene phases were combined and washed once with 100ml of saturated brine. Then, the reaction mixture was dried over anhydrous sodium sulfate to obtain a reaction solution of intermediate 6 described below.
EXAMPLE 2 selection of lead acetate concentration and amount
In the experiment, the desulfurization effect is evaluated mainly by adding dilute acid into the intermediate 6 to raise the temperature, releasing hydrogen sulfide gas, and then detecting by lead acetate test paper to see whether the color is changed. If no sulfur-containing impurities remain in the intermediate 6, the test paper can not see color spots; if sulfur-containing impurities remain substantially in intermediate 6, the test paper will have a noticeable stain.
50g of intermediate 6 reaction liquid is taken, distilled under normal pressure, and the solvent is distilled off to obtain 11.3g of product. Cooling to 30deg.C, adding different amounts of lead acetate water solutions with different concentrations, maintaining the temperature at 30deg.C, and stirring for 1 hr. 56.5g of toluene was added thereto, and stirring was continued for 0.5 hour, followed by standing and delamination. The aqueous phase was extracted twice with 11.3g of toluene; the toluene phases were combined and the toluene phase was washed once with 7.8g of pure water. The toluene phase is distilled off under reduced pressure at 90℃and a pressure of-0.08 MPa to give intermediate 6. The resulting intermediate 6 was subjected to a sulfur content test, and the test results are shown in table 1:
TABLE 1 lead acetate concentration and dosage screening test results
Screening test data show that the sulfur removal effect can be achieved by selecting 16 times of 0.4% lead acetate aqueous solution, but the problems of low productivity and excessive wastewater are caused by the fact that the water consumption is too large. Thus, a 2-fold 1% strength aqueous lead acetate solution was selected.
EXAMPLE 3 desulfurization treatment
500g of intermediate 6 reaction liquid is taken, distilled at normal pressure, and the solvent is distilled off to obtain 113g of product. Cooling to 30 ℃, adding 226g of 1% lead acetate aqueous solution, and stirring for 1 hour at 30 ℃. 565g of toluene was added and stirring was continued for 0.5 hours, and the mixture was allowed to stand for delamination. The aqueous phase is extracted twice with 113g of toluene; the toluene phases were combined and the toluene phase was washed once with 78g of pure water. Toluene phase is distilled off under reduced pressure at 90 ℃ and the pressure of minus 0.08MPa, 565g of methanol is added to dissolve all the toluene phase, all the solution is put into a hydrogenation kettle, and 17g of palladium carbon with the water content of 50% is put into the hydrogenation kettle. The hydrogenation kettle is vacuumized after being replaced by nitrogen for three times, and then hydrogen is introduced until the pressure in the reaction kettle is about 0.35 MPa; heating to 100-105 deg.c and maintaining the temperature for 4.5 hr. And supplementing hydrogen in time in the process, ensuring that the pressure in the kettle is not lower than 0.35MPa, and the final raw material residue of the hydrogenation liquid is 0.1 percent and the lead residue is 1.5ppm. Transferring the hydrogenation liquid in the kettle, leaving palladium-carbon at the bottom of the kettle, adding a new batch of intermediate methanol solution treated by the method, hydrogenating again according to the operation, and finally, keeping the residual quantity of the raw material of the hydrogenation liquid to be 0.35 ppm and lead to be 1.0ppm. Transferring the hydrogenation liquid in the kettle again, leaving palladium-carbon at the bottom of the kettle, adding a new batch of intermediate methanol solution treated by the method, hydrogenating again according to the operation, and finally, keeping 0.48% of the raw material of the hydrogenation liquid and detecting no lead residue.
EXAMPLE 4 desulfurization treatment
600g of intermediate 6 reaction solution is taken, distilled at normal pressure, and the solvent is distilled off to obtain 132g of product. Cooling to 30 ℃, adding 260g of 1% lead acetate aqueous solution, and stirring for 1 hour under heat preservation. 660g of toluene were added and stirring was continued for 0.5 hour. Standing for layering, and extracting the water phase with 130g of toluene for two times; the toluene phases were combined and the toluene phase was washed once with 92g of purified water. The toluene phase is distilled off under reduced pressure at 90 ℃ and the pressure of minus 0.08MPa, 660g of methanol is added to dissolve the toluene phase completely, the methanol solution is put into a hydrogenation kettle completely, and 20g of palladium carbon with the water content of 50% is put into the hydrogenation kettle. The hydrogenation kettle is vacuumized after being replaced by nitrogen for three times, and then hydrogen is introduced until the pressure of the reaction kettle is about 0.35 MPa; heating to 100-105 ℃, preserving heat and reacting for 4.5 hours, supplementing hydrogen in time in the process, ensuring that the pressure in the kettle is not lower than 0.35MPa, and finally keeping the raw material residue of the hydrogenation liquid at 0.1% and the lead residue at 1.8ppm. Transferring hydrogenation liquid in the kettle, leaving palladium-carbon at the bottom of the kettle, adding a new batch of intermediate methanol solution treated according to the method, and hydrogenating again according to the operation; transferring the hydrogenated liquid in the kettle again to leave palladium-carbon at the bottom of the kettle, adding a new batch of intermediate methanol solution treated by the method, and hydrogenating again according to the operation; the final hydrogenated liquid raw material remained 0.42% and the lead residual amount was 1.2ppm.
Comparative example 1 (untreated comparative group)
500g of intermediate 6 reaction liquid is taken, distilled at normal pressure, and the solvent is distilled off to obtain 113g of product. After the temperature was lowered to 30℃and 565g of methanol was added to dissolve the whole, the whole solution was charged into a hydrogenation reactor, and 17g of palladium on carbon having a water content of 50% was charged. The hydrogenation kettle is vacuumized after being replaced by nitrogen for three times, and then hydrogen is introduced until the pressure in the reaction kettle is about 0.35 MPa; heating to 100-105 deg.c and maintaining the temperature for 4.5 hr. And supplementing hydrogen in time in the process, ensuring that the pressure in the kettle is not lower than 0.35MPa, and finally ensuring that the raw material residue of the hydrogenation liquid is 0.15%. Transferring the hydrogenation liquid in the kettle, leaving palladium-carbon at the bottom of the kettle, adding a new batch of intermediate methanol solution treated by the method, hydrogenating again according to the operation, and finally leaving 6.62% of the hydrogenation liquid raw material. 2g of palladium carbon with new water content of 50% is added, hydrogenation is carried out again according to the operation, and the final hydrogenation liquid raw material residue is 0.21%. Transferring the hydrogenation liquid in the kettle again, leaving palladium-carbon at the bottom of the kettle, adding a new batch of intermediate methanol solution treated by the method, hydrogenating again according to the operation, and finally leaving 5.28% of the hydrogenation liquid raw material. 2g of palladium carbon with new water content of 50% is added, hydrogenation is carried out again according to the operation, and the final hydrogenation liquid raw material residue is 0.13%.
In the industrial production, when compound 7 was produced from compound 6 by the production process of comparative example 1, about 7.5 kg of fresh palladium on carbon was required for each batch, and the market price of palladium on carbon was about 2.2 ten thousand yuan/kg; on the premise of meeting the process requirements, the production cost of each batch can be reduced by about 16 ten thousand yuan after the treatment according to the method of the invention, and the production cost is obviously reduced.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. A process for desulfurizing vitamin H intermediate 6, said process comprising the steps of:
(1) Providing a mixture of crude intermediate 6 in an aqueous lead acetate solution; wherein the intermediate 6 crude product comprises sulfur-containing impurities; wherein, in the lead acetate aqueous solution, the concentration of lead acetate is 0.8-1.2wt%, and the mass ratio of the lead acetate aqueous solution to the crude product of the intermediate 6 is (1-3): 1; and
(2) Separating the mixture of step (1) to obtain a desulphurised intermediate 6.
2. The method of claim 1, wherein in step (1), the concentration of lead acetate in the aqueous lead acetate solution is 1wt%.
3. The method of claim 1, wherein in step (1), the mass ratio of the aqueous lead acetate solution to the crude intermediate 6 product is 2:1.
4. The method of claim 1, wherein in step (2), the mixture of step (1) is separated by extraction and the extractant of the extraction is toluene.
5. The method of claim 1, wherein in step (1), the temperature of the mixture is from 25 ℃ to 35 ℃.
6. The method of claim 1, wherein in step (1), the temperature of the mixture is 30 ℃.
7. The method of claim 1, wherein step (1) comprises the steps of:
an aqueous lead acetate solution was added to the crude intermediate 6 and stirred, thereby obtaining a mixture of the crude intermediate 6 in the aqueous lead acetate solution.
8. The method of claim 7, wherein in step (1), the stirring time of the stirring is 0.5 to 1.5 hours.
9. The method of claim 1, wherein step (2) comprises the steps of:
(2.1) adding toluene to the mixture in the step (1) and stirring;
(2.2) separating the liquid and taking the organic phase, thereby obtaining a mixture containing the desulphurized intermediate 6; and
(2.3) concentrating the mixture containing the desulfurized intermediate 6 obtained in the step (2.2), thereby obtaining the desulfurized intermediate 6.
10. The process according to claim 1, wherein the crude intermediate 6 is obtained by direct concentration of the reaction solution containing intermediate 6.
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| CN106732656A (en) * | 2016-12-27 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of biotin intermediate is hydrogenated with the process for reactivation of palladium carbon catalyst |
| CN107973806A (en) * | 2016-10-21 | 2018-05-01 | 大丰海嘉诺药业有限公司 | A kind of method for preparing D-Biotin bromide intermediate |
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| CN107973806A (en) * | 2016-10-21 | 2018-05-01 | 大丰海嘉诺药业有限公司 | A kind of method for preparing D-Biotin bromide intermediate |
| CN106732656A (en) * | 2016-12-27 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of biotin intermediate is hydrogenated with the process for reactivation of palladium carbon catalyst |
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