CN111377940A - Method for desulfurizing vitamin H intermediate - Google Patents
Method for desulfurizing vitamin H intermediate Download PDFInfo
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- CN111377940A CN111377940A CN201811644611.4A CN201811644611A CN111377940A CN 111377940 A CN111377940 A CN 111377940A CN 201811644611 A CN201811644611 A CN 201811644611A CN 111377940 A CN111377940 A CN 111377940A
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- lead acetate
- desulfurized
- carbon
- palladium
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- 238000000034 method Methods 0.000 title claims abstract description 56
- 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 18
- 229930003756 Vitamin B7 Natural products 0.000 title claims abstract description 17
- 239000011735 vitamin B7 Substances 0.000 title claims abstract description 17
- 235000011912 vitamin B7 Nutrition 0.000 title claims abstract description 17
- 230000003009 desulfurizing effect Effects 0.000 title description 7
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 229940046892 lead acetate Drugs 0.000 claims abstract description 33
- 239000000243 solution Substances 0.000 claims abstract description 25
- 239000007864 aqueous solution Substances 0.000 claims abstract description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 15
- 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
- 239000000047 product Substances 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 102
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 22
- 238000006477 desulfuration reaction Methods 0.000 claims description 17
- 230000023556 desulfurization Effects 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 24
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000005406 washing Methods 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000005984 hydrogenation reaction Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 239000012071 phase Substances 0.000 description 9
- 239000008346 aqueous phase Substances 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
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 231100000572 poisoning Toxicity 0.000 description 4
- 230000000607 poisoning effect Effects 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- -1 2- (5-bromopentyl) -4, 4-dimethyloxazoline Chemical compound 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004134 energy conservation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment 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
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000010992 reflux 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
- 230000001502 supplementing effect Effects 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
- 238000006555 catalytic 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
- 238000001704 evaporation Methods 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
- 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
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 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
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 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
- 238000005292 vacuum distillation Methods 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
- 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 a lead acetate aqueous solution. The method comprises the following steps: (1) providing a mixture of the intermediate 6 crude product in an aqueous solution of lead acetate; wherein the crude intermediate 6 product comprises sulfur-containing impurities; and (2) separating the mixture of step (1) to obtain a desulfurized intermediate 6. The palladium-carbon can be used indiscriminately for three times without adding new palladium-carbon in the process of obtaining the intermediate 7 by reducing the intermediate 6 through the palladium-carbon, so that the process production cost is obviously reduced.
Description
Technical Field
The invention belongs to the technical field of vitamin H production; more particularly relates to a method for desulfurizing a reaction liquid of a vitamin H intermediate.
Background
Vitamin H, also known as d-biotin, coenzyme R, is a water-soluble vitamin, also belonging to the vitamin B group, B7. It is an indispensable substance for normal metabolism of fat and protein, and is also a necessary nutrient for maintaining the natural growth and development of human bodies and the normal functional health of human bodies.
To date, several routes for the synthesis of vitamin H have been developed, but the currently accepted most industrially applicable route is that disclosed in the Hoffmann-La Roche (US 2489238):
the catalytic hydrogenation step from compound 6 to compound 7 in the route now mostly uses palladium on carbon as catalyst. The palladium-carbon catalysis has the advantages of small dosage, high activity, short reaction time, high conversion rate and the like; meanwhile, the method also has the defects of high price and easy poisoning. In the preparation of the compound 5 in the route, sulfide is used, so that the sulfide is inevitably carried into a subsequent intermediate, and trace sulfide can poison palladium carbon; the cyclic utilization rate of the palladium-carbon is reduced, and the production cost is greatly increased.
Nowadays, energy conservation and environmental protection are vigorously advocated, and how to improve the cyclic utilization rate of chemical reagents in industrial production, energy conservation and cost reduction are one of the main targets of industrial production.
In view of the above, there is an urgent need in the art to develop a new method capable of improving the recycling rate of palladium-carbon and reducing the production cost.
Disclosure of Invention
The invention aims to provide a method for removing sulfur-containing 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 a vitamin H intermediate 6, the process comprising the steps of:
(1) providing a mixture of the intermediate 6 crude product in an aqueous solution of lead acetate; wherein the crude intermediate 6 product comprises sulfur-containing impurities; and
(2) separating the mixture of step (1) to obtain a desulfurized intermediate 6.
In another preferred embodiment, the crude intermediate 6 product contains less than or equal to 0.9% of sulfur-containing impurities.
In another preferred example, the crude product of the intermediate 6 contains 97.5-98.5% of the intermediate 6.
In another preferred embodiment, the sulfur-containing impurities comprise: sodium thioacetate, and/or sodium sulfide.
In another preferred example, in the step (1), the concentration of the lead acetate in the lead acetate aqueous solution is 0.8-1.2 wt%; preferably 1 wt%.
In another preferred example, in the step (1), the mass ratio of the aqueous lead acetate solution to the crude intermediate 6 product is (1-3): 1; preferably 2: 1.
In another preferred example, in the step (1), the temperature of the mixture is 25-35 ℃; preferably 30 deg.c.
In another preferred example, the step (1) includes the steps of:
an aqueous solution of lead acetate was added to the crude intermediate 6 and stirred to obtain a mixture of the crude intermediate 6 in the aqueous solution of lead acetate.
In another preferred example, in the step (1), the stirring time for stirring is 0.5 to 1.5 hours.
In another preferred example, 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 for extraction is toluene.
In another preferred embodiment, the mass ratio of the extracting agent to the intermediate 6 crude product is (4-6): 1; preferably, it is 5: 1.
In another preferred example, the step (2) includes the steps of:
(2.1) adding toluene into the mixture obtained in the step (1) and stirring;
(2.2) separating liquid, and taking an organic phase to obtain a mixture containing the desulfurized intermediate 6; and
(2.3) concentrating the mixture comprising desulfurized intermediate 6 obtained in step (2.2) to obtain desulfurized intermediate 6.
In another preferred example, in the step (2.1), the stirring time for stirring is 0.5 to 1.5 hours.
In another preferred example, in the step (2.2), the liquid separation also obtains an aqueous phase;
and the method also comprises the following steps after liquid separation: extracting the aqueous phase with toluene, thereby obtaining an extract; the extract and the organic phase are combined to obtain a mixture containing desulfurized intermediate 6.
In another preferred example, in the step of extracting the aqueous phase with toluene, the weight ratio of toluene to the aqueous solution of lead acetate is 1 (1-3); preferably 1: 2.
In another preferred example, in the step (2.3), the concentration method is distillation under reduced pressure.
In another preferred example, in the step (2.3), the distillation temperature of the reduced pressure distillation is 85-95 ℃ (preferably 90 ℃), and/or the vacuum degree is less than or equal to 0.01 MPa.
In another preferred example, step (2.3) further comprises the step of washing the mixture containing desulfurized intermediate 6 with water before concentrating the mixture containing desulfurized intermediate 6.
In another preferred example, in the step of washing with water, the amount of water is 8 to 12 wt% of the total amount of toluene; preferably, 10 wt% (the total amount of toluene used is the total amount of toluene used in step (2.1) and step (2.2)).
In another preferred example, the crude intermediate 6 product is obtained by directly concentrating the reaction solution containing the intermediate 6.
In another preferred example, the solvent of the reaction solution containing intermediate 6 is methanol.
In another preferred example, the concentration of the intermediate 6 in the reaction solution containing the intermediate 6 is 20 to 24 wt%.
In another preferred embodiment, the reaction solution containing intermediate 6 is obtained by the following method:
the intermediate 5 is reacted with 2- (5-bromopentyl) -4, 4-dimethyloxazoline in an inert solvent to obtain a reaction solution containing an intermediate 6.
In another preferred embodiment, the inert solvent is THF.
In a second aspect of the invention, there is provided a desulphurised intermediate 6, the intermediate 6 being desulphurised by a process as in the first aspect.
In a third aspect of the invention there is provided a 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 to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
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 in a reaction system, cannot damage equipment and is thoroughly desulfurized as the desulfurization reagent. Moreover, the inventors have also confirmed, through numerous experiments, an optimal concentration of lead acetate which allows a thorough desulfurization of the intermediate 6 and guarantees an almost lead-free residue in the subsequent processes. Based on this, the inventors have completed the present invention.
Specifically, the inventors have conducted extensive studies on commonly used desulfurization reagents, such as iron oxide, activated carbon, molecular sieves, etc., which are susceptible to moisture, although the yield of elemental sulfur is high and the desulfurization efficiency is high. In addition, the common iron oxide desulfurizer can not be used for the desulfurization of the intermediate 6 in the invention when meeting water powder. The inventors have also examined metal salts capable of desulfurization and have found that desulfurization is not completely achieved by using zinc chloride and that damage to equipment is caused by using copper sulfate.
Method for desulfurizing vitamin H intermediate
Aims to solve the problem that trace sulfide is introduced into the synthesis route to cause palladium-carbon poisoning in the existing vitamin H production process; the invention reduces the cyclic utilization rate of palladium-carbon and greatly increases the production cost, and provides a new method for improving the cyclic utilization rate of palladium-carbon and reducing the production cost.
In one embodiment, the invention provides a method for removing sulfide in intermediate reaction liquid by washing and extracting lead acetate aqueous solution, namely a method for leading the compound 6 reaction liquid to be concentrated → washed → extracted → layered → washed → exsolution, and finally obtaining the intermediate from which sulfur-containing impurities are removed.
In one embodiment, the present invention provides a method comprising the steps of:
(a) taking the reaction liquid containing the intermediate 6, and concentrating to obtain a mixture 1 (namely the intermediate 6 crude product);
(b) an aqueous solution of lead acetate was added to the mixture 1 to obtain a mixture 2 (i.e., a mixture of the crude intermediate 6 in an aqueous solution of lead acetate)
(c) Adding toluene into the mixture 3 and stirring; separating, and taking an organic phase to obtain a mixture 3 (namely a mixture containing the desulfurized intermediate 6); the mixture 3 is concentrated to obtain the desulfurized intermediate 6.
In another preferred embodiment, the concentration of the aqueous solution of lead acetate in the step (b) is 1%.
In another preferred example, the weight ratio of the aqueous solution of lead acetate to the mixture 1 in the step (b) is 2: 1.
In another preferred embodiment, the step (c) further comprises stirring before adding toluene, and the stirring time is 0.5-1.5 hours.
In another preferred embodiment, the weight ratio of toluene to the mixture 1 in the step (c) is 5: 1.
In another preferred example, the concentration in step (c) is performed by vacuum distillation; preferably, the distillation temperature is 90 ℃, and the vacuum degree is controlled to be below 0.01 MPa.
In another preferred embodiment, the stirring in step (c) is performed for 0.5 to 1.5 hours.
In another preferred example, the step (c) of separating the liquid further comprises extracting the aqueous phase with toluene to obtain an extract; preferably, the weight ratio of toluene to aqueous lead acetate is 1:2, and the extract and organic phase are combined to obtain the mixture 2.
In another preferred embodiment, the mixture 2 of step (c) further comprises washing with water before concentration; preferably, the amount of water is 10% of the total amount of toluene.
The invention also provides the application of the method for desulfurizing the compound 6 in the method for preparing the compound 7.
The method for desulfurizing the compound 6 provided by the invention 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 the method can not influence substances except sulfur-containing impurities such as an intermediate 6 and introduce new impurities which are difficult to separate; the desulfurizing agent used in the method of the invention does not damage reaction equipment.
(2) The lead acetate used in the method of the invention is easy to remove, and almost no lead (only 1.2ppm lead at most) remains in the subsequent reaction system.
(3) Compared with other metal salts (such as zinc chloride), the lead acetate used in the method of the invention can remove sulfur more thoroughly.
(4) The method of the invention has good desulfurization effect and obviously improves the problem of sulfur poisoning of the catalyst.
Compared with the prior art, the compound 6 treated by the method is subjected to catalytic hydrogenation by using new palladium carbon, and the palladium carbon can be continuously applied for three times (without adding new palladium carbon), so that the utilization rate of the palladium carbon is improved, and the production cost is obviously reduced.
(5) The process is simple to operate, the technical requirement is low, the process only needs the condition of 30 ℃ at room temperature, the generation of three wastes is avoided, the waste water amount is small, and the industrial production of workshops is easy to realize.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
EXAMPLE 1 preparation of reaction solution for intermediate 6
9.6g of activated magnesium chips 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 (300ml) solution of 2- (5-bromoamyl) -4, 4-dimethyl oxazoline (38g) is slowly dripped immediately, meanwhile, the slow heating is started, the reaction solution is controlled to be in a micro-boiling state, and after the dripping is finished, the reflux heat preservation is continued for 1 hour. Cooling to room temperature, and then continuously cooling to-15 ℃; a THF (700ml) solution of intermediate 5(33.8g) was added dropwise over about 3h, then heated to reflux and allowed to react for 3 h. After the reaction is finished, 300g of 5% diluted hydrochloric acid is added, and the temperature is raised, refluxed and kept for reaction for 2 hours; standing for layering, removing an organic phase, and extracting an aqueous phase with 200ml of toluene for 3 times; the toluene phases were combined and washed once with 100ml of saturated brine. Then 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 diluted acid to the intermediate 6 to heat up, releasing hydrogen sulfide gas, and detecting by using lead acetate test paper to see whether the color is changed. If the intermediate 6 has no sulfur-containing impurities, the test paper can not see color spots basically; if sulfur impurities remain substantially in intermediate 6, the test strip will be visibly stained.
Taking 50g of intermediate 6 reaction liquid, distilling at normal pressure, and evaporating the solvent to obtain 11.3g of product. Cooling to 30 ℃, adding lead acetate aqueous solutions with different concentrations in different amounts, keeping the temperature at 30 ℃, and stirring for 1 hour. 56.5g of toluene was added thereto, and the mixture was stirred for 0.5 hour and allowed to stand for separation. 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. Toluene is evaporated under reduced pressure at 90 ℃ and-0.08 MPa to obtain an intermediate 6. The sulfur content of the intermediate 6 was measured and the results are shown in table 1:
TABLE 1 screening test results for lead acetate concentration and amount
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 yield and excessive wastewater are caused by too much water. Thus, a 2-fold 1% aqueous solution of lead acetate was selected.
Example 3 desulfurization treatment
500g of the intermediate 6 reaction solution is taken, distilled under normal pressure, and the solvent is evaporated to obtain 113g of a product. The temperature is reduced to 30 ℃, 226g of 1 percent lead acetate aqueous solution is added, and the mixture is stirred for 1 hour under the condition of heat preservation at 30 ℃. 565g of toluene was added, and the mixture was stirred for 0.5 hour and allowed to stand for separation. The aqueous phase was extracted twice with 113g of toluene; the toluene phases were combined and the toluene phase was washed once with 78g of pure water. The toluene phase was evaporated to dryness under reduced pressure at 90 ℃ and-0.08 MPa, and then 565g of methanol was added to dissolve the toluene, and the solution was charged into a hydrogenation reactor, and 17g of palladium on carbon having a water content of 50% was added. The hydrogenation kettle is replaced by nitrogen for three times, then vacuum pumping is carried out, and then hydrogen is introduced until the pressure in the reaction kettle is about 0.35 MPa; the temperature is raised to 100 ℃ and 105 ℃, and the reaction is kept for 4.5 hours. Supplementing hydrogen in time during the process, ensuring that the pressure in the kettle is not lower than 0.35MPa, the final hydrogenation liquid raw material residue is 0.1 percent, and the lead residue is 1.5 ppm. 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, and carrying out hydrogenation again according to the operation, wherein the raw material of the final hydrogenation liquid is 0.35 percent and the residual quantity of lead is 1.0 ppm. 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, and hydrogenating again according to the operation, wherein 0.48 percent of the raw material of the final hydrogenation liquid is remained, and no lead residue is detected.
Example 4 desulfurization treatment
600g of intermediate 6 reaction liquid is taken, distilled under normal pressure, and the solvent is evaporated to obtain 132g of product. The temperature is reduced to 30 ℃, 260g of 1 percent lead acetate aqueous solution is added, and the mixture is stirred for 1 hour under the condition of heat preservation. 660g of toluene were added thereto, and the stirring was continued for 0.5 hour. Standing for layering, and extracting the water phase twice by using 130g of toluene; the toluene phases were combined and the toluene phase was washed once with 92g of purified water. Toluene is evaporated under reduced pressure at 90 ℃ and-0.08 MPa, 660g of methanol is added to dissolve the toluene completely, the methanol solution is added into a hydrogenation kettle completely, and 20g of palladium-carbon with the water content of 50 percent is added. Replacing the hydrogenation kettle with nitrogen for three times, vacuumizing, and introducing hydrogen until the pressure of the reaction kettle is about 0.35 MPa; heating to 100 ℃ and 105 ℃, carrying out heat preservation reaction for 4.5 hours, replenishing hydrogen in time in the process, ensuring that the pressure in the kettle is not lower than 0.35MPa, the final hydrogenation liquid raw material residue is 0.1 percent, and the lead residual quantity is 1.8 ppm. 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 according to the method, and hydrogenating again according to the operation; 0.28 percent of the final hydrogenation liquid raw material is remained, the residual lead content is 1.1ppm, the hydrogenation liquid in the kettle is transferred again, palladium carbon at the bottom of the kettle is remained, a new batch of intermediate methanol solution treated according to the method is added, and hydrogenation is carried out again according to the operation; 0.42% of the final hydrogenation liquid raw material and a lead residue of 1.2 ppm.
COMPARATIVE EXAMPLE 1 (untreated control group)
500g of the intermediate 6 reaction solution is taken, distilled under normal pressure, and the solvent is evaporated to obtain 113g of a product. The temperature is reduced to 30 ℃, 565g of methanol is added to dissolve the palladium and carbon, the solution is all put into a hydrogenation kettle, and 17g of palladium and carbon with the water content of 50 percent are put into the hydrogenation kettle. The hydrogenation kettle is replaced by nitrogen for three times, then vacuum pumping is carried out, and then hydrogen is introduced until the pressure in the reaction kettle is about 0.35 MPa; the temperature is raised to 100 ℃ and 105 ℃, and the reaction is kept for 4.5 hours. Supplementing hydrogen in time during the process, ensuring that the pressure in the kettle is not lower than 0.35MPa and the final hydrogenation liquid raw material residue 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, and hydrogenating again according to the operation, wherein the raw material of the final hydrogenation liquid is 6.62 percent remained. And adding new 2g of palladium-carbon with the water content of 50%, and then carrying out hydrogenation again according to the operation, wherein the final hydrogenation liquid raw material is 0.21% in residue. 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, and hydrogenating again according to the operation, wherein the raw material of the final hydrogenation liquid is 5.28 percent. And adding new 2g of palladium-carbon with the water content of 50%, and then carrying out hydrogenation again according to the operation, wherein the final hydrogenation liquid raw material residue is 0.13%.
In industrial production, when compound 7 was prepared from compound 6 using the production process of comparative example 1, about 7.5 kg of new palladium on carbon was added to each batch, and the market price of palladium on carbon was about 2.2 ten thousand yuan/kg; after the treatment according to the method of the invention, on the premise of meeting the process requirements, the production cost of each batch can be reduced by about 16 ten thousand yuan, and the production cost is obviously reduced.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for the desulfurization of a vitamin H intermediate 6, said process comprising the steps of:
(1) providing a mixture of the intermediate 6 crude product in an aqueous solution of lead acetate; wherein the crude intermediate 6 product comprises sulfur-containing impurities; and
(2) separating the mixture of step (1) to obtain a desulfurized intermediate 6.
2. The method of claim 1, wherein in step (1), the concentration of lead acetate in the aqueous solution of lead acetate is 0.8-1.2 wt%; preferably 1 wt%.
3. The method according to claim 1, wherein in the step (1), the mass ratio of the aqueous lead acetate solution to the crude intermediate 6 product is (1-3: 1; preferably 2: 1.
4. The method of claim 1, wherein in step (1), the temperature of the mixture is 25-35 ℃; preferably 30 deg.c.
5. The method of claim 1, wherein step (1) comprises the steps of:
an aqueous solution of lead acetate was added to the crude intermediate 6 and stirred to obtain a mixture of the crude intermediate 6 in the aqueous solution of lead acetate.
6. The method of claim 5, wherein in step (1), the stirring time for stirring is 0.5 to 1.5 hours.
7. The method of claim 1, wherein step (2) comprises the steps of:
(2.1) adding toluene into the mixture obtained in the step (1) and stirring;
(2.2) separating liquid, and taking an organic phase to obtain a mixture containing the desulfurized intermediate 6; and
(2.3) concentrating the mixture comprising desulfurized intermediate 6 obtained in step (2.2) to obtain desulfurized intermediate 6.
8. The method of claim 1, wherein the crude intermediate 6 is obtained by directly concentrating a reaction solution containing intermediate 6.
9. A desulfurized intermediate 6 characterized in that said intermediate 6 is desulfurized by the process of claim 1.
10. Use of intermediate 6 according to claim 9,
for the preparation of intermediate 7, or for the preparation of vitamin H.
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| JPH11221434A (en) * | 1998-02-04 | 1999-08-17 | Mitsui Mining & Smelting Co Ltd | Removal of hydrogen sulfide in gas containing carbon dioxide |
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| JPH11221434A (en) * | 1998-02-04 | 1999-08-17 | Mitsui Mining & Smelting Co Ltd | Removal of hydrogen sulfide in gas containing carbon dioxide |
| 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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