CN113121444A - Method for synthesizing vitamin H intermediate through pipelining - Google Patents
Method for synthesizing vitamin H intermediate through pipelining Download PDFInfo
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- CN113121444A CN113121444A CN201911398313.6A CN201911398313A CN113121444A CN 113121444 A CN113121444 A CN 113121444A CN 201911398313 A CN201911398313 A CN 201911398313A CN 113121444 A CN113121444 A CN 113121444A
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 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 15
- 229930003756 Vitamin B7 Natural products 0.000 title claims abstract description 14
- 239000011735 vitamin B7 Substances 0.000 title claims abstract description 14
- 235000011912 vitamin B7 Nutrition 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 239000000243 solution Substances 0.000 claims abstract description 61
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 49
- 239000011259 mixed solution Substances 0.000 claims abstract description 30
- 239000012266 salt solution Substances 0.000 claims abstract description 18
- 238000002156 mixing Methods 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims abstract description 4
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 12
- 238000005070 sampling Methods 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 230000002572 peristaltic effect Effects 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940068840 d-biotin Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
-
- 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)
Abstract
The invention provides a method for synthesizing a vitamin H intermediate in a pipeline way. Specifically, the method comprises the following steps: (1) providing a salt solution of a compound of formula 2, a triphosgene (BTC) solution, and a potassium hydroxide solution; (2) mixing a salt solution of the compound shown in the formula 2, a triphosgene (BTC) solution and a potassium hydroxide solution, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction; and (3) adjusting the pH of the reaction solution after the reaction to acidity to obtain a compound shown in the formula 3; wherein the salt is a potassium salt and/or a sodium salt of the compound of formula 2. The method has high conversion rate of raw materials and very safe operation, and is suitable for industrial production of the vitamin H intermediate.
Description
Technical Field
The invention relates to the field of medicines, in particular to a method for synthesizing a vitamin H intermediate in a pipeline manner.
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):
in the route from the compound of formula 2 to the compound of formula 3, the conventional synthesis method is to add triphosgene solution and potassium hydroxide solution dropwise into the compound of formula 2 aqueous solution in a reaction kettle. However, the method has the disadvantages of large triphosgene dosage, low conversion rate and low safety.
Therefore, there is a strong need in the art to provide a method for preparing the compound of formula 3 with high conversion rate of raw materials and high safety.
Disclosure of Invention
The invention aims to provide a preparation method of a compound of formula 3, which has high conversion rate of raw materials and high safety.
In a first aspect of the present invention, there is provided a method for synthesizing a compound of formula 3, comprising the steps of:
(1) providing a salt solution of a compound of formula 2, a triphosgene (BTC) solution, and a potassium hydroxide solution;
(2) mixing a salt solution of the compound shown in the formula 2, a triphosgene (BTC) solution and a potassium hydroxide solution, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction; and
(3) adjusting the pH of the reaction solution after the reaction to be acidic to obtain a compound shown in the formula 3;
wherein the salt is a potassium salt and/or a sodium salt of the compound of formula 2.
In another preferred example, the mixing the feeding in the step (2) is feeding while mixing.
In another preferred example, step (2) is preceded by the steps of:
the salt solution of the compound of formula 2, the triphosgene (BTC) solution and the potassium hydroxide solution are pre-cooled to 5-15 c, preferably 10-15 c, respectively.
In another preferred example, the method further comprises the steps of: and sampling and detecting the pH value of the reaction liquid through a sampling port of the pipeline reactor, and controlling the reaction by adjusting the proportion of the reaction liquid.
In another preferred example, when the sampling port is positioned at l (0.5 +/-0.02) of the length l of the pipeline reactor pipe, the pH value of the reaction liquid of the sampling port is controlled to be 8-9.
In another preferred embodiment, the pH of the reaction solution is controlled by adjusting the amount of potassium hydroxide during mixing.
In another preferred embodiment, the pipeline reactor is selected from the group consisting of: horizontal tubular reactors, vertical tubular reactors, coil tubular reactors and U-shaped tubular reactors.
In another preferred embodiment, the pipe reactor has a length of 8 to 30m, preferably 10 to 20 m.
In another preferred embodiment, the pipe reactor has a pipe diameter of 0.8 to 5cm, preferably 1 to 3cm, more preferably 1 to 2 cm.
In another preferred example, the method further comprises the steps of: and (4) filtering and drying the compound of the formula 3 obtained in the step (3).
In another preferred embodiment, the residence time of the mixed liquid in the pipeline reactor is more than or equal to 10min or more than or equal to 15min, preferably 10-60min, and more preferably 15-30 min.
In another preferred embodiment, the solvent of the salt solution of the compound of formula 2 is water or an aqueous solvent.
In another preferred embodiment, the concentration of the compound of formula 2 in the salt solution of the compound of formula 2 is 1 to 25 wt%, preferably 5 to 20 wt%, more preferably 6 to 15 wt%, based on the compound of formula 2.
In another preferred embodiment, the salt solution of the compound of formula 2 is prepared by dissolving a salt of the compound of formula 2 in a solvent; or by dissolving the compound of formula 2 in a solution of sodium hydroxide and/or potassium hydroxide.
In another preferred embodiment, the salt of the compound of formula 2 is selected from the group consisting of: a disodium salt, a dipotassium salt, or a combination thereof.
In another preferred embodiment, the solvent of the triphosgene solution is selected from the group consisting of: toluene, diethyl ether, Tetrahydrofuran (THF), benzene, cyclohexane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, dichloromethane, ethanol, methanol, or combinations thereof.
In another preferred embodiment, the concentration of triphosgene in the triphosgene solution is 1 to 30 wt%, preferably 5 to 25 wt%, more preferably 10 to 20 wt%.
In another preferred embodiment, the solvent of the potassium hydroxide solution is water or an aqueous solvent.
In another preferred embodiment, the concentration of potassium hydroxide in the potassium hydroxide solution is 1 to 35 wt%, preferably 10 to 30 wt%, more preferably 15 to 28 wt%.
In another preferred embodiment, the mixed solution has one or more of the following characteristics:
1) the solvent of the mixed solution is a mixed solvent of water and an organic solvent;
2) the concentration of the compound of formula 2 is 1-15 wt%, preferably 5-12 wt%, more preferably 6-10 wt%, based on the total weight of the mixed solution;
3) the concentration of the triphosgene in the mixed solution is 1-10 wt%, preferably 2-8 wt%, more preferably 3-6 wt%, based on the total weight of the mixed solution;
4) the concentration of the potassium hydroxide in the mixed solution is 1-8 wt%, preferably 2-7 wt%, more preferably 3-5 wt%, based on the total weight of the mixed solution; and/or
5) In the mixture, the compound of formula 2: triphosgene: the weight ratio of the potassium hydroxide is 2-3:1-2: 1; preferably, 2-2.5:1-1.5: 1.
In another preferred embodiment, in the mixed solvent of water and the organic solvent, the volume ratio of water to the organic solvent is 1-8:1, preferably 2-6:1, and more preferably 3-5: 1.
In another preferred embodiment, in step (2), the reaction temperature of the reaction is 10 to 40 ℃, preferably 20 to 30 ℃.
In another preferred example, in the step (2), the mixed liquid is fed into the pipeline reactor through a peristaltic pump.
In another preferred embodiment, in the step (3), the reaction solution is adjusted to pH 1 to 3, preferably 1 to 2.
In another preferred embodiment, the pipeline reactor comprises: hollow pipeline, feed inlet, discharge gate and sample connection.
In another preferred example, the sampling port is located at (0.5 ± 0.02) l of the pipe length l.
In a second aspect of the present invention, there is provided a method for preparing vitamin H, comprising the steps of:
wherein a step of preparing compound 3 using a process as in the first aspect of the invention is included.
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.
Drawings
FIG. 1 is a schematic view of a pipeline reactor according to the first, second and fourth embodiments of the present invention.
FIG. 2 is a schematic view of a pipeline reactor used in the third and fifth embodiments of the present invention.
Detailed Description
The present inventors have conducted extensive and intensive studies and, as a result, have provided a method for the pipelined synthesis of a vitamin H intermediate (a compound of formula 3). The method adopts the pipeline type reactor to synthesize the compound of the formula 3, so that phosgene generated by triphosgene hydrolysis cannot be released out of the reactor, and can continue to react in a reaction solution, thereby improving the utilization rate of the triphosgene, having higher yield and essentially improving the operation safety. The present invention has been completed based on this finding.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
Reaction device
As used herein, the terms "tubular reactor", "pipeline reactor" or "pipeline reactor" are used interchangeably. The pipeline reactor is a continuously operated reactor with a large length-diameter ratio. The flow of material can be viewed approximately as plug flow. The tubular reactor has small back mixing, so that the tubular reactor has high volumetric efficiency (unit volume production capacity) and is particularly suitable for occasions requiring higher conversion rate or having series side reactions.
Typically, the pipeline reactor includes, but is not limited to: horizontal tubular reactors, vertical tubular reactors, coil tubular reactors and U-shaped tubular reactors. Preferably, the pipe reactor pipe has a diameter of 0.8 to 5cm, preferably 1 to 3cm, more preferably 1 to 2 cm.
Typically, the pipeline reactor comprises: hollow pipeline, feed inlet, discharge gate and sample connection. The sampling port is preferably located in the middle section of the pipeline, and the reaction condition can be sampled and detected from the sampling port. The sampler is optimally located at (0.5 ± 0.02) l of the tube length l. Alternatively, more than one sampler may be provided as desired. Typically, the hollow conduit is a seamless steel tube, such as medical grade stainless steel.
In the present invention, the apparatus for use with the pipe reactor further comprises: a feed vessel, a mixer, a pump and/or a receiving device. Typically, the salt solution of the compound of formula 2, the triphosgene (BTC) solution and the potassium hydroxide solution are transferred from their respective supply containers to the mixer by a driving force generated by a pump, and the mixed liquid is introduced from the inlet of the pipe reactor and discharged from the outlet of the pipe reactor to the receiving device after the reaction is completed. Preferably, the device forms a sealed system (connectable to an exhaust conduit (e.g. via a breather valve) to equalize air pressure).
In another preferred example, the pump is a peristaltic pump and is respectively connected with the feeding ports of the mixer and the pipeline reactor through hoses. The peristaltic pump enables the mixed liquid in the hose to move through extrusion without contacting with the mixed liquid, so that impurities can be prevented from being introduced.
Further, the amount of each solution to be sampled may be adjusted by adjusting the discharge valve of the supply container or by an electromagnetic valve.
Process for the preparation of compounds of formula 3
In a first aspect of the present invention, there is provided a method for synthesizing a compound of formula 3, comprising the steps of:
(1) providing a salt solution of a compound of formula 2, a triphosgene (BTC) solution, and a potassium hydroxide solution;
(2) mixing a salt solution of the compound shown in the formula 2, a triphosgene (BTC) solution and a potassium hydroxide solution, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction; and
(3) adjusting the pH of the reaction solution after the reaction to be acidic to obtain a compound shown in the formula 3;
wherein the salt is a potassium salt and/or a sodium salt of the compound of formula 2.
In another preferred example, the mixing the feeding in the step (2) is feeding while mixing.
In another preferred example, step (2) is preceded by the steps of:
the salt solution of the compound of formula 2, the triphosgene (BTC) solution and the potassium hydroxide solution are pre-cooled to 5-15 c, preferably 10-15 c, respectively.
In another preferred example, the method further comprises the steps of: and sampling and detecting the pH value of the reaction liquid through a sampling port of the pipeline reactor, and controlling the reaction by adjusting the proportion of the reaction liquid.
In another preferred example, the method further comprises the steps of: and (4) filtering and drying the compound of the formula 3 obtained in the step (3).
In another preferred embodiment, the residence time of the mixed liquid in the pipeline reactor is more than or equal to 10min or more than or equal to 15min, preferably 10-60min, and more preferably 15-30 min.
In another preferred embodiment, the solvent of the salt solution of the compound of formula 2 is water or an aqueous solvent.
In another preferred embodiment, the salt solution of the compound of formula 2 is prepared by dissolving a salt of the compound of formula 2 in a solvent; or by dissolving the compound of formula 2 in a solution of sodium hydroxide and/or potassium hydroxide.
In another preferred embodiment, the salt of the compound of formula 2 is selected from the group consisting of: a disodium salt, a dipotassium salt, or a combination thereof.
In another preferred embodiment, the solvent of the triphosgene solution is selected from the group consisting of: toluene, diethyl ether, Tetrahydrofuran (THF), benzene, cyclohexane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, dichloromethane, ethanol, methanol, or combinations thereof.
In another preferred embodiment, the mixed solution has one or more of the following characteristics:
1) the solvent of the mixed solution is a mixed solvent of water and an organic solvent;
2) the concentration of the compound of formula 2 is 1-15 wt%, preferably 5-12 wt%, more preferably 6-10 wt%, based on the total weight of the mixed solution;
3) the concentration of the triphosgene in the mixed solution is 1-10 wt%, preferably 2-8 wt%, more preferably 3-6 wt%, based on the total weight of the mixed solution;
4) the concentration of the potassium hydroxide in the mixed solution is 1-8 wt%, preferably 2-7 wt%, more preferably 3-5 wt%, based on the total weight of the mixed solution; and/or
5) In the mixture, the compound of formula 2: triphosgene: the weight ratio of the potassium hydroxide is 2-3:1-2: 1; preferably, 2-2.5:1-1.5: 1.
The concentration of the compound of formula 2 in the salt solution of the compound of formula 2 or the mixed solution is calculated as the original compound (non-salt form) of the compound of formula 2.
In another preferred embodiment, in the mixed solvent of water and the organic solvent, the volume ratio of water to the organic solvent is 1-8:1, preferably 2-6:1, and more preferably 3-5: 1.
In another preferred embodiment, in step (2), the reaction temperature of the reaction is 10 to 40 ℃, preferably 20 to 30 ℃.
In another preferred embodiment, in the step (3), the reaction solution is adjusted to pH 1 to 3, preferably 1 to 2.
Process for preparing vitamin H
The invention also provides a preparation method of the vitamin H, which comprises the following steps:
wherein the method comprises the step of preparing the compound 3 by using the method.
The embodiments of the process for the preparation of vitamin H, other steps than the preparation of compound 3, are well known to those skilled in the art, for example as described in US2489238, the entire contents of which are incorporated herein by reference for all purposes.
The main advantages of the invention include:
1. the method adopts the pipeline reaction, so that phosgene generated by triphosgene hydrolysis cannot be released out of a pipeline reactor and remains in a reaction solution, and can continuously participate in the reaction; not only improves the utilization rate of triphosgene, but also improves the safety degree essentially and reduces the safe operation risk.
2. The method has the advantages of safe process, high raw material conversion rate, high reaction yield, high product purity and low production cost, and is suitable for industrial production of the compound shown in the formula 3.
The invention is further illustrated with reference to specific embodiments. 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 by weight.
The reagents used in the present invention are commercially available.
HPLC detection method: instrument model, chromatographic column, and requirements.
A detection instrument: water 2695
A chromatographic column: diamonsil Plus 5. mu. m C18250X 4.6mm
Detection conditions are as follows: 70% of solvent A (1.5g of monopotassium phosphate and 1.0ml of phosphoric acid in 1000ml of pure water) and 30% of solvent B (acetonitrile)
Example 1
Dissolving 37.2g (0.100mol) of disodium salt of the compound of formula 2 in 200g of water (14.9% by mass) to obtain a solution A; 19.3g (0.065mol) of triphosgene (bis (trichloromethyl) carbonate) was dissolved in 77.0g (20% by mass) of toluene to obtain a solution B; the solution C is a potassium hydroxide aqueous solution with the mass concentration of 25%. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A: B: C being 3.83:1.57:1, feeding into a pipeline type reactor (the length of the pipe is 10 meters, the diameter of the pipe is 10 millimeters) through a peristaltic pump, and starting to react, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value of the middle sample of the pipeline reactor, controlling the pH value of the sample to be taken to be 8-9, and keeping the retention time of the mixed solution in the pipeline reactor to be about 15 min. After the reaction is finished, adjusting the pH of the reaction solution to 1-2 with acid, filtering, and washing a filter cake to be nearly neutral. After air-blast drying, 34.8g of solid is obtained, the yield is 98.3%, and the purity of liquid phase analysis is 96.5%.
Example 2
Dissolving 37.2g (0.100mol) of disodium salt of the compound of formula 2 in 200g of water (14.9% by mass) to obtain a solution A; dissolving 20.7g (0.070mol) of triphosgene in 83.0g of toluene (mass concentration is 20%) to obtain a solution B; the solution C is a potassium hydroxide aqueous solution with the mass concentration of 25%. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A: B: C being 3.80:1.65:1, slowly feeding into a pipeline type reactor (the length of the pipeline is 10 meters, the diameter of the pipeline is 10 millimeters) through a peristaltic pump, and starting to react, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value of the middle sample of the pipeline reactor, controlling the pH value of the sample to be taken to be 8-9, and keeping the retention time of the mixed solution in the pipeline reactor to be about 15 min. And (3) after the reaction in the reaction liquid at the discharge port is finished, adjusting the pH of the reaction liquid to 1-2 with acid, filtering, and washing a filter cake to be nearly neutral. After air-blast drying, 35.0g of solid is obtained, the yield is 98.7%, and the purity of liquid phase analysis is 96.8%.
Example 3
Dissolving 37.2g (0.100mol) of disodium salt of the compound of formula 2 in 200g of water (14.9% by mass) to obtain a solution A; 19.3g (0.065mol) of triphosgene was dissolved in 77.0g (mass concentration: 20%) of toluene to obtain a solution B; the solution C was a 25 mass% aqueous solution of potassium hydroxide. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A: B: C being 3.83:1.57:1, feeding into a pipeline type reactor (the length of the pipe is 20m, the diameter of the pipe is 25 mm) through a peristaltic pump, and starting to react, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value of the middle sample of the pipeline reactor, controlling the pH value of the sample to be taken to be 8-9, and keeping the retention time of the mixed solution in the pipeline reactor to be about 15 min. After the reaction is finished, adjusting the pH of the reaction solution to 1-2 with acid, filtering, and washing a filter cake to be nearly neutral. After forced air drying, 35.1g of solid is obtained, the yield is 99.1%, and the purity of liquid phase analysis is 96.9%.
Example 4
Dissolving 22.3g (0.060mol) of disodium salt of the compound of formula 2 in 120g of water (14.9% by mass) to obtain solution A; 11.6g (0.039mol) of triphosgene was dissolved in 46.2g (20% by mass) of toluene to obtain a solution B; the solution C is a potassium hydroxide aqueous solution with the mass concentration of 25%. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A: B: C being 3.83:1.57:1, feeding into a pipeline type reactor (the length of the pipe is 10 meters, the diameter of the pipe is 10 millimeters) through a peristaltic pump, and starting to react, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value of the middle sample of the pipeline reactor, controlling the pH value of the sample to be taken to be 8-9, and keeping the retention time of the mixed solution in the pipeline reactor to be about 25 min. After the reaction is finished, adjusting the pH of the reaction solution to 1-2 with acid, filtering, and washing a filter cake to be nearly neutral. After air-blast drying, 21.0g of solid is obtained, the yield is 98.8%, and the purity of liquid phase analysis is 96.8%.
Example 5
148.8g (0.400mol) of the disodium salt of the compound of formula 2 was dissolved in 800g of water (mass concentration: 14.9%) to obtain a solution A; 77.2g (0.260mol) of triphosgene was dissolved in 308.0g of toluene (mass concentration: 20%) to obtain a solution B; the solution C is a potassium hydroxide aqueous solution with the mass concentration of 25%. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A: B: C being 3.83:1.57:1, feeding into a pipeline type reactor (the length of the pipe is 20m, the diameter of the pipe is 25 mm) through a peristaltic pump, and starting to react, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value of the middle sample of the pipeline reactor, controlling the pH value of the sample to be taken to be 8-9, and keeping the retention time of the mixed solution in the pipeline reactor to be about 15 min. After the reaction is finished, adjusting the pH of the reaction solution to 1-2 with acid, filtering, and washing a filter cake to be nearly neutral. After air-blast drying, 139.5g of solid is obtained, the yield is 98.5%, and the purity of liquid phase analysis is 96.8%.
Comparative example 1
37.2g (0.100mol) of disodium salt of the compound of formula 2 and 200g of water are put into a reaction bottle, stirred to be clear and cooled to 10-15 ℃. Simultaneously dropwise adding 19.3g (0.065mol) of triphosgene into 77.0g of toluene (mass concentration is 20%) to obtain a solution B and a potassium hydroxide aqueous solution C with the mass concentration of 25%, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. And (4) finishing the dropwise adding for about 1-1.5 h, and then carrying out heat preservation reaction for 0.5 h. And adjusting the pH value of the reaction solution to 1-2 with acid, filtering, and washing a filter cake to be nearly neutral. After air-blast drying, 28.1g of solid was obtained with a yield of 79.3% and a purity of 94.2% by liquid phase analysis.
Comparative example 2
37.2g (0.100mol) of disodium salt of the compound of formula 2 and 200g of water are put into a reaction bottle, stirred to be clear and cooled to 10-15 ℃. And simultaneously dropwise adding 40.0g (0.135mol) of triphosgene into 160.0g of toluene (mass concentration is 20%) to obtain a solution B and a potassium hydroxide aqueous solution C with the mass concentration of 25%, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. And (4) finishing the dropwise adding for about 1-1.5 h, and then carrying out heat preservation reaction for 0.5 h. And adjusting the pH value of the reaction solution to 1-2 with acid, filtering, and washing a filter cake to be nearly neutral. After forced air drying, 33.4g of solid is obtained, the yield is 94.4%, and the purity of liquid phase analysis is 96.5%.
Comparing examples 1-4 and comparative examples 1-2, it can be seen that the yield and purity of the compound of formula 3 are greatly improved when the pipeline reactor is used, compared to when the pipeline reactor is not used. In the reaction process, as the pipeline of the pipeline type reactor is narrow and the materials in the pipeline are in an abundant state, toxic volatile substances such as phosgene and the like generated by triphosgene are always sealed in the pipeline and continuously participate in the reaction, so that the conversion rate and the reaction yield of reactants are improved, and the toxic substances are not released to the environment, so that the operation is very safe and efficient, and the method is suitable for large-scale application.
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 method of synthesizing a compound of formula 3, comprising the steps of:
(1) providing a salt solution of a compound of formula 2, a triphosgene (BTC) solution, and a potassium hydroxide solution;
(2) mixing a salt solution of the compound shown in the formula 2, a triphosgene (BTC) solution and a potassium hydroxide solution, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction; and
(3) adjusting the pH of the reaction solution after the reaction to be acidic to obtain a compound shown in the formula 3;
wherein the salt is a potassium salt and/or a sodium salt of the compound of formula 2.
2. The method of claim 1, wherein said mixing said feed in step (2) is a mix-while-feed.
3. The method of claim 1, wherein step (2) is preceded by the step of:
the salt solution of the compound of formula 2, the triphosgene (BTC) solution and the potassium hydroxide solution are pre-cooled to 5-15 c, preferably 10-15 c, respectively.
4. The method of claim 1, wherein the method further comprises the steps of: and sampling and detecting the pH value of the reaction liquid through a sampling port of the pipeline reactor, and controlling the reaction by adjusting the proportion of the reaction liquid.
5. The method of claim 1, wherein the pipeline reactor is selected from the group consisting of: horizontal tubular reactors, vertical tubular reactors, coil tubular reactors and U-shaped tubular reactors.
6. The process according to claim 1, wherein the pipe reactor pipe has a diameter of 0.8-5cm, preferably 1-3cm, more preferably 1-2 cm.
7. The process of claim 1, wherein the residence time of the mixed liquor in the pipeline reactor is 10min or more or 15min or more, preferably 10-60min, more preferably 15-30 min.
8. The method of claim 1, wherein the mixed liquor has one or more of the following characteristics:
1) the solvent of the mixed solution is a mixed solvent of water and an organic solvent;
2) the concentration of the compound of formula 2 is 1-15 wt%, preferably 5-12 wt%, more preferably 6-10 wt%, based on the total weight of the mixed solution;
3) the concentration of the triphosgene in the mixed solution is 1-10 wt%, preferably 2-8 wt%, more preferably 3-6 wt%, based on the total weight of the mixed solution;
4) the concentration of the potassium hydroxide in the mixed solution is 1-8 wt%, preferably 2-7 wt%, more preferably 3-5 wt%, based on the total weight of the mixed solution; and/or
5) In the mixture, the compound of formula 2: triphosgene: the weight ratio of the potassium hydroxide is 2-3:1-2: 1; preferably, 2-2.5:1-1.5: 1.
9. The method of claim 1, wherein in step (2), the reaction temperature of the reaction is 10-40 ℃, preferably 20-30 ℃.
10. A method for preparing vitamin H, which is characterized by comprising the following steps:
comprising the step of preparing compound 3 using the process of claims 1-9.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2489238A (en) * | 1948-06-08 | 1949-11-22 | Hoffmann La Roche | Debenzylation of benzylated imidazolido-thiophane compounds |
| JP2006193480A (en) * | 2005-01-14 | 2006-07-27 | Sumitomo Chemical Co Ltd | Method for producing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid |
| CN106831592A (en) * | 2017-03-15 | 2017-06-13 | 安徽泰格维生素实业有限公司 | A kind of preparation method of naphthenic acid |
| CN110327848A (en) * | 2019-05-29 | 2019-10-15 | 江苏蓝丰生物化工股份有限公司 | A kind of production technology of device for phosgenation reaction, phosgenation reaction |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2489238A (en) * | 1948-06-08 | 1949-11-22 | Hoffmann La Roche | Debenzylation of benzylated imidazolido-thiophane compounds |
| JP2006193480A (en) * | 2005-01-14 | 2006-07-27 | Sumitomo Chemical Co Ltd | Method for producing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid |
| CN106831592A (en) * | 2017-03-15 | 2017-06-13 | 安徽泰格维生素实业有限公司 | A kind of preparation method of naphthenic acid |
| CN110327848A (en) * | 2019-05-29 | 2019-10-15 | 江苏蓝丰生物化工股份有限公司 | A kind of production technology of device for phosgenation reaction, phosgenation reaction |
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