CN113121444B - Method for synthesizing vitamin H intermediate through pipeline - Google Patents
Method for synthesizing vitamin H intermediate through pipeline Download PDFInfo
- Publication number
- CN113121444B CN113121444B CN201911398313.6A CN201911398313A CN113121444B CN 113121444 B CN113121444 B CN 113121444B CN 201911398313 A CN201911398313 A CN 201911398313A CN 113121444 B CN113121444 B CN 113121444B
- Authority
- CN
- China
- Prior art keywords
- solution
- compound
- formula
- triphosgene
- mixed solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 43
- 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 abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 72
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 239000000243 solution Substances 0.000 claims abstract description 65
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000011259 mixed solution Substances 0.000 claims abstract description 34
- 239000012266 salt solution Substances 0.000 claims abstract description 18
- 238000002156 mixing Methods 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 4
- 239000011591 potassium Substances 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 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 17
- 230000001276 controlling effect Effects 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000005070 sampling Methods 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 230000002572 peristaltic effect Effects 0.000 description 9
- 239000002253 acid Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000007864 aqueous solution Substances 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 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
- 239000000126 substance Substances 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
- 238000011161 development Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 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
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection 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
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 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
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 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
- 238000012360 testing 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
- 238000005406 washing Methods 0.000 description 1
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 through pipelining. Specifically, the method comprises the following steps: (1) Providing a salt solution, triphosgene (BTC) solution, and potassium hydroxide solution of the compound of formula 2; (2) Mixing the salt solution of the compound of formula 2, triphosgene (BTC) solution and potassium hydroxide solution, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction; and (3) adjusting the pH of the reacted reaction solution to be acidic to obtain a compound of formula 3; wherein the salt is potassium and/or sodium salt of the compound of formula 2. The method has high raw material conversion rate and very safe operation, and is suitable for industrialized 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 through pipelining.
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 route, the cyclization reaction from the compound of formula 2 to the compound of formula 3 is carried out by dripping triphosgene solution and potassium hydroxide solution into the aqueous solution of the compound of formula 2 in a reaction kettle. However, the method has the advantages of large consumption of triphosgene and the like, low conversion rate and low safety.
Therefore, there is an urgent need in the art to provide a method for preparing a 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 raw material conversion rate and high safety.
In a first aspect of the present invention, there is provided a method of synthesizing a compound of formula 3 comprising the steps of:
(1) Providing a salt solution, triphosgene (BTC) solution, and potassium hydroxide solution of the compound of formula 2;
(2) Mixing the salt solution of the compound of formula 2, triphosgene (BTC) solution and potassium hydroxide solution, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction; and
(3) Regulating the pH value of the reaction liquid after the reaction to be acidic to obtain a compound shown in a formula 3;
wherein the salt is potassium and/or sodium salt of the compound of formula 2.
In another preferred embodiment, the mixing of the feeds in step (2) is a mixing-while-feed.
In another preferred embodiment, the step (2) further comprises the steps of:
the salt solution, triphosgene (BTC) solution and potassium hydroxide solution of the compound of formula 2 are respectively precooled to 5-15 ℃, preferably 10-15 ℃.
In another preferred embodiment, the method further comprises the steps of: the pH value of the reaction liquid is sampled and detected through a sampling port of the pipeline reactor, and the reaction is controlled by adjusting the proportion of the reaction liquid.
In another preferred example, when the sampling port is located at (0.5.+ -. 0.02) l of the pipe length l of the pipe reactor, the pH value of the reaction solution at the sampling port is controlled to 8-9.
In another preferred embodiment, the pH of the reaction solution is controlled by adjusting the amount of potassium hydroxide at the time of mixing.
In another preferred embodiment, the pipeline reactor is selected from the group consisting of: horizontal tubular reactors, riser reactors, coil reactors and U-tube reactors.
In another preferred embodiment, the pipe reactor tube length is 8-30m, preferably 10-20m.
In another preferred embodiment, the pipe diameter of the pipe reactor is 0.8-5cm, preferably 1-3cm, more preferably 1-2cm.
In another preferred embodiment, the method further comprises the steps of: filtering and drying the compound of the formula 3 obtained in the step (3).
In another preferred embodiment, the residence time of the mixed liquor in the pipeline reactor is not less than 10min or not less than 15min, preferably 10-60min, more preferably 15-30min.
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 25wt%, preferably 5 to 20wt%, more preferably 6 to 15wt%, 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 sodium hydroxide and/or potassium hydroxide solution.
In another preferred embodiment, the salt of the compound of formula 2 is selected from the group consisting of: disodium salt, dipotassium salt, or combinations 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, methylene chloride, ethanol, methanol, or combinations thereof.
In another preferred embodiment, the concentration of triphosgene in the triphosgene solution is 1-30wt%, preferably 5-25wt%, more preferably 10-20wt%.
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 35wt%, preferably 10 to 30wt%, more preferably 15 to 28wt%.
In another preferred embodiment, the mixture 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 1-15wt%, preferably 5-12wt%, more preferably 6-10wt%, based on the total weight of the mixture;
3) The concentration of triphosgene in the mixture is 1-10wt%, preferably 2-8wt%, more preferably 3-6wt%, based on the total weight of the mixture;
4) The concentration of potassium hydroxide in the mixture is 1-8wt%, preferably 2-7wt%, more preferably 3-5wt%, based on the total weight of the mixture; and/or
5) In the mixed solution, 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, the volume ratio of water to organic solvent in the mixed solvent of water and organic solvent is 1-8:1, preferably 2-6:1, more preferably 3-5:1.
In another preferred embodiment, in step (2), the reaction temperature of the reaction is 10-40 ℃, preferably 20-30 ℃.
In another preferred embodiment, in step (2), the mixed liquor is fed to the pipeline reactor by a peristaltic pump.
In another preferred embodiment, in step (3), the reaction solution is adjusted to a pH of 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 embodiment, the sampling port is located at (0.5±0.02) l of the pipe length l of the pipe.
In a second aspect of the present invention, there is provided a method for preparing vitamin H, the method comprising the steps of:
comprising the step of preparing compound 3 using the method according to the first aspect of the invention.
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.
Drawings
FIG. 1 is a schematic diagram of a first, second, and fourth embodiment of the present invention.
FIG. 2 is a schematic diagram of a pipeline reactor used in the third and fifth embodiments of the present invention.
Detailed Description
The present inventors have made extensive and intensive studies and, through extensive screening and testing, have provided a method for the pipelined synthesis of vitamin H intermediates (compounds of formula 3). The invention synthesizes the compound of the formula 3 by adopting the pipeline reactor, so that phosgene generated by triphosgene hydrolysis can not be released out of the reactor, and can still continue to react in the reaction liquid, thereby improving the utilization rate of triphosgene, having higher yield and essentially improving the operation safety. The present invention has been completed on the basis of this finding.
Terminology
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, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" 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", "pipe reactor" or "pipe reactor" are used interchangeably. The pipeline reactor is a continuous operation reactor with a large length-diameter ratio. The flow of material can be regarded approximately as plug flow. The back mixing of the tubular reactor is small, so that the volumetric efficiency (unit volume production capacity) is high, and the tubular reactor is particularly suitable for occasions requiring higher conversion rate or serial side reactions.
Typically, the pipeline reactor includes, but is not limited to: horizontal tubular reactors, riser reactors, coil reactors and U-tube reactors. Preferably, the conduit diameter of the conduit reactor is from 0.8 to 5cm, preferably from 1 to 3cm, more preferably from 1 to 2cm.
Typically, the pipeline reactor comprises: hollow pipeline, feed inlet, discharge gate and sample connection. The sampling port is preferably positioned in the middle section of the pipeline, and the reaction condition can be detected by sampling from the sampling port. The sampler is optimally located at (0.5±0.02) l of the tube length. Alternatively, more than one sampler may be provided as desired. Typically, the hollow tubing is a seamless steel tube, such as medical grade stainless steel.
In the present invention, the apparatus for use with the pipeline reactor further comprises: feed vessels, mixers, pumps and/or receiving devices. Typically, the salt solution, triphosgene (BTC) solution and potassium hydroxide solution of the compound of formula 2 are transferred from their respective feed vessels to the mixer by a pump generating a driving force, and the mixed liquid is introduced from the feed port of the pipe reactor, and discharged from the discharge port of the pipe reactor to the receiving device after the reaction is completed. Preferably, the device forms a sealing system (connectable to the exhaust conduit (e.g. via a breather valve) to equalize the air pressure).
In another preferred embodiment, the pump is a peristaltic pump connected to the feed inlet of the mixer and the pipe reactor, respectively, by hoses. The peristaltic pump enables the mixed liquid in the hose to move through extrusion, and the peristaltic pump is not contacted with the mixed liquid, so that the introduction of impurities can be avoided.
Further, the sample injection amount of each solution can be adjusted by adjusting a discharge valve of the feed container or by an electromagnetic valve.
Process for preparing compounds of formula 3
In a first aspect of the present invention, there is provided a method of synthesizing a compound of formula 3 comprising the steps of:
(1) Providing a salt solution, triphosgene (BTC) solution, and potassium hydroxide solution of the compound of formula 2;
(2) Mixing the salt solution of the compound of formula 2, triphosgene (BTC) solution and potassium hydroxide solution, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction; and
(3) Regulating the pH value of the reaction liquid after the reaction to be acidic to obtain a compound shown in a formula 3;
wherein the salt is potassium and/or sodium salt of the compound of formula 2.
In another preferred embodiment, the mixing of the feeds in step (2) is a mixing-while-feed.
In another preferred embodiment, the step (2) further comprises the steps of:
the salt solution, triphosgene (BTC) solution and potassium hydroxide solution of the compound of formula 2 are respectively precooled to 5-15 ℃, preferably 10-15 ℃.
In another preferred embodiment, the method further comprises the steps of: the pH value of the reaction liquid is sampled and detected through a sampling port of the pipeline reactor, and the reaction is controlled by adjusting the proportion of the reaction liquid.
In another preferred embodiment, the method further comprises the steps of: filtering and drying the compound of the formula 3 obtained in the step (3).
In another preferred embodiment, the residence time of the mixed liquor in the pipeline reactor is not less than 10min or not less than 15min, preferably 10-60min, more preferably 15-30min.
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 sodium hydroxide and/or potassium hydroxide solution.
In another preferred embodiment, the salt of the compound of formula 2 is selected from the group consisting of: disodium salt, dipotassium salt, or combinations 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, methylene chloride, ethanol, methanol, or combinations thereof.
In another preferred embodiment, the mixture 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 1-15wt%, preferably 5-12wt%, more preferably 6-10wt%, based on the total weight of the mixture;
3) The concentration of triphosgene in the mixture is 1-10wt%, preferably 2-8wt%, more preferably 3-6wt%, based on the total weight of the mixture;
4) The concentration of potassium hydroxide in the mixture is 1-8wt%, preferably 2-7wt%, more preferably 3-5wt%, based on the total weight of the mixture; and/or
5) In the mixed solution, 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, the volume ratio of water to organic solvent in the mixed solvent of water and organic solvent is 1-8:1, preferably 2-6:1, more preferably 3-5:1.
In another preferred embodiment, in step (2), the reaction temperature of the reaction is 10-40 ℃, preferably 20-30 ℃.
In another preferred embodiment, in step (3), the reaction solution is adjusted to a pH of 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.
In the preparation of vitamin H, embodiments of other steps than 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 pipelining reaction, so that phosgene generated by triphosgene hydrolysis can not be released out of a pipeline reactor, and can still stay in reaction liquid to continue to participate in the reaction; not only improves the utilization rate of triphosgene, but also improves the safety degree essentially and reduces the safety 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 industrialized production of the compound shown in the formula 3.
The invention is further described below in conjunction with the specific embodiments. 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 by weight unless otherwise indicated.
The reagents used in the present invention may be obtained by commercial sources.
HPLC detection method: instrument model, chromatographic column, and requirements.
Detection instrument: water 2695
Chromatographic column: diamond Plus 5 mu m C, 18X 250, 4.6mm
Detection conditions: 70% solvent A (1.5 g of potassium dihydrogen phosphate and 1.0ml of phosphoric acid dissolved in 1000ml of pure water) and 30% solvent B (acetonitrile)
Example 1
37.2g (0.100 mol) of disodium salt of the compound of formula 2 are dissolved in 200g of water (mass concentration 14.9%) to obtain a solution A; 19.3g (0.065 mol) of triphosgene (bis (trichloromethyl) carbonate) were dissolved in 77.0g of toluene (mass concentration 20%) to obtain a solution B; solution C is 25% potassium hydroxide aqueous solution by mass. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A to B to C=3.83 to 1.57 to 1, feeding into a pipeline reactor (the pipe length is 10m and the pipe diameter is 10 mm) by a peristaltic pump, starting the reaction, and controlling the reaction temperature to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value sampled in the middle of the pipeline reactor, controlling the pH value of the sampled sample to be 8-9, and controlling the residence time of the mixed solution in the pipeline reactor to be about 15min. After the reaction is completed, the pH value of the reaction solution is regulated to 1-2 by acid, the reaction solution is filtered, and a filter cake is washed to be nearly neutral by water. After air blast drying 34.8g of solid was obtained with a yield of 98.3% and a purity of 96.5% by liquid phase analysis.
Example 2
37.2g (0.100 mol) of disodium salt of the compound of formula 2 are dissolved in 200g of water (mass concentration 14.9%) to obtain a solution A; 20.7g (0.070 mol) of triphosgene was dissolved in 83.0g of toluene (mass concentration: 20%) to obtain solution B; solution C is 25% potassium hydroxide aqueous solution by mass. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A to B to C=3.80 to 1.65 to 1, slowly feeding the mixture into a pipeline reactor (the pipe length is 10m and the pipe diameter is 10 mm) by a peristaltic pump, and starting the reaction, 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 sampled in the middle of the pipeline reactor, controlling the pH value of the sampled sample to be 8-9, and controlling the residence time of the mixed solution in the pipeline reactor to be about 15min. And (3) after the reaction in the reaction liquid at the discharge port is finished, adjusting the pH value of the reaction liquid to 1-2 by using acid, filtering, and washing a filter cake until the pH value is nearly neutral. After air blast drying 35.0g of solid was obtained with a yield of 98.7% and a liquid phase analysis purity of 96.8%.
Example 3
37.2g (0.100 mol) of disodium salt of the compound of formula 2 are dissolved in 200g of water (mass concentration 14.9%) to obtain a solution A; 19.3g (0.065 mol) of triphosgene was dissolved in 77.0g of toluene (mass concentration 20%) to obtain a solution B; solution C is 25% strength by mass aqueous potassium hydroxide solution. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A to B to C=3.83 to 1.57 to 1, feeding into a pipeline reactor (the length of a pipe is 20m and the diameter of the pipe is 25 mm) by a peristaltic pump, starting the reaction, and controlling the reaction temperature to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value sampled in the middle of the pipeline reactor, controlling the pH value of the sampled sample to be 8-9, and controlling the residence time of the mixed solution in the pipeline reactor to be about 15min. After the reaction is completed, the pH value of the reaction solution is regulated to 1-2 by acid, the reaction solution is filtered, and a filter cake is washed to be nearly neutral by water. After air blast drying 35.1g of solid was obtained with a yield of 99.1% and a liquid phase analysis purity of 96.9%.
Example 4
22.3g (0.060 mol) of disodium salt of the compound of formula 2 are dissolved in 120g of water (mass concentration 14.9%) to obtain a solution A; 11.6g (0.039 mol) of triphosgene were dissolved in 46.2g of toluene (mass concentration 20%) to obtain a solution B; solution C is 25% potassium hydroxide aqueous solution by mass. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A to B to C=3.83 to 1.57 to 1, feeding into a pipeline reactor (the pipe length is 10m and the pipe diameter is 10 mm) by a peristaltic pump, starting the reaction, and controlling the reaction temperature to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value sampled in the middle of the pipeline reactor, controlling the pH value of the sampled sample to be 8-9, and controlling the residence time of the mixed solution in the pipeline reactor to be about 25min. After the reaction is completed, the pH value of the reaction solution is regulated to 1-2 by acid, the reaction solution is filtered, and a filter cake is washed to be nearly neutral by water. After air-blast drying, 21.0g of solid is obtained, the yield is 98.8%, and the liquid phase analysis purity is 96.8%.
Example 5
148.8g (0.400 mol) of disodium salt of the compound of formula 2 are dissolved in 800g of water (mass concentration 14.9%) to obtain solution A; 77.2g (0.260 mol) of triphosgene were dissolved in 308.0g of toluene (mass concentration 20%) to obtain a solution B; solution C is 25% potassium hydroxide aqueous solution by mass. Pre-cooling A, B, C three solutions to 10-15 ℃, mixing in a mixer according to the mass ratio of A to B to C=3.83 to 1.57 to 1, feeding into a pipeline reactor (the length of a pipe is 20m and the diameter of the pipe is 25 mm) by a peristaltic pump, starting the reaction, and controlling the reaction temperature to be 10-30 ℃ in the reaction process. And (3) finely adjusting the feeding speed of the solution C according to the pH value sampled in the middle of the pipeline reactor, controlling the pH value of the sampled sample to be 8-9, and controlling the residence time of the mixed solution in the pipeline reactor to be about 15min. After the reaction is completed, the pH value of the reaction solution is regulated to 1-2 by acid, the reaction solution is filtered, and a filter cake is washed to be nearly neutral by water. After air blast drying 139.5g of solid was obtained with a yield of 98.5% and a purity of 96.8% by liquid phase analysis.
Comparative example 1
37.2g (0.100 mol) of disodium salt of the compound of formula 2 and 200g of water are put into a reaction flask, the mixture is stirred and dissolved, and the temperature is reduced to 10-15 ℃. Meanwhile, 19.3g (0.065 mol) of triphosgene is added dropwise and dissolved in 77.0g of toluene (the 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, and the reaction temperature is controlled to be 10-30 ℃. After the dripping is completed for about 1 to 1.5 hours, the reaction is carried out for 0.5 hour after the dripping is completed. Then the pH value of the reaction solution is regulated to 1-2 by acid, and the reaction solution is filtered, and the filter cake is washed to be nearly neutral by water. After air-blast drying 28.1g of solid was obtained, the yield was 79.3%, and the liquid phase analysis purity was 94.2%.
Comparative example 2
37.2g (0.100 mol) of disodium salt of the compound of formula 2 and 200g of water are put into a reaction flask, the mixture is stirred and dissolved, and the temperature is reduced to 10-15 ℃. Simultaneously, 40.0g (0.135 mol) of triphosgene is added dropwise and dissolved in 160.0g of toluene (the 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, and the reaction temperature is controlled to be 10-30 ℃. After the dripping is completed for about 1 to 1.5 hours, the reaction is carried out for 0.5 hour after the dripping is completed. Then the pH value of the reaction solution is regulated to 1-2 by acid, and the reaction solution is filtered, and the filter cake is washed to be nearly neutral by water. After air-blast drying, 33.4g of solid was obtained, the yield was 94.4%, and the purity of the liquid phase analysis was 96.5%.
As can be seen from comparative examples 1-4 and comparative examples 1-2, the yield and purity of the compound of formula 3 were greatly improved after the use of the pipeline reactor, as compared with those without the use of the pipeline reactor. The method has the advantages that the triphosgene can be hydrolyzed under the alkaline condition to release phosgene, the released phosgene not only can cause safety risk, but also can increase the consumption of triphosgene and potassium hydroxide, in the reaction process, because the pipeline of the pipeline type reactor is narrow and the materials in the pipeline are in a full state, the toxic volatile substances such as phosgene generated by the triphosgene are always sealed in the pipeline, but continue to participate in the reaction, thereby not only improving the conversion rate and the reaction yield of reactants, but also ensuring that the toxic substances are not released into the environment, so that the operation is very safe and efficient, and the method is suitable for large-scale application.
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 (18)
1. A continuous synthesis process of a compound of formula 3, comprising the steps of:
(1) Providing a salt solution, a triphosgene BTC solution, and a potassium hydroxide solution of the compound of formula 2;
(2) Pre-cooling the salt solution of the compound of the formula 2, the triphosgene BTC solution and the potassium hydroxide solution to 5-15 ℃ respectively, then mixing, and continuously feeding the obtained mixed solution into a pipeline reactor for reaction, wherein the reaction temperature is 10-30 ℃; and
(3) Sampling and detecting the pH value of the reaction liquid through a sampling port of the pipeline reactor, and controlling the pH value of the extracted sample to be 8-9 by adjusting the ratio of the reaction liquid;
(4) Regulating the pH value of the reaction liquid after the reaction to 1-3 to obtain a compound of formula 3;
wherein the salt is potassium and/or sodium salt of the compound of formula 2;
the mixed liquid has 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 1-15wt%, based on the total weight of the mixed solution;
3) The concentration of triphosgene in the mixed solution is 1-10wt%, based on the total weight of the mixed solution;
4) The concentration of potassium hydroxide in the mixed solution is 1-8wt%, based on the total weight of the mixed solution; and
5) In the mixed solution, the compound of formula 2: triphosgene: the weight ratio of potassium hydroxide is (2-3): 1-2): 1.
2. The method of claim 1, wherein said mixing said feeds in step (2) is mixing while feeding.
3. The method of claim 1, wherein in step (2), the salt solution of the compound of formula 2, the triphosgene BTC solution and the potassium hydroxide solution are pre-cooled to 10-15 ℃ respectively.
4. The method of claim 1, wherein the solvent of the triphosgene solution is selected from the group consisting of: toluene, diethyl ether, tetrahydrofuran, benzene, cyclohexane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, dichloromethane, ethanol, methanol, or combinations thereof.
5. The method of claim 1, wherein the pipeline reactor is selected from the group consisting of: horizontal tubular reactors, riser reactors, coil reactors and U-tube reactors.
6. The method of claim 1, wherein the conduit reactor conduit has a diameter of 0.8 cm to 5cm.
7. The method of claim 1, wherein the conduit reactor conduit has a diameter of 1-3cm.
8. The method of claim 1, wherein the conduit reactor conduit has a diameter of 1-2cm.
9. The method of claim 1, wherein the mixed liquor has a residence time in the pipeline reactor of from 10 to 60 minutes.
10. The method of claim 1, wherein the mixed liquor has a residence time in the pipeline reactor of 15 to 30 minutes.
11. The method of claim 1, wherein the concentration of triphosgene in the triphosgene solution is from 5 to 25wt%.
12. The method of claim 1, wherein the concentration of triphosgene in the triphosgene solution is from 10 to 20wt%.
13. The method of claim 1, wherein the mixture has 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 5-12wt%, based on the total weight of the mixed solution;
3) The concentration of triphosgene in the mixed solution is 2-8wt%, based on the total weight of the mixed solution;
4) The concentration of potassium hydroxide in the mixed solution is 2-7wt%, based on the total weight of the mixed solution; and
5) In the mixed solution, the compound of formula 2: triphosgene: the weight ratio of potassium hydroxide is (2-2.5): 1-1.5): 1.
14. The method of claim 1, wherein the mixture has 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 6-10wt%, based on the total weight of the mixed solution;
3) The concentration of triphosgene in the mixed solution is 3-6wt%, based on the total weight of the mixed solution; and
4) The concentration of potassium hydroxide in the mixed solution is 3-5wt%, based on the total weight of the mixed solution.
15. The method according to claim 1, wherein the volume ratio of water to organic solvent in the mixed solvent of water and organic solvent is (1-8): 1.
16. The method according to claim 1, wherein the volume ratio of water to organic solvent in the mixed solvent of water and organic solvent is (2-6): 1.
17. The method according to claim 1, wherein in the step (2), the reaction temperature of the reaction is 20 to 30 ℃.
18. A method for preparing vitamin H, comprising the steps of:
comprising the step of preparing compound 3 using the method of any one of claims 1-17.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911398313.6A CN113121444B (en) | 2019-12-30 | 2019-12-30 | Method for synthesizing vitamin H intermediate through pipeline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911398313.6A CN113121444B (en) | 2019-12-30 | 2019-12-30 | Method for synthesizing vitamin H intermediate through pipeline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113121444A CN113121444A (en) | 2021-07-16 |
| CN113121444B true CN113121444B (en) | 2024-03-15 |
Family
ID=76768094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911398313.6A Active CN113121444B (en) | 2019-12-30 | 2019-12-30 | Method for synthesizing vitamin H intermediate through pipeline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113121444B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117903057A (en) * | 2023-12-25 | 2024-04-19 | 大丰海嘉诺药业有限公司 | Optimization method of amination ring combination process |
| CN118079832A (en) * | 2024-01-12 | 2024-05-28 | 大丰海嘉诺药业有限公司 | Decoloration reation kettle is used in vitamin H production |
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 |
-
2019
- 2019-12-30 CN CN201911398313.6A patent/CN113121444B/en active Active
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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113121444A (en) | 2021-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113121444B (en) | Method for synthesizing vitamin H intermediate through pipeline | |
| CN112979461B (en) | Full continuous flow preparation method of 3-chloro-4-oxoacetic acid amyl ester | |
| CN103450225B (en) | The preparation method of cefoxitin sodium | |
| CN103857390A (en) | Process for manufacturing hmb and salts thereof | |
| CN107033066A (en) | The method and special equipment of a kind of heterogeneous catalysis synthesis triacetonamine | |
| CN108658882A (en) | A kind of preparation method of Cyclen -1,4,7,10- tetraacethyls | |
| US20220119330A1 (en) | Method for preparing resorcinol through micro-channel reaction | |
| CN111004162B (en) | Method and device for preparing L-selenocysteine by using sodium triacetoxyborohydride as reducing agent | |
| CN111100088B (en) | Method for continuously synthesizing ethyl dithiahydroxamate | |
| CN112961135A (en) | Method for continuously synthesizing benzyl substituted gluconolactone by adopting microchannel reaction device | |
| CN107243307A (en) | Enamine reaction unit | |
| US11834425B2 (en) | Full continuous-flow preparation method of vitamin B1 | |
| CN206951165U (en) | Enamine reaction unit | |
| CN103242190A (en) | Synthetic method of propyzamide | |
| CN110105261A (en) | A method of continuous, rapid synthesis and purification epiphysin using microreactor | |
| CN114682183B (en) | Continuous flow production method of lipoic acid bulk drug | |
| CN114105761A (en) | Synthesis process of alpha-ketoglutaric acid sodium salt | |
| CN113666805A (en) | Method and production system for continuously producing 4-chloro-3, 5-dimethylphenol | |
| CN113461212A (en) | Waste plastic processing wastewater treatment device and method | |
| CN105693759B (en) | The method for preparing chloropropyl alkylalkoxy silane using pathway reaction device | |
| EP3245194A1 (en) | Facile method for preparation of sodium 5-nitrotetrazolate using a flow system | |
| CN115536568B (en) | Method for continuously synthesizing chlorfenapyr | |
| CN106673978B (en) | 3,5- Dichloro-2-pentanone is continuously synthesizing to method | |
| CN220951450U (en) | Continuous quenching device for azide reagent wastewater based on kettle type reactor | |
| CN110256294A (en) | A kind of technique of continuous production N- cyano-ethyl acetimidate hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |