CN116693461A - Novel synthetic method of 4, 6-dichloro-5-methoxypyrimidine - Google Patents
Novel synthetic method of 4, 6-dichloro-5-methoxypyrimidine Download PDFInfo
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- CN116693461A CN116693461A CN202310775166.XA CN202310775166A CN116693461A CN 116693461 A CN116693461 A CN 116693461A CN 202310775166 A CN202310775166 A CN 202310775166A CN 116693461 A CN116693461 A CN 116693461A
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- Prior art keywords
- dichloro
- methoxypyrimidine
- trichloropyrimidine
- synthesizing
- novel
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- IJQIGKLDBGKSNT-UHFFFAOYSA-N 4,6-dichloro-5-methoxypyrimidine Chemical compound COC1=C(Cl)N=CN=C1Cl IJQIGKLDBGKSNT-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000010189 synthetic method Methods 0.000 title description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 30
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 28
- AUWPHGWEYHEAIG-UHFFFAOYSA-N 4,5,6-trichloropyrimidine Chemical compound ClC1=NC=NC(Cl)=C1Cl AUWPHGWEYHEAIG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 239000007788 liquid Substances 0.000 claims abstract description 15
- 238000004321 preservation Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 9
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000003197 catalytic effect Effects 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract 7
- 238000001308 synthesis method Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract description 3
- 239000011574 phosphorus Substances 0.000 abstract description 3
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 3
- 239000002910 solid waste Substances 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- -1 2-methoxy methyl ethyl Chemical group 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- JSEPQQUEVRZWST-UHFFFAOYSA-N 4-hydroxy-5-methoxy-1h-pyrimidin-6-one Chemical compound COC1=C(O)N=CNC1=O JSEPQQUEVRZWST-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004673 sulfadoxine Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/14—Phosphorus; Compounds thereof
- B01J27/16—Phosphorus; Compounds thereof containing oxygen, i.e. acids, anhydrides and their derivates with N, S, B or halogens without carriers or on carriers based on C, Si, Al or Zr; also salts of Si, Al and Zr
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a novel method for synthesizing 4, 6-dichloro-5-methoxypyrimidine, which comprises the following steps: s1, taking 4, 6-dichloropyrimidine as a raw material and an organic solution of carbon tetrachloride, adding an organic solvent and phosphorus oxychloride catalytic amount, and preparing the 4,5, 6-trichloropyrimidine by a microreactor; s2, taking 4,5, 6-trichloropyrimidine, heating liquid sodium methoxide in a reactor for reaction, and controlling the residence time of the heat preservation reaction to prepare the 4, 6-dichloro-5-methoxypyrimidine. The invention has high reaction yield, reduces the chlorination risk and greatly reduces the phosphorus-containing solid waste.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a novel synthesis method of 4, 6-dichloro-5-methoxypyrimidine.
Background
4, 6-dichloro-5-methoxypyrimidine is a sulfadoxine intermediate, and the demand is huge. However, the existing industrialized synthesis adopts formamide and 2-methoxy ethyl malonate to prepare 4, 6-dihydroxy-5-methoxy pyrimidine, and uses phosphorus oxychloride as a solvent to perform a traditional kettle reaction for substitution two-step synthesis. The production and matching enterprises of the 2-methoxy methyl ethyl malonate are not more, the industrial chain is required to be increased by self-matching, and meanwhile, a large amount of phosphorus-containing waste salt is generated by chlorination, so that the environmental protection pressure and the disposal cost are increased.
Improvements are therefore needed.
Disclosure of Invention
The invention aims at providing a novel preparation method of a synthetic method of 4, 6-dichloro-5-methoxypyrimidine aiming at the defects and the shortcomings of the prior art.
In order to achieve the above purpose, the invention adopts the following technical scheme: the novel synthesis method of the 4, 6-dichloro-5-methoxypyrimidine is characterized by comprising the following steps of:
s1, taking 4, 6-dichloropyrimidine as a raw material and an organic solution of carbon tetrachloride, adding an organic solvent and phosphorus oxychloride catalytic amount, and preparing the 4,5, 6-trichloropyrimidine by a microreactor;
s2, dissolving 4,5, 6-trichloropyrimidine in a solvent, heating liquid sodium methoxide in a reactor for reaction, and controlling the residence time of the heat preservation reaction to prepare the 4, 6-dichloro-5-methoxypyrimidine.
Further, the organic solvent is any one of chloroform, trichloroethylene, xylene and ethyl acetate.
Further, the dosage of phosphorus oxychloride is 0.05-0.1eq; the carbon tetrachloride consumption is 2.0-2.5eq.
Further, the temperature rise and the heat preservation reaction temperature are 70-100 DEG C
Further, the residence time of the heat preservation reaction is 5-30 h.
Further, the preferred molar ratio of 4,5, 6-trichloropyrimidine to liquid sodium methoxide is 1: (0.8-1.2).
Further, the reactor for methoxy substitution is a tubular reactor.
The invention has the beneficial effects that:
the invention takes 4, 6-dichloropyrimidine with low industrialization cost as a raw material, chlorine as a raw material, carbon tetrachloride as a solvent and phosphorus oxychloride as a catalytic amount, 4,5, 6-trichloropyrimidine is prepared by a micro-reactor, and 4,5, 6-trichloropyrimidine is prepared by liquid sodium methoxide in a tubular reactor. The invention has high reaction yield, reduces the chlorination risk and greatly reduces the phosphorus-containing solid waste.
Description of the embodiments
The following examples are provided to further illustrate the invention.
The present invention will be described in further detail with reference to specific embodiments in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the detailed description is presented by way of example only and is not intended to limit the invention.
Example 1
A novel synthesis method of 4, 6-dichloro-5-methoxypyrimidine comprises the following steps:
s1, taking 4, 6-dichloropyrimidine as a raw material and an organic solution of carbon tetrachloride, adding chloroform and phosphorus oxychloride in catalytic amount, and preparing 4,5, 6-trichloropyrimidine by a microreactor; wherein the carbon tetrachloride dosage is 2.0eq; the dosage of phosphorus oxychloride is 0.05eq;
s2, taking 4,5, 6-trichloropyrimidine, heating liquid sodium methoxide (10%) in a tubular reactor to react at 70 ℃, and controlling the retention time of the heat preservation reaction for 5 hours to prepare the 4, 6-dichloro-5-methoxypyrimidine. Wherein the preferred molar ratio of 4,5, 6-trichloropyrimidine to liquid sodium methoxide is 1:0.8.
the purity of the prepared product is more than 99 percent, and the yield is 63 percent.
Example 2
A novel synthesis method of 4, 6-dichloro-5-methoxypyrimidine comprises the following steps:
s1, taking 4, 6-dichloropyrimidine as a raw material and an organic solution of carbon tetrachloride, adding trichloroethylene and phosphorus oxychloride in catalytic amount, and preparing 4,5, 6-trichloropyrimidine by a microreactor; wherein the carbon tetrachloride dosage is 2.3eq; the dosage of phosphorus oxychloride is 0.07eq;
s2, taking 4,5, 6-trichloropyrimidine, heating up to 80 ℃ in a tube type reactor by using liquid sodium methoxide (12%) to react, and controlling the retention time of the heat preservation reaction for 15 hours to prepare the 4, 6-dichloro-5-methoxypyrimidine. Wherein the preferred molar ratio of 4,5, 6-trichloropyrimidine to liquid sodium methoxide is 1:1.0.
the purity of the prepared product is more than 99 percent, and the yield is 71 percent.
Example 3
A novel synthesis method of 4, 6-dichloro-5-methoxypyrimidine comprises the following steps:
s1, taking 4, 6-dichloropyrimidine as a raw material and an organic solution of carbon tetrachloride, adding dimethylbenzene and phosphorus oxychloride in catalytic amount, and preparing 4,5, 6-trichloropyrimidine by a microreactor; wherein the carbon tetrachloride dosage is 2.4eq; the dosage of phosphorus oxychloride is 0.09eq;
s2, taking 4,5, 6-trichloropyrimidine, heating up to 90 ℃ in a tube type reactor to react with liquid sodium methoxide (13%), and controlling the retention time of the heat preservation reaction to 20h to prepare the 4, 6-dichloro-5-methoxypyrimidine. Wherein the preferred molar ratio of 4,5, 6-trichloropyrimidine to liquid sodium methoxide is 1:1.1.
the purity of the prepared product is more than 99 percent, and the yield is 65 percent.
Example 4
A novel synthesis method of 4, 6-dichloro-5-methoxypyrimidine comprises the following steps:
s1, taking 4, 6-dichloropyrimidine as a raw material and an organic solution of carbon tetrachloride, adding dimethylbenzene and phosphorus oxychloride in catalytic amount, and preparing 4,5, 6-trichloropyrimidine by a microreactor; wherein the carbon tetrachloride dosage is 2.5eq; the dosage of phosphorus oxychloride is 0.1eq;
s2, taking 4,5, 6-trichloropyrimidine, heating up to 100 ℃ in a tube type reactor to react with liquid sodium methoxide (15%), and controlling the retention time of the heat preservation reaction for 30 hours to prepare the 4, 6-dichloro-5-methoxypyrimidine. Wherein the preferred molar ratio of 4,5, 6-trichloropyrimidine to liquid sodium methoxide is 1:1.2.
the purity of the prepared product is more than 99 percent, and the yield is 60 percent.
The foregoing is merely illustrative of the present invention and not restrictive, and other modifications and equivalents thereof may occur to those skilled in the art without departing from the spirit and scope of the present invention.
Claims (7)
1. A novel synthesis method of 4, 6-dichloro-5-methoxypyrimidine, which is characterized by comprising the following steps:
s1, taking 4, 6-dichloropyrimidine as a raw material and an organic solution of carbon tetrachloride, adding an organic solvent and phosphorus oxychloride catalytic amount, and preparing the 4,5, 6-trichloropyrimidine by a microreactor;
s2, taking 4,5, 6-trichloropyrimidine, heating liquid sodium methoxide in a reactor for reaction, and controlling the residence time of the heat preservation reaction to prepare the 4, 6-dichloro-5-methoxypyrimidine.
2. The method for synthesizing the novel 4, 6-dichloro-5-methoxypyrimidine according to claim 1, wherein the method comprises the following steps: the organic solvent is any one of chloroform, trichloroethylene, xylene and ethyl acetate.
3. The method for synthesizing the novel 4, 6-dichloro-5-methoxypyrimidine according to claim 1, wherein the method comprises the following steps: the dosage of phosphorus oxychloride is 0.05-0.1eq; the carbon tetrachloride consumption is 2.0-2.5eq.
4. A novel method for synthesizing 4, 6-dichloro-5-methoxypyrimidine according to claim 2, wherein: the temperature rise and the heat preservation reaction temperature are 70-100 ℃.
5. A novel method for synthesizing 4, 6-dichloro-5-methoxypyrimidine according to claim 2, wherein: the residence time of the heat preservation reaction is 5-30 h, and different temperatures correspond to different residence times.
6. A novel method for synthesizing 4, 6-dichloro-5-methoxypyrimidine according to claim 2, wherein: the preferred molar ratio of the 4,5, 6-trichloropyrimidine to the liquid sodium methoxide is 1: (0.8-1.2); the mass fraction of the liquid sodium methoxide is 10-15%.
7. A novel method for synthesizing 4, 6-dichloro-5-methoxypyrimidine according to claim 2, wherein: the reactor for methoxy substitution is a tubular reactor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310775166.XA CN116693461A (en) | 2023-06-28 | 2023-06-28 | Novel synthetic method of 4, 6-dichloro-5-methoxypyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310775166.XA CN116693461A (en) | 2023-06-28 | 2023-06-28 | Novel synthetic method of 4, 6-dichloro-5-methoxypyrimidine |
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| Publication Number | Publication Date |
|---|---|
| CN116693461A true CN116693461A (en) | 2023-09-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310775166.XA Pending CN116693461A (en) | 2023-06-28 | 2023-06-28 | Novel synthetic method of 4, 6-dichloro-5-methoxypyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116693461A (en) |
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2023
- 2023-06-28 CN CN202310775166.XA patent/CN116693461A/en active Pending
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