CN105175325A - Preparation method of 4-chlorine-2-pyridine methyl formate - Google Patents
Preparation method of 4-chlorine-2-pyridine methyl formate Download PDFInfo
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- CN105175325A CN105175325A CN201510682078.0A CN201510682078A CN105175325A CN 105175325 A CN105175325 A CN 105175325A CN 201510682078 A CN201510682078 A CN 201510682078A CN 105175325 A CN105175325 A CN 105175325A
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- pyridine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 title abstract 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 25
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical group OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims abstract description 15
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical group [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 13
- 239000012535 impurity Substances 0.000 abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 5
- 230000003647 oxidation Effects 0.000 abstract description 5
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 abstract 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 abstract 2
- 229960003787 sorafenib Drugs 0.000 abstract 2
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- 238000006735 epoxidation reaction Methods 0.000 abstract 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 1
- 238000002844 melting Methods 0.000 abstract 1
- 230000008018 melting Effects 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- -1 methane amide Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940055725 xarelto Drugs 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- HFAFXVOPGDBAOK-UHFFFAOYSA-N pyridine-2-carbonyloxidanium;chloride Chemical compound Cl.OC(=O)C1=CC=CC=N1 HFAFXVOPGDBAOK-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BTRIVKDXFFFIEU-UHFFFAOYSA-N C(=O)O.[N+]1(=CC=CC=C1)[O-] Chemical compound C(=O)O.[N+]1(=CC=CC=C1)[O-] BTRIVKDXFFFIEU-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- IHIZJRICNGUMFO-UHFFFAOYSA-N formyl chloride;hydrochloride Chemical compound Cl.ClC=O IHIZJRICNGUMFO-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Abstract
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of a sorafenib intermediate of 4-chlorine-2-pyridine methyl formate. The occurrence of the condition that 2-pyridine carboxylic acid forms oxidation products to mediate various impurities in the preparation process of the 4-chlorine-2-pyridine methyl formate is avoided, so that the high-purity 4-chlorine-2-pyridine methyl formate is obtained. The method is concretely characterized in that a certain amount of water is added into a system consisting of 2-pyridine carboxylic acid and chlorinated aliphatics or chlorinated aromatic hydrocarbon solvents; at a certain temperature range, thionyl chloride is added to take a chlorination reaction to prevent pyridine epoxidation. Therefore the method has the obvious advantages when 2-pyridine formate is used for chlorination under the same condition; the synthesized 4-chlorine-2-pyridine methyl formate has high purity and light color. The melting point of N-methyl-4-chlorine-2-pyridine formamide synthesized by the 4-chlorine-2-pyridine methyl formate can be raised to 55 to 56 DEG C; the purity of sorafenib is favorably improved, but the chlorination reaction time is not obviously prolonged.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of preparation method of Xarelto intermediate 4-Chloro-2-Pyridyle methyl-formiate.
Background technology
4-Chloro-2-Pyridyle methyl-formiate is the important intermediate preparing cancer therapy drug Xarelto.The synthetic method of bibliographical information generally with 2-pyridine carboxylic acid and sulfur oxychloride reflux when having solvent or solvent-free existence under DMF or Sodium Bromide catalysis generate 4-Chloro-2-Pyridyle formyl chloride hydrochloride after react with methyl alcohol again and generate object, be shown below.
But the nitrogen-atoms that sulfur oxychloride decomposes in the sulfurous gas meeting pyridine oxide formic acid produced in reaction process forms oxide compound, is shown below:
This oxide compound can mediate generation plurality of impurities.Partial impurities is difficult to be separated with 4-Chloro-2-Pyridyle methyl-formiate thus bring later reactions steps into until in the finished product, affects product purity and color.The reaction of bringing into is below affected intermediate quality by these impurity, the fusing point of the N-methyl-4-Chloro-2-Pyridyle methane amide such as synthesized by 4-Chloro-2-Pyridyle methyl-formiate is according to OrganicProcessResearch & Development2002,6, the report of the documents such as 777-781 is about 40 DEG C, its foreign matter content is higher, but the N-methyl-4-Chloro-2-Pyridyle methane amide fusing point adopting highly purified 4-Chloro-2-Pyridyle methyl-formiate to synthesize can reach 55 ~ 57 DEG C, and purity increases greatly.
So the generation of oxynitride should be avoided in synthesis 4-Chloro-2-Pyridyle methyl-formiate process as far as possible.Bibliographical information elder generation is had in the sulfur oxychloride of low temperature, to add a small amount of water and then attempt to avoid the oxidation of nitrogen-atoms on pyridine ring with the method that 2-pyridine carboxylic acid carries out reacting, but adding water in sulfur oxychloride is breakneck operation, and the effect done like this is very unstable.
Summary of the invention
The situation that the present invention will avoid 2-pyridine carboxylic acid in preparation 4-Chloro-2-Pyridyle methyl-formiate process to form oxidation products mediation plurality of impurities occurs, and obtains highly purified 4-Chloro-2-Pyridyle methyl-formiate.A kind of method first making 2-pyridine carboxylic acid salify stop oxidation is we have developed for achieving the above object.
Contriver finds in 2-pyridine carboxylic acid suspension, first to add a small amount of water in the presence of a solvent, then adds the method that sulfur oxychloride carries out chloro; But the method controls comparatively strict to condition, such as add water reaction system thickness at most, and add water the effect that can not play at least and prevent oxynitride from producing; For another example add the temperature of sulfur oxychloride, temperature is low, still can generate a large amount of oxynitride, and temperature height then reacts too acutely easily causes danger.So contriver determines the amount of water in reaction through great many of experiments and adds water temp; Make this method safer, effect is more stable.
Reaction formula is as follows:
A preparation method for 4-Chloro-2-Pyridyle methyl-formiate, comprises the steps:
1st step, in the system of 2-pyridine carboxylic acid and solvent composition, add water, after mixing, then drip sulfur oxychloride and carry out chlorination;
2nd step, the chloro-product the 1st step obtained again and methyl alcohol carry out esterification, prepare 4-Chloro-2-Pyridyle methyl-formiate.
Solvent in the 1st described step refers to chlorinated aliphatic hydrocarbon or chlorination aromatic hydrocarbon.
The water added in the 1st described step and the mol ratio of 2-pyridine carboxylic acid are (5 ~ 10): 100.
Dropping sulfur oxychloride temperature in the 1st described step is 60 ~ 72 DEG C.
Described chlorination aromatic hydrocarbon refers to chlorobenzene.
Catalyzer is selected from Sodium Bromide or DMF(dimethyl formamide).
As long as it can not be key factor that the amount of the sulfur oxychloride used in the present invention, methyl alcohol and catalyzer makes reaction complete.
Beneficial effect of the present invention is:
(1) situation that the present invention can avoid 2-pyridine carboxylic acid in preparation 4-Chloro-2-Pyridyle methyl-formiate process to form oxidation products mediation plurality of impurities occurs, and obtains highly purified 4-Chloro-2-Pyridyle methyl-formiate.In the system of the solvent composition of 2-pyridine carboxylic acid and chlorinated aliphatic hydrocarbon or chlorination aromatic hydrocarbon, add certain water gaging, in certain temperature range, add sulfur oxychloride carry out chlorination pyridine ring can be stoped to be oxidized.Have a clear superiority in so the preparation method of 4-Chloro-2-Pyridyle methyl-formiate of the present invention carries out chloro than under similarity condition with 2-pyridine carboxylic acid hydrochloride, the 4-Chloro-2-Pyridyle methyl-formiate purity of synthesis is high, of light color.The fusing point of the N-methyl-4-Chloro-2-Pyridyle methane amide synthesized by 4-Chloro-2-Pyridyle methyl-formiate can bring up to 55 ~ 56 DEG C, is conducive to the purity improving Xarelto.
(2) 2-pyridine carboxylic acid hydrochloride in halogenated alkane or aromatic hydrocarbons and in sulfur oxychloride solubleness little compared with 2-pyridine carboxylic acid, so the chlorination time can greatly extend.But start to only have part 2-pyridine carboxylic acid salify in the present invention, the reaction times can't be made obviously to extend.Institute has a clear superiority in than carrying out chloro with 2-pyridine carboxylic acid hydrochloride under similarity condition in this way, and the 4-Chloro-2-Pyridyle methyl-formiate purity of synthesis is high, and while the purity improving Xarelto and intermediate thereof, the chlorination time does not but obviously extend.
Embodiment
Embodiment 1
77Kg chlorobenzene, 50Kg2-pyridine carboxylic acid, 6.7Kg Sodium Bromide, 360g water, stirring is warming up to 72 DEG C, sulfur oxychloride 270Kg instills by control temperature between 60 ~ 72 DEG C, slowly be warming up to backflow, react 16 hours, decompression steams most of sulfur oxychloride, adds 160Kg toluene, evaporated under reduced pressure sulfur oxychloride.Be cooled to 10 DEG C, drip 70Kg methyl alcohol, reflux 1 hour, evaporated under reduced pressure methyl alcohol, filter, obtain yellow solid.Add 150Kg water dissolution, drop into sodium carbonate solid under stirring gradually and be neutralized to pH7, filter and obtain yellow solid.Solid water recrystallization, 40 DEG C of air blast are dried and are obtained white crystals 49.5Kg, yield 71.0%.Mp40~42℃，HPLC99.6%。
MS：M
+H172.0；H-NMR：δ4.029（S，3H），δ7.50（d，1H），δ8.147（s，1H），δ8.65（d，1H）。
4-Chloro-2-Pyridyle methyl-formiate prepared by employing the present embodiment is as raw material, according to OrganicProcessResearch & Development2002,6, the method recorded in 777-781, prepare next step intermediate N methyl-4-Chloro-2-Pyridyle methane amide for white, fusing point 55 ~ 57 DEG C.
Embodiment 2
(add-on of water is 150g, 300g, 600g, 1200g respectively for 77Kg chlorobenzene, 50Kg2-pyridine carboxylic acid, 6.7Kg Sodium Bromide, water, respectively as 1st ~ 4 groups), stirring is warming up to 72 DEG C, sulfur oxychloride 270Kg instills by control temperature between 60 ~ 72 DEG C, slowly be warming up to backflow, react 16 hours, decompression steams most of sulfur oxychloride, add 160Kg toluene, evaporated under reduced pressure sulfur oxychloride.Be cooled to 10 DEG C, drip 70Kg methyl alcohol, reflux 1 hour, evaporated under reduced pressure methyl alcohol, filter, obtain yellow solid.Add 150Kg water dissolution, drop into sodium carbonate solid under stirring gradually and be neutralized to pH7, filter and obtain yellow solid.Solid water recrystallization, 40 DEG C of air blast are dried and are obtained white crystals yield 70.6%, Mp40 ~ 42 DEG C, HPLC99.7%
| 1st group | 2nd group | 3rd group | 4th group | |
| Yield | 60.3% | 68.1% | 70.6% | 70.3% |
| HPLC purity | 99.1% | 99.5% | 99.7% | 99.8% |
。[0021]4-Chloro-2-Pyridyle methyl-formiate prepared by employing the present embodiment the 1st group is as raw material, according to OrganicProcessResearch & Development2002,6, the method recorded in 777-781, prepare next step intermediate N methyl-4-Chloro-2-Pyridyle methane amide for white, fusing point 55 ~ 57 DEG C.
Reference examples 1
Be with the difference of embodiment 1: first in sulfur oxychloride, add water and react
At 0 DEG C, in the mixture of 77Kg chlorobenzene and 270Kg sulfur oxychloride, slowly drip 600g water, react very violent.After water injection drop into 50Kg2-pyridine carboxylic acid, 6.7Kg Sodium Bromide afterwards, keep less than 10 DEG C stirrings to be then slowly warming up to backflow in 4 hours, react 16 hours, decompression steams most of sulfur oxychloride, adds 160Kg toluene, evaporated under reduced pressure sulfur oxychloride.Be cooled to 10 DEG C, drip 70Kg methyl alcohol, reflux 1 hour, evaporated under reduced pressure methyl alcohol, filter, obtain yellow solid.Add 150Kg water dissolution, drop into sodium carbonate solid under stirring gradually and be neutralized to pH7, filter and obtain yellow solid.Solid water recrystallization, 40 DEG C of air blast are dried and are obtained yellowish brown crystallization 47.0Kg, yield 67.45%.Mp40～42℃，HPLC96.3%。
The 4-Chloro-2-Pyridyle methyl-formiate adopting this reference examples to prepare is as raw material, according to OrganicProcessResearch & Development2002,6, the method recorded in 777-781, prepare next step intermediate N methyl-4-Chloro-2-Pyridyle methane amide for white, fusing point 41 ~ 43 DEG C.
Can be found out compared with reference examples 1 by embodiment 1, the reaction conditions adding water can improve the safety and stability of the yield of reaction product, purity and reaction effectively.
Claims (6)
1. a preparation method for 4-Chloro-2-Pyridyle methyl-formiate, is characterized in that, comprises the steps:
1st step, in the system of 2-pyridine carboxylic acid and solvent composition, add water, after mixing, then drip sulfur oxychloride and carry out chlorination;
2nd step, the chloro-product the 1st step obtained again and methyl alcohol carry out esterification, prepare 4-Chloro-2-Pyridyle methyl-formiate.
2. the preparation method of 4-Chloro-2-Pyridyle methyl-formiate according to claim 1, is characterized in that: the solvent in the 1st described step refers to chlorinated aliphatic hydrocarbon or chlorination aromatic hydrocarbon.
3. the preparation method of 4-Chloro-2-Pyridyle methyl-formiate according to claim 2, is characterized in that: described chlorination aromatic hydrocarbon refers to chlorobenzene.
4. the preparation method of 4-Chloro-2-Pyridyle methyl-formiate according to claim 1, is characterized in that: the water added in the 1st described step and the mol ratio of 2-pyridine carboxylic acid are (5 ~ 10): 100.
5. the preparation method of 4-Chloro-2-Pyridyle methyl-formiate according to claim 1, is characterized in that: dripping sulfur oxychloride temperature in the 1st described step is 60 ~ 72 DEG C.
6. the preparation method of 4-Chloro-2-Pyridyle methyl-formiate according to claim 1, is characterized in that: catalyzer is selected from Sodium Bromide or DMF(dimethyl formamide).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114656401A (en) * | 2022-04-19 | 2022-06-24 | 江苏恒沛药物科技有限公司 | Method for preparing 4-chloropyridine-2-methyl formate serving as sorafenib key intermediate and suitable for industrial production |
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| CN102675197A (en) * | 2012-05-11 | 2012-09-19 | 上海奥博生物医药技术有限公司 | Method for preparing 4-chlorin-N-methylpyridine-2-formamide serving as sorafenib intermediate |
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| WO2001038326A2 (en) * | 1999-11-23 | 2001-05-31 | Merck Sharp & Dohme Limited | Imidazo-pyridine derivatives as ligands for gaba receptors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114656401A (en) * | 2022-04-19 | 2022-06-24 | 江苏恒沛药物科技有限公司 | Method for preparing 4-chloropyridine-2-methyl formate serving as sorafenib key intermediate and suitable for industrial production |
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