CN102603620A - Synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of chloromethylpyridine - Google Patents
Synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of chloromethylpyridine Download PDFInfo
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- CN102603620A CN102603620A CN2012100109700A CN201210010970A CN102603620A CN 102603620 A CN102603620 A CN 102603620A CN 2012100109700 A CN2012100109700 A CN 2012100109700A CN 201210010970 A CN201210010970 A CN 201210010970A CN 102603620 A CN102603620 A CN 102603620A
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- pyridine
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- pyridine derivate
- chlorination
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- -1 pyridine derivative hydrochloride Chemical class 0.000 title claims abstract description 8
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 title abstract 5
- 238000010189 synthetic method Methods 0.000 title abstract 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 106
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 14
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 8
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 238000007336 electrophilic substitution reaction Methods 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical compound OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 229910000497 Amalgam Inorganic materials 0.000 claims description 2
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- VTQLKSBTYJTJNF-UHFFFAOYSA-N [N].[O-][N+]1=CC=CC=C1 Chemical compound [N].[O-][N+]1=CC=CC=C1 VTQLKSBTYJTJNF-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 1
- 238000007265 chloromethylation reaction Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 abstract 2
- 150000003222 pyridines Chemical class 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 238000010792 warming Methods 0.000 description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 229910017053 inorganic salt Inorganic materials 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- 238000005070 sampling Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000003317 industrial substance Substances 0.000 description 5
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 5
- 229960000344 thiamine hydrochloride Drugs 0.000 description 5
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 5
- 239000011747 thiamine hydrochloride Substances 0.000 description 5
- MFEIKQPHQINPRI-UHFFFAOYSA-N 3-Ethylpyridine Chemical compound CCC1=CC=CN=C1 MFEIKQPHQINPRI-UHFFFAOYSA-N 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- JPMRGPPMXHGKRO-UHFFFAOYSA-N 2-(chloromethyl)pyridine hydrochloride Chemical compound Cl.ClCC1=CC=CC=N1 JPMRGPPMXHGKRO-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000010970 precious metal Substances 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- KBCDOXSSYLFMHH-UHFFFAOYSA-N (3,5-dimethyl-4-nitropyridin-2-yl)methanol Chemical compound CC1=CN=C(CO)C(C)=C1[N+]([O-])=O KBCDOXSSYLFMHH-UHFFFAOYSA-N 0.000 description 1
- CQKHUAFREIMBJI-UHFFFAOYSA-N (4-chloro-3,5-dimethylpyridin-2-yl)methanol Chemical compound CC1=CN=C(CO)C(C)=C1Cl CQKHUAFREIMBJI-UHFFFAOYSA-N 0.000 description 1
- YJMAOKXCSURAIP-UHFFFAOYSA-N 2-(chloromethyl)-3-ethylpyridine;hydrochloride Chemical compound Cl.CCC1=CC=CN=C1CCl YJMAOKXCSURAIP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of the chloromethylpyridine. The synthetic method is characterized in that according to the method, the positioning effect of substitutional groups is used for carrying out chloromethylation reaction, raw materials of pyridine or pyridine derivatives are subjected to Friedel-Crafts acylation reaction under the catalyst effect, No.2 sites or No.6 sites of the pyridine or the pyridine derivatives take electrophilic substitution reaction, then, hydroxymethylpyridine or hydroxymethylpyridine derivatives are obtained through reduction reaction, next, the chloromethylpyridine or the pyridine derivative hydrochloride is obtained through chlorination reaction, and the structure of the obtained product is shown as the accompanying drawing. The method has the advantages that the reaction steps are few, the cost is low, the purity is high, the yield is high, the operation is safe, and the method is suitable for large-scale industrial production.
Description
Technical field:
The invention belongs to chemical field; Be specifically related to the compound method of a kind of PMC or its pyridine derivate hydrochloride; PMC and pyridine derivate hydrochloride are the important industrial chemicals of various agricultural chemicals, medicine intermediate, Insecticides (tech) & Herbicides (tech), sterilant, and present method directly generates 2-PMC and pyridine derivate from pyridine or its pyridine derivate.
Background technology:
PMC and pyridine derivate hydrochloride are the important industrial chemicals of various agricultural chemicals, medicine intermediate, Insecticides (tech) & Herbicides (tech), sterilant.Pyridine and pyridine derivate are directly gone up methyl at present, and with expensive precious metal industrial chemicals such as lithium methide, methyl iodide, perhaps just direct cyclization becomes methyl is arranged on the 2-position, leads to chlorine again, carries out chlorination.The technology that has is on oxygen, to methylate for pyridine nitric oxide with methyl-sulfate; And then carry out making 2-4-hydroxymethylpiperidine and pyridine derivate after the oxidation; Chlorination gets 2-PMC and pyridine derivate hydrochloride again, as: US4620008, CN101337924A, SE0103553 etc.Pyridine and pyridine derivate carry out connecing synthetic industrial chemicals midbody and the bulk drug that high added value is arranged of other groups more easily behind the chloromethylation.But use lithium methide, methyl iodide etc. to be raw material, cost value pressure is big, and it is cumbersome to reclaim precious metal and iodine element; Big with methyl-sulfate toxicity, for the operation hazardous that feeds intake.
Summary of the invention
The compound method that the purpose of this invention is to provide a kind of PMC and pyridine derivate hydrochloride.
The objective of the invention is through following scheme implementation:
The compound method of a kind of PMC or pyridine derivate hydrochloride, this method be with pyridine or pyridine derivate through peroxo-, catalysis ethanoylization, restore with chlorination and obtain PMC or pyridine derivate hydrochloride.
The present invention is through following scheme implementation:
The compound method of a kind of PMC or its pyridine derivate hydrochloride; It is characterized in that this method uses substituent orientation effect to carry out chloromethylation; This method comprises carries out friedel-crafts acylation reaction with pyridine or pyridine derivate and acylting agent under catalyst action; Electrophilic substitution reaction takes place in No. 2 positions or No. 6 positions at pyridine or pyridine derivate; Obtain 4-hydroxymethylpiperidine or 4-hydroxymethylpiperidine verivate through reduction then, obtain PMC or pyridine derivate hydrochloride through chlorination again.The product structure that obtains is following:
Described pyridine derivate is preferably nitrogen pyridine oxide verivate, wherein, and preferred R
1Be H, CH
3, CH
2CH
3, Cl, OCH
3, NH
2Or NO
2Preferred R
2Be H, CH
3, CH
2CH
3, Cl, OCH
3, NH
2Or NO
2Preferred R
3Be H, CH
3, CH
2CH
3, Cl, OCH
3, NH
2Or NO
2Has only H on No. 2 positions of the pyridine ring of described raw material pyridine and pyridine derivate, No. 6 positions.
The temperature of reaction of described acylation reaction is 45 ℃～95 ℃, the reaction times be 4～16h (preferred 4～6h), raw material pyridine or pyridine derivate: acylting agent: catalyzer=1: 1～2.5: 0.1～0.5 (mol ratio); The temperature of reaction of described reduction reaction is 45 ℃～95 ℃, and the reaction times is 5～16h (preferred 5～12h, most preferably 5～7h); Chlorination temperature is in the described chlorination :-20 ℃～-5 ℃, the reaction times is 1～3h.
The used acylting agent of described friedel-crafts acylation reaction is carboxylic acid halides or acid anhydrides.Preferred acylting agent is: RCOI, RCOBr, RCOCl, RCOF, (RCO) O; Described R is preferably CH
3, CH
3CH
2, CH
2=CH or CH
3(CH
2)
n, 3>=n>=1 wherein.
The catalyzer that friedel-crafts acylation reaction of the present invention adopts is Lewis acid; The preferred AlCl of described Lewis acid
3, ZnCl
2, MgO, ZnO, K
2CO
3Or Na
2CO
3
The preferred Fe/AcOH of reductive agent, Na/EtOH, Zn/NaOH, zinc amalgam, Peng Qinghuana, Lithium Aluminium Hydride, tetrahydro boron sodium, Raney nickel or palladium charcoal that reduction step of the present invention adopts; The reductive agent consumption is the mass ratio 1 with raw material pyridine or pyridine derivate: 0.5-2; The preferred SOCl of reagent that described chlorination adopts
2, POCl
3, PCl
3, Cl
2Or HCl.The consumption of chlorination reagent for raw material pyridine or pyridine derivate mass ratio be 1: 0.5-4.
With the raw material is that pyridine is that example is reacted as follows:
Wherein, R
1, R
2And R
3Be H.
With prior art beneficial effect more of the present invention: the present invention adopts the industrial chemicals that contains pyridine ring commonly used to carry out the acetyl glycosylation reaction, and reactions step is few, and cost is low, and purity is high, and yield is high, and operational safety, the inventive method are suitable for large-scale industrial production.
Embodiment:
Further understand the present invention through following examples, but can not limit content of the present invention.
Embodiment 1
The 4-methoxyl group-3 that in the flask of 500ml, adds 9.2g, 5-lutidine oxynitride, the methyl alcohol of 60ml; Add the 0.8g aluminum chloride, be cooled to and begin to drip Vinyl chloroformate 7.8g below 0 ℃, after dropwising; Being warming up to temperature of reaction is 45 ℃～95 ℃, back flow reaction 4～6 hours, sampling analysis; Until raw material 4-methoxyl group-3, till 5-lutidine oxynitride does not reduce; In system, add the 6.75g tetrahydro boron sodium, temperature of reaction is 55-65 ℃, reduces.Reacted 5 hours, and filtered, filter out inorganic salt, filtrating steaming is removed methyl alcohol; Go out 2-methylol-4-methoxyl group-3,5-lutidine, dry methylene chloride phase with dichloromethane extraction; Be cooled to-10 ℃ and begin to drip the 14g sulfur oxychloride, and then be warming up to room temperature reaction naturally 2～3 hours, get 2-chloromethyl-4-methoxyl group-3; 5-dimethyl pyrazole thiamine hydrochloride, weigh the 10.8g white solid, analyze through HPLC: purity is 98.37%.The three-step reaction total recovery is 81.2%.
Embodiment 2
The 4-nitro-3 that in the flask of 500ml, adds 10g, 5-lutidine oxynitride, the methyl alcohol of 60ml; Add 0.5g Natural manganese dioxide, be cooled to and begin to drip diacetyl oxide 6.2g below 0 ℃, after dropwising; Being warming up to temperature of reaction is 45 ℃～95 ℃, back flow reaction 4～6 hours, sampling analysis; Until raw material 4-nitro-3, till 5-lutidine oxynitride does not reduce; In system, add the 6.75g Lithium Aluminium Hydride, temperature of reaction is 85-95 ℃, reduces.Reacted 7 hours, and filtered, leach inorganic salt, filtrating steaming is removed methyl alcohol; Go out 2-methylol-4-nitro-3,5-lutidine, dry methylene chloride phase with dichloromethane extraction; Be cooled to-20 ℃ and begin to drip the 18g phosphorus trichloride, and then be warming up to room temperature reaction naturally 2～3 hours, get 2-chloromethyl-4-nitro-3; 5-dimethyl pyrazole thiamine hydrochloride, weigh 11.9g off-white color solid, analyze through HPLC: purity is 97.73%.The three-step reaction total recovery is 84.4%.
Embodiment 3
In the flask of 500ml, add 3 of 7.3g, 5-lutidine oxynitride, the methyl alcohol of 60ml adds the 4.0g zinc chloride, is cooled to begin to drip chloracetyl (CH below 0 ℃
3COCl) 9.3g, after dropwising, being warming up to temperature of reaction is 45 ℃～95 ℃, back flow reaction 4～6 hours, sampling analysis is until raw material 3, till 5-lutidine oxynitride does not reduce; In system, add 6.75gFe/10mlAcOH, temperature of reaction is 45-55 ℃, reduces.Reacted 12 hours, and filtered out inorganic salt, steam and remove methyl alcohol; Go out 2-methylol-3 with dichloromethane extraction, 5-lutidine, dry methylene chloride phase; Be cooled to-5 ℃ and begin to feed 8.4g chlorine, and then be warming up to room temperature reaction naturally 1～2 hour, get 2-chloromethyl-3; 5-dimethyl pyrazole thiamine hydrochloride, weigh the 9.1g white solid, analyze through HPLC: purity is 98.45%.The three-step reaction total recovery is 80.5%.
Embodiment 4
The pyridine nitric oxide that in the flask of 500ml, adds 5.6g, the methyl alcohol of 60ml adds 1.6g salt of wormwood; Be cooled to and begin to drip propionic anhydride 19.2g below 0 ℃, after dropwising, being warming up to temperature of reaction is 45 ℃～95 ℃; Back flow reaction 4～6 hours; Sampling analysis is until raw material 3, till 5-lutidine oxynitride does not reduce; In system, add 10gRaney nickel, reduce, temperature of reaction is 55-65 ℃, reacts 5 hours; Filter out inorganic salt, steam and remove methyl alcohol, go out 2-methylol-3 with dichloromethane extraction, the 5-lutidine; The dry methylene chloride phase is cooled to-15 ℃ and feeds 4.3g hydrogenchloride, and then was warming up to room temperature reaction naturally 2～3 hours; The 2-chloromethyl pyridine hydrochloride, weigh the 8.9g colorless solid, analyze through HPLC: purity is 95.83%.The three-step reaction total recovery is 88.7%.
Embodiment 5
The pyridine that in the flask of 500ml, adds 4g, the methyl alcohol of 60ml adds the 2.0g aluminum chloride; Be cooled to and begin to drip Vinyl chloroformate 12.6g below 0 ℃, after dropwising, being warming up to temperature of reaction is 45 ℃～95 ℃; Back flow reaction 4～6 hours; Sampling analysis is until raw material 4-methoxyl group-3, till 5-lutidine oxynitride does not reduce; In system, add the 6.75g tetrahydro boron sodium, reduce.Temperature of reaction is 55-65 ℃, reacts 5 hours, filters; Filter out inorganic salt, filtrating steaming is removed methyl alcohol, goes out the 2-4-hydroxymethylpiperidine with dichloromethane extraction; The dry methylene chloride phase is cooled to-10 ℃ and begins to drip the 14g sulfur oxychloride, and then was warming up to room temperature reaction naturally 2～3 hours; The 2-chloromethyl pyridine hydrochloride, weigh the 6.8g white solid, analyze through HPLC: purity is 99.3%.The three-step reaction total recovery is 81.9%.
Embodiment 6
The 4-amino-3 that in the flask of 500ml, adds 8.2g, 5-lutidine oxynitride, the methyl alcohol of 60ml; Add 0.84g Natural manganese dioxide, be cooled to and begin to drip diacetyl oxide 9.7g below 0 ℃, after dropwising; Being warming up to temperature of reaction is 45 ℃～95 ℃, back flow reaction 4～6 hours, sampling analysis; Until raw material 4-amino-3, till 5-lutidine oxynitride does not reduce; In system, add the 6.75g Lithium Aluminium Hydride, reduce.Temperature of reaction is 85-95 ℃, reacts 5 hours, filters, and leaches inorganic salt; Filtrating steaming is removed methyl alcohol, goes out 2-methylol-4-amino-3,5-lutidine, dry methylene chloride phase with dichloromethane extraction; Be cooled to-10 ℃ and begin to drip the 18g phosphorus trichloride, and then be warming up to room temperature reaction naturally 2～3 hours, get 2-chloromethyl-4-amino-3; 5-dimethyl pyrazole thiamine hydrochloride, weigh 10.5g off-white color solid, analyze through HPLC: purity is 97.73%.The three-step reaction total recovery is 85.4%.
Embodiment 7
The 4-chloro-3 that in the flask of 500ml, adds 9.3g, 5-lutidine oxynitride, the methyl alcohol of 60ml adds the 3.2g zinc chloride, is cooled to begin to drip chloracetyl (CH below 0 ℃
3COCl) 10.65g, after dropwising, being warming up to temperature of reaction is 45 ℃～95 ℃, back flow reaction 9～10 hours, sampling analysis is until raw material 4-chlorine 3, till 5-lutidine oxynitride does not reduce; In system, add 6.75gFe/10mlAcOH, reduce.Temperature of reaction is 55-65 ℃, reacts 5 hours, filters out inorganic salt, steams and removes methyl alcohol; Go out 2-methylol-4-chloro-3,5-lutidine, dry methylene chloride phase with dichloromethane extraction; Be cooled to subzero 10 ℃ and begin to feed 8.4g chlorine, and then be warming up to room temperature reaction naturally 2～3 hours, get 2-chloromethyl-4-chloro-3; 5-dimethyl pyrazole thiamine hydrochloride, weigh the 11.1g white solid, analyze through HPLC: purity is 98.65%.The three-step reaction total recovery is 82.8%.
Embodiment 8
The 3-ethylpyridine oxynitride that in the flask of 500ml, adds 7.3g, the methyl alcohol of 60ml adds 1.6g salt of wormwood; Be cooled to and begin to drip propionic anhydride 19.3g below 0 ℃; After dropwising, being warming up to temperature of reaction is 45 ℃～95 ℃, back flow reaction 4～6 hours; Sampling analysis is not till raw material 3-ethylpyridine oxynitride reduces; In system, add 10gRaney nickel, reduce.Temperature of reaction is 75-85 ℃, reacts 5 hours, filters out inorganic salt; Steam and remove methyl alcohol, go out 2-methylol-3 with dichloromethane extraction, the 5-lutidine; The dry methylene chloride phase is cooled to subzero 10 ℃ and feeds 4.3g hydrogenchloride, and then was warming up to room temperature reaction naturally 2～3 hours; 2-chloromethyl 3-ethylpyridine hydrochloride, weigh the 9.6g colorless solid, analyze through HPLC: purity is 95.83%.The three-step reaction total recovery is 85%.
Claims (10)
1. the compound method of a PMC or its pyridine derivate hydrochloride is characterized in that this method may further comprise the steps:
Raw material pyridine or pyridine derivate and acylting agent are carried out friedel-crafts acylation reaction under catalyst action; Electrophilic substitution reaction takes place in No. 2 positions or No. 6 positions at pyridine or pyridine derivate; Obtain 4-hydroxymethylpiperidine or 4-hydroxymethylpiperidine verivate through reduction reaction then; Obtain PMC or pyridine derivate hydrochloride through chlorination again, the product structure that obtains is following:
2. compound method according to claim 1; The temperature of reaction that it is characterized in that described friedel-crafts acylation reaction is 45 ℃～95 ℃; Reaction times is 4～16h, wherein, and raw material pyridine or pyridine derivate: acylting agent: catalyzer=1: 1～2.5: 0.1～0.5; The temperature of reaction of described reduction reaction is 45 ℃～95 ℃, and the reaction times is 5～16h; Chlorination temperature is in the described chlorination :-20 ℃～-5 ℃, the reaction times is 1～3h.
3. compound method according to claim 1 is characterized in that described pyridine derivate is a nitrogen pyridine oxide verivate.
4. compound method according to claim 1 is characterized in that described R
1Be H, CH
3, CH
2CH
3, Cl, OCH
3, NH
2Or NO
2R
2Be H, CH
3, CH
2CH
3, Cl, OCH
3, NH
2Or NO
2R
3Be H, CH
3, CH
2CH
3, Cl, OCH
3, NH
2Or NO
2
5. compound method according to claim 1 and 2 is characterized in that the used acylting agent of described friedel-crafts acylation reaction is carboxylic acid halides or acid anhydrides.
6. compound method according to claim 5 is characterized in that described acylting agent is: RCOI, RCOBr, RCOCl, RCOF, (RCO) O; Described R is CH
3, CH
3CH
2, CH
2=CH or CH
3(CH
2)
n, 3>=n>=1 wherein.
7. compound method according to claim 1 and 2 is characterized in that the catalyzer that described friedel-crafts acylation reaction adopts is Lewis acid.
8. compound method according to claim 7 is characterized in that described Lewis acid is AlCl
3, ZnCl
2, MgO, ZnO, K
2CO
3Or Na
2CO
3
9. compound method according to claim 1 and 2 is characterized in that the reductive agent that described reduction reaction adopts is: Fe/AcOH, Na/EtOH, Zn/NaOH, zinc amalgam, Peng Qinghuana, Lithium Aluminium Hydride, tetrahydro boron sodium, Raney nickel or palladium charcoal; The reductive agent consumption is 1 for the mass ratio with raw material pyridine or pyridine derivate: 0.5-2.
10. compound method according to claim 1 and 2 is characterized in that the reagent that described chlorination adopts is SOCl
2, POCl
3, Cl
2, PCl
3, or HCl; The consumption of chlorination reagent for raw material pyridine or pyridine derivate mass ratio be 1: 0.5-4.
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| CN104974078A (en) * | 2015-06-25 | 2015-10-14 | 黄荣辉 | Preparation method of 2-methyl-6-chloromethylpyridinehydrochloride |
| CN105198799A (en) * | 2015-11-03 | 2015-12-30 | 江苏梦得电镀化学品有限公司 | Preparation method of 2-methyl-6-(chloromethyl) pyridine hydrochloride |
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| CN105198799A (en) * | 2015-11-03 | 2015-12-30 | 江苏梦得电镀化学品有限公司 | Preparation method of 2-methyl-6-(chloromethyl) pyridine hydrochloride |
| CN111638303A (en) * | 2020-06-08 | 2020-09-08 | 安徽大学 | Distinguish metal ion Al3+And Zn2+Method (2) |
| CN111638303B (en) * | 2020-06-08 | 2022-06-24 | 安徽大学 | Distinguish metal ion Al3+And Zn2+Method (2) |
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| CN102603620B (en) | 2014-10-29 |
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Application publication date: 20120725 Assignee: Nanjing Red Sun Pharmaceutical Research Institute Co.,Ltd. Assignor: Jiangsu Zhongbang Pharmaceutical Co.,Ltd. Contract record no.: X2022980010825 Denomination of invention: A synthetic method of chloromethyl pyridine or its pyridine derivative hydrochloride Granted publication date: 20141029 License type: Common License Record date: 20220721 |