CN109206363A - A kind of novel environment-friendly process preparing 2- chlorine apellagrin - Google Patents
A kind of novel environment-friendly process preparing 2- chlorine apellagrin Download PDFInfo
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- CN109206363A CN109206363A CN201710572452.0A CN201710572452A CN109206363A CN 109206363 A CN109206363 A CN 109206363A CN 201710572452 A CN201710572452 A CN 201710572452A CN 109206363 A CN109206363 A CN 109206363A
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- niacin
- chlorine apellagrin
- chlorine
- synthetic method
- oxidation
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- 239000000460 chlorine Substances 0.000 title claims abstract description 37
- 229910052801 chlorine Inorganic materials 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000008569 process Effects 0.000 title abstract description 8
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 38
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 38
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 38
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 26
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 22
- 230000003647 oxidation Effects 0.000 claims abstract description 19
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 15
- 230000009471 action Effects 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000007530 organic bases Chemical class 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 8
- -1 niacin nitrogen oxides Chemical class 0.000 claims description 5
- VLAPMBHFAWRUQP-UHFFFAOYSA-L molybdic acid Chemical group O[Mo](O)(=O)=O VLAPMBHFAWRUQP-UHFFFAOYSA-L 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 229910001882 dioxygen Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 9
- 238000010438 heat treatment Methods 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 235000019504 cigarettes Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 2
- 239000005740 Boscalid Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 239000005507 Diflufenican Substances 0.000 description 2
- 239000005586 Nicosulfuron Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 description 2
- 229940118790 boscalid Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- WYEHFWKAOXOVJD-UHFFFAOYSA-N diflufenican Chemical compound FC1=CC(F)=CC=C1NC(=O)C1=CC=CN=C1OC1=CC=CC(C(F)(F)F)=C1 WYEHFWKAOXOVJD-UHFFFAOYSA-N 0.000 description 2
- 239000000383 hazardous chemical Substances 0.000 description 2
- 231100000206 health hazard Toxicity 0.000 description 2
- RTCOGUMHFFWOJV-UHFFFAOYSA-N nicosulfuron Chemical compound COC1=CC(OC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CN=2)C(=O)N(C)C)=N1 RTCOGUMHFFWOJV-UHFFFAOYSA-N 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- PCYWMDGJYQAMCR-UHFFFAOYSA-N 1h-pyrrole-3-carbonitrile Chemical compound N#CC=1C=CNC=1 PCYWMDGJYQAMCR-UHFFFAOYSA-N 0.000 description 1
- RKVUCIFREKHYTL-UHFFFAOYSA-N 2-chloro-3-methylpyridine Chemical compound CC1=CC=CN=C1Cl RKVUCIFREKHYTL-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000002699 waste material Substances 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
- C07D213/80—Acids; Esters in position 3
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of novel environment-friendly process for preparing 2- chlorine apellagrin, it is with niacin (I) for raw material, it is aoxidized under aqueous systems catalyst action through hydrogen peroxide N- and N- oxidation niacin (II) is made, then under the action of organic base, 2- chloronicotinoyl chloride (III) is synthesized through phosphorus oxychloride chlorination, then hydrolyzed, be refining to obtain 2- chlorine apellagrin (IV).This method avoid the use of benzene and acetic acid, process flow is short, safety and environmental protection, good product quality and high income, is an environmental-friendly green syt route, is suitable for industrialized production.
Description
Technical field
The invention belongs to medication chemistries and pesticide field, are related to a kind of green synthesis method of 2- chlorine apellagrin.
Background technique
2- chlorine apellagrin is mainly used for new and effective herbicide nicosulfuron (Nicosulfuron) and Diflufenican
(Diflufenican), novel systemic fungicide Boscalid (Boscalid), antibacterial agent and Anti-cancer medicament intermediate 2- chlorine
The agricultures such as the synthesis of pyridine -3- phosphinylidyne-nitrogen-containing heterocycle compound and hiv reverse transcriptase inhibitor nevirapine (Nevirapine)
The synthesis of medicine and medicine intermediate.Research for 2- chlorine apellagrin, foreign countries begin to early in the 1970s.Earliest is special
Benefit is the Lonza company application of Switzerland in 1977, and patent is preferably at most Japan, such as the glorious chemistry of Japan, Japanese organic synthesis one
A little well-known companies have all applied for patent (JP5914459).And the country is the research just begun with from 2003 to 2- chlorine apellagrin
Article and patent report (CN101367760A, CN101117332A).The synthetic route of 2- chlorine apellagrin is main both at home and abroad at present
There are two major classes: first is that based on existing pyridine ring parent, chlorination or introducing relevant functional group directly on pyridine ring to synthesize
Target product；Second is that selecting suitable straight chain reactive compound, target product is synthesized by grafting and closed loop.These two types of routes
All respectively there is its advantage and disadvantage: it is first kind route simple process, low in cost, but product purity is undesirable；Second class route produces
Product purity is high, meets pharmaceutical requirements, but complex process, the cost is relatively high.By raw material point, niacin method, 3- cyano pyrrole can be divided into
The chloro- 3- picoline oxidizing process of pyridine method, 2-, cyan-acetic ester method, malonaldehyde method etc..The side of chlorine is introduced directly on pyridine ring
Method mainly includes niacin method and cigarette cyanogen method, and the method for main use industrial at present.Chlorination is mainly wrapped on pyridine ring
Niacin method and cigarette cyanogen method are included, this is also the method industrially mainly used at present.
It is industrial at present that N- oxidation cigarette is made through hydrogen peroxide oxidation in toluene and acetic acid solvent with niacin (or nicotinic acid nitrile)
Acid (or N- aoxidize nicotinic acid nitrile), then through phosphorus oxychloride and phosphorus pentachloride chlorination, hydrolyze, be refining to obtain to obtain 2- chlorine apellagrin.According to document report
Road, this method yield and product purity be not high (mainly 6- chlorine apellagrin impurity content is higher), to obtain qualified products need to be through more
Secondary purification process, high production cost, and use a large amount of benzene and acetic acid as solvent, synthesis 2- chlorine cigarette when synthesizing N- oxide
POCl is removed when sour3It also needs using a large amount of PCl outside5, generate a large amount of acid environmental protection pressure for causing the disposal of three wastes containing chlorine and phosphorus-containing wastewater
Power is significantly increased and the problems such as production process occupational health hazards increased risk.
Summary of the invention
It is an object of the invention to: one kind is provided using niacin as raw material, and the ring of 2- chlorine apellagrin is synthesized through N- oxidation and chlorination
The problems such as protecting, green syt new method, solving using niacin as the environmental protection of Material synthesis 2- chlorine apellagrin, cost, product quality.
Technical scheme is as follows: with niacin (I) for raw material, under the action of catalyst through dioxygen water oxygen in aqueous systems
Change and N- oxidation niacin (II) is made, then obtain 2- chloronicotinoyl chloride (III) through phosphorus oxychloride chlorination under the action of organic base, finally
Hydrolyze to obtain 2- chlorine apellagrin (IV).Its synthetic route is as follows:
Method of the invention specifically comprises the following steps:
(1) N- aoxidizes the preparation of niacin (II): being raw material under the action of catalyst through H with niacin (I)2O2It is anti-that oxidation occurs
It answers, is made niacin nitrogen oxides (II).
(2) preparation of 2- chlorine apellagrin (IV): above walk obtained niacin nitrogen oxides under the action of organic base with trichlorine oxygen
Phosphorus is reacted to obtain 2- chloronicotinoyl chloride (III), is most hydrolyzed afterwards, purifies to obtain 2- chlorine apellagrin.
As a preferred technical solution, in step (1), the molar ratio of the niacin and hydrogen peroxide is 1.05~1.5: 1, into
One step is preferably 1.05~1.2: 1
As a preferred technical solution, in step (1), oxidant hydrogen peroxide concentration is 20~35%, further preferably
30~35%
As a preferred technical solution, in step (1), the catalyst is molybdic acid, and dosage is niacin (I) quality
0.1~1.0%, further preferably 0.5~0.8.
As a preferred technical solution, in step (1), the temperature of the dropwise addition of hydrogen peroxide is preferably 90~95 DEG C, further
Preferably 92~95 DEG C；90~100 DEG C of the reaction time of insulation reaction temperature control, it is excellent to be further selected as 95~100 DEG C.
As a preferred technical solution, in step (1), after oxidation reaction, reaction solution is cooled to 0~5 DEG C, N- oxygen
Change niacin to be largely precipitated, filter the N- oxidation niacin of precipitation, 80 DEG C or less dryings to moisture can carry out in next step lower than 0.5%
Chlorination reaction.
As a preferred technical solution, in step (1), the N- in the unreacted niacin of oxidation reaction and mother liquor aoxidizes niacin
Recycling circuits sequentially set the following steps are included: the mother liquor that oxidation reaction is obtained by filtration put into time batch oxidation reaction based on water
With.
As a preferred technical solution, in step (2), the organic base is the alkylamines such as triethylamine, tri-n-butylamine, preferably
For triethylamine, the molar ratio of triethylamine and N- oxidation niacin (II) is 1.9: 1.
As a preferred technical solution, in step (2), phosphorus oxychloride and N- oxidation niacin (II) molar ratio be 5.0~
7.7: 1, preferably 6.8: 1.
As a preferred technical solution, in step (2), triethylamine dropping temperature is controlled in 0~20 DEG C, preferably 10~20
℃；Chlorination reaction temperature is controlled at 10~100 DEG C, and preferably 15~100 DEG C of 5~10h of section at the uniform velocity gradient increased temperature reacts.
As a preferred technical solution, in step (2), water ring vacuum pump is decompressed to 5000Pa distillation after chlorination reaction
Unreacted phosphorus oxychloride is recycled, when no distillate, switching oil pump is decompressed to 400Pa and carries out rectifying, collects 97-98 DEG C of fraction
White solid 2- chloronicotinoyl chloride is obtained, 2- chlorine apellagrin is hydrolyzed to obtain.
Remarkable result of the invention:
1, it after catalyst is added in the present invention, using water as oxidation solvent, effectively prevents conventional acetic acid and toluene is made
Solvent is to the burn into occupational health of equipment and the harm of environment.
2, the present invention selects chlorination reagent and solvent of the phosphorus oxychloride as chlorination reaction, and unreacted phosphorus oxychloride is complete
Recycled is recycled, instead of traditional phosphorus pentachloride and methanol as solvent bring occupational health hazards.
3, the present invention synthesizes 2- chlorine apellagrin through oxidation, chlorination and hydrolysis three-step reaction, product contains using niacin as starting material
Amount up to 99.8%, yield is up to 91.6%.
4, reaction condition of the present invention is mild, process flow is short, production cost is low, oxidation and chlorination reaction process using water and
The recyclable recycled of phosphorus oxychloride, it is an environmental-friendly green syt route that no waste water, which generates, is suitable for commercial scale
Metaplasia produces.
Specific embodiment
Embodiment 1:
It is added into three-necked flask and sequentially adds water 100ml, niacin 100g, molybdic acid 0.66g, 92 DEG C are warming up to, to temperature
Start that hydrogen peroxide 104ml is added dropwise after stabilization, at the uniform velocity dropwise addition 3h, 95 DEG C of heat preservations 3h, TLC detect Nicotinic Acid Content < after being added dropwise
0.5%, heat preservation terminates to be down to 0-5 DEG C, stirs 0.5h, filtering, and mother liquor waits for that lower batch oxidation reaction is recycled, and 60 DEG C of filter cake true
It is empty dry that white crystalline powder N- aoxidizes niacin 108.7g, yield 97.4% [HPLC content 99.8%, moisture 0.22%, mp
DEG C 261.4-261.6 (260-262 DEG C of document)].
Phosphorus oxychloride 146ml is added into three-necked flask, ice bath stirring is cooled to 10 DEG C and starts to be slowly added to N- oxidation cigarette
Then 36ml triethylamine (0.26mol) is added dropwise at 15 DEG C in sour 32g (0.23mol), drop finish at the uniform velocity gradient increased temperature to 100 DEG C it is anti-
Answer 6h.
Above-mentioned reaction solution is cooled to 50 DEG C, and water ring vacuum pump is decompressed to 5000Pa and is distilled to recover phosphorus oxychloride, when nothing distillates
When object, switching oil pump is decompressed to 400Pa and carries out rectifying, will be collected into 97-98 DEG C of fraction colourless transparent liquid (60 DEG C) and slowly adds
Enter in 0-5 DEG C of water of stirring, hydrolysis 0.5h, with 30% liquid alkaline adjusting pH value to 1.5 ± 0.1, stir 0.5h, filter,
Mother liquor waits for that lower batch hydrolysis uses, and 60 DEG C of filter cake are dried in vacuo to obtain white crystalline powder 2- chlorine apellagrin 32.0g, yield
87.7% [HPLC content 99.8%, moisture 0.22%, mp178.6-178.9 DEG C (178-180 DEG C of document)].
Embodiment 2:
It is added into three-necked flask and sequentially adds N- oxidation niacin mother liquor 100ml, niacin 100g, molybdic acid 0.66g, be warming up to
92 DEG C, temperature starts that hydrogen peroxide 104ml is added dropwise after stablizing, at the uniform velocity dropwise addition 3h, and 95 DEG C of heat preservations 3h, TLC detect cigarette after being added dropwise
Acid content < 0.5%, heat preservation terminate to be down to 0-5 DEG C, stir 0.5h, filtering, and mother liquor waits for that lower batch oxidation reaction is recycled, filter
60 DEG C of cake are dried in vacuo to obtain white crystalline powder N- oxidation niacin 111.7g, yield 99.6% [HPLC content 99.8%, moisture
0.21%, mp261.4-261.6 DEG C (260-262 DEG C of document)].
Recycling phosphorus oxychloride is added into three-necked flask and fresh phosphorus oxychloride amounts to 146ml, ice bath stirring is cooled to 10
DEG C start to be slowly added to N- oxidation niacin 32g, 36ml triethylamine is then added dropwise at 15 DEG C, drips and finish gradient and be at the uniform velocity warming up to 100
DEG C reaction 6h.
Above-mentioned reaction solution is cooled to 50 DEG C, and water ring vacuum pump is decompressed to 5000Pa and is distilled to recover phosphorus oxychloride, when nothing distillates
When object, switching oil pump is decompressed to 400Pa and carries out rectifying, will be collected into 97-98 DEG C of fraction colourless transparent liquid (60 DEG C) and slowly adds
Enter in 0-5 DEG C of water of stirring, hydrolysis 0.5h, with 30% liquid alkaline adjusting pH value to 1.5 ± 0.1, stir 0.5h, filter,
Mother liquor waits for that lower batch hydrolysis uses, and 60 DEG C of filter cake are dried in vacuo to obtain white crystalline powder 2- chlorine apellagrin 33.6g, yield
92.0% [HPLC content 99.8%, moisture 0.19%, mp178.6-178.9 DEG C (178-180 DEG C of document)].
Claims (10)
1. a kind of green synthesis method for preparing 2- chlorine apellagrin, it is characterised in that: with niacin (I) for raw material, in catalyst action
N- oxidation niacin (II) is made through hydrogen peroxide oxidation in lower aqueous systems, then is obtained under the action of organic base through phosphorus oxychloride chlorination
2- chloronicotinoyl chloride (III) by hydrolyzing to obtain 2- chlorine apellagrin (IV),
Method of the invention specifically comprises the following steps:
It (1) is raw material under the action of catalyst through H with niacin (I)2O2Oxidation reaction occurs, is made niacin nitrogen oxides (II).
(2) the niacin nitrogen oxides (II) walked on, is reacted to obtain 2- chlorine with phosphorus oxychloride under the action of organic base
Nicotinoyl chlorine (III) is most hydrolyzed afterwards, purifies to obtain 2- chlorine apellagrin (IV).
2. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the catalyst is
Molybdic acid.
3. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the catalyst is used
Amount is the 0.1~1.0% of niacin quality.
4. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the hydrogen peroxide is dense
Degree is 20~35%.
5. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the hydrogen peroxide with
Niacin molar ratio is 1.05~1.5: 1.
6. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the dioxygen water droplet
Heating degree is 90~98 DEG C, and hydrogen peroxide rate of addition is 15~20ml/s.
7. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the reaction temperature
It is 95~100 DEG C.
8. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (2), it is characterised in that the guarantor of the chlorination
The warm reaction time is 2~4h.
9. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (2), it is characterised in that the phosphorus oxychloride
It is 4.0~6.0: 1 with N- oxidation niacin (II) molar ratio.
10. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (2), it is characterised in that the organic base is
Triethylamine, tri-n-butylamine etc., preferably triethylamine, the molar ratio of triethylamine and nitrogen oxides (II) are 1.9: 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109836376A (en) * | 2019-04-10 | 2019-06-04 | 江苏汉阔生物有限公司 | One kind is in the method that 2,3- pyridinedicarboxylic acid is that raw material prepares 2- chloro-nicotinic acid |
| CN111454203A (en) * | 2020-05-25 | 2020-07-28 | 山东京博生物科技有限公司 | Synthetic method of 2-chloro-N, N-dimethylnicotinamide |
-
2017
- 2017-07-06 CN CN201710572452.0A patent/CN109206363A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109836376A (en) * | 2019-04-10 | 2019-06-04 | 江苏汉阔生物有限公司 | One kind is in the method that 2,3- pyridinedicarboxylic acid is that raw material prepares 2- chloro-nicotinic acid |
| CN109836376B (en) * | 2019-04-10 | 2022-03-22 | 江苏汉阔生物有限公司 | Method for preparing 2-chloronicotinic acid by using 2, 3-dipicolinic acid as raw material |
| CN111454203A (en) * | 2020-05-25 | 2020-07-28 | 山东京博生物科技有限公司 | Synthetic method of 2-chloro-N, N-dimethylnicotinamide |
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