CN109851552A - A kind of N- cyanogen methyl -4-(trifluoromethyl) niacinamide synthetic method - Google Patents
A kind of N- cyanogen methyl -4-(trifluoromethyl) niacinamide synthetic method Download PDFInfo
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- CN109851552A CN109851552A CN201811629998.6A CN201811629998A CN109851552A CN 109851552 A CN109851552 A CN 109851552A CN 201811629998 A CN201811629998 A CN 201811629998A CN 109851552 A CN109851552 A CN 109851552A
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- Prior art keywords
- trifluoromethyl
- niacinamide
- acid
- synthetic method
- cyanogen methyl
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- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 235000005152 nicotinamide Nutrition 0.000 title claims abstract description 31
- 239000011570 nicotinamide Substances 0.000 title claims abstract description 31
- 229960003966 nicotinamide Drugs 0.000 title claims abstract description 31
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 32
- LMRJHNFECNKDKH-UHFFFAOYSA-N 4-(trifluoromethyl)nicotinic acid Chemical compound OC(=O)C1=CN=CC=C1C(F)(F)F LMRJHNFECNKDKH-UHFFFAOYSA-N 0.000 claims abstract description 29
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 17
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000011230 binding agent Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000007858 starting material Substances 0.000 claims abstract description 8
- 239000007791 liquid phase Substances 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000005457 ice water Substances 0.000 claims description 18
- 238000001514 detection method Methods 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims description 2
- FEKWWZCCJDUWLY-UHFFFAOYSA-N 3-methyl-1h-pyrrole Chemical compound CC=1C=CNC=1 FEKWWZCCJDUWLY-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000000575 pesticide Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000012670 alkaline solution Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000006396 nitration reaction Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- 229940113088 dimethylacetamide Drugs 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- -1 methylene amino Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 239000005900 Flonicamid Substances 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- BAOWVDHYZBLYMB-UHFFFAOYSA-N [F].C1=CC=NC=C1 Chemical compound [F].C1=CC=NC=C1 BAOWVDHYZBLYMB-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RLQJEEJISHYWON-UHFFFAOYSA-N flonicamid Chemical compound FC(F)(F)C1=CC=NC=C1C(=O)NCC#N RLQJEEJISHYWON-UHFFFAOYSA-N 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical class NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000004562 water dispersible granule Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a kind of N- cyanogen methyl -4-(trifluoromethyls) synthetic method of niacinamide, belong to technical field of pesticide.Its technical solution are as follows: use 4- trifluoromethyl nicotinic acid and mesyl chloride is starting material, acid anhydrides is made in reaction under conditions of acid binding agent and solvent, then under acid binding agent existence condition, acid anhydrides is reacted with aminoacetonitrile HCl salt is made N- aminomethyl -4-(trifluoromethyl) niacinamide.The present invention is starting material using 4- trifluoromethyl nicotinic acid and mesyl chloride, acid anhydrides is synthesized first, using acid anhydrides not facile hydrolysis the characteristics of, reacted with aminoacetonitrile HCl salt synthesis N- aminomethyl -4-(trifluoromethyl) niacinamide, high conversion rate (>=96%), purity is high, yield is good (>=90%), avoids using hypertoxic phosgene being raw material, substantially increases the safety of production, and it is easy to operate, it is suitble to industrialized production.
Description
Technical field
The present invention relates to technical field of pesticide, more particularly to a kind of conjunction of N- cyanogen methyl -4- (trifluoromethyl) niacinamide
At method.
Background technique
N- cyanogen methyl -4- (trifluoromethyl) niacinamide, english common name: flonicamid, Universal Chinese character title: fluorine pyridine
Insect amide.N- cyanogen methyl -4- (trifluoromethyl) niacinamide is that a kind of novel low-toxicity picolinamide class insect growth regulator, IGR class is killed
Worm agent, preparation are 10% water dispersible granules.N- cyanogen methyl -4- (trifluoromethyl) niacinamide has various suckings pest
Effect, and there is good osmosis.It can be permeated from root to stem, leaf portion, but from leaf portion to stem, root osmosis phase
To weaker.The medicament is by hindering pest act of sucking to cause to imitate.Pest stops sucking quickly after taking in medicament, it is last hungry and
Extremely.According to the preparation method of N- cyanogen methyl -4- (trifluoromethyl) niacinamide of current domestic and foreign literature report, mainly 4- trifluoro
Methylnicotinic acid is raw material, but all has that yield is relatively low, and the higher problem of production cost is unfavorable for widely promoting and applying.
The synthetic method of N- cyanogen methyl -4- (trifluoromethyl) niacinamide mainly include the following types:
(1) using 4- trifluoromethyl nicotinic acid and methylene amino second cyanogen as starting material, prepare after corresponding acyl chlorides with methylene ammonia
Base second cyanogen reacts to obtain amide, then N- cyanogen methyl -4- (trifluoromethyl) niacinamide, four step total recoverys are made through 2 one-step hydrolysis
The disadvantages of 55.7%, product purity is higher, but reaction step is long, and yield is low, and investment is big, high production cost, is not suitable for industrialization；
(2) using 4- trifluoromethyl nicotinic acid and aminoacetonitrile HCl salt as starting material, prepare after corresponding acyl chlorides with amino
Acetonitrilehydrochlorate reaction, can be made N- cyanogen methyl -4- (trifluoromethyl) niacinamide, and two step total recoverys 43.5%, product content is low,
It is difficult to purify, is unfavorable for industrialized production；
(3) using 4- trifluoromethyl nicotinic acid, aminoacetonitrile HCl salt and phosgene as starting material, one pot process N- cyanogen first
Base -4- (trifluoromethyl) niacinamide, for reaction yield 90% or more, product purity is also higher, but needs to use hypertoxic phosgene, raw
It is big to produce security risk.
Summary of the invention
The present invention provides a kind of synthetic methods of N- cyanogen methyl -4- (trifluoromethyl) niacinamide, solve with 4- trifluoro
Methylnicotinic acid is made acyl chlorides and reacts with aminoacetonitrile HCl salt, and acyl chlorides can have hydrolysis, improve the purity of product with
Yield reduces production cost, improves production security, is easy to implement industrialized production.
The technical solution of the present invention is as follows:
The use of 4- trifluoromethyl nicotinic acid and mesyl chloride is starting material, reacts and be made under conditions of acid binding agent and solvent
Acid anhydrides, then under acid binding agent existence condition, acid anhydrides is reacted with aminoacetonitrile HCl salt is made N- aminomethyl -4- (trifluoromethyl)
Niacinamide.
Its chemical equation is as follows:
The synthetic method specifically includes the following steps:
(1) 4- trifluoromethyl nicotinic acid is dissolved in solvent, after ice water cooling, mesyl chloride is slowly added dropwise, until liquid phase is examined
It surveys and is generated without new product；
(2) reaction temperature is increased, acid binding agent is slowly added dropwise into the reaction solution of step (1), reaction to liquid spectrum tracking is without original
Material stops, and obtains acid anhydrides；
(3) reaction solution of step (2) is washed, acid anhydrides is dissolved in spare in solvent layer；
(4) aminoacetonitrile HCl salt is dissolved in solvent, after ice water cooling, dropping liquid aqueous slkali adds after completion of dropwise addition
Enter acid binding agent, the acid anhydrides in a dropping step (3), without raw material, then filters up to N- cyanogen methyl -4- (trifluoro to liquid phase detecting and tracking
Methyl) niacinamide.
Preferably, the acid binding agent is potassium carbonate, sodium bicarbonate, n,N-Dimethylaniline, N, N- diethylaniline, three second
At least one of amine, pyridine, 3- picoline.
Preferably, the solvent is at least one of aprotic polar solvent, benzene class, chlorinated hydrocarbon and nitrile.Wherein,
Aprotic polar solvent can be for N-Methyl pyrrolidone, dimethylformamide, dimethyl acetamide or dimethyl sulfoxide at least
It is a kind of.
Preferably, in step (1), the molar ratio of the 4- trifluoromethyl nicotinic acid and mesyl chloride is (1.1-5): 1.
Preferably, in step (1), the weight ratio of the 4- trifluoromethyl nicotinic acid and solvent is (2-15): 1.
Preferably, in step (1), the reaction time of the 4- trifluoromethyl nicotinic acid and mesyl chloride is 6~8h, reaction temperature
Degree is 20~40 DEG C.
Preferably, in step (4), the molar ratio of the 4- trifluoromethyl nicotinic acid and acid binding agent is (2.2-5): 1.
Preferably, in step (4), the molar ratio of the 4- trifluoromethyl nicotinic acid and aminoacetonitrile HCl salt is (1.2-3):
1。
Preferably, in step (4), the reaction temperature of the acid anhydrides and aminoacetonitrile HCl salt is 0~10 DEG C, the reaction time
3~6h.
The invention has the benefit that
The synthetic method of N- cyanogen methyl -4- (trifluoromethyl) niacinamide of the invention, uses 4- trifluoromethyl nicotinic acid and first
Sulfonic acid chloride is starting material, first synthesis acid anhydrides, using acid anhydrides not facile hydrolysis the characteristics of, synthesis is reacted with aminoacetonitrile HCl salt
N- aminomethyl -4- (trifluoromethyl) niacinamide, high conversion rate (>=96%), purity is high, yield is good (>=90%), avoids using play
Malicious phosgene is raw material, substantially increases the safety of production, and easy to operate, is suitble to industrialized production.
Specific embodiment
For a better understanding of the present invention, below with specific embodiment come the technical solution that the present invention will be described in detail, still
The present invention is not limited thereto.
Embodiment 1
4- trifluoromethyl nicotinic acid, the 7.5g of 15g (0.075mol) are added in the 250mL reactor with reflux condenser
Toluene, ice water are cooled to 5 DEG C, and 2.88g (0.025mol) mesyl chloride is slowly added dropwise, and liquid phase detection is generated without new product, increased
Triethylamine is slowly added dropwise into reaction system to 20 DEG C for reaction temperature, and reaction 6h to tracking stops without raw material.After reaction
The washing of 50g water is added, it is spare that acid anhydrides is dissolved in toluene layer.
Aminoacetonitrile HCl salt 2.6g (0.0275mol) is added in another 250ml reactor, toluene 20g, ice water drop
The liquid alkaline solution 7.45g of 30% concentration is added dropwise to 0-5 DEG C in temperature, and 2.6g sodium bicarbonate solid is added after completion of dropwise addition, then will be upper
It walks obtained nitration mixture acid anhydride to be slowly dropped in system, reacts 4h, after liquid phase detecting and tracking is without raw material, filter up to product.Liquid
Phase chromatogram quantification detection level 96.4%, yield 90%.
Embodiment 2
4- trifluoromethyl nicotinic acid, the 2.2g of 11g (0.055mol) are added in the 250mL reactor with reflux condenser
Dichloroethanes, ice water are cooled to 5 DEG C, and 5.75g (0.050mol) mesyl chloride is slowly added dropwise, and liquid phase detection is generated without new product,
Reaction temperature is increased to 20 DEG C, triethylamine is slowly added dropwise into reaction system, reaction 8h to tracking stops without raw material.Reaction knot
The washing of 50g water is added after beam, it is spare that acid anhydrides is dissolved in dichloroethanes layer.
Aminoacetonitrile HCl salt 4.3g (0.046mol) is added in another 250ml reactor, dichloroethanes 20g, ice
Water is cooled to 0-5 DEG C, and the liquid alkaline solution 7.45g of 30% concentration is added dropwise, and 3.45g potash solid is added after completion of dropwise addition, then
The nitration mixture acid anhydride that upper step obtains is slowly dropped in system, 3h is reacted, liquid phase detecting and tracking is filtered without raw material up to product.It is fixed
Measure testing product content 96.5%, yield 90.8%.
Embodiment 3
With reflux condenser 250mL reactor in be added 5g (0.025mol) 4- trifluoromethyl nicotinic acid,
0.625g N-Methyl pyrrolidone, ice water are cooled to 5 DEG C, and 0.572g (0.005mol) mesyl chloride, liquid phase detection is slowly added dropwise
No new product generates, and increases system temperature to 40 DEG C, and 3- picoline, reaction 6.5h to tracking are slowly added dropwise into reaction system
No raw material stops.The washing of 50g water is added after reaction, it is spare that acid anhydrides is dissolved in toluene layer.
Aminoacetonitrile HCl salt 1.576g (0.0166mol) is added in another 250ml reactor, N- crassitude
Ketone 20g, ice water are cooled to 0-5 DEG C, and the liquid alkaline solution 7.45g of 30% concentration is added dropwise, and 0.66g pyridine are added after completion of dropwise addition, so
The nitration mixture acid anhydride that upper step obtains is slowly dropped in system afterwards, reacts 5.5h, liquid phase detecting and tracking filters to produce without raw material
Product.Quantitative detection product content 96.6%, yield 90.5%.
Embodiment 4
4- trifluoromethyl nicotinic acid, the 0.5g of 5g (0.025mol) are added in the 250mL reactor with reflux condenser
Dimethyl acetamide, ice water are cooled to 5 DEG C, and 0.719g (0.00625mol) mesyl chloride is slowly added dropwise, and liquid phase detection is produced without new
Product generate, and increase system temperature to 30 DEG C, N are slowly added dropwise into reaction system, N- diethylaniline, reaction 7h to tracking is without original
Material stops.The washing of 50g water is added after reaction, it is spare that acid anhydrides is dissolved in toluene layer.
Aminoacetonitrile HCl salt 1.18g (0.0125mol) is added in another 250ml reactor, dimethyl acetamide
30g, ice water are cooled to 5-10 DEG C, and the liquid alkaline solution 7.45g of 30% concentration is added dropwise, and 0.582g 3- methyl is added after completion of dropwise addition
Then the nitration mixture acid anhydride that upper step obtains is slowly dropped in system by pyridine, react 5h, and liquid phase detecting and tracking is without raw material suction filtration
Obtain product.Quantitative detection product content 96%, yield 90.7%.
Embodiment 5
4- trifluoromethyl nicotinic acid, the 0.42g of 5g (0.025mol) are added in the 250mL reactor with reflux condenser
Dimethyl sulfoxide, ice water are cooled to 5 DEG C, and 1.44g (0.0125mol) mesyl chloride is slowly added dropwise, and liquid phase detection is raw without new product
At raising system temperature n,N-Dimethylaniline is slowly added dropwise into reaction system, reaction 7.5h to tracking is without raw material to 25 DEG C
Stop.The washing of 50g water is added after reaction, it is spare that acid anhydrides is dissolved in toluene layer.
Aminoacetonitrile HCl salt 0.945g (0.01mol) is added in another 250ml reactor, dimethyl sulfoxide 20g,
Ice water is cooled to 5-10 DEG C, and the liquid alkaline solution 7.45g of 30% concentration is added dropwise, and 0.562g triethylamine is added after completion of dropwise addition, then
The nitration mixture acid anhydride that upper step obtains is slowly dropped in system, 3.5h is reacted, liquid phase detecting and tracking is filtered without raw material up to product.
Quantitative detection product content 97%, yield 90.4%.
Embodiment 6
4- trifluoromethyl nicotinic acid, the 0.33g of 5g (0.025mol) are added in the 250mL reactor with reflux condenser
Dimethylformamide, ice water are cooled to 5 DEG C, and 1.15g (0.01mol) mesyl chloride is slowly added dropwise, and liquid phase detection is raw without new product
At raising system temperature triethylamine is slowly added dropwise into reaction system, reaction 8h to tracking is without raw material i.e. stopping to 35 DEG C.Instead
The washing of 50g water is added after answering, it is spare that acid anhydrides is dissolved in toluene layer.
Aminoacetonitrile HCl salt 0.79g (0.0083mol) is added in another 250ml reactor, dimethylformamide
20g, ice water are cooled to 5-10 DEG C, and the liquid alkaline solution 7.45g of 30% concentration is added dropwise, 0.746gN, N- diethyl are added after completion of dropwise addition
Then the nitration mixture acid anhydride that upper step obtains is slowly dropped in system by base aniline, react 6h, and liquid phase detecting and tracking is filtered without raw material
Up to product.Quantitative detection product content 96.5%, yield 91.5%.
Embodiment 7
4- trifluoromethyl nicotinic acid, the 125g of 500g (2.5mol) are added in the 250mL reactor with reflux condenser
Acetonitrile, ice water are cooled to 5 DEG C, and 115g (1mol) mesyl chloride is slowly added dropwise, and liquid phase detection is generated without new product, increase system temperature
Triethylamine is slowly added dropwise into reaction system to 20 DEG C for degree, and reaction 6h to tracking stops without raw material.It is added after reaction
The washing of 5000g water, it is spare that acid anhydrides is dissolved in toluene layer.
Aminoacetonitrile HCl salt 94.55g (1mol) is added in another 250ml reactor, acetonitrile 2000g, ice water drop
The liquid alkaline solution 745g of 30% concentration is added dropwise to 0-5 DEG C in temperature, and 79.1g pyridine is added after completion of dropwise addition, then obtains upper step
Nitration mixture acid anhydride is slowly dropped in system, reacts 3h, and liquid phase detecting and tracking is filtered without raw material up to product.Quantitative detection product contains
Amount 96%, yield 92%.
Claims (10)
1. a kind of N- cyanogen methyl -4-(trifluoromethyl) synthetic method of niacinamide, it is characterised in that: use 4- trifluoromethyl nicotinic acid
It is starting material with mesyl chloride, acid anhydrides is made in reaction under conditions of acid binding agent and solvent, then in acid binding agent existence condition
Under, acid anhydrides is reacted with aminoacetonitrile HCl salt is made N- aminomethyl -4-(trifluoromethyl) niacinamide.
2. the N- cyanogen methyl -4-(trifluoromethyl according to claim 1) synthetic method of niacinamide, it is characterised in that: tool
Body the following steps are included:
4- trifluoromethyl nicotinic acid is dissolved in solvent, after ice water cooling, mesyl chloride is slowly added dropwise, until liquid phase detection is produced without new
Product generate；
Reaction temperature is increased, acid binding agent is slowly added dropwise into the reaction solution of step (1), reaction to liquid spectrum tracking stops without raw material
Only, acid anhydrides is obtained；
The reaction solution of step (2) is washed, acid anhydrides is dissolved in spare in solvent layer；
Aminoacetonitrile HCl salt is dissolved in solvent, after ice water cooling, dropping liquid aqueous slkali is added after completion of dropwise addition and ties up acid
Agent, the acid anhydrides in a dropping step (3), without raw material, then filter up to N- cyanogen methyl -4-(trifluoromethyl to liquid phase detecting and tracking)
Niacinamide.
3. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that: institute
Stating acid binding agent is potassium carbonate, sodium bicarbonate, n,N-Dimethylaniline, N, N- diethylaniline, triethylamine, pyridine, 3- methyl pyrrole
At least one of pyridine.
4. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that: institute
Stating solvent is at least one of aprotic polar solvent, benzene class, chlorinated hydrocarbon and nitrile.
5. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that: step
Suddenly in (1), the molar ratio of the 4- trifluoromethyl nicotinic acid and mesyl chloride is (1.1-5): 1.
6. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that: step
Suddenly in (1), the weight ratio of the 4- trifluoromethyl nicotinic acid and solvent is (2-15): 1.
7. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that: step
Suddenly in (1), the reaction time of the 4- trifluoromethyl nicotinic acid and mesyl chloride is 6 ~ 8h, and reaction temperature is 20 ~ 40 DEG C.
8. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that: step
Suddenly in (4), the molar ratio of the 4- trifluoromethyl nicotinic acid and acid binding agent is (2.2-5): 1.
9. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that: step
Suddenly in (4), the molar ratio of the 4- trifluoromethyl nicotinic acid and aminoacetonitrile HCl salt is (1.2-3): 1.
10. the N- cyanogen methyl -4-(trifluoromethyl according to claim 2) synthetic method of niacinamide, it is characterised in that:
In step (4), the reaction temperature of the acid anhydrides and aminoacetonitrile HCl salt is 0 ~ 10 DEG C, 3 ~ 6h of reaction time.
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