CN110452165A - A kind of preparation method of 2- picoline -4- formic acid - Google Patents
A kind of preparation method of 2- picoline -4- formic acid Download PDFInfo
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- CN110452165A CN110452165A CN201810427394.7A CN201810427394A CN110452165A CN 110452165 A CN110452165 A CN 110452165A CN 201810427394 A CN201810427394 A CN 201810427394A CN 110452165 A CN110452165 A CN 110452165A
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- 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
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- 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
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
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Abstract
The present invention provides a kind of preparation method of 2- picoline -4- formic acid, utilize 4,4- dialkoxy n-Butyronitrile or 4,4- dialkoxy n-butyric acie ester (II) and acetone dichloride are substituted reaction, or with propylene oxide through opening, oxidation reaction preparation 6, the positive hex- 2- ketone of 6- dialkoxy -4- cyano or 6, the positive hex- 2- ketone (III) of 6- dialkoxy -4- alkoxy carbonyl, then with ammonia, ammonium salt through cyclization, most afterwards through oxidation reaction, hydrolysis, hydrochloric acid acidification preparation 2- picoline -4- formic acid (I).Method mild condition of the invention, process flow is succinct, simple and safe operation；Spent acid waste water yield is few, environmentally protective；Good reaction selectivity, product cost is low, product yield and purity is high, is conducive to the green industrialized production and the popularization of product downstream of 2- picoline -4- formic acid.
Description
Technical field
The present invention relates to a kind of preparation methods of 2- picoline -4- formic acid, belong to technical field of medical chemistry.
Background technique
2- picoline -4- formic acid or 2- methyl-Isonicotinic acid are a kind of important pyridine derivates, can be used for making
The medicine, pesticide activity such as standby Nazartinib.Nazartinib, referred to as EGF816 or NVS-816, be by
The oral non-small cell lung cancer new chemical entities drug of Novartis company exploitation is currently under third stage research, shows
Good therapeutic effect out；Wherein 2- picoline -4- formic acid is the intermediate for preparing Nazartinib, optimizes 2- picoline -
The preparation method of 4- formic acid is of great significance for Nazartinib clinical research and drug production.
Summary of the invention
In view of the deficienciess of the prior art, the present invention provides a kind of preparation method of 2- picoline -4- formic acid.This hair
Bright method mild condition, process flow is succinct, simple and safe operation；Spent acid waste water yield is few, environmentally protective；Selecting response
Property is good, and product cost is low, product yield and purity is high, be conducive to 2- picoline -4- formic acid green industrialized production and its
The popularization of downstream product.
Term explanation:
II compound of formula: 4,4- dialkoxy n-Butyronitrile or 4,4- dialkoxy n-butyric acie ester；
III compound of formula: the positive hex- 2- ketone of 6,6- dialkoxy -4- cyano or 6,6- dialkoxy -4- alkoxy carbonyl are just
Hex- 2- ketone；
IV compound of formula: 2- methyl-1,4- dihydro-Isonicotinic acid ester or 2- methyl-1,4- dihydro -4- pyridine carbonitrile；
Type I compound: 2- picoline -4- formic acid.
Technical scheme is as follows:
A kind of preparation method of 2- picoline -4- formic acid, comprising steps of
(1) using II compound of formula as III compound of initial feed preparation formula；
Wherein, in III compound of formula II and formula, R is methyl, ethyl, isopropyl, normal-butyl or tert-butyl；G be-CN or-
COOR ' ,-COOR ' middle R ' are methyl, ethyl, isopropyl, normal-butyl or tert-butyl, and R ' and R are identical or different；
(2) in solvent B, in the presence of ammonia and ammonium salt, IV compound of formula is made through cyclization in III compound of formula, so
Afterwards through oxidation reaction under oxidant effect, alkaline reagent effect is lower to be hydrolyzed, and hydrochloric acid is acidified to obtain 2- picoline -4- formic acid (I)；
Wherein, the meaning of G is identical as the meaning of G in II compound of formula in IV compound of formula.
According to the present invention, II compound of formula can be commercially available, or by acrylonitrile or acrylate through hydroformylation reaction
It is prepared with acetalation.
According to the present invention, it is respectively by the method for III compound of initial feed preparation formula of II compound of formula in step (1)
Approach 1 or approach 2；Wherein,
Approach 1 comprising steps of
In solvent A, in the presence of acid binding agent, II compound of formula and acetone dichloride are substituted and react to obtain III chemical combination of formula
Object；
Approach 2 comprising steps of
In the presence of base catalyst, opening occurs for II compound of formula and propylene oxide；Then in oxidant
Under effect, III compound of formula is obtained through oxidation reaction.
In the approach 1 of step (1), the solvent A is tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl-methyl ether, N, N-
One of dimethylformamide, toluene or combination；The mass ratio of II compound of the solvent A and formula is (3-15): 1；Preferably, institute
The mass ratio for stating II compound of solvent A and formula is (4.5-10): 1.
In the approach 1 of step (1), the acid binding agent be inorganic base or organic base, inorganic base be selected from potassium carbonate, sodium carbonate,
Sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium hydroxide, saleratus, sodium bicarbonate, calcium bicarbonate, potassium acetate, acetic acid
One of sodium, calcium acetate or combination, organic base are selected from one of triethylamine, tri-n-butylamine or combination；II chemical combination of the acid binding agent and formula
The molar ratio of object is (1.0-2.0): 1；Preferably, the molar ratio of II compound of the acid binding agent and formula is (1.0-1.5): 1.
In the approach 1 of step (1), the molar ratio of II compound of the acetone dichloride and formula is (1.0-1.5): 1.
In the approach 1 of step (1), the temperature of the substitution reaction is 30-100 DEG C；Preferably, the temperature of the substitution reaction
Degree is 60-80 DEG C.The substitution reaction time is 2-8 hours；Preferably, the substitution reaction time is 3-5 hours.
In the approach 2 of step (1), the base catalyst be 1,8- diazabicyclo [5.4.0] -7- endecatylene (DBU),
One of 1,5- diazabicyclo [4.3.0] -5- nonene (DBN), piperidines, 4-dimethylaminopyridine or combination；The base catalyst
Quality be II compound quality of formula 1-5%；Preferably, the quality of the base catalyst is the 1.5- of II compound quality of formula
4%.
In the approach 2 of step (1), the molar ratio of II compound of the propylene oxide and formula is (1.0-1.5): 1.
In the approach 2 of step (1), the temperature of the opening is 20-70 DEG C；Preferably, the open loop addition
The temperature of reaction is 40-55 DEG C.The opening time is 2-10 hours；Preferably, when the opening
Between be 4-6 hours.
In the approach 2 of step (1), the oxidant is one of hydrogen peroxide, tertbutanol peroxide, m-chloro-benzoic acid peroxide
Or combination；The molar ratio of II compound of the oxidant and formula is (1.0-1.3): 1.
In the approach 2 of step (1), the temperature of the oxidation reaction is 40-100 DEG C；Preferably, the temperature of the oxidation reaction
Degree is 60-80 DEG C.The oxidation time is 2-7 hours；Preferably, the oxidation time is 3-5 hours.
Reaction in the approach 2 of step (1) is " one kettle way " progress, and intermediate product is without isolation.
, according to the invention it is preferred to, solvent B described in step (2) is water, acetonitrile, methanol, ethyl alcohol, isopropanol or toluene
One or more of combination；The mass ratio of III compound of the solvent B and formula is (2-20): 1；Preferably, described
The mass ratio of III compound of solvent B and formula is (4-10): 1.
, according to the invention it is preferred to, ammonia described in step (2) is molten using ammonia, ammonium hydroxide, methanolic ammonia solution or cholamine
Liquid；Ammonium salt is ammonium chloride, ammonium sulfate, ammonium nitrate or ammonium phosphate；The molar ratio of III compound of the ammonia, ammonium salt and formula is (2.0-
5.0): (0.5-1.5): 1.
, according to the invention it is preferred to, cyclization temperature described in step (2) is 20-100 DEG C；Preferably, the cyclisation
Reaction temperature is 50-70 DEG C.The cyclization time is 2-8 hours, it is preferred that the cyclization time is 3-5 hours.
, according to the invention it is preferred to, in step (2), by the method for III preparation of compounds of formula of formula, IV compound comprising steps of
Ammonia and ammonium salt are dissolved in solvent B, at 20-100 DEG C, III compound of formula is added dropwise, after being added dropwise, 20-100 DEG C of reaction 2-8 is small
When.
, according to the invention it is preferred to, oxidant described in step (2) is hydrogen peroxide, tertbutanol peroxide, m-chloro peroxidating
One or a combination set of benzoic acid；The molar ratio of III compound of the oxidant and formula is (1.0-1.5): 1.
, according to the invention it is preferred to, the temperature of oxidation reaction described in step (2) is 20-100 DEG C；Preferably, the oxygen
The temperature for changing reaction is 50-80 DEG C.The oxidation time is 2-7 hours；Preferably, the oxidation time is 3-5
Hour.
, according to the invention it is preferred to, alkaline reagent described in step (2) be sodium hydroxide, potassium hydroxide, lithium hydroxide it
One or combination；The molar ratio of III compound of the alkaline reagent and formula is (1.0-1.5): 1.
, according to the invention it is preferred to, the temperature of hydrolysis described in step (2) is 20-100 DEG C；Preferably, the water
The temperature of solution reaction is 30-90 DEG C.The hydrolysis time is 0.5-5 hours；Preferably, the hydrolysis time is 1-
3 hours.
, according to the invention it is preferred to, the acidification of hydrochloric acid described in step (2) is the hydrochloric acid for the use of mass concentration being 20-30%
The pH value that aqueous solution is acidified to system is 3.0-3.5.
, according to the invention it is preferred to, step (2) is " one kettle way " reaction, and intermediate product is without isolation.
Method of the invention is described as following synthetic route 1:
Wherein, in III compound of formula II and formula, R is methyl, ethyl, isopropyl, normal-butyl or tert-butyl；G be-CN or-
COOR ' ,-COOR ' middle R ' are methyl, ethyl, isopropyl, normal-butyl or tert-butyl, and R ' and R are identical or different；IV compound of formula
The meaning of middle G is identical as the meaning of G in II compound of formula.
Technical characterstic of the invention and the utility model has the advantages that
1, the present invention provides two kinds of III compounds of approach preparation formula, and one kind to be prepared by III compound of formula " one kettle way "
The method of 2- picoline -4- formic acid.The present invention is substituted II chemical combination of reaction or formula using II compound of formula and acetone dichloride
Object and propylene oxide are through opening, III compound of oxidation reaction preparation formula, and III compound of gained formula and ammonia, ammonium salt are through ring
Change to react and 2- methyl-1,4- dihydro-Isonicotinic acid ester or 2- methyl-1,4- dihydro -4- pyridine carbonitrile, then through aoxidizing is made
Reaction, hydrolysis, hydrochloric acid acidification preparation 2- picoline -4- formic acid (I).
2, highway route design of the present invention is reasonable, and involved reaction selectivity is high, steady under alkaline condition using II compound of formula
Qualitative high and unique active methylene group position and acetone dichloride or propylene oxide reaction obtain carbonyl or obtain carbonyl through aoxidizing hydroxyl
III compound of based compound, that is, formula, III compound of formula acetal hydro under ammonia, ammonium salt system, cyclisation immediately is made after generating aldehyde radical
IV compound of formula, then through oxidation reaction, hydrolysis, hydrochloric acid acidification preparation 2- picoline -4- formic acid (I).Each step reaction site
It is single, in conjunction with preferred III compound of dropwise addition formula control material low concentration effect to reduce intermolecular side reaction, ensured product
High-purity and high yield.
3, method mild condition of the invention, process flow are succinct, it is only necessary to which two steps can be prepared, safe operation letter
Just, product cost is low；Spent acid waste water yield is few, environmentally protective；Good reaction selectivity, product yield and purity is high, total recovery
Up to 84.2%, be conducive to the green industrialized production and the popularization of product downstream of 2- picoline -4- formic acid.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
4,4- dialkoxy n-Butyronitrile and 4 used in embodiment, 4- dialkoxy n-butyric acie ester, the auspicious limited public affairs of brightness medicine company in Shandong
It takes charge of on sale.Remaining raw materials and reagents is commercial product.
" % " described in embodiment is weight percentage, except special instruction.Yield in embodiment is mole
Yield.
The preparation (1 method of approach) of the positive hex- 2- ketone (III 1) of embodiment 1:6,6- dimethoxy-4 '-cyano
To with stirring, thermometer, reflux condensing tube reaction flask in, be added 400 grams of tetrahydrofurans, 64.5 gram (0.5
Mole) 4,4- dimethoxy n-Butyronitrile (II 1), 55.5 grams of (0.6 mole) acetone dichlorides, 83.0 grams of (0.6 mole) potassium carbonate,
60-65 DEG C is stirred to react 4 hours, is subsequently cooled to 20-25 DEG C, and filtering, filter cake is washed twice with tetrahydrofuran, and 20 grams every time,
Merging filtrate, is distilled to recover solvent, and vacuum distillation (85-105 DEG C/2-3mmHg) obtains 84.6 grams of 6,6- dimethoxy-4 '-cyano
Positive hex- 2- ketone (III 1), yield 91.5%, gas phase purity 99.6%.
The preparation (2 method of approach) of the positive hex- 2- ketone (III 1) of embodiment 2:6,6- dimethoxy-4 '-cyano
Into 250 milliliters of stainless steel pressure kettles, 64.5 grams of (0.5 mole) 4,4- dimethoxy n-Butyronitriles (II 1) are added,
35.0 grams of (0.6 mole) propylene oxide, 1.5 grams of DBU, 50-55 DEG C is stirred to react 5 hours, 20-25 DEG C is subsequently cooled to, by institute
It obtains reaction liquid to be transferred to stirring, in the reaction flask of thermometer, 68.0 grams of (0.6 mole) 30wt% hydrogen peroxide is added,
75-80 DEG C is stirred to react 4 hours, is subsequently cooled to 20-25 DEG C, and 200 grams of methylene chloride are added, layering, water layer methylene chloride
Extraction 2 times 50 grams every time, merges organic phase, is distilled to recover methylene chloride, and then vacuum distillation collects (85-105 DEG C/2- of fraction
3mmHg), the positive hex- 2- ketone (III 1) of 81.2 grams of 6,6- dimethoxy-4 '-cyano, yield 87.8%, gas phase purity 99.2% are obtained.
The preparation (1 method of approach) of the positive hex- 2- ketone (III 2) of embodiment 3:6,6- dimethoxy-4 '-methoxycarbonyl
To with stirring, thermometer, reflux condensing tube reaction flask in, 400 grams of n,N-Dimethylformamide are added,
81.0 grams of (0.5 mole) 4,4- dimethoxy methyl butyls (II 2), 55.5 grams of (0.6 mole) acetone dichlorides, 83.0 gram (0.6
Mole) potassium carbonate, 75-80 DEG C is stirred to react 3 hours, is subsequently cooled to 20-25 DEG C, filters, filter cake N, N- dimethyl formyl
Amine washes twice, and 20 grams every time, merging filtrate is distilled to recover solvent, and vacuum distillation (90-115 DEG C/2-3mmHg) obtains 100.8
Gram positive hex- 2- ketone (III 2) of 6,6- dimethoxy-4 '-methoxycarbonyl, yield 92.5%, gas phase purity 99.3%.
The preparation (2 method of approach) of the positive hex- 2- ketone (III 2) of embodiment 4:6,6- dimethoxy-4 '-methoxycarbonyl
Into 250 milliliters of stainless steel pressure kettles, 81.0 grams of (0.5 mole) 4,4- dimethoxy methyl butyls (II are added
2), 35.0 grams (0.6 mole) propylene oxide, 1.5 grams of DBU, 45-50 DEG C is stirred to react 6 hours, is subsequently cooled to 20-25 DEG C, will
Gained reaction liquid is transferred to stirring, in the reaction flask of thermometer, and 68.0 grams of (0.6 mole) 30wt% dioxygens are added
Water, 75-80 DEG C is stirred to react 4 hours, is subsequently cooled to 20-25 DEG C, and 200 grams of methylene chloride are added, layering, water layer dichloromethane
Alkane extracts 2 times, merges methylene chloride organic phase, is distilled to recover solvent, and vacuum distillation (90-115 DEG C/2-3mmHg) obtains 96.8
Gram positive hex- 2- ketone (III 2) of 6,6- dimethoxy-4 '-methoxycarbonyl, yield 88.8%, gas phase purity 99.2%.
The preparation of embodiment 5:2- picoline -4- formic acid (I)
Into the reaction flask with stirring, thermometer, reflux condensing tube and constant pressure funnel, 100 grams of water are added,
At 60-65 DEG C, 18.5 grams of 2 institutes of (0.1 mole) embodiment are added dropwise in 40.0 grams of (0.4 mole) 17wt% ammonium hydroxide, 3.0 grams of ammonium chlorides
The positive hex- 2- ketone (III 1) of 6,6- dimethoxy-4 '-cyano, be added dropwise within about 1 hour, hereafter, 65-70 DEG C to be stirred to react 3 small
When, it is cooled to 20-25 DEG C, 17.0 grams of (0.15 mole) 30wt% hydrogen peroxide are added, 65-70 DEG C is stirred to react 4 hours, is cooled to
20-25 DEG C, 4.8 grams of (0.12 mole) sodium hydroxides are added, 85-90 DEG C is stirred to react 2 hours, is cooled to 0-5 DEG C, uses 30wt%
It is 3.0-3.5 that hydrochloric acid, which adjusts reaction liquid pH value, and filtering, 10 grams of ice water washings are dry, obtains 11.8 grams of white solid 2- methyl
Pyridine-4-formic acid (I), yield 86.1%, liquid phase purity 99.7%.
The nuclear magnetic data of products therefrom is as follows:
1HNMR(DMSO-D6,δ,ppm):2.32(s,3H),7.76(s,1H),7.82(d,1H),8.62(d,1H),10.19
(s,1H)。
The preparation of embodiment 6:2- picoline -4- formic acid (I)
To with stirring, thermometer, condenser pipe and constant pressure funnel reaction flask in, be added 50 grams of water, 40.0 grams
At 60-65 DEG C, 18.5 grams of 1 institutes of (0.1 mole) embodiment are added dropwise in (0.4 mole) 17wt% methanolic ammonia solution, 3.5 grams of ammonium chlorides
The solution for obtaining 6,6- dimethoxy-4 '-cyano positive hex- 2- ketone (III 1) and 50 grams of methanol, is added dropwise for about 2 hours, hereafter, 65-
70 DEG C are stirred to react 3 hours, are cooled to 20-25 DEG C, and 17.0 grams of (0.15 mole) 30wt% hydrogen peroxide, 65-70 DEG C of stirring is added
Reaction 4 hours, is cooled to 20-25 DEG C, is added 4.8 grams of (0.12 mole) sodium hydroxides, and 80-85 DEG C is stirred to react 2 hours, simultaneously
The methanol steamed is recycled, is cooled to 0-5 DEG C, adjusting reaction liquid pH value with 30wt% hydrochloric acid is 3.0-3.5, filtering, 10 grams of ice
Water washing, it is dry, obtain 12.6 grams of white solid 2- picoline -4- formic acid (I), yield 92.0%, liquid phase purity 99.6%.
The preparation of embodiment 7:2- picoline -4- formic acid (I)
Into the reaction flask with stirring, thermometer, reflux condensing tube and constant pressure funnel, 120 grams of water are added,
At 65-70 DEG C, 21.8 grams of 3 institutes of (0.1 mole) embodiment are added dropwise in 40.0 grams of (0.4 mole) 17wt% ammonium hydroxide, 5.0 grams of ammonium chlorides
The positive hex- 2- ketone (III 2) of 6,6- dimethoxy-4 '-methoxycarbonyl is obtained, is added dropwise within about 1 hour, hereafter, 65-70 DEG C of stirring is anti-
It answers 3 hours, is cooled to 20-25 DEG C, 14.0 grams of (0.11 mole) 70wt% tertbutanol peroxides are added, 50-55 DEG C is stirred to react 3
Hour, it is cooled to 20-25 DEG C, 4.8 grams of (0.12 mole) sodium hydroxides are added, 40-45 DEG C is stirred to react 2 hours, is cooled to 0-5
DEG C, adjusting reaction liquid pH value with 30wt% hydrochloric acid is 3.0-3.5, filtering, the washing of 10 grams of ice water, dry, obtain 12.1 grams it is white
Color solid 2- picoline -4- formic acid (I), yield 88.3%, liquid phase purity 99.8%.
The preparation of embodiment 8:2- picoline -4- formic acid (I)
To with stirring, thermometer, condenser pipe and constant pressure funnel reaction flask in, be added 50 grams of water, 40.0 grams
At 60-65 DEG C, 21.8 grams of 4 institutes of (0.1 mole) embodiment are added dropwise in (0.4 mole) 17wt% methanolic ammonia solution, 4.0 grams of ammonium chlorides
The solution for obtaining 6,6- dimethoxy-4 '-methoxycarbonyl positive hex- 2- ketone (III 2) and 50 grams of methanol, is added dropwise for about 2 hours, this
Afterwards, it is stirred to react 3 hours for 65-70 DEG C, is cooled to 20-25 DEG C, 17.0 grams of (0.15 mole) 30wt% hydrogen peroxide, 65-70 is added
It DEG C is stirred to react 4 hours, while the methanol that recycling steams, is cooled to 20-25 DEG C, 4.8 grams of (0.12 mole) sodium hydroxides are added,
35-40 DEG C is stirred to react 2 hours, is cooled to 0-5 DEG C, and adjusting reaction liquid pH value with 30wt% hydrochloric acid is 3.0-3.5, filtering,
10 grams of ice water washings, it is dry, obtain 12.3 grams of white solid 2- picoline -4- formic acid (I), yield 89.8%, liquid phase purity
99.5%.
The preparation of comparative example 1:2- picoline -4- formic acid (I)
To with stirring, thermometer, reflux condensing tube reaction flask in, be added 100 grams of water, 40.0 grams (0.4 mole)
17wt% ammonium hydroxide, 3.0 grams of ammonium chlorides, 18.5 grams of 16,6- of gained dimethoxy-4 ' of (0.1 mole) embodiment-positive hex- 2- ketone of cyano
(III 1), 65-70 DEG C is stirred to react 4 hours, is cooled to 20-25 DEG C, and 17.0 grams of (0.15 mole) 30wt% hydrogen peroxide, 65- is added
70 DEG C are stirred to react 4 hours, are cooled to 20-25 DEG C, 4.8 grams of (0.12 mole) sodium hydroxides are added, 85-90 DEG C is stirred to react 2
Hour, it is cooled to 0-5 DEG C, adjusting reaction liquid pH value with 30wt% hydrochloric acid is 3.0-3.5, filtering, and 10 grams of ice water washings are done
It is dry, 12.1 grams of sticky white solids are obtained, are dissolved by heating 1 hour with 100 grams of acetonitriles, are filtered to remove insoluble matter while hot, recycle second
Nitrile obtains 8.3 grams of 2- picoline -4- formic acid (I), yield 60.6%, liquid phase purity 99.1%.
By this comparative example it is found that the dropwise addition of positive hex- 2- ketone (III 1) material of 6,6- dimethoxy-4 's-cyano is conducive to pass through
Its concentration is controlled, intermolecular side reaction is reduced, to improve the yield and purity of final product.
The preparation of comparative example 2:2- picoline -4- formic acid (I)
To with stirring, thermometer, condenser pipe reaction flask in, 50 grams of water are added, 50 grams of methanol, 40.0 grams (0.4 rubs
You) 17wt% methanolic ammonia solution, 4.0 grams of ammonium chlorides, 21.8 grams of 36,6- of gained dimethoxy-4 ' of (0.1 mole) embodiment-methoxies
The positive hex- 2- ketone (III 2) of base carbonyl, 65-70 DEG C is stirred to react 4 hours, is cooled to 20-25 DEG C, and 17.0 grams (0.15 mole) is added
30wt% hydrogen peroxide, 65-70 DEG C is stirred to react 4 hours, while the methanol that recycling steams, and is cooled to 20-25 DEG C, is added 4.8 grams
(0.12 mole) sodium hydroxide, 35-40 DEG C is stirred to react 2 hours, is cooled to 0-5 DEG C, adjusts reaction liquid with 30wt% hydrochloric acid
PH value is 3.0-3.5, filtering, 10 grams of ice water washings, dry, obtains 12.3 grams of sticky white solids, molten with 100 grams of acetonitrile heating
Solution 1 hour, is filtered to remove insoluble matter while hot, recycles acetonitrile, obtains 7.6 grams of 2- picoline -4- formic acid (I), yield 55.5%,
Liquid phase purity 98.6%.
By this comparative example it is found that disposable material adding manner, causes intermolecular and ammonia side reaction more, and generate big
Weight polymers；The positive hex- 2- ketone (III 2) of 6,6- dimethoxy-4 '-methoxycarbonyl is added dropwise to be conducive to subtract by control system concentration
Few intermolecular side reaction, to improve the yield and purity of final product.
Claims (10)
1. a kind of preparation method of 2- picoline -4- formic acid, comprising steps of
(1) using II compound of formula as III compound of initial feed preparation formula；
Wherein, in III compound of formula II and formula, R is methyl, ethyl, isopropyl, normal-butyl or tert-butyl；G be-CN or-
COOR ' ,-COOR ' middle R ' are methyl, ethyl, isopropyl, normal-butyl or tert-butyl, and R ' and R are identical or different；
(2) in solvent B, in the presence of ammonia and ammonium salt, IV compound of formula is made through cyclization in III compound of formula, then in
Through oxidation reaction under oxidant effect, alkaline reagent effect is lower to be hydrolyzed, and hydrochloric acid is acidified to obtain 2- picoline -4- formic acid (I)；
Wherein, the meaning of G is identical as the meaning of G in II compound of formula in IV compound of formula.
2. the preparation method of 2- picoline -4- formic acid according to claim 1, which is characterized in that with formula in step (1)
II compound is that the method for III compound of initial feed preparation formula is approach 1 or approach 2 respectively；Wherein,
Approach 1 comprising steps of
In solvent A, in the presence of acid binding agent, II compound of formula and acetone dichloride are substituted and react to obtain III compound of formula；
Approach 2 comprising steps of
In the presence of base catalyst, opening occurs for II compound of formula and propylene oxide；Then in the effect of oxidant
Under, III compound of formula is obtained through oxidation reaction.
3. the preparation method of 2- picoline -4- formic acid according to claim 2, which is characterized in that the approach of step (1)
In 1, including one or more in the following conditions:
A, the solvent A is tetrahydrofuran, in 2- methyltetrahydrofuran, cyclopentyl-methyl ether, N,N-dimethylformamide, toluene
One of or combination；The mass ratio of II compound of the solvent A and formula is (3-15): 1；Preferably, II chemical combination of the solvent A and formula
The mass ratio of object is (4.5-10): 1；
B, the acid binding agent is inorganic base or organic base, and inorganic base is selected from potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, carbonic acid
One of calcium, sodium hydroxide, potassium hydroxide, saleratus, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate, calcium acetate or group
It closes, organic base is selected from one of triethylamine, tri-n-butylamine or combination；The molar ratio of II compound of the acid binding agent and formula is (1.0-
2.0):1；Preferably, the molar ratio of II compound of the acid binding agent and formula is (1.0-1.5): 1；
C, the molar ratio of II compound of the acetone dichloride and formula is (1.0-1.5): 1；
D, the temperature of the substitution reaction is 30-100 DEG C；Preferably, the temperature of the substitution reaction is 60-80 DEG C.
4. the preparation method of 2- picoline -4- formic acid according to claim 2, which is characterized in that the approach of step (1)
In 2, including one or more in the following conditions:
A, the base catalyst is 1,8- diazabicyclo [5.4.0] -7- endecatylene (DBU), 1,5- diazabicyclo
One of [4.3.0] -5- nonene (DBN), piperidines, 4-dimethylaminopyridine or combination；The quality of the base catalyst is that formula II is changed
Close the 1-5% of amount of substance；Preferably, the quality of the base catalyst is the 1.5-4% of II compound quality of formula；
B, the molar ratio of II compound of the propylene oxide and formula is (1.0-1.5): 1；
C, the temperature of the opening is 20-70 DEG C；Preferably, the temperature of the opening is 40-55 DEG C；
D, the oxidant is one of hydrogen peroxide, tertbutanol peroxide, m-chloro-benzoic acid peroxide or combination；The oxidant and
The molar ratio of II compound of formula is (1.0-1.3): 1；
E, the temperature of the oxidation reaction is 40-100 DEG C；Preferably, the temperature of the oxidation reaction is 60-80 DEG C.
5. the preparation method of 2- picoline -4- formic acid according to claim 2, which is characterized in that the approach of step (1)
Reaction in 2 is " one kettle way " progress, and intermediate product is without isolation.
6. the preparation method of 2- picoline -4- formic acid according to claim 1, which is characterized in that in step (2), packet
It includes one or more in the following conditions:
A, the solvent B is the combination of one or more of water, acetonitrile, methanol, ethyl alcohol, isopropanol or toluene；It is described
The mass ratio of III compound of solvent B and formula is (2-20): 1；Preferably, the mass ratio of III compound of the solvent B and formula is (4-
10):1；
B, the ammonia is using ammonia, ammonium hydroxide, methanolic ammonia solution or cholamine solution；Ammonium salt is ammonium chloride, ammonium sulfate, ammonium nitrate
Or ammonium phosphate；The molar ratio of III compound of the ammonia, ammonium salt and formula is (2.0-5.0): (0.5-1.5): 1；
C, the cyclization temperature is 20-100 DEG C；Preferably, the cyclization temperature is 50-70 DEG C.
7. the preparation method of 2- picoline -4- formic acid according to claim 1, which is characterized in that in step (2), by
The method of III preparation of compounds of formula of formula, IV compound at 20-100 DEG C, is added dropwise comprising steps of ammonia and ammonium salt are dissolved in solvent B
III compound of formula, after being added dropwise, 20-100 DEG C reaction 2-8 hours.
8. the preparation method of 2- picoline -4- formic acid according to claim 1, which is characterized in that in step (2), packet
It includes one or more in the following conditions:
A, the oxidant is one or a combination set of hydrogen peroxide, tertbutanol peroxide, m-chloro-benzoic acid peroxide；The oxidant
Molar ratio with III compound of formula is (1.0-1.5): 1；
B, the temperature of the oxidation reaction is 20-100 DEG C；Preferably, the temperature of the oxidation reaction is 50-80 DEG C.
9. the preparation method of 2- picoline -4- formic acid according to claim 1, which is characterized in that in step (2), packet
It includes one or more in the following conditions:
A, the alkaline reagent is one of sodium hydroxide, potassium hydroxide, lithium hydroxide or combination；The alkaline reagent and formula III are changed
The molar ratio for closing object is (1.0-1.5): 1；
B, the temperature of the hydrolysis is 20-100 DEG C；Preferably, the temperature of the hydrolysis is 30-90 DEG C；
C, it is 3.0- that the hydrochloric acid acidification, which is the pH value that the aqueous hydrochloric acid solution for the use of mass concentration being 20-30% is acidified to system,
3.5。
10. the preparation method of 2- picoline -4- formic acid according to claim 1, which is characterized in that step (2) is " one
Pot method " reaction, intermediate product is without isolation.
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| CN101056857A (en) * | 2004-11-05 | 2007-10-17 | 弗·哈夫曼-拉罗切有限公司 | Process for preparation of isonicotinic acid derivatives |
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| WO2016125192A2 (en) * | 2015-02-06 | 2016-08-11 | Mylan Laboratories Limited | Process for the preparation of dolutegravir |
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