CN110483480A - The synthetic method of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate - Google Patents
The synthetic method of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate Download PDFInfo
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- CN110483480A CN110483480A CN201910856756.9A CN201910856756A CN110483480A CN 110483480 A CN110483480 A CN 110483480A CN 201910856756 A CN201910856756 A CN 201910856756A CN 110483480 A CN110483480 A CN 110483480A
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- chloropyridine
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of synthetic methods of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate, including the chloro- 2-aminopyridine of 3- is dissolved in the mixed liquor of organic acid or inorganic acid and solvent A, diazotising is carried out in the presence of -5 ~ 10 DEG C of conditions, diazo reagents, obtains diazo liquid；Gained diazo liquid is added drop-wise to reaction in diethyl succinate (positive diethyl succinate), in the process plus alkali, heat preservation and etc..The present invention uses diazotising, coupling, cyclization route, and reaction condition is mild；Meanwhile the diazonium salt of the chloro- 2-aminopyridine of 3- is more stable, it is not easy to decompose, explode, synthesis is safe and reliable.The present invention does not use metallic sodium or sodium ethoxide, reduces the security risk in synthesis process.Target product yield can achieve 72% or more, be higher than current conventional process method.
Description
Technical field
The present invention relates to a kind of synthetic methods of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate.
Background technique
2- (3- chloropyridine -2- base) its structural formula of -5- hydroxyl -3- pyrazolidinecarboxylate is as follows:
Rynaxypyr (chlorantraniliprole) is the O-formammidotiazol-benzamide chemical combination of Du Pont's exploitation
First insecticide in object (world patent WO0170671, Chinese patent CN1419537B, United States Patent (USP) US6747047), it is existing
More than 100 country's sale in the world, almost covers all staple markets in the whole world, has been global agrochemical market since 2012
First big insecticide, the third-largest insecticide of rice, whole world sales volume in 2016 are 13.65 hundred million dollars；2011-2016 years
Compound annual growth rate be up to 15.1%.2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate is synthesis chlorine worm
The important intermediate of benzamide.
2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate and 2- (3- chloropyridine -2- base) -5- oxo -
3- pyrazolidinecarboxylate is tautomerism, as follows:
Domestic various kinds of document reports the compound synthesis method with different names, such as " Hebei University of Technology's journal " 2011
In October in year (the 5th phase of volume 40), Guo Jianlan etc. " synthesis of the bromo- 1- of 3- (3- chloro-2-pyridyl) -1H- pyridine -5- formic acid " one
Text proposes a kind of synthetic method, and the ethanol solution that metallic sodium is configured to sodium ethoxide is added in dehydrated alcohol, it is chloro- that 3- is then added
2- hydrazino pyridine is handled with glacial acetic acid wash again after reaction in 55 DEG C or so dropwise addition diethyl maleates, obtains target production
Object, yield 53.3%；" 2- (3- chloropyridine -2- the base) -5- hydroxyls such as " Anhui chemical industry " in October, 2014 phase leaf person of outstanding talent of volume 40 the 5th
The synthesis of pyrazoles -3- Ethyl formate " the method is similar to the method for Guo Jianlan, and yield described in text is 44.6%；It is Chinese special
Sharp CN103058993A proposes a kind of synthetic method: 3- chloride-2-hydrazinopyridine, alkali are added in solvent, and Malaysia is added dropwise under ice bath
The mixed liquor of sour mono ethyl ester acyl chlorides and acetonitrile obtains 2- (3- chloropyridine -2- base) -5- through neutralized, extraction, concentration, recrystallization again
Oxo pyrazoles -3- Ethyl formate, yield 52.4%.Yield is all relatively low.
Summary of the invention
The purpose of the present invention is to provide a kind of synthesis securely and reliably, 2- (3- chloropyridine -2- base) -5- hydroxyl of high income
The synthetic method of base -3- pyrazolidinecarboxylate.
The technical solution of the invention is as follows:
A kind of synthetic method of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate, it is characterized in that: including
The following steps:
(1) the chloro- 2-aminopyridine of 3- is dissolved in the mixed liquor of organic acid or inorganic acid and solvent A, at -5~10 DEG C
Diazotising is carried out in the presence of condition, diazo reagent, obtains diazo liquid；
(2) diazo liquid obtained by step (1) is added drop-wise to reaction in diethyl succinate (positive diethyl succinate), in the process
Add alkali, keeps the temperature；
(3) after step (2) heat preservation, heat temperature raising adds alkali to adjust pH value to 8~12, the pH value and temperature 15~
0.5~6 hour is kept the temperature at 75 DEG C；
(4) after step (3) heat preservation, it is cooled to room temperature, then acid adding is neutralized to pH value 6.5~7, is further processed
To target product 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate.
In step (1), the solvent A includes but is not limited to acetonitrile, dichloroethanes, ethyl alcohol, glacial acetic acid, ethyl acetate, just
Butanol, diethyl ether, butyl oxide, butanone, pentanone, n-amyl alcohol, isoamyl alcohol, n-butyl acetate, n-amyl acetate, in isoamyl acetate
One or more of solvents mixture.
In step (1), the diazo reagent is nitrite, nitrosyl sulfuric acid salt, nitrosyl sulfuric acid or nitrous acid ester.
Step (2) reaction temperature is -15~30 DEG C；Step (2) pH value in reaction is 3~7.
Step (2) and step (3) alkali are ammonia, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Step (3) reaction temperature is 15~75 DEG C；The control of step (3) pH value in reaction is 8~12.
The invention has the following advantages that
1, this programme uses diazotising, coupling, cyclization route, and reaction condition is mild；Meanwhile the chloro- 2-aminopyridine of 3-
Diazonium salt is more stable, it is not easy to decompose, explode, synthesis is safe and reliable.
2, this programme does not use metallic sodium or sodium ethoxide, reduces the security risk in synthesis process.
3, using this programme, target product yield can achieve 72% or more, be higher than current conventional process method.
Below with reference to embodiment, the invention will be further described.
Specific embodiment
Example 1
1000ml four-hole bottle with agitating device is mounted in water-bath, water-bath salt water on the rocks.It is added into four-hole bottle
Glacial acetic acid 100.5g (98%, 1.64mol), n-butanol 250g, stirring, the addition chloro- 2-aminopyridine 81.2g of 3- (98.3%,
0.621mol).After separately sodium nitrite 45.6g (98.5%, 0.651mol) being taken to be dissolved in 57g water, it is added to constant pressure funnel, is connected to
On above-mentioned four-hole bottle.When temperature in four-hole bottle drops to -2~-5 DEG C, sodium nitrite solution in constant pressure funnel is added drop-wise to four mouthfuls
In bottle.It controls temperature in bottle to be added dropwise between -5~10 DEG C, be kept the temperature at 0 DEG C or so, the detection chloro- 2-aminopyridine of 3- contains
< 0.5% is measured, reaction terminates, about addition urea 1.8g, until the detection of starch-KI test paper is non-discolouring.
Example 2
1000ml four-hole bottle with agitating device is mounted in water-bath, water-bath salt water on the rocks.It is added into four-hole bottle
Diethyl succinate 109.5g (98.8%, 0.621mol).Two constant pressure funnels are taken to be separately added into the weight of 30% ammonium hydroxide and example 1
Nitrogen liquid, is connected on four-hole bottle.When temperature in four-hole bottle drops to 0 DEG C or less, while ammonium hydroxide and diazo liquid being added dropwise into four-hole bottle,
Temperature -5~15 DEG C in four-hole bottle are kept, pH value 4~6.5, heat preservation is kept the temperature at 0~15 DEG C after completion of dropwise addition, sampling, HPLC detection
After diazonium salt disappears, it is changed to heating water bath, ammonium hydroxide is added dropwise to pH value 9~10.5, it is cooled to after keeping the temperature 2 hours at 30~95 DEG C
Room temperature, acetic acid on the rocks are neutralized to pH value 6.5.Material in four-hole bottle is transferred to separatory funnel, stands one hour.Organic phase washing one
The concentration of negative pressure precipitation, is cooled to 0~-5 DEG C after secondary after concentration, crystallizes 12 hours in this temperature, separates crystal, and vacuum is dry
It is dry, obtain faint yellow solid 124.3g, fusing point 131.6~132.8, HPLC detection level 97.8%, yield 72.58%.
Example 3
1000ml four-hole bottle with agitating device is mounted in water-bath, water-bath salt water on the rocks.It is added into four-hole bottle
Glacial acetic acid 101.2g (98%, 1.65mol), n-butanol 250g, stirring, the addition chloro- 2-aminopyridine 81.3g of 3- (98.3%,
0.622mol).Separately take nitrous acid straight butyl butanol solution 82.2g (82.0%, 0.654mol) that constant pressure funnel is added.To four mouthfuls
When temperature drops to -2~-5 DEG C in bottle, nitrous acid straight butyl in constant pressure funnel is added drop-wise in four-hole bottle.Control bottle in temperature-
It between 5~10 DEG C, is added dropwise, is kept the temperature at 0 DEG C or so, detect the chloro- 2-aminopyridine content < 0.5% of 3-, reaction terminates, about
Urea 1.9g is added, until the detection of starch-KI test paper is non-discolouring.
Example 4
1000ml four-hole bottle with agitating device is mounted in water-bath, water-bath salt water on the rocks.It is added into four-hole bottle
Diethyl succinate 109.8g (98.8%, 0.623mol).The diazo liquid of example 3 is packed into constant pressure funnel in several times, separately four
Mouth bottle connects snorkel, and phial interpolation of ventilating is to liquid level hereinafter, being external in the ammonia tank of 5~10kPa of pressure.Start four-hole bottle
It stirs, when temperature drops to 0 DEG C or less in bottle, diazo liquid is added dropwise into bottle, while being passed through ammonia into bottle, keep temperature in four-hole bottle
- 5~15 DEG C of degree, pH value 4~6.5, heat preservation is kept the temperature at 0~15 DEG C after completion of dropwise addition, sampling, after HPLC detection diazonium salt disappears,
It is changed to heating water bath, continues logical ammonia to pH value 9~10.5, room temperature, acetic acid on the rocks are cooled to after keeping the temperature 2 hours at 30~95 DEG C
It is neutralized to pH value 6.5.By material in four-hole bottle at 1~5mmHg of absolute pressure, 85 DEG C of maximum temperature precipitation to close to being evaporated,
Room temperature is naturally cooled under vacuum, is obtained lark loose solid particles and, with a small amount of ethanol washing, it is white to be obtained class after washing, drying
Color solid powder 129.8g, fusing point 132.3~133.0, HPLC detection level 98.05%, yield 75.89%.
Claims (6)
1. a kind of synthetic method of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate, it is characterized in that: under including
Column step:
(1) the chloro- 2-aminopyridine of 3- is dissolved in the mixed liquor of organic acid or inorganic acid and solvent A, -5 ~ 10 DEG C of conditions,
Diazotising is carried out in the presence of diazo reagent, obtains diazo liquid；
(2) diazo liquid obtained by step (1) is added drop-wise in diethyl succinate and is reacted, in the process plus alkali, heat preservation；
(3) after step (2) heat preservation, heat temperature raising adds alkali to adjust pH value to 8 ~ 12, at the pH value and 15 ~ 75 DEG C of temperature
Heat preservation 0.5 ~ 6 hour；
(4) after step (3) heat preservation, it is cooled to room temperature, then acid adding is neutralized to pH value 6.5 ~ 7, is further processed to obtain mesh
Mark product 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate.
2. the synthetic method of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate according to claim 1,
It is characterized in that: in step (1), the solvent A includes but is not limited to acetonitrile, dichloroethanes, ethyl alcohol, glacial acetic acid, ethyl acetate, just
Butanol, diethyl ether, butyl oxide, butanone, pentanone, n-amyl alcohol, isoamyl alcohol, n-butyl acetate, n-amyl acetate, in isoamyl acetate
One or more of solvents mixture.
3. the synthesis side of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate according to claim 1 or 2
Method, it is characterized in that: the diazo reagent is nitrite, nitrosyl sulfuric acid salt, nitrosyl sulfuric acid or nitrous in step (1)
Acid esters.
4. the synthesis side of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate according to claim 1 or 2
Method, it is characterized in that: step (2) reaction temperature is -15 ~ 30 DEG C；Step (2) pH value in reaction is 3 ~ 7.
5. the synthesis side of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate according to claim 1 or 2
Method, it is characterized in that: step (2) and step (3) alkali are ammonia, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or hydrogen-oxygen
Change potassium.
6. the synthesis side of 2- (3- chloropyridine -2- base) -5- hydroxyl -3- pyrazolidinecarboxylate according to claim 1 or 2
Method, it is characterized in that: step (3) reaction temperature is 15 ~ 75 DEG C；The control of step (3) pH value in reaction is 8 ~ 12.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH250900A (en) * | 1944-12-01 | 1947-09-30 | Ilford Ltd | Process for the preparation of a pyrazol-5-one compound. |
| CN1250440A (en) * | 1997-03-12 | 2000-04-12 | 罗纳-普朗克农业公司 | Process for preparing pyrazole derivatives |
| CN1541206A (en) * | 2001-08-13 | 2004-10-27 | ��Ļ���Ű˾ | Substituted dihydro 3-hylo-1H-pyrazoloe-5-carboxylates their prepn. and use |
| CN1764658A (en) * | 2003-03-26 | 2006-04-26 | 杜邦公司 | Preparation and use of 2-substituted-5-oxo-3- pyrazolidinecarboxylates |
| CN103396366A (en) * | 2013-08-06 | 2013-11-20 | 盐城工学院 | Production method of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole |
| CN103483261A (en) * | 2013-09-10 | 2014-01-01 | 中国乐凯集团有限公司 | Preparation method of 1-substitued phenyl-3-carboxymethyl-5-pyrazolone |
-
2019
- 2019-09-11 CN CN201910856756.9A patent/CN110483480A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH250900A (en) * | 1944-12-01 | 1947-09-30 | Ilford Ltd | Process for the preparation of a pyrazol-5-one compound. |
| US2459226A (en) * | 1944-12-01 | 1949-01-18 | Ilford Ltd | Production of pyrazole-5-ones |
| CN1250440A (en) * | 1997-03-12 | 2000-04-12 | 罗纳-普朗克农业公司 | Process for preparing pyrazole derivatives |
| CN1541206A (en) * | 2001-08-13 | 2004-10-27 | ��Ļ���Ű˾ | Substituted dihydro 3-hylo-1H-pyrazoloe-5-carboxylates their prepn. and use |
| CN1764658A (en) * | 2003-03-26 | 2006-04-26 | 杜邦公司 | Preparation and use of 2-substituted-5-oxo-3- pyrazolidinecarboxylates |
| CN103396366A (en) * | 2013-08-06 | 2013-11-20 | 盐城工学院 | Production method of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole |
| CN103483261A (en) * | 2013-09-10 | 2014-01-01 | 中国乐凯集团有限公司 | Preparation method of 1-substitued phenyl-3-carboxymethyl-5-pyrazolone |
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Application publication date: 20191122 |