CN102746219A - Method for synthesizing 2-carboxyl-3-bromopyridine hydrochloride - Google Patents
Method for synthesizing 2-carboxyl-3-bromopyridine hydrochloride Download PDFInfo
- Publication number
- CN102746219A CN102746219A CN2012102232818A CN201210223281A CN102746219A CN 102746219 A CN102746219 A CN 102746219A CN 2012102232818 A CN2012102232818 A CN 2012102232818A CN 201210223281 A CN201210223281 A CN 201210223281A CN 102746219 A CN102746219 A CN 102746219A
- Authority
- CN
- China
- Prior art keywords
- bromopyridine
- carboxyl
- hydrochloride
- cyanic acid
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- TVGMINLRJVVAJO-UHFFFAOYSA-N 3-bromopyridine-2-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=NC=CC=C1Br TVGMINLRJVVAJO-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 15
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 7
- MNNQIBXLAHVDDL-UHFFFAOYSA-N 5-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)C=N1 MNNQIBXLAHVDDL-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- 150000002978 peroxides Chemical class 0.000 claims description 5
- 101100373011 Drosophila melanogaster wapl gene Proteins 0.000 claims description 3
- CGXUKNKFRNOKCG-UHFFFAOYSA-N [O-]C#N.C[NH+](C)C Chemical compound [O-]C#N.C[NH+](C)C CGXUKNKFRNOKCG-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 210000004483 pasc Anatomy 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims 2
- FOKAURNXFDVQOK-UHFFFAOYSA-N CN(C)C.N#CO.[SiH4] Chemical compound CN(C)C.N#CO.[SiH4] FOKAURNXFDVQOK-UHFFFAOYSA-N 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- KBDIRPOTVAODSA-UHFFFAOYSA-N 3-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1Br KBDIRPOTVAODSA-UHFFFAOYSA-N 0.000 abstract description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract 2
- JTFNEJMJBLVPJY-UHFFFAOYSA-N 5-bromopyridine-2-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=C(Br)C=N1 JTFNEJMJBLVPJY-UHFFFAOYSA-N 0.000 abstract 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000003921 oil Substances 0.000 description 5
- -1 3-bromopyridine nitrogen Chemical compound 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 3
- HNEBPTAKURBYRM-UHFFFAOYSA-N 6-bromopyridine-2-carbonitrile Chemical class BrC1=CC=CC(C#N)=N1 HNEBPTAKURBYRM-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a method for synthesizing 2-carboxyl-3-bromopyridine hydrochloride. Easily-available 3-bromopyridine, being used as a raw material, is firstly nitrogen-oxidized by hydrogen peroxide in acetic acid and then reacted with trimethyl-cyano-silicon in the presence of triethylamine to get a mixture of 2-carboxyl-3-bromopyridine and 6-carboxyl-3-bromopyridine, and the mixture is then hydrolyzed in concentrated hydrochloric acid to precipitate a white solid 2-carboxyl-3-bromopyridine hydrochloride, directly separating from the 6-carboxyl-3-bromopyridine hydrochloride.
Description
Technical field
The present invention relates to the synthesis technique of a kind of 2-carboxyl-3-bromopyridine hydrochloride, belong to medicine, chemical technology field.
Background technology
2-carboxyl-3-bromopyridine hydrochloride is a kind of white solid, is the important intermediate raw materials of many medicine intermediates.
Summary of the invention
The present invention is a raw material with the 3-bromopyridine that is easy to get; Earlier with after the oxidation of 3-bromopyridine nitrogen; In the presence of triethylamine, obtain the mixture of 2-cyanic acid-3-bromopyridine and 6-cyanic acid-3-bromopyridine again, after hydrolysis in the concentrated hydrochloric acid, separate out white solid again and be 2-carboxyl-3-bromopyridine hydrochloride with trimethylammonium cyanic acid pasc reaction.
The compound method of 2-carboxyl according to the invention-3-bromopyridine hydrochloride is that the 3-bromopyridine is dissolved in the acetic acid, adds 30% ydrogen peroxide 50; Be heated to 80 degree; Stir 8 hours postcooling to room temperature, stirred overnight, concentrating under reduced pressure obtains oily matter; With in the solid sodium carbonate with after add chloroform and stir after-filtration, concentrate after the mother liquor drying and obtain oil and directly be used for next step reaction.After refluxing 4 hours, directly oily and trimethylammonium cyanic acid silicon, the triethylamine that a last step obtains concentrated; With using dichloromethane extraction behind the aqueous sodium carbonate accent alkali; The dry back that concentrates is with the mixture that obtains 2-cyanic acid-3-bromopyridine and 6-cyanic acid-3-bromopyridine behind the column chromatography purification; This mixture filters out institute's solid of separating out and just is 2-carboxyl-3-bromopyridine hydrochloride with concentrated hydrochloric acid 24 hours postcooling hold over night after the room temperature that refluxes, and three step total recoverys are more than 50%.
Above-mentioned with the 3-bromopyridine, trimethylammonium cyanic acid silicon, concentrated hydrochloric acid etc. are that the hydrochlorate chemical reaction and the reaction formula of raw material Synthetic 2-carboxyl-3-bromopyridine salt is following:
(1) the 3-bromopyridine is dissolved in the acetic acid, with the reaction equation of 30% ydrogen peroxide 50 is:
(2) 3-bromopyridine oxynitride and trimethylammonium cyanic acid pasc reaction equation are:
(3) mixture and the concentrated hydrochloric acid reaction equation of 2-cyanic acid-3-bromopyridine and 6-cyanic acid-3-bromopyridine are:
Embodiment
Embodiment:
30% ydrogen peroxide 50 (41ml, 0.404 mole) joins in the acetic acid (120 milliliters) that has dissolved 3-bromopyridine (32 grams, 0.202 mole); Be heated to 90 ° of C and stirred 8 hours, stirred overnight behind the cool to room temperature, underpressure distillation obtains oily matter; Be adjusted to alkalescence with solid sodium carbonate, add chloroform (100 milliliters) and stir after-filtration half a hour, the mother liquor dried over mgso is filtered the back concentrating under reduced pressure and is obtained black oil (33.5 grams; 95% yield), directly be used for next step reaction.
The 3-bromopyridine oxynitride that a last step obtains (5 grams, 28.8 mmoles), trimethylammonium cyanic acid silicon (8.55 grams; 86.4 mmole) and triethylamine (5.8 the gram; 57.5 mmole) be stirred and heated to backflow together, 4 hours postcooling sodium carbonate solution with 3 mol after the room temperature that refluxes is adjusted to alkalescence, with twice of dichloromethane extraction; Organic phase after the merging obtains oil after concentrating; This oil is used silica gel column chromatography, use sherwood oil than methylene dichloride be five to one eluent obtain 3.5 restrain 2-cyanic acid-3-bromopyridines and 3 bromo-6-cyanopyridines mixture, yield 75%.
Mixture (7.5 grams of 2-cyanic acid-3-bromopyridine that a last step obtains and 3 bromo-6-cyanopyridines; 40.9 mmole) be dissolved in the concentrated hydrochloric acid (150 milliliters); 24 hours postcooling of reflux are to room temperature; Hold over night is filtered then and is obtained pure article 2-carboxyl-3-bromopyridine hydrochloride (8.4 grams, 80% yield).Nuclear magnetic data:
1HNMR (500MHz, d-DMSO): 7.46-7.49 (m, 1H), 8.20 (d, 1H), 8.58 (d, 1H).
Claims (5)
1. the compound method of 2-carboxyl according to the invention-3-bromopyridine hydrochloride; Be to be raw material with the 3-bromopyridine that is easy to get; Earlier with the 3-bromopyridine in the acetic acid with 30% ydrogen peroxide 50 nitrogen oxidation after; In the presence of triethylamine, obtain the mixture of 2-cyanic acid-3-bromopyridine and 6-cyanic acid-3-bromopyridine again, after hydrolysis in the concentrated hydrochloric acid, separate out white solid again and be 2-carboxyl-3-bromopyridine hydrochloride with trimethylammonium cyanic acid pasc reaction.
2. the compound method of 2-carboxyl-3-bromopyridine hydrochloride as claimed in claim, it is characterized in that: described initial feed is meant that the 3-bromopyridine is a raw material.
3. the compound method the first step of above-mentioned 2-carboxyl-3-bromopyridine hydrochloride is synthesized 3-bromopyridine oxynitride, and it is characterized in that: solvent is an acetic acid, and raw material, oxygenant are ydrogen peroxide 50.
4. second step of the compound method Synthetic 2-cyanic acid-3-bromopyridine of above-mentioned 2-carboxyl-3-bromopyridine hydrochloride and the mixture of 6-cyanic acid-3-bromopyridine, it is characterized in that: the reagent of going up cyanic acid is trimethylammonium cyanic acid silane, has avoided using other hypertoxic prussiates.
5. the 3rd step of the compound method Synthetic 2-carboxyl-3-bromopyridine hydrochloride of above-mentioned 2-carboxyl-3-bromopyridine hydrochloride; It is characterized by and separate out 2-carboxyl-3-bromopyridine hydrochloride after raw material leaves standstill with the cooling of concentrated hydrochloric acid back hydrolysis, separated with 6-carboxyl-3-bromopyridine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102232818A CN102746219A (en) | 2012-07-02 | 2012-07-02 | Method for synthesizing 2-carboxyl-3-bromopyridine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102232818A CN102746219A (en) | 2012-07-02 | 2012-07-02 | Method for synthesizing 2-carboxyl-3-bromopyridine hydrochloride |
Publications (1)
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|---|---|
| CN102746219A true CN102746219A (en) | 2012-10-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012102232818A Pending CN102746219A (en) | 2012-07-02 | 2012-07-02 | Method for synthesizing 2-carboxyl-3-bromopyridine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102746219A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2815654B2 (en) * | 1990-01-16 | 1998-10-27 | 東京田辺製薬株式会社 | Novel 4-substituted-3,5-dimethylpicolinic acid compound and method for producing the same |
| CN101489556A (en) * | 2006-07-14 | 2009-07-22 | 伊莱利利公司 | Glucocorticoid receptor modulator and methods of use |
| CN101835777A (en) * | 2007-10-25 | 2010-09-15 | 尔察祯有限公司 | Carbacephem β-lactam antibiotics |
-
2012
- 2012-07-02 CN CN2012102232818A patent/CN102746219A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2815654B2 (en) * | 1990-01-16 | 1998-10-27 | 東京田辺製薬株式会社 | Novel 4-substituted-3,5-dimethylpicolinic acid compound and method for producing the same |
| CN101489556A (en) * | 2006-07-14 | 2009-07-22 | 伊莱利利公司 | Glucocorticoid receptor modulator and methods of use |
| CN101835777A (en) * | 2007-10-25 | 2010-09-15 | 尔察祯有限公司 | Carbacephem β-lactam antibiotics |
Non-Patent Citations (1)
| Title |
|---|
| 恽魁宏: "《有机化学》", 31 May 1990 * |
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Application publication date: 20121024 |