CN101117331A - Method for preparing 3-pyridine acetic acid hydrochloride - Google Patents
Method for preparing 3-pyridine acetic acid hydrochloride Download PDFInfo
- Publication number
- CN101117331A CN101117331A CNA200610069863XA CN200610069863A CN101117331A CN 101117331 A CN101117331 A CN 101117331A CN A200610069863X A CNA200610069863X A CN A200610069863XA CN 200610069863 A CN200610069863 A CN 200610069863A CN 101117331 A CN101117331 A CN 101117331A
- Authority
- CN
- China
- Prior art keywords
- acid hydrochloride
- pyridine
- morpholine
- morphine quinoline
- thioacetyl
- 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
Links
- XVCCOEWNFXXUEV-UHFFFAOYSA-N 2-pyridin-3-ylacetic acid;hydrochloride Chemical compound Cl.OC(=O)CC1=CC=CN=C1 XVCCOEWNFXXUEV-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- DPZYLEIWHTWHCU-UHFFFAOYSA-N 3-ethenylpyridine Chemical compound C=CC1=CC=CN=C1 DPZYLEIWHTWHCU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 38
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 36
- 229960005181 morphine Drugs 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 5
- 235000011194 food seasoning agent Nutrition 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 14
- 239000005864 Sulphur Substances 0.000 abstract description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 abstract 8
- 125000000446 sulfanediyl group Chemical group *S* 0.000 abstract 3
- 239000005457 ice water Substances 0.000 abstract 2
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 238000001556 precipitation Methods 0.000 abstract 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 229960000759 risedronic acid Drugs 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- -1 quinoline 3-Pyridineacetic Acid hydrochloride Chemical compound 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation process for 3-Pyridylacetic acid hydrochloride. The 3-vinylpyridine is taken as the raw material, is reacted with the morpholine and the sulphur, and then is poured into the ice water to be filtered; the crystal is washed by ice water and is naturally dried in the air to produce the 3-pyridyi thio aeid morpholine; the 3-pyridyi thio aeid morpholine is hydrolyzed by the hydrochloric acid, after the dehydration, the 3-pyridyi thio aeid morpholine is decolored by the activated carbon, is made a pressure reduction concentration, is cooled and made a crystal precipitation to produce the 3-Pyridylacetic acid hydrochloride. The invention directly takes 3-vinylpyridine as the raw material, produces the 3-Pyridylacetic acid hydrochloride only by two steps chemical reactions, develops a new path for the preparation of 3-Pyridylacetic acid hydrochloride; moreover, the preparation process is greatly shortened, the operation is simple, the yields are above 86 percent, and the quality of the product is apparently improved.
Description
Technical field
The present invention relates to the synthetic method of pharmaceutical intermediate 3-Pyridineacetic Acid hydrochloride.
Background technology
The 3-Pyridineacetic Acid hydrochloride, its chemical structural formula is:
It is key intermediate for synthetic anti-osteoporotic risedronate sodium (Risedronate sodium).Osteoporosis is a kind of general metabolism disease, with the microstructure degeneration of the minimizing of bone amount, bone, the fragility increase and the easy fracture of bone is feature, become the elderly, especially postmenopausal women's common disease, frequently-occurring disease, once being called by the western medicine expert is " 21st century is endangered one of three maximum big diseases to the mankind ".Risedronate sodium is a third generation bisphosphonates bone resorption inhibitor, is applicable to post-menopausal osteoporosis and the osteoporosis because of using cortin to cause, the osteoporosis that also can prevent high risk population among the women.Its safety, effective, better tolerance, application prospect is good.
Chinese Journal of Pharmaceuticals (2003,33 (9): 427) disclose a kind of method for preparing the 3-Pyridineacetic Acid hydrochloride: with the Nikithan is raw material, through lithium aluminium hydride reduction, thionyl chloride chlorination, potassium cyanide replacement, hydrolysis and must the 3-Pyridineacetic Acid hydrochloride.This method is used valuable raw material lithium aluminium hydride and violent in toxicity potassium cyanide, and total recovery is lower, the cost height.
Also have, J Am Chem Soc.1957,79:4226 and J Am Chem Soc, 1947,69 (7): 1797 also disclose a kind of preparation method of 3-Pyridineacetic Acid hydrochloride: be raw material with the Nikithan, get 3-acetylpyridine through condensation and hydrolysis, again through the Willgerodt of improvement reaction, obtain 3-pyridine thioacetyl morphine quinoline, after hydrolysis gets the 3-Pyridineacetic Acid hydrochloride.This law total recovery is higher, and cost is lower.But the first step reaction needs with sodium hydride and sodium methylate (or sodium ethylate) in this law, yield 81-85%, and the sodium hydride price is more expensive, and sodium methylate (or sodium ethylate) is difficult for preserving.Basic hydrolysis is used in final step, the aftertreatment more complicated, and sodium-chlor is difficult to eliminate, yield 74%, mp153-155 ℃.
In addition, Chinese invention patent application CN1431198A also discloses a kind of preparation method of 3-Pyridineacetic Acid hydrochloride, substituted catalyzer sodium methylate (or sodium ethylate) in the above-mentioned second method with sodium Metal 99.5 in this method, changed hydrolysising condition, the shortcoming of this method is that sodium Metal 99.5 has certain danger aborning.
Summary of the invention
Technical problem to be solved by this invention is: a kind of method for preparing the 3-Pyridineacetic Acid hydrochloride is provided, and this method steps is simple, the yield height, and quality product obviously improves.
For solving the problems of the technologies described above, technical scheme of the present invention is: prepare the method for 3-Pyridineacetic Acid hydrochloride, may further comprise the steps:
With the 3-vinyl pyridine is raw material, after finishing with morphine quinoline and sulfur reaction, pours in the frozen water and filters, and crystal washs with frozen water, and seasoning in air makes 3-pyridine thioacetyl morphine quinoline;
3-pyridine thioacetyl morphine quinoline is hydrolyzed with hydrochloric acid, after hydrolysis finishes, through activated carbon decolorizing, concentrating under reduced pressure, cooling crystallization makes the 3-Pyridineacetic Acid hydrochloride.
In conjunction with chemical equation, the preparation method is as follows more specifically:
A) preparation process of 3-pyridine thioacetyl morphine quinoline
3-vinyl pyridine 3-pyridine thioacetyl morphine quinoline
In the presence of sulphur, 3-vinyl pyridine and the reaction of morphine quinoline, reaction is finished, and pours in the frozen water and filters, and crystal washs with frozen water, and seasoning promptly gets 3-pyridine thioacetyl morphine quinoline in the air;
B) preparation process of 3-Pyridineacetic Acid hydrochloride
3-pyridine thioacetyl morphine quinoline 3-Pyridineacetic Acid hydrochloride
3-pyridine thioacetyl morphine quinoline is hydrolyzed with hydrochloric acid, and hydrolysis finishes, behind activated carbon decolorizing, and concentrating under reduced pressure, cooling crystallization, refining pure 3-Pyridineacetic Acid hydrochloride.
Because the present invention is a raw material with the 3-vinyl pyridine directly, just can make the 3-Pyridineacetic Acid hydrochloride by two step chemical reactions, so it opens up a new way for the preparation of 3-Pyridineacetic Acid hydrochloride, and preparation process shortens greatly, easy and simple to handle, yield reaches more than 86%, and quality product obviously improves.
Embodiment
Embodiment 1
A) preparation process of 3-pyridine thioacetyl morphine quinoline
3-vinyl pyridine 86.8g is added 79g morphine quinoline, add sulphur 29g, heating reflux reaction 12 hours under the condition of stirring, reactant poured in the frozen water filter, crystal washs with frozen water, and seasoning promptly gets faint yellow crystallization 160.2g, yield 87.3% in the air.
B) preparation process of 3-Pyridineacetic Acid hydrochloride
3-pyridine thioacetyl morphine quinoline 160.2g and 182ml mixed in hydrochloric acid, reflux 6 hours is filtered, concentrating under reduced pressure, cooling crystallization, refining with concentrated hydrochloric acid 130ml, dry 107.6g white crystals 3-Pyridineacetic Acid hydrochloride, the yield 86% of getting.
Embodiment 2
A) preparation process of 3-pyridine thioacetyl morphine quinoline
3-vinyl pyridine 86.8g is added 79g morphine quinoline, add sulphur 29g under the condition of stirring, heating reflux reaction 14 hours is poured reactant in the frozen water into and to be filtered, and crystal washs with frozen water, and seasoning promptly gets faint yellow crystallization 165g, yield 90% in the air.
B) preparation process of 3-Pyridineacetic Acid hydrochloride
3-pyridine thioacetyl morphine quinoline 160.2g and 182ml mixed in hydrochloric acid, reflux 5 hours is filtered, concentrating under reduced pressure, cooling crystallization, refining with concentrated hydrochloric acid 110ml, dry 110g white crystals 3-Pyridineacetic Acid hydrochloride, the yield 88% of getting.
Claims (1)
1. the method for preparing the 3-Pyridineacetic Acid hydrochloride is characterized in that may further comprise the steps:
With the 3-vinyl pyridine is raw material, after finishing with morphine quinoline and sulfur reaction, pours in the frozen water and filters, and crystal washs with frozen water, and seasoning in air makes 3-pyridine thioacetyl morphine quinoline;
3-pyridine thioacetyl morphine quinoline is hydrolyzed with hydrochloric acid, after hydrolysis finishes, through activated carbon decolorizing, concentrating under reduced pressure, cooling crystallization makes the 3-Pyridineacetic Acid hydrochloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610069863XA CN101117331A (en) | 2006-08-05 | 2006-08-05 | Method for preparing 3-pyridine acetic acid hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610069863XA CN101117331A (en) | 2006-08-05 | 2006-08-05 | Method for preparing 3-pyridine acetic acid hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101117331A true CN101117331A (en) | 2008-02-06 |
Family
ID=39053620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200610069863XA Pending CN101117331A (en) | 2006-08-05 | 2006-08-05 | Method for preparing 3-pyridine acetic acid hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101117331A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242222A (en) * | 2013-05-22 | 2013-08-14 | 徐云根 | Preparation method of 3-pyridineacetic acid hydrochloride |
| CN106366034A (en) * | 2016-08-17 | 2017-02-01 | 南京红太阳生物化学有限责任公司 | Preparation method of 3-pyridylacetic acid hydrochloride |
| CN108467358A (en) * | 2018-05-29 | 2018-08-31 | 湖南华腾制药有限公司 | A kind of compound and preparation method thereof of 2- substitutions -5- pyridine acetic acid hydrochlorides |
| CN108530347A (en) * | 2018-05-29 | 2018-09-14 | 湖南华腾制药有限公司 | A kind of compound and preparation method thereof of 2- substitutions -4- pyridine acetic acid hydrochlorides |
-
2006
- 2006-08-05 CN CNA200610069863XA patent/CN101117331A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242222A (en) * | 2013-05-22 | 2013-08-14 | 徐云根 | Preparation method of 3-pyridineacetic acid hydrochloride |
| CN103242222B (en) * | 2013-05-22 | 2016-04-27 | 徐云根 | A kind of preparation method of 3-Pyridineacetic Acid hydrochloride |
| CN106366034A (en) * | 2016-08-17 | 2017-02-01 | 南京红太阳生物化学有限责任公司 | Preparation method of 3-pyridylacetic acid hydrochloride |
| CN106366034B (en) * | 2016-08-17 | 2019-09-03 | 南京红太阳生物化学有限责任公司 | A kind of preparation method of 3-Pyridineacetic Acid hydrochloride |
| CN108467358A (en) * | 2018-05-29 | 2018-08-31 | 湖南华腾制药有限公司 | A kind of compound and preparation method thereof of 2- substitutions -5- pyridine acetic acid hydrochlorides |
| CN108530347A (en) * | 2018-05-29 | 2018-09-14 | 湖南华腾制药有限公司 | A kind of compound and preparation method thereof of 2- substitutions -4- pyridine acetic acid hydrochlorides |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0778032B2 (en) | Method for producing ferulic acid | |
| CN104230777A (en) | Synthetic method of oxiracetam | |
| CN101941963A (en) | Synthesis method of erdosteine | |
| CN101117331A (en) | Method for preparing 3-pyridine acetic acid hydrochloride | |
| CN106365986A (en) | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam | |
| CN113582880B (en) | Preparation method of (3-aminobicyclo [1.1.1] pentane-1-yl) carbamic acid tert-butyl ester | |
| NO782230L (en) | PROCEDURES FOR THE PREPARATION OF N-AMIDINO-3,5-DIAMINO-6-SUBSTITUTED-2-PYRAZINE CARBOXAMIDE | |
| CN103242222B (en) | A kind of preparation method of 3-Pyridineacetic Acid hydrochloride | |
| CN103467445B (en) | Preparation method of alogliptin benzoate | |
| CN102757390B (en) | Method for preparing 2-methoxy-4-diazanyl-5-fluoropyrimidine | |
| CN101967120A (en) | Preparation method of 2-p-chlorobenzyl pyridine | |
| CN109516960B (en) | Preparation method of urapidil hydrochloride | |
| CN100522936C (en) | Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid | |
| CN105085485B (en) | A kind of preparation method of HKI-272 | |
| KR102693201B1 (en) | Method for the synthesis of SGLT inhibitor intermediates | |
| CN105753735B (en) | Preparation method of high-efficiency low-toxicity vasopressin antagonist | |
| CN1431198A (en) | New method for preparing 3-pyridine acetic hydrochloride | |
| CN102924362A (en) | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride | |
| CN104151295B (en) | A kind of synthetic method of 2-[(4-chloro-phenyl-) (4-piperidyl oxygen base) methyl] pyridine | |
| CN102206185B (en) | Process for refining bendazac lysine and analogs thereof | |
| JP3954121B2 (en) | Process for producing 3-hydroxy-N-benzimidazolone-5-yl-2-naphthamide with high purity required for azo pigments | |
| CN102276522A (en) | Method for preparing roflumilast and intermediate of roflumilast | |
| CN105085496A (en) | Method for preparing Lapatinib and intermediate | |
| CN101759582A (en) | New process for producing DL-p-hydroxyphenylglycine | |
| CN100497330C (en) | Thiophene-2,5-dicarboxylic acid synthesis method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20080206 |