CN104031040B - The synthetic method of 2-sulfydryl-4-pyridyl thiazole - Google Patents
The synthetic method of 2-sulfydryl-4-pyridyl thiazole Download PDFInfo
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- CN104031040B CN104031040B CN201410246198.1A CN201410246198A CN104031040B CN 104031040 B CN104031040 B CN 104031040B CN 201410246198 A CN201410246198 A CN 201410246198A CN 104031040 B CN104031040 B CN 104031040B
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- sulfydryl
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- pyridyl thiazole
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 10
- CMHWFELWUFCKOF-UHFFFAOYSA-N 4-(1,3-thiazol-2-yl)-1H-pyridine-2-thione Chemical compound SC1=NC=CC(=C1)C=1SC=CN1 CMHWFELWUFCKOF-UHFFFAOYSA-N 0.000 title claims description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 9
- YNNGZCVDIREDDK-UHFFFAOYSA-N aminocarbamodithioic acid Chemical compound NNC(S)=S YNNGZCVDIREDDK-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 4 pyridyl thiazoles Chemical class 0.000 claims abstract description 4
- 239000012043 crude product Substances 0.000 claims description 12
- 238000010792 warming Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- 125000001246 bromo group Chemical class Br* 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 230000006378 damage Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 150000001649 bromium compounds Chemical group 0.000 abstract description 2
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical class CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WMQUKDQWMMOHSA-UHFFFAOYSA-N 1-pyridin-4-ylethanone Chemical compound CC(=O)C1=CC=NC=C1 WMQUKDQWMMOHSA-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- DCYNAHFAQKMWDW-UHFFFAOYSA-N azane;carbamodithioic acid Chemical class N.NC(S)=S DCYNAHFAQKMWDW-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The synthetic method technical scheme of 2 sulfydryl 4 pyridyl thiazoles of the present invention is to be raw material by 4 acetylpyridines, after bromo-reaction, more directly add ammonium dithiocarbamate reaction obtain 2 sulfydryl 4 pyridyl thiazoles.The method is succinct, efficient, mild condition, and intermediate is bromide, and the most purified, one kettle way obtains target product, can greatly reduce the intermediate harm to human body, and the product purity obtained is high, and productivity is high, is especially suitable for industrialized production.
Description
Technical field
The present invention relates to medicine synthesis technical field, particularly relate to the synthetic method of 2-sulfydryl-4-pyridyl thiazole.
Background technology
CPT is a kind of 5th generation cephalosporins.It is for including methicillin-resistant staphylococcus Fructus Vitis viniferae ball
Bacterium (MRSA) has powerful antibacterial action at interior gram positive bacteria, maintains suitable with nearest several generations cephalosporin
The activity of anti-gram negative bacteria, at present, it just evaluated for treating community acquired pneumonia and compound skin
Soft tissue infection.CPT is by Foresst Laboratories development and production, and by the military field pharmaceutical industries strain formula meeting of Japan
Society provides and authorizes.On October 29th, 2010, CPT obtains U.S. FDA certification, and license is used for treating community acquired pneumonia
And acute bacterial skin infection.
2-sulfydryl-4-pyridyl thiazole is the important intermediate of synthesis CPT, studies its technique synthesized at present
Seldom.4-(acetyl bromide) pyridine hydrobromide salt (such as formula II) has a following synthetic method: world patent Publication No. WO
2010028193, WO 2009158393, WO 2009114552 and WO 2008011557, and Journal of
Medicinal Chemistry, 53(2),787-797;2010 is medium, is all to utilize 4-acetylpyridine (such as formula I), hydrobromic acid
Reacting under organic solvent acetic acid with bromine and obtain, productivity is at 87%-97%..About 2-sulfydryl-4-pyridyl thiazole synthesis
It is disclosed in world patent WO2004060362, utilizes 4-(acetyl bromide) pyridine hydrobromide salt (such as formula II) and dithio base
Reacting 18 hours prepared 2-sulfydryl-4-pyridyl thiazole (such as formula IV) under ammonium formate (such as formula III) room temperature in ethanol, yield is
74%, this response time is long, and productivity is low.
。
Art methods need to be carried out step by step, and two step total recoverys are 64%-72%, intermediate 4-(acetyl bromide) pyridine hydrogen bromine
Hydrochlorate has intense stimulus, the physical and mental health of people is had bigger harm, and the existing method response time is longer, cost
High.
Summary of the invention
The purpose of the present invention is aiming at the defect of above-mentioned existence and provides the synthesis of a kind of 2-sulfydryl-4-pyridyl thiazole
Method.The method is succinct, efficient, mild condition, and intermediate is bromide, and the most purified, one kettle way obtains target product, can be big
The big minimizing intermediate harm to human body, the product purity obtained is more than 99.5%, and productivity is more than 80%, and cost is relatively low,
It is especially suitable for industrialized production.
The synthetic method technical scheme of the 2-sulfydryl-4-pyridyl thiazole of the present invention is to be raw material by 4-acetylpyridine, warp
After bromo-reaction, more directly adding ammonium dithiocarbamate reaction and obtain 2-sulfydryl-4-pyridyl thiazole, synthesis chemical formula is such as
Under:
。
Described bromo-reaction agents useful for same is bromine or pyridinium tribromide.
Preferably, described bromo-reaction agents useful for same is bromine.
Described bromo-reaction solvent is methanol or water.
Preferably, described bromo-reaction solvent is water.
With 4-acetylpyridine as raw material, in water after bromo, it is cooled to 20 DEG C and adds ammonium dithiocarbamate directly below
Reaction obtains 2-sulfydryl-4-pyridyl thiazole.
The synthetic method of a kind of 2-sulfydryl-4-pyridyl thiazole, concrete preparation process is, in 1000mL methanol, adds
60 grams of 4-acetylpyridines, at 10-15 DEG C, after adding 101 gram of 40% hydrobromic acid, slowly 87.9 grams of bromines of dropping, after dropping
After reacting 1 hour at 10-15 DEG C, it is warming up to 30-35 DEG C and reacts 4 hours, after HPLC detection raw material reaction is complete, be cooled to 0 DEG C,
Add 66 grams of ammonium dithiocarbamates, add rear 0 DEG C react 1 hour, then be warming up to 20-25 DEG C reaction 4 hours after, filter,
Obtaining 2-sulfydryl-4-pyridyl thiazole crude product, crude product refluxes 2 hours in water, and cooled and filtered obtains 2-sulfydryl-4-pyridine radicals
Thiazole fine work.
The synthetic method of a kind of 2-sulfydryl-4-pyridyl thiazole, concretely comprises the following steps, and in 1000mL water, adds 60 grams of 4-
Acetylpyridine, at 10-15 DEG C, after adding 101 gram of 40% hydrobromic acid, slowly 87.9 grams of bromines of dropping, after dropping 10-15 DEG C
After lower reaction 1 hour, it is warming up to 30-35 DEG C and reacts 4 hours, after HPLC detection raw material reaction is complete, be cooled to 0 DEG C, add 66
Gram ammonium dithiocarbamate, adds latter 0 DEG C and reacts 1 hour, then after being warming up to 20-25 DEG C of reaction 4 hours, filters, obtain 2-
Sulfydryl-4-pyridyl thiazole crude product, crude product refluxes 2 hours in water, and cooled and filtered obtains 2-sulfydryl-4-pyridyl thiazole essence
Product.
The synthetic method technical scheme that the invention have the benefit that the 2-sulfydryl-4-pyridyl thiazole of the present invention is, by
4-acetylpyridine is raw material, after bromo-reaction, more directly add ammonium dithiocarbamate reaction obtain 2-sulfydryl-4-pyridine radicals
Thiazole.The method is succinct, efficient, mild condition, and intermediate need not purify, and one kettle way obtains target product, and the product obtained is pure
Degree height, productivity is high, and avoids intermediate 4-(acetyl bromide) injury to human body of the pyridine hydrobromide salt, the response time is short,
Low cost, is especially suitable for industrialized production.
Detailed description of the invention:
In order to be more fully understood that the present invention, describe technical scheme in detail with instantiation below, but this
Invention is not limited thereto.
Embodiment 1
In 1000mL methanol, add 60 grams of 4-acetylpyridines, at 10-15 DEG C, after adding 101 gram of 40% hydrobromic acid, slowly
Dripping 87.9 grams of bromines, after reacting 1 hour, be warming up to 30-35 DEG C and react 4 hours after dropping at 10-15 DEG C, HPLC detects
After raw material reaction is complete, it is cooled to 0 DEG C, adds 66 grams of ammonium dithiocarbamates, add latter 0 DEG C and react 1 hour, then be warming up to
After 20-25 DEG C of reaction 4 hours, filtering, obtain 2-sulfydryl-4-pyridyl thiazole crude product 80.7 grams, crude product refluxes 2 little in water
Time, cooled and filtered obtains 2-sulfydryl-4-pyridyl thiazole fine work 78.2 grams, and productivity 80.5%, for front yellow solid, HPLC is pure
Degree is 99.7%.
Embodiment 2
In 1000mL methanol, add 60 grams of 4-acetylpyridines, at 0 DEG C, add 175.9 grams of pyridinium tribromide, add
React 1 hour at latter 0 DEG C, then be warming up to 20-25 DEG C of reaction 2 hours, after HPLC detection raw material reaction is complete, is cooled to 0 DEG C, adds
Enter 66 grams of ammonium dithiocarbamates (2), add rear 0 DEG C react 1 hour, then be warming up to 20-25 DEG C reaction 4 hours after, filter,
Obtaining 2-sulfydryl-4-pyridyl thiazole crude product 80.1 grams, crude product refluxes 2 hours in water, and cooled and filtered obtains 2-sulfydryl-4-
Pyridyl thiazole fine work 77.6 grams, productivity 79.9 %, for front yellow solid, HPLC purity is 99.8%.
Embodiment 3
In 1000mL water, add 60 grams of 4-acetylpyridines, at 10-15 DEG C, after adding 101 gram of 40% hydrobromic acid, slowly drip
Adding 87.9 grams of bromines, after reacting 1 hour, be warming up to 30-35 DEG C and react 4 hours after dropping at 10-15 DEG C, HPLC detection is former
After material reaction completely, it is cooled to 0 DEG C, adds 66 grams of ammonium dithiocarbamates, add latter 0 DEG C and react 1 hour, then be warming up to
After 20-25 DEG C of reaction 4 hours, filtering, obtain 2-sulfydryl-4-pyridyl thiazole crude product 81.7 grams, crude product refluxes 2 little in water
Time, cooled and filtered obtains 2-sulfydryl-4-pyridyl thiazole fine work 80.2 grams, and productivity 82.6%, for light yellow solid, HPLC is pure
Degree is 99.7%.
Claims (1)
1. the synthetic method of a 2-sulfydryl-4-pyridyl thiazole, it is characterised in that in 1000mL water, adds 60 grams of 4-second
Acyl pyridine, at 10-15 DEG C, after adding 101 gram of 40% hydrobromic acid, slowly 87.9 grams of bromines of dropping, after dropping at 10-15 DEG C
After reacting 1 hour, it is warming up to 30-35 DEG C and reacts 4 hours, after HPLC detection raw material reaction is complete, is cooled to 0 DEG C, adds 66 grams
Ammonium dithiocarbamate, add rear 0 DEG C react 1 hour, then be warming up to 20-25 DEG C reaction 4 hours after, filter, obtain 2-mercapto
Base-4-pyridyl thiazole crude product, crude product refluxes 2 hours in water, and cooled and filtered obtains 2-sulfydryl-4-pyridyl thiazole essence
Product.
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| CN201410246198.1A CN104031040B (en) | 2014-06-05 | 2014-06-05 | The synthetic method of 2-sulfydryl-4-pyridyl thiazole |
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| CN104031040B true CN104031040B (en) | 2016-09-14 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105566313A (en) * | 2016-03-22 | 2016-05-11 | 陕西思尔生物科技有限公司 | Synthesis method of ceftaroline fosamil intermediate 4-(4'-pyridyl)-1,3-thiazolyl-2-thiol |
| CN106632001A (en) * | 2016-12-28 | 2017-05-10 | 山东诚汇双达药业有限公司 | Preparation method of 4-(bromoacetyl) pyridine hydrobromide |
| CN107602503A (en) * | 2017-09-22 | 2018-01-19 | 山东金城医药化工有限公司 | The synthetic method of the thiazolyl acetic acid of 2 sulfydryl, 4 methyl 5 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060362A2 (en) * | 2003-01-02 | 2004-07-22 | Millennium Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR INHIBITING TGF-β |
| US20050176776A1 (en) * | 2004-02-06 | 2005-08-11 | Coleman Paul J. | Mitotic kinesin inhibitors |
| CN102558094A (en) * | 2011-11-30 | 2012-07-11 | 浙江工业大学 | Method for preparing ceftaroline side-chain acid |
| WO2013084171A1 (en) * | 2011-12-07 | 2013-06-13 | Ranbaxy Laboratories Limited | Process for preparing ceftaroline salts or hydrates thereof |
-
2014
- 2014-06-05 CN CN201410246198.1A patent/CN104031040B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060362A2 (en) * | 2003-01-02 | 2004-07-22 | Millennium Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR INHIBITING TGF-β |
| US20050176776A1 (en) * | 2004-02-06 | 2005-08-11 | Coleman Paul J. | Mitotic kinesin inhibitors |
| CN102558094A (en) * | 2011-11-30 | 2012-07-11 | 浙江工业大学 | Method for preparing ceftaroline side-chain acid |
| WO2013084171A1 (en) * | 2011-12-07 | 2013-06-13 | Ranbaxy Laboratories Limited | Process for preparing ceftaroline salts or hydrates thereof |
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| CN104031040A (en) | 2014-09-10 |
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Denomination of invention: Synthesis of 2-mercapto-4-pyridyl thiazole Effective date of registration: 20220616 Granted publication date: 20160914 Pledgee: Shandong Pingyuan Rural Commercial Bank Co.,Ltd. Pledgor: SHANDONG CHENGHUI SHUANGDA PHARMACEUTICAL CO.,LTD. Registration number: Y2022980007784 |
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