CN102875453B - A kind of preparation method of the pyridine medical intermediate for the synthesis of anticancer assisted class medicine - Google Patents
A kind of preparation method of the pyridine medical intermediate for the synthesis of anticancer assisted class medicine Download PDFInfo
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title claims abstract description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 17
- SMTKGMYGLYWNDL-UHFFFAOYSA-N 2-bromo-3-chloro-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CN=C(Br)C(Cl)=C1 SMTKGMYGLYWNDL-UHFFFAOYSA-N 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims abstract description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 chloro-5-trifluoromethyl-2 hydroxy pyrimidine Chemical compound 0.000 claims abstract description 8
- 238000000605 extraction Methods 0.000 claims abstract description 8
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000013019 agitation Methods 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- QHMQWEPBXSHHLH-UHFFFAOYSA-N sulfur tetrafluoride Chemical compound FS(F)(F)F QHMQWEPBXSHHLH-UHFFFAOYSA-N 0.000 claims abstract description 7
- BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000001556 precipitation Methods 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 3
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 5
- BJBLBYLZKIVDFZ-UHFFFAOYSA-N ClN1C(N=CC(=C1)C(F)(F)F)O Chemical compound ClN1C(N=CC(=C1)C(F)(F)F)O BJBLBYLZKIVDFZ-UHFFFAOYSA-N 0.000 claims description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002209 hydrophobic effect Effects 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000005304 joining Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QFSVCKPZRHZALP-CTQIIAAMSA-N CC([C@H]1C(CN)C(F)(F)F)C1Cl Chemical compound CC([C@H]1C(CN)C(F)(F)F)C1Cl QFSVCKPZRHZALP-CTQIIAAMSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000003260 anti-sepsis Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Abstract
The present invention relates to medicinal chemistry arts, disclose the synthetic method of the bromo-3-chloro-5-trifluoromethylpyridine of a kind of pyridine medical intermediate 2-for the synthesis of anticancer assisted class medicine, step is: (1) 6-hydroxy niacin and hydrofluoric acid, sulfur tetrafluoride 100 ~ 120 DEG C, react under 0.1 ~ 0.3MPa pressure, add water and obtain 2-hydroxyl-5-5-flumethiazine; (2) react with N-chlorosuccinimide, obtain the chloro-5-trifluoromethyl-2 hydroxy pyrimidine of 3-with water precipitation; (3) add excessive tribromo oxygen phosphorus, 145 ~ 160 DEG C are reacted 5 ~ 8 hours;-5 ~ 0 DEG C of high degree of agitation after cooling, merges organic phase after extraction, dry, filter, be spin-dried for and use silica column purification.The method raw material is easy to get, and the lower applicable suitability for industrialized production of cost, productive rate is more than 38%.
Description
Technical field
The present invention relates to medicinal chemistry arts, be specially a kind of synthetic method of the pyridine medical intermediate for the synthesis of anticancer assisted class medicine, more particularly, the synthetic method of the bromo-3-chloro-5-trifluoromethylpyridine of 2-.
Background technology
Along with the development of medicament research and development technology and the expansion of searching medicine scope, increasing medicine contains the structure of pyridine ring; Therefore the pyridine intermediate of being correlated with is as the important component part introducing pyridine ring, receives increasing attention, wide market.
The bromo-3-chloro-5-trifluoromethylpyridine of 2-(CAS 75806-84-7), structure is such as formula shown in I:
Formula I
2-bromo-3-chloro-5-trifluoromethylpyridine is a kind of pyridine intermediate, there are trifluoromethyl and bromine two active groups (structure is such as formula shown in I), be useful in a lot of drug patent or document, a kind of intermediate for the synthesis of medicines such as antisepsis and anti-inflammations, and for the synthesis of the medicine of anticancer assisting therapy.But the synthetic route of itself and technique seldom have document or patent report, and price is higher.
Summary of the invention
The present invention aims to provide a kind of preparation method of the pyridine medical intermediate for the synthesis of anticancer assisted class medicine, i.e. the synthetic method of the bromo-3-chloro-5-trifluoromethylpyridine of pyridine intermediate 2-.
Technical scheme is, the preparation method of the bromo-3-chloro-5-trifluoromethylpyridine of this pyridine medical intermediate 2-comprises the steps:
(1) 6-hydroxy niacin and hydrofluoric acid, sulfur tetrafluoride are heated to 100 ~ 120 DEG C in confined conditions, under the pressure of 0.1 ~ 0.3MPa, and reaction 10 ~ 14hr; Products therefrom adds water after removing hydrogen fluoride, and pH regulator to neutral (6 ~ 8), and obtains 2-hydroxyl-5-5-flumethiazine with organic solvent I extraction;
(2) 2-hydroxyl-5-5-flumethiazine and N-chlorosuccinimide join in organic solvent II, react 6 ~ 10 hours at normal temperature and under agitation condition; Again reactant is mixed with water, get precipitation and obtain the chloro-5-trifluoromethyl-2 hydroxy pyrimidine of 3-;
(3) 3-chloro-5-trifluoromethyl-2 hydroxy pyrimidine joins in excessive tribromo oxygen phosphorus, and 145 ~ 160 DEG C are reacted 5 ~ 8 hours; Join after reactant being cooled to normal temperature in frozen water ,-5 ~ 0 DEG C and high degree of agitation (50 ~ 800rpm) 40 minutes ~ 2 hours, with organic solvent II I extraction 2 ~ 5 times; Merge organic phase.
Preferably, organic solvent I is chloroform in step (1), and the mol ratio of 6-hydroxy niacin and hydrofluoric acid, sulfur tetrafluoride is 1:1 ~ 1.2:3 ~ 3.6.
Organic solvent II in step (2) is hydrophobic solvent, is preferably methylene dichloride, ethyl acetate.2-hydroxyl-5-5-flumethiazine and N-succimide mol ratio are 1:1 ~ 1.3.
In step (3), the chloro-5-trifluoromethyl-2 hydroxy pyrimidine of 3-and tribromo oxygen phosphorus amount ratio are 0.1 ~ 1mol/L.
In step (3) by merge the organic phase that obtains dry, filter, be spin-dried for the thick product obtained and cross silica column purification, with methylene chloride/methanol system gradient elution.Condition of gradient elution: the wash-out concentration of methylene dichloride and methyl alcohol is 100:1 ~ 20:1.
Synthetic method of the present invention, reactions steps is such as formula shown in II:
Formula II
Method of the present invention, with 6-hydroxy niacin for raw material, first replaces carboxyl with trifluoromethyl, obtains 2-hydroxyl-5-5-flumethiazine; Replace hydrogen atom with chlorine again and obtain the chloro-5-trifluoromethyl-2 hydroxy pyrimidine of 3-; Then use bromine substituted hydroxy, obtain the bromo-3-chloro-5-trifluoromethylpyridine of 2-.The productive rate of the method is more than 38%.
The method raw material is easy to get, the lower applicable suitability for industrialized production of cost.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic spectrogram of embodiment 1 product.
Embodiment
Embodiment 1
(1) by 0.13mol6-hydroxy niacin (18.2 grams), anhydrous hydrofluoric acid 2.6 milliliters of (more than concentration 95wt%) (0.13mol), sulfur tetrafluoride 42.1 grams (0.39mol) to join in the vexed tank of stainless steel pressure and is heated to 100 DEG C, react 12 hours under 0.15MPa, gaseous product device for absorbing tail gas process.
Resultant product is transferred in polytetrafluoroethylcontainer container, be heated to 40 DEG C, remove the hydrogen fluoride of trace.Products therefrom is joined in 150 ml waters, by saturated sodium carbonate solution adjust ph 6.8 ~ 7.2, and with chloroform extraction, drying, filter, be spin-dried for and obtain 2-hydroxyl-5-5-flumethiazine 15.3 grams (0.094mol), yield 72%.
(2) 0.094mol2-hydroxyl-5-5-flumethiazine (15.3 grams) and 14.4 grams of N-chlorosuccinimides (0.108mol) are joined in 50 milliliters of dry DMF/nitrogen methyl-2-pyrrolidone, react 8 hours at normal temperature and under agitation condition.Reactant is slowly joined in 250 ml waters, has pale yellow precipitate to separate out.Gained precipitation will be filtered, dry the chloro-5-trifluoromethyl-2 hydroxy pyrimidine 17.1 grams (0.087mol) of 3-, yield 92%.
(3) chloro-for 0.087mol3-5-trifluoromethyl-2 pyridone (17.1 grams) joined in 150 milliliters of tribromo oxygen phosphorus, temperature of reaction is risen to 150 degrees Celsius, the reaction times is 6 hours.Reactant is cooled to normal temperature slowly carefully joining in frozen water ,-5 ~ 0 DEG C, 200rpm high degree of agitation 1 hour, by gained mixture dichloromethane extraction three times.Extracted organic phase is merged, dry, filter, be spin-dried for and obtain thick product.Thick product being crossed silicagel column methylene chloride-methanol as eluent is gradient elution (volume ratio 100:1 ~ 20:1), and obtain 2-bromo-3-chloro-5-trifluoromethylpyridine 13.1 grams (0.05mol), yield is 58%.
As shown in Figure 1, checking products obtained therefrom is the bromo-3-chloro-5-trifluoromethylpyridine of 2-to the nuclear magnetic spectrogram of products therefrom.The total recovery of above-mentioned reaction is 38.4%.
Embodiment 2
(1) 0.15mol6-hydroxy niacin, anhydrous hydrofluoric acid (content 0.16mol), sulfur tetrafluoride 0.5mol to be joined in the vexed tank of stainless steel pressure and to be heated to 120 DEG C, reacting 12 hours at 0.2 mpa; Gaseous product device for absorbing tail gas process.Resultant product is transferred in polytetrafluoroethylcontainer container, be heated to about 40 DEG C, remove the hydrogen fluoride of trace.Products therefrom is joined in 150 ml waters, by saturated sodium carbonate solution adjust ph 6.5 ~ 7.4, and with chloroform extraction, drying, filter, be spin-dried for and obtain 2-hydroxyl-5-5-flumethiazine 17.8 grams (0.109mol), yield 72.6%.
(2) 17.8 grams of 2-hydroxyl-5-5-flumethiazines and 0.12molN-chlorosuccinimide (133.54 mol ratios are 1:1.1 ~ 1.3) are joined in 50 milliliters of dry DMF/nitrogen methyl-2-pyrrolidone.Reactant is slowly joined in 250 ml waters, has pale yellow precipitate to separate out.To filter gained precipitation, dry the chloro-5-trifluoromethyl-2 hydroxy pyrimidine 19.5 grams (0.099mol) of 3-, yield is 91%.
(3) 19.5 grams of 3-chloro-5-trifluoromethyls-2 pyridone (163.0973) are joined in 150 milliliters of tribromo oxygen phosphorus, temperature of reaction is risen to 155 degrees Celsius of reactions 7 hours.Reactant is cooled to normal temperature slowly carefully joining in frozen water ,-5 ~ 0 DEG C, 500rpm high degree of agitation 1 hour, be extracted with ethyl acetate three times by gained mixture.Extracted organic phase is merged, dry, filter, be spin-dried for and obtain thick product.Thick product is crossed silicagel column, and by methylene chloride/methanol system as eluent, gradient elution (volume ratio 100:1 ~ 20:1) obtains the bromo-3-chloro-5-trifluoromethylpyridine of 2-13.1 grams, and yield is 58.1%.
Product empirical tests be the bromo-3-chloro-5-trifluoromethylpyridine of 2-, the total recovery of above-mentioned reaction is 38.3%.
Embodiment 3
(1) embodiment 1 or the obtained bromo-3-chloro-5-trifluoromethylpyridine of 2-of embodiment 2, record according to US2009/186879A1, for the preparation of compd A 1, reaction formula is as follows:
Wherein compd A 1 has good pharmaceutical activity, can be used for anticancer ancillary drug.
(2) embodiment 1 or the obtained bromo-3-chloro-5-trifluoromethylpyridine of 2-of embodiment 2, according to the record of WO2005/4606, prepare compd A 2, reaction formula is as follows:
Wherein, compd A 2 has good antimycotic bacterium and anti-infection activity, can be used for anticancer ancillary drug.
Claims (3)
1., for the synthesis of a preparation method for the pyridine medical intermediate of anticancer assisted class medicine, the described pyridine medical intermediate for the synthesis of anticancer assisted class medicine is the bromo-3-chloro-5-trifluoromethylpyridine of 2-, it is characterized in that, comprises the steps:
(1) 6-hydroxy niacin and hydrofluoric acid, sulfur tetrafluoride be heated to 100 ~ 120 DEG C in confined conditions, press 0.1 ~ 0.3MPa pressure under react 10 ~ 14hr; Products therefrom adds water after removing HF, and pH regulator to neutral, and obtains 2-hydroxyl-5-5-flumethiazine with organic solvent I extraction; The mol ratio of described 6-hydroxy niacin and hydrofluoric acid, sulfur tetrafluoride is 1:1 ~ 1.2:3 ~ 3.6;
(2) 2-hydroxyl-5-5-flumethiazine and N-chlorosuccinimide join in organic solvent II, react 6 ~ 10 hours; Again reactant is mixed with water, get precipitation and obtain the chloro-5-trifluoromethyl-2 hydroxy pyrimidine of 3-; Organic solvent II is hydrophobic solvent; 2-hydroxyl-5-5-flumethiazine and N-succimide mol ratio are 1:1 ~ 1.3;
(3) 3-chloro-5-trifluoromethyl-2 hydroxy pyrimidine joins in excessive tribromo oxygen phosphorus, and 145 ~ 160 DEG C are reacted 5 ~ 8 hours; The chloro-5-trifluoromethyl-2 hydroxy pyrimidine of 3-and tribromo oxygen phosphorus amount ratio are 0.1 ~ 1mol/L; Join in frozen water after reactant being cooled to normal temperature, and with the speed high degree of agitation 40 minutes ~ 2 hours of 50 ~ 800rpm, with organic solvent II I extraction 2 ~ 5 times; Merge organic phase;
By dry for the organic phase obtained, filter, be spin-dried for the thick product obtained and cross silica column purification, with methylene chloride-methanol system gradient elution.
2. described in claim 1 for the synthesis of the preparation method of the pyridine medical intermediate of anticancer assisted class medicine, it is characterized in that, organic solvent I is chloroform in step (1).
3. described in claim 1 for the synthesis of the preparation method of the pyridine medical intermediate of anticancer assisted class medicine, it is characterized in that, in step (2), described organic solvent II is methylene dichloride or ethyl acetate.
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| CN103601671B (en) * | 2013-10-22 | 2016-08-17 | 上海泰坦科技股份有限公司 | The preparation method of iodo trifluoro methyl pyridine |
| CN107840828B (en) * | 2017-12-14 | 2020-11-03 | 金凯(辽宁)化工有限公司 | Synthesis method of 2-chloro-5-trifluoromethylpyrazine |
| CN110117217B (en) * | 2018-12-19 | 2021-09-28 | 浙江普洛家园药业有限公司 | Preparation method of 1-bromomethyl-2, 3,5, 6-tetrafluoro-4- (trifluoromethyl) benzene |
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|---|---|---|---|---|
| US4230864A (en) * | 1979-01-29 | 1980-10-28 | Reilly Tar & Chemical Corp. | Process for making 5-trifluoromethyl pyridone |
| JPS56115776A (en) * | 1980-02-20 | 1981-09-11 | Ishihara Sangyo Kaisha Ltd | Preparation of 2-bromo-trifluoromethylpyridine |
| US4546191A (en) * | 1979-03-19 | 1985-10-08 | Ishihara Sangyo Kaisha Ltd. | Trifluoromethyl-2-pyridinone or pyridinthione compounds and process for the preparation of the same |
| CN1263094A (en) * | 1999-12-29 | 2000-08-16 | 中国科学院上海有机化学研究所 | Method for synthesizing 4-trifluoromethyl pyridine compound |
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2012
- 2012-06-08 CN CN201210189379.6A patent/CN102875453B/en active Active
Patent Citations (4)
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|---|---|---|---|---|
| US4230864A (en) * | 1979-01-29 | 1980-10-28 | Reilly Tar & Chemical Corp. | Process for making 5-trifluoromethyl pyridone |
| US4546191A (en) * | 1979-03-19 | 1985-10-08 | Ishihara Sangyo Kaisha Ltd. | Trifluoromethyl-2-pyridinone or pyridinthione compounds and process for the preparation of the same |
| JPS56115776A (en) * | 1980-02-20 | 1981-09-11 | Ishihara Sangyo Kaisha Ltd | Preparation of 2-bromo-trifluoromethylpyridine |
| CN1263094A (en) * | 1999-12-29 | 2000-08-16 | 中国科学院上海有机化学研究所 | Method for synthesizing 4-trifluoromethyl pyridine compound |
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Address after: 200235 Qinzhou Road, Xuhui District, No. 100, building No. 1110, room Patentee after: SHANGHAI TITAN TECHNOLOGY Co.,Ltd. Address before: 200235, building 1, building 100, No. 10, Qinzhou Road, Shanghai, Xuhui District Patentee before: Shanghai Titan Chemical Co.,Ltd. |
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Denomination of invention: A preparation method of pyridine pharmaceutical intermediates for the synthesis of anticancer auxiliary drugs Effective date of registration: 20220615 Granted publication date: 20160203 Pledgee: The Bank of Shanghai branch Caohejing Limited by Share Ltd. Pledgor: SHANGHAI TITAN TECHNOLOGY Co.,Ltd. Registration number: Y2022310000059 |
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Denomination of invention: A preparation method for pyridine pharmaceutical intermediates used in the synthesis of anticancer adjuvant drugs Effective date of registration: 20230829 Granted publication date: 20160203 Pledgee: The Bank of Shanghai branch Caohejing Limited by Share Ltd. Pledgor: SHANGHAI TITAN TECHNOLOGY Co.,Ltd. Registration number: Y2023310000500 |
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