CN108484581A - A kind of new Candesartan dimer impurity and its synthetic method - Google Patents
A kind of new Candesartan dimer impurity and its synthetic method Download PDFInfo
- Publication number
- CN108484581A CN108484581A CN201810543719.8A CN201810543719A CN108484581A CN 108484581 A CN108484581 A CN 108484581A CN 201810543719 A CN201810543719 A CN 201810543719A CN 108484581 A CN108484581 A CN 108484581A
- Authority
- CN
- China
- Prior art keywords
- formula
- new
- candesartan cilexetil
- dimer impurity
- candesartan
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of new candesartan Cilexetil dimer impurities and preparation method thereof, the present invention has chanced on a kind of new candesartan Cilexetil dimer impurity in process of production, impurity content in the synthesis of trityl group candesartan cilexetil is higher, it has a significant effect to the quality of finished product, and the impurity refining effect is poor in refining step, it is easy to cause the single contaminant overstandard of candesartan Cilexetil, therefore, study the way of production of the impurity, controlled syntheses impurity, to the quality control important in inhibiting of Candesartan bulk pharmaceutical chemicals；The synthetic method of new candesartan Cilexetil dimer impurity provided by the invention has the advantages that reaction step is short, raw material is easy to get, high income, purity are high.
Description
Technical field
The present invention relates to a kind of new Candesartan dimer impurities and its synthetic method.
Background technology
Candesartan Cilexetil is a kind of novel blood-pressure drug, for treating essential hypertension.Its chemistry is entitled (±)-
1- (hexamethylene oxo carbonyl oxo) ethyl-[2- ethyoxyls -1- [[2 '-(1H- tetrazoles base -5) xenyl -4] methyl] -1H- benzene
And imidazoles -7] carboxylate, shown in the following Formula IV of structural formula：
Candesartan Cilexetil trityl candesartan shown in formula IV is original with 1- chloroethene butylcyclohexyl carbonic esters
Material obtains trityl group candesartan cilexetil shown in Formula V, compound V is again through deprotection by condensation reaction under alkaline condition
Reaction removing trityl-protecting group obtains candesartan Cilexetil.
The synthetic route of candesartan Cilexetil is as follows：
Candesartan Cilexetil impurity is particularly important for the research of candesartan Cilexetil, and inventor has chanced on one in production
Kind candesartan Cilexetil dimer impurity, there are no the pertinent literature for disclosing the impurity in the prior art.
Invention content
The technical problem to be solved by the invention for the present situation of prior art is to provide a kind of new candesartan Cilexetils two
Aggressiveness impurity, the impurity are that the research of candesartan Cilexetil further provides condition.
Another technical problem to be solved by this invention is the present situation for the prior art, and it is husky to provide a kind of new candy
The synthetic method of smooth ester dimer impurity.
Technical solution is used by the present invention solves above-mentioned technical problem：A kind of new candesartan Cilexetil dimer is miscellaneous
Matter, it is characterised in that：Structural formula is following formula I,
The compound of formula I1H NMR spectra parameters are：1H NMR(400MHz,DMSO-d6)δ7.7-7.4(m,12H),
7.1 (m, 4H), 6.7 (m, 2H), 5.9 (s, 2H), 5.4 (s, 4H), 4.5 (q, J=6.8Hz, 4H), 1.3 (t, J=6.8Hz,
3H)；13C NMR spectra parameters are：13C NMR(400MHz,DMSO-d6)δ164.4,158.8,142.2,141.1,138.7,
138.6,131.8,130.8,129.3,126.6,123.9,123.1,114.3,80.9,67.2,46.8,14.8；IR parameters are：
IR(KBr,cm-1):3029,2982,2901,1732,1615,1551,1430；ESI-MS m/z 893(M+H+),915(M+Na+),931(M+K+)。
A kind of synthetic method of above-mentioned new candesartan Cilexetil dimer impurity, it is characterised in that：Include the following steps
(1) trityl candesartan shown in following formula I V is reacted to generate with chlorosulfonic acid chloromethyl ester and be changed shown in Formula Il I
Close object；
(2) formula III compound is reacted with trityl candesartan shown in Formula IV generates Formula Il compound represented；
(3) it is miscellaneous to obtain Candesartan dimer shown in following formula I for Formula II compound represented removing trityl-protecting group
Matter, the compound of formula I are target product,
The reaction condition of step (1) is：Using dichloromethane and water as reaction medium, using 4-butyl ammonium hydrogen sulfate as phase transfer
Catalyst, using sodium bicarbonate as acid binding agent.
The reaction solution branch vibration layer of step (1) is obtained into dichloromethane layer, dichloromethane layer is washed and crosses silica gel post separation
Purifying obtains formula III compound.
The reaction condition of step (2) is：Using n,N-Dimethylformamide as reaction medium, using potassium carbonate as acid binding agent, instead
It is 40-55 DEG C to answer temperature.
Step (2) is down to room temperature after completion of the reaction, and water, dichloromethane extraction is added, separates dichloromethane layer, then through water
It washes, be concentrated to give Formula II compound.
The reaction condition of step (3) is：Using methanol and dichloromethane as reaction medium, in the presence of anhydrous zinc chloride.
Step (3) is after completion of the reaction plus water quenching is gone out reaction, is then layered, the organic layer separated through drying, be concentrated to give Formulas I
Compound.
Compared with the prior art, the advantages of the present invention are as follows：The present invention has chanced on a kind of new in process of production
Candesartan Cilexetil dimer impurity, impurity content in the synthesis of trityl group candesartan cilexetil is higher, to the quality of finished product
It has a significant effect, and the impurity refining effect is poor in refining step, is easy to cause the single contaminant overstandard of candesartan Cilexetil, because
This, studies the way of production of the impurity, and the controlled syntheses impurity has important meaning to the quality control of Candesartan bulk pharmaceutical chemicals
Justice；The synthetic method of new candesartan Cilexetil dimer impurity provided by the invention, with reaction step is short, raw material is easy to get, receives
The advantage that rate is high, purity is high.
Description of the drawings
Fig. 1 is the ESI-MS collection of illustrative plates of candesartan Cilexetil dimer impurity shown in Formulas I in the embodiment of the present invention；
Fig. 2 is the IR collection of illustrative plates of candesartan Cilexetil dimer impurity shown in Formulas I in the embodiment of the present invention；
Fig. 3 is candesartan Cilexetil dimer impurity shown in Formulas I in the embodiment of the present invention1H NMR spectras；
Fig. 4 is candesartan Cilexetil dimer impurity shown in Formulas I in the embodiment of the present invention13C NMR spectras；
Fig. 5 is the ESI-MS collection of illustrative plates of candesartan Cilexetil dimer impurity shown in formula III in the embodiment of the present invention；
Fig. 6 is the IR collection of illustrative plates of candesartan Cilexetil dimer impurity shown in formula III in the embodiment of the present invention；
Fig. 7 is candesartan Cilexetil dimer impurity shown in formula III in the embodiment of the present invention1H NMR spectras；
Fig. 8 is candesartan Cilexetil dimer impurity shown in formula III in the embodiment of the present invention13C NMR spectras；
Fig. 9 is the ESI-MS collection of illustrative plates of candesartan Cilexetil dimer impurity shown in Formula II in the embodiment of the present invention；
Figure 10 is the IR collection of illustrative plates of candesartan Cilexetil dimer impurity shown in Formula II in the embodiment of the present invention；
Figure 11 is candesartan Cilexetil dimer impurity shown in Formula II in the embodiment of the present invention1H NMR spectras；
Figure 12 is candesartan Cilexetil dimer impurity shown in Formula II in the embodiment of the present invention13C NMR spectras.
Specific implementation mode
Below in conjunction with attached drawing embodiment, present invention is further described in detail.
The new candesartan Cilexetil dimer impurity structural formula of the present invention is following formula I,
The synthetic method of new candesartan Cilexetil dimer impurity is as follows in the present embodiment：
(1) 3.5g trityl candesartans (formula IV) and 35mL dichloromethane, stirring are added into 250mL reaction bulbs makes
Dissolving, add 35mL water, 0.17g 4-butyl ammonium hydrogen sulfates and 2.5g sodium bicarbonates, stir, then be slowly added into 1.0g chlorine sulphurs
Reaction 30 minutes is stirred at room temperature in sour chloromethyl ester.Layering, dichloromethane layer are concentrated under reduced pressure after being washed with 25mL and are evaporated, and obtain solid mistake
Silica gel column purification, with ethyl acetate and n-hexane volume ratio 1:4 be eluant, eluent, and concentration is dry after collecting target components, obtains 3.0g
White solid powder compound III, yield 80%.Such as the characterize data that Fig. 5~8 are compound III, wherein1H NMR
(400MHz,DMSO-d6)δ7.8-7.7(m,2H),7.5-7.4(m,3H),7.3-7.2(m,11H),6.9-6.7(m,10H),
5.8 (s, 2H), 5.4 (s, 2H), 4.5 (q, J=7.0Hz, 2H), 1.3 (t, J=7.0Hz)；13C NMR(400MHz,DMSO-d6)
δ163.8,158.8,142.2,141.4,141.2,139.5,135.9,131.8,131.0,130.8,130.7,129.9,
129.5,128.6,128.2,126.5,126.0,123.9,123.3,121.5,114.0,82.7,70.4,67.2,46.9,
14.7；IR(KBr,cm-1):2959,2918,2849,1752,1616,1583,1459；ESI-MS m/z 753(M+Na+),
769(M+K+)。
(2) 2.0g compound III and 40mLDMF are added into 100mL reaction flasks, adds 1.2g potassium carbonate powders.
It is heated to 45-50 DEG C of reaction overnight.It is cooled to room temperature after reaction, 20mL water and the stirring of 20mL dichloromethane is added, uses 1M
Hydrochloric acid tune pH to 6.5-7.0 is then allowed to stand layering, separates organic layer and is dried with anhydrous magnesium sulfate, and concentration obtains 4.5g solids,
3.6g white solid powder compound II, yield 95.7% are obtained after re-crystallizing in ethyl acetate is added.If Fig. 9~12 are compound
The characterize data of II, wherein1H NMR (400MHz, DMSO-d6) δ 7.7 (d, J=7.0Hz, 2H), 7.6 (d, J=7.0Hz,
2H), 7.4 (m, 5H), 7.3-7.2 (m, 20H), 7.0 (t, J=7.8Hz, 2H), 6.9 (d, J=7.5Hz, 2H), 6.8 (d, J=
7.5Hz, 11H), 6.6 (q, J=8.4MHz, 8H), 5.9 (s, 2H), 5.4 (s, 4H), 4.5 (q, J=7.0MHz, 4H), 1.2 (t,
J=7.0MHz, 3H)；13C NMR(400MHz,DMSO-d6)δ167.4,167.3,166.7,161.7,145.1,144.1,
142.4,138.8,134.8,133.5,132.9,132.3,131.6,131.1,129.4,128.8,126.9,124.2,
117.1,85.6,73.2,70.4,17.7；IR(KBr,cm-1):2978,2957,1723,1617,1552,1460,1426；
ESI-MS m/z 1377(M+H+),1399(M+Na+),1416(M+K+)。
(3) 36mL methanol and 12mL dichloromethane are added in 100mL reaction bulbs, 3.2g compound II is added, add
0.3g anhydrous zinc chlorides.It is added to back flow reaction 4 hours, 10ml water quenchings is added after being cooled to room temperature and go out reaction, then separate organic
Layer, concentration is dry to obtain grease, solid is obtained by filtration followed by being added after 20mL methyl tertiary butyl ether(MTBE)s stir 1 hour, solid is used
Isopropyl acetate recrystallizes, dry, obtains 1.0g candesartan Cilexetil dimer impurity I, is white powder, yield 50%.Such as Fig. 1
~4 be the characterize data of compound I, wherein as shown in Figure 1, ESI-MS m/z893 (M+H+), 915 (M+Na+),931(M+K+)；As shown in Fig. 2, IR (KBr, cm-1):3029,2982,2901,1732,1615,1551,1430；As shown in figure 3,1H NMR
(400MHz,DMSO-d6)δ7.7-7.4(m,12H),7.1(m,4H),6.7(m,2H),5.9(s,2H),5.4(s,4H),4.5
(q, J=6.8Hz, 4H), 1.3 (t, J=6.8Hz, 3H)；As shown in figure 4,13C NMR(400MHz,DMSO-d6)δ164.4,
158.8,142.2,141.1,138.7,138.6,131.8,130.8,129.3,126.6,123.9,123.1,114.3,80.9,
67.2,46.8,14.8。
Claims (9)
1. a kind of new candesartan Cilexetil dimer impurity, it is characterised in that：Structural formula is following formula I,
2. new candesartan Cilexetil dimer impurity according to claim 1, it is characterised in that：The compound of formula I1H
NMR spectra parameter is：1H NMR(400MHz,DMSO-d6)δ7.7-7.4(m,12H),7.1(m,4H),6.7(m,2H),5.9
(s, 2H), 5.4 (s, 4H), 4.5 (q, J=6.8Hz, 4H), 1.3 (t, J=6.8Hz, 3H)；13C NMR spectra parameters are：13C
NMR(400MHz,DMSO-d6)δ164.4,158.8,142.2,141.1,138.7,138.6,131.8,130.8,129.3,
126.6,123.9,123.1,114.3,80.9,67.2,46.8,14.8；IR parameters are：IR(KBr,cm-1):3029,2982,
2901,1732,1615,1551,1430；ESI-MS m/z 893(M+H+),915(M+Na+),931(M+K+)。
3. the synthetic method of new candesartan Cilexetil dimer impurity described in a kind of claims 1 or 2, it is characterised in that：Including
Following steps
(1) trityl candesartan shown in following formula I V is reacted with chlorosulfonic acid chloromethyl ester generates Formula Il I compounds represented；
(2) formula III compound is reacted with trityl candesartan shown in Formula IV generates Formula Il compound represented；
(3) Formula II compound represented removing trityl-protecting group obtains Candesartan dimer impurity shown in following formula I, should
Compound of formula I is target product,
4. the synthetic method of new candesartan Cilexetil dimer impurity according to claim 3, it is characterised in that：Step
(1) reaction condition is：Using dichloromethane and water as reaction medium, using 4-butyl ammonium hydrogen sulfate as phase transfer catalyst, with carbon
Sour hydrogen sodium is acid binding agent.
5. the synthetic method of new candesartan Cilexetil dimer impurity according to claim 4, it is characterised in that：By step
(1) reaction solution branch vibration layer obtains dichloromethane layer, and dichloromethane layer, which is washed and crosses silica gel column separating purification, obtains formula III
Close object.
6. the synthetic method of new candesartan Cilexetil dimer impurity according to claim 3, it is characterised in that：Step
(2) reaction condition is：Using n,N-Dimethylformamide as reaction medium, using potassium carbonate as acid binding agent, reaction temperature 40-55
℃。
7. the synthetic method of new candesartan Cilexetil dimer impurity according to claim 6, it is characterised in that：Step
(2) it is down to room temperature after completion of the reaction, water, dichloromethane extraction is added, separates dichloromethane layer, then through washing, being concentrated to give formula
II compounds.
8. the synthetic method of new candesartan Cilexetil dimer impurity according to claim 3, it is characterised in that：Step
(3) reaction condition is：Using methanol and dichloromethane as reaction medium, in the presence of anhydrous zinc chloride.
9. the synthetic method of new candesartan Cilexetil dimer impurity according to claim 8, it is characterised in that：Step
(3) after completion of the reaction plus water quenching is gone out reaction, be then layered, the organic layer separated through drying, be concentrated to give compound of formula I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810543719.8A CN108484581A (en) | 2018-05-29 | 2018-05-29 | A kind of new Candesartan dimer impurity and its synthetic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810543719.8A CN108484581A (en) | 2018-05-29 | 2018-05-29 | A kind of new Candesartan dimer impurity and its synthetic method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108484581A true CN108484581A (en) | 2018-09-04 |
Family
ID=63351371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810543719.8A Pending CN108484581A (en) | 2018-05-29 | 2018-05-29 | A kind of new Candesartan dimer impurity and its synthetic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108484581A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004223A (en) * | 2020-03-11 | 2020-04-14 | 长沙晨辰医药科技有限公司 | Preparation and separation method of olmesartan medoxomil dimer impurities |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702176A (en) * | 2012-06-05 | 2012-10-03 | 江西同和药业有限责任公司 | Preparation method for triphenyl candesartan |
| CN103396408A (en) * | 2013-08-13 | 2013-11-20 | 河南华商药业有限公司 | Preparation method of impurity B in candesartan cilexetil |
-
2018
- 2018-05-29 CN CN201810543719.8A patent/CN108484581A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702176A (en) * | 2012-06-05 | 2012-10-03 | 江西同和药业有限责任公司 | Preparation method for triphenyl candesartan |
| CN103396408A (en) * | 2013-08-13 | 2013-11-20 | 河南华商药业有限公司 | Preparation method of impurity B in candesartan cilexetil |
Non-Patent Citations (2)
| Title |
|---|
| BHANU RAMAN ET AL.: "Investigation and structural elucidation of a process related impurity in candesartan cilexetil by LC/ESI-ITMS and NMR", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 蔡鹏俊等: "几种沙坦类药物的杂质谱研究现状", 《药物分析杂质》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004223A (en) * | 2020-03-11 | 2020-04-14 | 长沙晨辰医药科技有限公司 | Preparation and separation method of olmesartan medoxomil dimer impurities |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102766185B (en) | Method for respectively recovering ursodesoxycholic acid and chenodeoxycholic acid from ursodesoxycholic acid waste mother liquor | |
| CN114315534A (en) | Preparation method of dapagliflozin intermediate | |
| CN108484581A (en) | A kind of new Candesartan dimer impurity and its synthetic method | |
| CN106946722A (en) | A kind of deuterium exchanges synthesis L aspartic acids（3,3‑D2）Method | |
| CN103864802A (en) | Preparation method of high-purity asenapine maleate | |
| CN111440154A (en) | Synthetic method of tegaserod dimer impurity | |
| CN116606236A (en) | Synthesis method of 6-benzyloxy tryptophan | |
| JPH1045656A (en) | Production of fluorene derivative | |
| CN106565581B (en) | The comprehensive reutilization method of mixed salt containing lithium in a kind of polyphenylene sulfide production process | |
| CN103497120A (en) | Process for synthesizing diatrizoic acid by using solid-phase load method | |
| CN107001250A (en) | It is a kind of to prepare the method that Ao Dangka replaces intermediate | |
| CN111454214B (en) | Synthetic method of 2-methoxy-1-pyrimidineethylamine hydrochloride | |
| CN111320664A (en) | Preparation method of 24-cholenenoic acid ethyl ester | |
| CN101492388A (en) | Method for synthesis of Miqujing medicament material | |
| CN111533699B (en) | Synthesis method of 2- (trifluoromethyl) pyrimidine-5-alcohol | |
| CN115872882B (en) | Synthesis method of 3-chloro-alanine | |
| CN114380729B (en) | Preparation method of high-purity vildagliptin | |
| CN117800906A (en) | Synthesis method of 5-cyano-2-methoxy nicotinic acid | |
| JP4895510B2 (en) | Method for producing variolamine | |
| CN113801082B (en) | Preparation method of ranimivir octoate | |
| CN108424372A (en) | The purifying process of 2,2,2- tri- fluoro- N- [(S) -4- carbonyl naphthane -1- bases]-acetamides | |
| CN107721954A (en) | The novel preparation method of the benzofuranacetic acid of 2,3 dihydro of darifenacin intermediate 5 | |
| CN117447459A (en) | Method for synthesizing rotigorskite key intermediate by using chiral phase transfer catalyst as catalyst | |
| CN115109077A (en) | Preparation method of Reidesciclovir intermediate | |
| CN117800863A (en) | Preparation method of 2, 2-bis [3- (3-nitro-benzamido) -4-hydroxyphenyl ] hexafluoropropane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180904 |