CN101298447B - Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol - Google Patents
Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol Download PDFInfo
- Publication number
- CN101298447B CN101298447B CN2008101227426A CN200810122742A CN101298447B CN 101298447 B CN101298447 B CN 101298447B CN 2008101227426 A CN2008101227426 A CN 2008101227426A CN 200810122742 A CN200810122742 A CN 200810122742A CN 101298447 B CN101298447 B CN 101298447B
- Authority
- CN
- China
- Prior art keywords
- methyl
- chloro
- benzyloxy
- ethyl
- benzoic 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.)
- Expired - Fee Related
Links
- UOWGLBYIKHMCIS-HNNXBMFYSA-N CC(C)C[C@@H](c(ccc(Oc(c(CO1)cc(C)c2)c2O)c2C1=O)c2OC)O Chemical compound CC(C)C[C@@H](c(ccc(Oc(c(CO1)cc(C)c2)c2O)c2C1=O)c2OC)O UOWGLBYIKHMCIS-HNNXBMFYSA-N 0.000 description 1
- FBTRVJZJFOHHLE-UHFFFAOYSA-N CCc(c(C)c(c(CO)c1O)Cl)c1OCc1ccccc1 Chemical compound CCc(c(C)c(c(CO)c1O)Cl)c1OCc1ccccc1 FBTRVJZJFOHHLE-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
A synthetic method of 2-benzyloxy-3-ethide-4-methyl-5-chlorin-6-[(tetrahydrophthalic anhydride-2H-pyrans-2-oxyl)methyl] phenol belongs to the technical field of medical synthesis which prepares the 2-benzyloxy-3-ethide-4-methyl-5-chlorin-6-[(tetrahydrophthalic anhydride-2H-pyrrole-2-oxyl)methyl] phenol by five reaction steps and taking 2-hydroxide radical-3-benzyloxy-3-ethide-4-methyl-5-chlorin-6-chlorobenzoic acid as initial material. The 2-benzyloxy-3-ethide-4-methyl-5-chlorin-6-[(tetrahydrophthalic anhydride -2H-pyrrole-2-oxyl)methyl] phenol prepared by the invention is used for synthesizing dibenzo dioxide octanone compounds and has the effects of improving the synthetic ratio and reducing the synthesizing cost.
Description
Technical field
The invention belongs to medical synthesis technical field, relate to the new key intermediate synthesis preparation method of dibenzo dioxy octanone compounds of formula (I).
Background technology
The dibenzo dioxy octanone compounds is separated from natural product by Sassa T. first and obtains, and called after Penicillide (the 11-hydroxyl-3-[(1S)-1-hydroxy-3-methyl butyl]-4-methoxyl group-9-methyl-5H, 7H-dibenzo [b, g] [1,5] dioxy octane-5-ketone (Tetrahedron Letter 1974,15,45,3941-3942).
By the high-throughput screening active ingredients, find that the dibenzo dioxy octanone compounds is a kind of brand-new cholesterol transferase inhibitor (CETP), can selectivity high density lipoprotein increasing cholesterol, can treat cardiovascular system diseases such as coronary heart disease.Beyer Co., Ltd is guide's thing with Penicillide, is pharmacological model with the cholesterol transferring enzyme, has carried out the research of the structure activity relationship of system, finds that Compound I has IC
50(nM)=15, t
1/2(rat plasma) outstanding drug effect (the patent W02004039453 of Beyer Co., Ltd, Bioorganic ﹠amp (h)=4.2; Medicinal Chemistry Letter, 15 (2005), 3611-3614).
Compare with WO2004039453 patent and Chinese patent application 200610119528.6, the present invention is from the angle of chemical economics, made up compound (I) as key intermediate, thereby with in the first two piece patent, in the end the upward work of ethyl of a step advances to two fragments and docks to come to finish.Ethyl in the final step of WO2004039453 patent utilizes the Still coupling, its yield only 22%; And in the Chinese patent application 200610119528.6, with ethyl on the Negeish linked reaction, its yield is 45%; Greatly reduce the total recovery of synthesising target compound like this, and increased cost.
Summary of the invention
The purpose of this invention is to provide and a kind ofly can overcome prior art defective, new synthetic dibenzo dioxy octanone compound intermediate---the 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base that is used for) methyl] synthetic method of phenol.
The present invention includes following steps:
1) be raw material with 2-hydroxyl-3-benzyloxy-5-methyl-6-chloro-benzoic acid, the employing simple substance bromine is a brominated reagent, makes 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid;
2) with 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid and nitrogen, nitrogen-dimethyl formamide, sodium hydride, bromobenzene reaction make 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid;
3) under nitrogen protection, with 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid with ethyl in the Suzuki-Miyaura reaction, adopting triethyl-boron is the ethyl source, tetrahydrofuran (THF) or nitrogen, nitrogen-dimethyl formamide is a solvent, Palladous chloride is a catalyzer, and cesium acetate is an alkali, and reaction generates 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid under 20～120 ℃ of temperature condition;
4), generate 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol with 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid and tetrahydrochysene lithium reactive aluminum;
5) with 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol and 3, the reaction of 4-dihydropyrane generates 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] phenol.
The present invention compared with prior art possesses following characteristics:
First, the present invention is from chemical economic angle, made up 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] phenol is as key intermediate, thereby in former two pieces of patents, in the end the upward work of ethyl of a step advances to two fragments and docks to come to finish.The reasonableness and the economy of reaction have been improved.
Second, the present invention is at the preparation midbody compound---and each reactant in 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid process, catalyzer, solvent, the technologies of selecting for use such as alkali all can make the formation of avoiding the debrominate by product effectively, and reaction yield is 50～70%.To guarantee the generation of final compound.
2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base by the present invention preparation) methyl] phenol is used for the synthetic dibenzo dioxy octanone compound, has the effect that improves synthetic ratio, reduces synthetic cost.
In the step 1) of the present invention, 2-hydroxyl-3-benzyloxy-5-methyl-6-chloro-benzoic acid is dissolved in the Glacial acetic acid, adds bromine, leach white crystals after stirring under the room temperature, wash, dry again, filtration with sherwood oil, make white, needle-shaped crystals, be 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid.
Step 2) in, with 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid is dissolved in nitrogen, in nitrogen-dimethyl formamide, be cooled to 0 ℃ under stirring, add sodium hydride again, further stir, drip bromobenzene at last in room temperature, be warming up to 50 ℃, stir simultaneously, remove most of solvent, residuum ethyl acetate and water dispenser, organic phase is washed with salt, anhydrous magnesium sulfate drying filters, and organic phase reclaims, the separation and purification of residuum silica gel column chromatography, the eluent washing of adopting chloroform and methanol mixed to form makes light red needle crystal, is 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid.
In the step 3); under nitrogen protection; with 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid; Palladous chloride; cesium acetate is dissolved in tetrahydrofuran (THF) or nitrogen; in nitrogen-dimethyl formamide; stir down; add the tetrahydrofuran solution of triethyl-boron during room temperature, keep adding diethoxy amine again after 2 hours; aqueous ammonium chloride solution and ethyl acetate; the water ethyl acetate extraction; with the salt washing, use anhydrous magnesium sulfate drying more earlier, filter; get the silica gel column chromatography separation and purification; the mixture wash-out that employing is made up of chloroform and methyl alcohol makes the colourless crystallization powder, is 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid.
In the step 4), 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid is dissolved in the anhydrous tetrahydro furan, in the time of 0 ℃, add tetrahydrochysene lithium aluminium in batches, reflux, stir, be cooled to room temperature after, drip water saturated ethyl acetate, transferring the pH value of system with saturated ammonium chloride solution is 6, water with ethyl acetate extraction after, with salt washing, use anhydrous magnesium sulfate drying again, after the filtration, reclaim organic phase, the mixture wash-out of being made up of sherwood oil and ethyl acetate is adopted in the separation and purification of residuum silica gel column chromatography, make white crystals, be 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol.
In the step 5), 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol and tosic acid are dissolved in the methylene dichloride, in the time of 0 ℃, drip 3, the 4-dihydropyrane, after the stirring, add triethylamine again, tell organic phase, with salt washing, anhydrous magnesium sulfate drying, filter, reclaim organic phase, the eluent washing of being made up of sherwood oil and acetone is adopted in the separation and purification of residuum silica gel column chromatography, make white crystalline powder, be 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] phenol.
Description of drawings
Fig. 1 is a synthetic route chart of the present invention.
Fig. 2 is the route map of synthetic dibenzo dioxy octanone compound of the present invention.
Embodiment
One, the inventive method adopts synthetic route as shown in Figure 1.
Wherein, the synthetic method of starting raw material adopts the method that is adopted in the Chinese patent application 200610119528.6, and reaction respectively goes on foot the gained compound and is all new compound.
Two, concrete operations step and method:
Synthesizing of (2) 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid:
2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid molecular structural formula:
Get 6.5 gram 2-hydroxyl-3-benzyloxy-5-methyl-6-chloro-benzoic acids and be dissolved in the 30ml Glacial acetic acid, add the bromine of 1.7ml, stirred 5 hours under the room temperature.Filter out white crystals, wash with sherwood oil, drying is filtered, and obtains 5.3 gram (yield is 86%) white, needle-shaped crystals compounds, and promptly 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid.
Check:
1H-NMR(CD
3C1)：δ：2.42(s，3H)；6.18(br.，s，1H)；11.56(br.，s，1H)ppm.
13C-NMR(CD
3C1)：δ：20.2；115.0；119.4；123.6；126.3；142.0；142.8；166.3ppm.MS(EI)：m/z＝282(M+2H)
++
Conclusion: obtained 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid.
(2) 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid is synthetic:
The molecular structural formula of 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid:
With 8 grams 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid is dissolved in 125ml nitrogen, in nitrogen-dimethyl formamide, be cooled to 0 ℃ under stirring, add 2.875 gram sodium hydrides in batches, further stirred 3 hours, drip the bromobenzene of 2.8ml in room temperature, stirred 5 hours at 50 degree, remove most of solvent, residuum ethyl acetate and water dispenser, organic phase is washed with salt, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (volume ratio of chloroform and methyl alcohol is 30: 1 to 10: 1) obtains 9.1 gram (yield is 88%) light red needle crystal compounds, is 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid.
Check:
1H-NMR(CD
3OD)：δ：2.46(s，3H)；5.01(s，2H)；7.32-7.56(m，5H)ppm.
The result represents, has obtained 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid.
(3) 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid is synthetic:
The molecular structure of 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid shows:
Under nitrogen protection, with 3.7 gram 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acids, 293 milligrams of PdCl
2Be dissolved in tetrahydrofuran (THF) or the nitrogen of 90ml with the cesium acetates of 9.78 grams, in nitrogen-dimethyl formamide, under agitation adding concentration during room temperature is the tetrahydrofuran solution 30ml of the triethyl-boron of 1M (1 mole of triethyl-boron molecule is dissolved in 1000 milliliters of tetrahydrofuran (THF)s), under this temperature, kept 2 hours, add a small amount of diethoxy amine in reaction system, add aqueous ammonium chloride solution and ethyl acetate again, water ethyl acetate extraction 2 times, merge organic phase, wash with salt, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (volume ratio of chloroform and methyl alcohol is 50: 1～25: 1) obtains 3.23 gram (yield is 75%) colourless crystallization powder compounds.With this powder compounds check, have following feature:
1H-NMR(CD
3Cl)：δ：0.95(t，3H)；2.10(s，3H)；2.60(q，2H)；4.95(s，2H)；7.20-7.46(m，5H)ppm.
Proof: above-mentioned powder compounds is 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid.
(4) 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol is synthetic:
The molecular structural formula of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol:
2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-the chloro-benzoic acid of 1.41 grams is dissolved in the 30ml anhydrous tetrahydro furan, the tetrahydrochysene lithium aluminium that in the time of 0 ℃, in batches adds 0.5 gram, further when refluxing, stirred 1 hour, be cooled to room temperature, the water saturated ethyl acetate of careful dropping is in reaction solution, transferring the pH value of system with saturated ammonium chloride solution is 6, water ethyl acetate extraction 2 times merge organic phase, wash with salt, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (volume ratio of sherwood oil and ethyl acetate is 10: 1～6: 1) obtains 1.2 gram (yield is 90%) white crystalline compound.
This white crystalline compound is tested, has following feature:
1H-NMR(CD
3Cl)：δ：1.15(t，3H)；2.30(s，3H)；2.78(q，2H)；4.92(s，2H)；4.94(s，2H)；7.35-7.50(m，5H)ppm.
Proof has obtained 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol
(5) methyl 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base)] phenol synthetic:
2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] molecular structural formula of phenol:
1.2 gram 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenols and 0.5 milligram of tosic acid are dissolved in the methylene dichloride of 10ml, in the time of 0 ℃, slowly drip 0.266ml 3, the 4-dihydropyrane, further stirred 5 hours, add a spot of triethylamine in reaction solution, tell organic phase, wash with salt, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (volume ratio of sherwood oil and acetone is 30: 1) obtains 1.3 gram (yield is 86%) white crystalline powder compounds.
This white crystalline powder compound is tested, has following feature:
1H-NMR(CD
3Cl)：δ：1.13(t，3H)；1.50-1.90(m，6H)；2.31(s，3H)；2.72(q，2H)；3.65(m，1H)；3.98(m，1H)；5.00(s，2H)；5.01(s，2H)；7.37-7.58(m，5H)ppm.
Proof: obtained 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] phenol.
Three, use:
Compound (the I)-2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base that makes by the present invention) methyl] phenol is as intermediate; through a few step reactions such as butt joint, deprotection, cyclization; thereby synthetic dibenzo dioxy octanone compound effectively, as shown in Figure 2.
Total recovery of the present invention can reach 4.67%, and the total recovery of WO2004039453 patent has only 0.12%, and Chinese patent application 200610119528.6 total recoverys have only 1.68%.
Claims (5)
1.2-methyl benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base)] a kind of synthetic method of phenol, may further comprise the steps:
1) be raw material with 2-hydroxyl-3-benzyloxy-5-methyl-6-chloro-benzoic acid, the employing simple substance bromine is a brominated reagent, makes 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid;
2) with 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid and nitrogen, nitrogen-dimethyl formamide, sodium hydride, bromobenzene reaction make 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid;
3) under nitrogen protection, with 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid, Palladous chloride, cesium acetate is dissolved in tetrahydrofuran (THF) or nitrogen, in nitrogen-dimethyl formamide, stir down, the tetrahydrofuran solution that adds triethyl-boron earlier, and then adding diethoxy amine, aqueous ammonium chloride solution and ethyl acetate, the water ethyl acetate extraction, with the salt washing, use anhydrous magnesium sulfate drying more earlier, filter, get the silica gel column chromatography separation and purification, the mixture wash-out that employing is made up of chloroform and methyl alcohol makes the colourless crystallization powder, is 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid;
4), generate 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol with 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid and tetrahydrochysene lithium reactive aluminum;
5) with 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol and 3, the reaction of 4-dihydropyrane generates 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] phenol;
It is characterized in that in the described step 3), under room temperature, add the tetrahydrofuran solution of triethyl-boron, keep adding diethoxy amine, aqueous ammonium chloride solution and ethyl acetate again after 2 hours.
2. according to the described 2-benzyloxy of claim 1-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] a kind of synthetic method of phenol, it is characterized in that in the step 1), 2-hydroxyl-3-benzyloxy-5-methyl-6-chloro-benzoic acid is dissolved in the Glacial acetic acid, add bromine, leach white crystals after stirring under the room temperature, wash with sherwood oil, dry again, filtration, make white, needle-shaped crystals, be 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid.
3. according to the described 2-benzyloxy of claim 1-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] a kind of synthetic method of phenol, it is characterized in that step 2) in, with 2,3-dihydroxyl-4-bromo-5-methyl-6-chloro-benzoic acid is dissolved in nitrogen, in nitrogen-dimethyl formamide, be cooled to 0 ℃ under stirring, add sodium hydride again, further stir in room temperature, drip bromobenzene at last, be warming up to 50 ℃, stir simultaneously, remove most of solvent, residuum ethyl acetate and water dispenser, organic phase is washed with salt, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, the eluent washing of adopting chloroform and methanol mixed to form, make light red needle crystal, be 2-hydroxyl-3-benzyloxy-4-bromo-5-methyl-6-chloro-benzoic acid.
4. according to the described 2-benzyloxy of claim 1-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] a kind of synthetic method of phenol, it is characterized in that in the step 4), 2-hydroxyl-3-benzyloxy-4-ethyl-5-methyl-6-chloro-benzoic acid is dissolved in the anhydrous tetrahydro furan, in the time of 0 ℃, add tetrahydrochysene lithium aluminium in batches, reflux, stir, after being cooled to room temperature, drip water saturated ethyl acetate, transferring the pH value of system with saturated ammonium chloride solution is 6, water with ethyl acetate extraction after, wash with salt, use anhydrous magnesium sulfate drying again, after the filtration, reclaim organic phase, the separation and purification of residuum silica gel column chromatography, the mixture wash-out that employing is made up of sherwood oil and ethyl acetate makes white crystals, is 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol.
5. according to the described 2-benzyloxy of claim 1-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] a kind of synthetic method of phenol, it is characterized in that in the step 5), 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-methylolphenol and tosic acid are dissolved in the methylene dichloride, in the time of 0 ℃, drip 3, the 4-dihydropyrane, after the stirring, add triethylamine again, tell organic phase, wash with salt, anhydrous magnesium sulfate drying filters, and reclaims organic phase, the separation and purification of residuum silica gel column chromatography, the eluent washing that employing is made up of sherwood oil and acetone makes white crystalline powder, is 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrans-2-oxygen base) methyl] phenol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101227426A CN101298447B (en) | 2008-06-27 | 2008-06-27 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101227426A CN101298447B (en) | 2008-06-27 | 2008-06-27 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101298447A CN101298447A (en) | 2008-11-05 |
| CN101298447B true CN101298447B (en) | 2011-05-25 |
Family
ID=40078419
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101227426A Expired - Fee Related CN101298447B (en) | 2008-06-27 | 2008-06-27 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101298447B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004039453A2 (en) * | 2002-10-31 | 2004-05-13 | Bayer Healthcare Ag | 7h-dibenzo[b,g][1,5]dioxocin-5-one derivatives and use thereof |
| CN101066967A (en) * | 2006-12-12 | 2007-11-07 | 复旦大学 | Synthesis process of dibenzo dioxy octanone compound |
| CN101298448A (en) * | 2008-06-27 | 2008-11-05 | 扬州慧清医药科技开发有限公司 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6- [ (tetrahydro-2H-pyrrole-2-oxyl) methyl ] phenol |
-
2008
- 2008-06-27 CN CN2008101227426A patent/CN101298447B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004039453A2 (en) * | 2002-10-31 | 2004-05-13 | Bayer Healthcare Ag | 7h-dibenzo[b,g][1,5]dioxocin-5-one derivatives and use thereof |
| CN101066967A (en) * | 2006-12-12 | 2007-11-07 | 复旦大学 | Synthesis process of dibenzo dioxy octanone compound |
| CN101298448A (en) * | 2008-06-27 | 2008-11-05 | 扬州慧清医药科技开发有限公司 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6- [ (tetrahydro-2H-pyrrole-2-oxyl) methyl ] phenol |
Non-Patent Citations (3)
| Title |
|---|
| David Bruckner et al.Dibenzodioxocinones—A new class of CETP inhibitors.《Bioorganic & Medicinal Chemistry Letters》.2005,第15卷3611－3614. |
| David Bruckner et al.Dibenzodioxocinones—A new class of CETP inhibitors.《Bioorganic & * |
| Medicinal Chemistry Letters》.2005,第15卷3611-3614. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101298447A (en) | 2008-11-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103819475B (en) | Synthetic method of sitagliptin and salt thereof | |
| CN110330500B (en) | Stereoselective synthesis method of 6 beta-hydroxy-7, 8-dihydro-morphine derivative | |
| JP2008545683A (en) | Process for the dynamic resolution of (substituted) (R)-or (S) -mandelic acid | |
| CN111187269A (en) | Synthetic method of Reidesciclovir intermediate | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| CN101863948A (en) | High-purity (2 beta, 3 alpha, 5 alpha, 16 beta, 17 beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol or composition thereof and preparation method thereof | |
| JP2018532718A (en) | Phosphoramidate compound, production method thereof and crystal | |
| CN101298448B (en) | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol | |
| US20140200355A1 (en) | Method for Preparing Optically Pure (-)-Clausenamide Compound | |
| CN105712919A (en) | Application of amide condensing agent in vildagliptin synthetic method | |
| CN108314688B (en) | A kind of synthetic method of sitagliptin | |
| CN101298447B (en) | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol | |
| JP6947354B2 (en) | How to make linagliptin | |
| CN111320664B (en) | Preparation method of 24-cholenenoic acid ethyl ester | |
| CN110790708B (en) | Preparation method of Ailixipine intermediate | |
| CN111777554A (en) | Method for synthesizing cisatracurium besilate | |
| CN107629039B (en) | The preparation method and intermediate of deuterated acrylamide | |
| CN111747926A (en) | Improved method for synthesis process of free hydroxypiperone alkali | |
| CN115417803B (en) | Synthesis method of Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid | |
| CN111233616A (en) | Pyrenyl [4] helicene and synthesis method and application thereof | |
| CN109400493A (en) | Sha Ku is than bent and its intermediate preparation method | |
| CN111072543B (en) | Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound | |
| CN116903468B (en) | Preparation method of milbelin intermediate | |
| CN113999239B (en) | Method for synthesizing diaza-bridge compound | |
| CN111320663B (en) | Preparation method of 24-cholenenoic acid ethyl ester intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110525 Termination date: 20120627 |
|
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20081105 Assignee: Yangzhou Sanyao Pharmaceutical Co., Ltd. Assignor: Yangzhou Huiqing Pharmaceutical Technology Development Co., Ltd. Contract record no.: 2011320000603 Denomination of invention: Synthesis method of 2- benzyl group -3- ethyl -4- methyl -5- chloro -6-[(four hydrogen -2H- pyrrole -2- oxygen) methyl] phenol License type: Exclusive License Record date: 20110418 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |