CN102464663A - Synthesis method of 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid - Google Patents
Synthesis method of 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid Download PDFInfo
- Publication number
- CN102464663A CN102464663A CN2010105388373A CN201010538837A CN102464663A CN 102464663 A CN102464663 A CN 102464663A CN 2010105388373 A CN2010105388373 A CN 2010105388373A CN 201010538837 A CN201010538837 A CN 201010538837A CN 102464663 A CN102464663 A CN 102464663A
- Authority
- CN
- China
- Prior art keywords
- chroman
- reaction
- piperidines
- spiral shell
- tertbutyloxycarbonyl
- 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.)
- Granted
Links
Abstract
The invention discloses a synthesis method of 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid. The synthesis method solves the technical problems that the prior art has a long synthesis route, complex post-treatment processes, high raw material costs and a narrow application range. The synthesis method comprises the following steps that (1), 1'-tert-butyloxycarbonyl-spiro[benzindane-4,4'-piperidine]-1-ketone and an oxidant undergo a reaction in the presence of a solvent to produce a spiro[chroman-4,4'-piperidine]-2-ketone compound 2; (2), the spiro[chroman-4,4'-piperidine]-2-ketone compound 2 and di-tert-butyl dicarbonate undergo a reaction in the presence of a solvent under alkaline conditions to produce a 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-ketone compound 3; (3), the 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-ketone compound 3 is reduced by a reducing agent under a low-temperature condition to form a 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-alcohol compound 4; (4), the 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-alcohol compound 4 and an acetylation reagent undergo a reaction in the presence of an alkalization agent to produce a 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-acetate compound 5; (5), the 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-acetate compound 5 and a cyanation agent undergo a reaction in the presence of a Lewis acid agent to produce a 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-nitrile compound 6; and (6), the 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-nitrile compound 6 and an alkalization agent undergo a hydrolysis reaction to produce 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid.
Description
Technical field
The present invention relates to the compound method of a kind of important medicine intermediate 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid.
Background technology
1'-tertbutyloxycarbonyl-spiral shell [chroman-4; The 4'-piperidines]-2-formic acid is a kind of important medicine intermediate; Because carboxylic acid and nitrogen-atoms on its molecule have high reaction activity and high, can synthesize the drug molecule of various different demands with other molecule coupling, so can extensively be used in the design of drug molecule; Therefore 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid has wide research prospect.Document (
WX2007/57775) reported the synthetic route of 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-ethyl formate, but this synthetic route is very long, expensive raw materials, and yield is extremely low, and aftertreatment is complicated, and practical value is not high.
Summary of the invention
The object of the present invention is to provide a kind of 1'-tertbutyloxycarbonyl-spiral shell [chroman-4; The 4'-piperidines]-new synthetic method of 2-formic acid; It is long mainly to solve the route that has the synthetic route existence now through a kind of method of rapidly and efficiently introducing hydroxy-acid group; Technical problems such as aftertreatment is complicated, and expensive raw materials, suitability are wideless.
Technical scheme of the present invention: the compound method of 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid may further comprise the steps:
The first step reaction is that raw material obtains spiral shell [chroman-4,4'-piperidines]-2-ketone 2 with the reaction of oxygenant SPC-D in the trifluoroacetic acid solvent with 1'-tertbutyloxycarbonyl-spiral shell [benzindan-4,4'-piperidines]-1-ketone;
The reaction of second step under compound 2 alkaline conditions, generates 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-ketone 3 with the tert-Butyl dicarbonate reaction in solvent;
Three-step reaction, compound 3 generate 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-alcohol 4 after coldcondition is with reductive agent diisobutyl aluminum hydrogen reduction carbonyl;
Four-step reaction, compound 4 react in the presence of alkalizing agent with acetylation reagent and generate 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-acetic ester 5;
The reaction of the 5th step, compound 5 are reacted in the presence of Lewis acid reagent with cyanic acid reagent and are generated 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-nitrile 6;
Six-step process, compound 6 generates 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid with the alkalizing agent hydrolysis.
Reaction formula is following:
。
The consumption of the first step reaction SPC-D is counted 1.0～3.0 equivalents with molar weight, and temperature of reaction is room temperature (25～30 ℃); Reaction times is 10～12 hours.
Second step was reflected in the alkalizing agent triethylamine and carries out, and solvent is a kind of in methyl alcohol, ethanol or the methylene dichloride, and tert-Butyl dicarbonate consumption molar weight is 1.0～2.0 equivalents, and temperature of reaction is room temperature (25～30 ℃); Reaction times is 3～4 hours.
The temperature of reaction of three-step reaction is-78～-60 ℃; Reaction times is 3～4 hours.
Four-step reaction carries out in solvent, and solvent is a kind of in methyl alcohol, ethanol or the methylene dichloride; Alkalizing agent is with pyridine or cesium carbonate; Acetylation reagent is with Acetyl Chloride 98Min. or diacetyl oxide; The consumption molar weight of alkalizing agent is 1.0～2.0 equivalents; Temperature of reaction is 20～50 ℃; Reaction times is 6～18 hours.
The 5th step was reflected in the solvent carries out, and solvent is toluene or methylene dichloride; Lewis acid reagent is with tin tetrachloride or titanium tetrachloride; Cyanic acid reagent is with sodium cyanide or the silica-based nitrile of front three; The consumption molar weight of Lewis acid reagent is 0.2～0.5 equivalent; The consumption molar weight of cyanic acid reagent is 1.0～5.0 equivalents; Temperature of reaction is-78～10 ℃; Reaction times is 1～5 hour.
Six-step process carries out in alcohol solvent, and alkalizing agent is an alkali metal hydroxide, and molar weight is 1.0～5.0 equivalents, and temperature of reaction is 50～80 ℃; Reaction times is 3～8 hours.
The invention has the beneficial effects as follows: the invention provides a kind of synthetic route of novelty, can be from starting compound cheap, that be easy to get
1Prepare a kind of important medicine intermediate 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid quickly and easily.This technology is six-step process altogether, and total recovery can reach 18%.
Embodiment
Following instance helps to understand content of the present invention, the present invention includes but is not limited to following related content.
Spiral shell [chroman-4,4'-piperidines]-2-ketone
2Synthetic
Embodiment 1
Instance 1: with 1'-tertbutyloxycarbonyl-spiral shell [benzindan-4,4'-piperidines]-1-ketone
1(160 g, 0.53 mol) is dissolved in 1.5 liters the trifluoroacetic acid, under 0 ℃ of condition, adds SPC-D (500 g, 3.18 mol) in batches.Slowly be warming up to room temperature after adding, react slow S-WAT (500 g, 3.18 mol) the reduction SPC-D that adds after 12 hours.Gained spiral shell [chroman-4,4'-piperidines]-2-ketone
2Solution directly is used for next step reaction;
Instance 2: the reaction times is 10 hours, and all the other are identical with instance 1.
1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-ketone
3Synthetic
Embodiment 2
Instance 1: in solvent methanol with above-mentioned bullion spiral shell [chroman-4,4'-piperidines]-2-ketone
2The middle triethylamine that adds adds tert-Butyl dicarbonate (136 g, 0.63 mol) again to pH=10; React and add 3L water after 3 hours; With ethyl acetate extraction (500 ml*3), merge organic phase and use saturated common salt water washing, anhydrous sodium sulfate drying again; Concentrated filtrate obtains 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-ketone after removing by filter siccative
3(136.1 g, 75%);
Instance 2: solvent is an ethanol, and the reaction times is 4 hours, and all the other are identical with instance 1;
Instance 3: solvent is a methylene dichloride, and the reaction times is 3.5 hours, and all the other are identical with instance 1.
1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-alcohol
4Synthetic
Embodiment 3
Instance 1: with 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-ketone
3(147 g; 0.46 mol) be dissolved in the dry toluene (1.5 L), in this mixture, slowly splash into diisobutyl aluminum hydrogen (696 ml, 0.69 mol) down at-78 ℃; Temperature is controlled at-78 ℃ in the whole dropping process, stirs after 4 hours and will react cancellation with 300 ml methyl alcohol and 300 ml water.With ethyl acetate extraction (500 ml*3), organic phase is used the saturated common salt water washing, and anhydrous sodium sulfate drying removes by filter that concentrated filtrate obtains 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-alcohol behind the siccative
4(147 g, 99%);
Instance 2: temperature of reaction is controlled at-60 ℃, and the reaction times is 3.5 hours, and all the other are identical with instance 1;
Instance 3: temperature of reaction is controlled at-70 ℃, and the reaction times is 3 hours, and all the other are identical with instance 1.
1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-acetic ester
5Synthetic
Embodiment 4
Instance 1: with 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-alcohol
4(156 g, 0.40 mol) is dissolved in the anhydrous methylene chloride (1.5 l), adds diacetyl oxide (55.0 g, 0.54 mol), pyridine (77.4 g, 0.58 mol), 4-Dimethylamino pyridine (60.0 g, 0.49 mol).Said mixture washs with 500 ml*3 1N aqueous hydrochloric acids after 6 hours in stirring at room.Organic phase is used the saturated common salt water washing, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-acetic ester
5(135 g, 77%);
Instance 2: solvent is a methyl alcohol, and alkalizing agent is used cesium carbonate, and acetylation reagent is used Acetyl Chloride 98Min., 40 ℃ of temperature of reaction, and in 10 hours reaction times, all the other are identical with instance 1;
Instance 3: solvent is an ethanol, 50 ℃ of temperature of reaction, and in 16 hours reaction times, all the other are identical with instance 1.
1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-nitrile
6Synthetic
Embodiment 5
Instance 1: with 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-acetic ester
5(25.0 g; 69.3 mmol) be dissolved in the anhydrous methylene chloride (300 ml), in this mixture, slowly splash into anhydrous stannic chloride (8.98 g down at-78 ℃ with trimethylchloro-silicane cyanogen (20.5 g, 207 mmol); 34.5 mmol), be warming up to 0 ℃ of reaction 1 hour after the dropping.Reaction finishes the back with methyl alcohol (50 ml) and triethylamine (50 ml) cancellation.Revolve the organic solvent in the system dried; With ETHYLE ACETATE (500 ml) and water (100 ml) extraction, organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying; Concentrated filtrate obtains 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-nitrile after removing by filter siccative
6(17.4 g, 76.6%);
Instance 2: solvent is a toluene, and Lewis acid reagent is used titanium tetrachloride, and cyanic acid reagent is used sodium cyanide, and the reaction times is 3 hours, and all the other are identical with instance 1.
1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid
7Synthetic
Embodiment 6
Instance 1:1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-nitrile
6(46.2 g, 0.14 mol) is dissolved in the ethanol (600 ml), in this solution, adds 30 ml water and Pottasium Hydroxide (30.0 g, 0.54 mol), is reflected at 80 ℃ and stirs 3 hours.Reaction is revolved the organic solvent in the system dried after finishing; With ETHYLE ACETATE (500 ml) and water (100 ml) extraction; Organic phase is used the saturated common salt water washing; Anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid
7(32.0 g, 42.1%);
Instance 2: alkalizing agent is a sodium hydroxide, and temperature of reaction is 50 ℃, and the reaction times is 8 hours, and all the other are identical with instance 1;
Instance 3: alkalizing agent is a Lithium Hydroxide MonoHydrate, and temperature of reaction is 65 ℃, and the reaction times is 5 hours, and all the other are identical with instance 1.
Claims (7)
1.1'-the compound method of tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid may further comprise the steps:
The first step reaction is that raw material obtains spiral shell [chroman-4,4'-piperidines]-2-ketone 2 with the reaction of oxygenant SPC-D in the trifluoroacetic acid solvent with 1'-tertbutyloxycarbonyl-spiral shell [benzindan-4,4'-piperidines]-1-ketone;
The reaction of second step under compound 2 alkaline conditions, generates 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-ketone 3 with the tert-Butyl dicarbonate reaction in solvent;
Three-step reaction, compound 3 generate 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-alcohol 4 after coldcondition is with reductive agent diisobutyl aluminum hydrogen reduction carbonyl;
Four-step reaction, compound 4 react in the presence of alkalizing agent with acetylation reagent and generate 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-acetic ester 5;
The reaction of the 5th step, compound 5 are reacted in the presence of Lewis acid reagent with cyanic acid reagent and are generated 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-nitrile 6;
Six-step process, compound 6 generates 1'-tertbutyloxycarbonyl-spiral shell [chroman-4,4'-piperidines]-2-formic acid with the alkalizing agent hydrolysis.
2. the compound method of 1'-tertbutyloxycarbonyl-spiral shell according to claim 1 [chroman-4,4'-piperidines]-2-formic acid is characterized in that, the consumption molar weight of the first step reaction SPC-D is 1.0～3.0 equivalents, and temperature of reaction is a room temperature; Reaction times is 12 hours.
3. 1'-tertbutyloxycarbonyl-spiral shell [chroman-4 according to claim 1; The 4'-piperidines]-compound method of 2-formic acid; It is characterized in that; The alkalizing agent of second step reaction alkaline condition is a triethylamine, and tert-Butyl dicarbonate consumption molar weight is 1.0～2.0 equivalents, and temperature of reaction is a room temperature; Reaction times is 3～4 hours.
4. the compound method of 1'-tertbutyloxycarbonyl-spiral shell according to claim 1 [chroman-4,4'-piperidines]-2-formic acid is characterized in that the temperature of reaction of three-step reaction is-78～-60 ℃; Reaction times is 3～4 hours.
5. the compound method of 1'-tertbutyloxycarbonyl-spiral shell according to claim 1 [chroman-4,4'-piperidines]-2-formic acid is characterized in that four-step reaction carries out in solvent, solvent is a kind of in methyl alcohol, ethanol or the methylene dichloride; Alkalizing agent is with pyridine or cesium carbonate; Acetylation reagent is with Acetyl Chloride 98Min. or diacetyl oxide; The consumption molar weight of alkalizing agent is 1.0～2.0 equivalents; Temperature of reaction is 20～50 ℃; Reaction times is 6～18 hours.
6. the compound method of 1'-tertbutyloxycarbonyl-spiral shell according to claim 1 [chroman-4,4'-piperidines]-2-formic acid is characterized in that, the 5th step was reflected in the solvent carries out, and solvent is toluene or methylene dichloride; Lewis acid reagent is with tin tetrachloride or titanium tetrachloride; Cyanic acid reagent is with sodium cyanide or the silica-based nitrile of front three; The consumption molar weight of Lewis acid reagent is 0.2～0.5 equivalent; The consumption molar weight of cyanic acid reagent is 1.0～5.0 equivalents; Temperature of reaction is-78～10 ℃; Reaction times is 1～5 hour.
7. 1'-tertbutyloxycarbonyl-spiral shell [chroman-4 according to claim 1; The 4'-piperidines]-compound method of 2-formic acid; It is characterized in that six-step process carries out in alcohol solvent, alkalizing agent is an alkali metal hydroxide; Consumption is 1.0～5.0 equivalents, and temperature of reaction is 50～80 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010538837.3A CN102464663B (en) | 2010-11-11 | 2010-11-11 | Synthesis method of 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010538837.3A CN102464663B (en) | 2010-11-11 | 2010-11-11 | Synthesis method of 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102464663A true CN102464663A (en) | 2012-05-23 |
| CN102464663B CN102464663B (en) | 2015-05-27 |
Family
ID=46068822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010538837.3A Active CN102464663B (en) | 2010-11-11 | 2010-11-11 | Synthesis method of 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102464663B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017268A (en) * | 2014-04-16 | 2015-11-04 | 上海药明康德新药开发有限公司 | 2-tertbutyloxycarbonyl-7-carbonyl-5-O-2-azaspiro(3.4)octane synthesis method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060079505A1 (en) * | 2004-08-19 | 2006-04-13 | Vertex Pharmaceuticals, Incorporated | Modulators of muscarinic receptors |
| WO2007057775A1 (en) * | 2005-11-21 | 2007-05-24 | Pfizer Limited | Spiropiperidine derivatives |
| CN101415423A (en) * | 2006-04-06 | 2009-04-22 | 阿得罗公司 | Spirocyclic heterocyclic derivatives and methods of their use |
-
2010
- 2010-11-11 CN CN201010538837.3A patent/CN102464663B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060079505A1 (en) * | 2004-08-19 | 2006-04-13 | Vertex Pharmaceuticals, Incorporated | Modulators of muscarinic receptors |
| WO2007057775A1 (en) * | 2005-11-21 | 2007-05-24 | Pfizer Limited | Spiropiperidine derivatives |
| CN101415423A (en) * | 2006-04-06 | 2009-04-22 | 阿得罗公司 | Spirocyclic heterocyclic derivatives and methods of their use |
Non-Patent Citations (2)
| Title |
|---|
| NOAL COHEN 等: "Lewis Acid Mediated Nucleophilic Substitution Reactions of 2-Alkoxy-3,4-dihydro-2H-l-benzopyrans: Regiochemistry and Utility in the Synthesis of 3,4-Dihydro-2H-l-benzopyran-2-carboxylic Acids", 《J. ORG. CHEM.》, vol. 54, no. 14, 31 December 1989 (1989-12-31) * |
| 邢其毅 等: "《基础有机化学（第三版）》", 30 June 2005, article "羧酸的制备", pages: 589 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017268A (en) * | 2014-04-16 | 2015-11-04 | 上海药明康德新药开发有限公司 | 2-tertbutyloxycarbonyl-7-carbonyl-5-O-2-azaspiro(3.4)octane synthesis method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102464663B (en) | 2015-05-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101935324B (en) | Method for preparing penicillanic acid sulfoxide diphenyl methyl ester | |
| CN101397323A (en) | Preparation of hydrocortisone | |
| CN102153567B (en) | Method for preparing cefoxitin acid | |
| CN105669733A (en) | Synthetic method of 1-methyl-1H-pyrazole-3-boronic acid pinacol ester | |
| CN104072565B (en) | A kind of simple preparation method of 17 α hydroxyl progesterones of high yield | |
| CN104109157B (en) | The preparation method that Ka Gelie is clean | |
| CN102464663A (en) | Synthesis method of 1'-tert-butyloxycarbonyl-spiro[chroman-4,4'-piperidine]-2-formic acid | |
| CN103965191A (en) | Synthesis method of 6-bromoimidazo[1,2-alpha]pyridyl-3-formic acid | |
| CN103772400A (en) | Preparation method of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | |
| CN103524486A (en) | N-quinolyl substituted beta-lactam compound, as well as pharmaceutical composition, synthetic method and application of compound | |
| CN103374018A (en) | Novel method for preparing ceftibuten parent nucleus 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (7-NACABH) | |
| CN105315231A (en) | Preparation method of linezolid related substance | |
| CN101891686A (en) | Synthesizing method of N-beta-alanyl-(tau-methyl) histidine | |
| CN101508679B (en) | Synthesis of D(-)-alpha-(4-ethyl-2,3-dioxygen ethylene imine-1-formamido) p-hydroxybenzene acetic acid | |
| CN101007772B (en) | Synthesis method of chiral norvaline | |
| CN103709155A (en) | Preparation method of azilsartan | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN109574830B (en) | Rosuvastatin calcium intermediate, and preparation method and application thereof | |
| CN104876872B (en) | A kind of method for preparing the methylol indazole of 1 tert-butoxycarbonyl 3 and application | |
| CN103288764B (en) | Quinhydroxy ketone alanine ester hydrochloride and preparation method thereof | |
| CN113045475A (en) | Preparation method of 5-bromo-7-methylindole | |
| CN102093247B (en) | Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid | |
| CN112079781A (en) | Synthesis method of 5-bromo-1-methyl-1H-pyrazol-3-amine | |
| CN102212042A (en) | Synthetic method of tetra-azacrown ether | |
| CN101633626A (en) | L-m-aminophenyl glycine, derivatives, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Free format text: FORMER OWNER: TIANJIN YAOMING KANGDE NEW MEDICINE DEVELOPMENT CO., LTD. Effective date: 20150420 Owner name: SHANGHAI STA PHARMACEUTICAL R + D CO., LTD. Free format text: FORMER OWNER: SHANGHAI YAOMING KANGDE NEW MEDICINE DEVELOPMENT CO., LTD. Effective date: 20150420 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20150420 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288, building 1, room 602604 Applicant after: Shanghai STA Pharmaceutical R & D Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |