CN101463006A - 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation - Google Patents
2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation Download PDFInfo
- Publication number
- CN101463006A CN101463006A CNA2007100946032A CN200710094603A CN101463006A CN 101463006 A CN101463006 A CN 101463006A CN A2007100946032 A CNA2007100946032 A CN A2007100946032A CN 200710094603 A CN200710094603 A CN 200710094603A CN 101463006 A CN101463006 A CN 101463006A
- Authority
- CN
- China
- Prior art keywords
- reaction
- octane
- compound
- azabicyclo
- ether
- 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
-
- 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
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a 2-diazabicyclo (2.2.2) octane-3-carboxylic acid derivative and a preparing method thereof, mainly solving the current technical problems that bridged ring compound of 2-diazabicyclo (2.2.2) octane structure is confined in space structural extension and the water solubility of the compound is poor. Chemical structural formulas are shown in formula I and formula II. Main reacting formulas in the preparing method are shown in formula III and formula IV. The III is adopted as raw material to obtain IV by dihydroxylation reaction and the IV reacts with halogenated hydrocarbons to generate ethers, or the IV reacts with alkane acid esters to generate the ethers, or the IV reacts with aryl halogenated matters to generate the ethers, or the IV reacts with alcohol to generate the ethers, or the IV reacts with anhydride and acyl halide to generate ester compound, or the IV reacts with hydroxide radical protecting groups to generate I; or the halogenated reaction is carried out on IV to obtain II.
Description
Technical field: the present invention relates to 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation method, particularly 5,6-dihydroxyl (or halogeno-group)-2-azabicyclo [2.2.2] octane-3-carboxyl acid and derivative and preparation method thereof.
Background technology: the bridged ring class formation couples together the pharmacophore unit of key or is incorporated in its rigid structure, formation has the molecule of special space configuration conformation, the space structure that can mate different biomacromolecules in the organism, produce different biological activity or effectiveness, a lot of compounds have different biological activitys, so have wide application value, particularly in the drug research process as template compound.The endocyclic compound that contains 2-azabicyclo structure is had various biological activitys by a lot of experimental results show that, with the lower section be in partial monopoly and the document disclosed and with the more closely-related examples of the technology of the present invention.
Patent WO2005042533 reported contain azabicyclo 2-cyano group Pyrrolidine amides formula 1 as the inhibition activity of dipeptide peptidase-IV (DPP_IV) with as the pharmaceutical cpd, the particularly diabetes (NIDDM) of relying on of dipeptide peptidase-IV (DPP_IV) relative disease as non-insulin.
Patent US5260293j has reported pyrazine, pyridazine, the muscarinic acetylcholine acceptor that the azabicyclic derivatives formula 2 of pyrimidine can the excitomotor center nerve, thereby can be used for treating nervus centralis or psychotic disorder, as, degenerative brain disorder, motion function is excited, and is demented etc.
Patent US5583140 report dicyclic compound formula 3 has the exciting characteristic of nicotine receptor or increases the biological activitys such as secretion of nerve conduction thing; thereby can be used for the nervus centralis disorder disease; perhaps can increase patient's nicotine receptor, the neuroprotective cell.
WO2006096807 has reported that the Azabicyclic compounds formula 4 as figure is antagonists of integrin alpha 4 acceptors, the antagonist of α 4 β 1 and α 4 β 7 acceptors particularly, these compounds can be used for treating the relevant disease of antagonist of integrin alpha 4 acceptors, as inflammation, autoimmune disorder, or the hyperplasia venereal disease becomes.
EP0978280 has reported that the Azabicyclic compounds formula 5 as figure is Nicotine acetyl choline receptor agonists, thereby can be used for treating nerve degenerative diseases as, degenerative brain disorder, parkinsonism, and analgesia etc.
Document J.Med.Chem.; EN; 34; 1; 1991; The analogue of 140-151 report compound formula 6 is 5-HT3 receptor antagonists, be the 5-HT3 receptor antagonist and a large amount of medicines that applies to the cancer chemotherapy vomiting is arranged clinically, and this class antagonist also has the potential migraine that applies to, schizophrenia and anxiety disorder.
Document J.Med.Chem.; EN; 40; 12; 1997; 1906-1918., report that this a series of Azabicyclic compounds formula 7 can suppress human leukocyte elastase, and lipid peroxidation, thereby stop because pulmonary emphysema are had difficulty in breathing the pulmonary lesion that tissue fibrosis causes.
Bioorg.Med.Chem.Lett.; EN; 7; 15; 1997; 1989-1994. report compound formula 8 arrhythmia activity are that potassium and calcium channel stop characteristic simultaneously.Bioorganic ﹠amp; Medicinal ChemistryLetters 11 (2001) 2597-2602. have reported that structural formula 9 is gonadotropin releasing hormone (GnRH; OrLHRH) non-peptide receptoroid antagonist is expected to be used for the treatment of the cancer that hormone relies on, endometriosis, fibroma uteri etc.
Bioorg.Med.Chem.Lett.; EN; 14; 3; 2004; 591-596. azabicyclo amino acid sulphur county amide compound formula 11 is antagonists of integrin alpha 4 acceptors, the antagonist of α 4 β 1 and α 4 β 7 acceptors particularly, these compounds can be used for treating the relevant disease of antagonist of integrin alpha 4 acceptors, as inflammation, autoimmune disorder, or the hyperplasia venereal disease becomes.
Bioorg.Med.Chem.Lett.; EN; 15; 15; 2005; 3501-3505. report formula 11 is melanocortin-4 receptor (MC4R) selective agonists, is expected to be used for the treatment of obesity or sexual dysfunction.
The antagonist that the compound formula 12 of patent EP937069 report and analogue thereof are neurokinin, thereby be the medicine of potential treatment respiratory tract disease, as asthma.Bioorg.Med.Chem.; EN; 13; 24; 2005; 6693-6702. the compound formula 13 of report, Bioorg.Med.Chem.; EN; 14; 12; 2006; 4208-4216. the compound formula 14 of report is the antagonist of integrin alpha 4 acceptors, particularly the antagonist of α 4 β 1 and α 4 β 7 acceptors, these compounds can be used for treating the relevant disease of antagonist of integrin alpha 4 acceptors, as inflammation, autoimmune disorder, or the hyperplasia venereal disease becomes.
Though we can see that the azabicyclo structure finds in a large amount of active compounds from top example, yet, yet, present twin nuclei depends on 1 carboxyl and 2 nitrogen mostly and removes to modify or be connected other group on the space structure bearing of trend, thereby the space extension is restricted, can't satisfy the various enzymes of organism, acceptor diversity structurally.And present a lot of azabicyclos are not owing to there is hydrophilic radical, and the certain structure rigidity is arranged, thereby cause the poorly water-soluble of most compounds, and bioavailability is not high.Therefore, we further improve its quasi-medicated property matter at the specific structural modification of needs.
Summary of the invention:
The objective of the invention is to be to provide a kind of 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation method.The endocyclic compound that mainly solves present 2-azabicyclo [2.2.2] octane structure extends at space structure and is restricted and the technical problem of the poorly water-soluble of compound.Change the polarity or the biological metabolism performance of existing dicyclo [2.2.2] octane-3-carboxyl acid derivative, and can better meet organism, various enzyme, acceptor diversity structurally.
Technical scheme is: 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, and chemical structure of general formula is:
R1 is selected from alkyl, the benzyl, 2 of H, C1～C6 for replacing functional group, a kind of in the 4-dimethoxy-benzyl; R2 is selected from alkyl, the benzyl, 2 of H, C1～C6 for replacing functional group or amino protecting group, a kind of in 4-dimethoxy-benzyl, tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), alkyloyl (RCO-), the aroyl (ArCO); R3 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, a kind of in 4-dimethoxy-benzyl, trimethyl silicon based (TMS), tertiary butyl dimethyl silica-based (TDBMS), phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl, furyl, alkyloyl (RCO-), the aroyl (ArCO); R4 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, a kind of in 4-dimethoxy-benzyl, trimethyl silicon based (TMS), tertiary butyl dimethyl silica-based (TDBMS), phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl, furyl, alkyloyl (RCO-), the aroyl (ArCO); Wherein R is the alkyl of H or C1～C6, and Ar is various aromatic substituents, is selected from a kind of in benzene, substituted benzene, pyridine, pyrimidine, thiophene, the furans; X is a halogen.
5 shown in some above-claimed cpd I have been the present invention relates to, 6-dihydroxyl (or halogeno-group)-2-azabicyclo [2.2.2] octane-3-carboxyl acid compounds, include but not limited to (a) (3S, 5S, 6R)-2-tertbutyloxycarbonyl 5,6-dihydroxyl (or halogeno-group)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (b) (3S, 5S, 6R)-5,6-dimethoxy-2-azabicyclo [2.2.2] octane-3-carboxyl acid (c) (3S, 5S, 6R)-2-tertbutyloxycarbonyl 5,6-mesyloxy-2-azabicyclo [2.2.2] octane-3-carboxyl acid (d) (3S, 5S, 6R)-and 6-sec.-propyl-5-(pyridine-2-oxygen)-2-azabicyclo [2.2.2] octane-3-carboxyl acid (e) (3S, 5R, 6S)-2-tertbutyloxycarbonyl-5,6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (f) (3S, 5R, 6S)-5,6-two fluoro-2-(pyridine-2-oxygen)-2-azabicyclo [2.2.2] octane-3-carboxyl acid.G) (3S, 5R, 6S)-and 2-ethanoyl-5,6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters, h) 3S, 5R, 6S)-and 2-isobutyl--5,6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters.The above-mentioned structural formula of compound of mentioning is as follows:
Above-claimed cpd is the also cyclic cpds of a class formation novelty, does not have its structure of any bibliographical information and synthetic method at present.
The preparation method of 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative may further comprise the steps:
Suffering-5-alkene-3-carboxylicesters is an important intermediate to adopt 2-azabicyclo [2.2.2], through the bishydroxy reaction, obtain 5,6-dihydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester cpds IV, and then generate ether with halogenated alkane reaction, or compound IV and alkane sulfonic acid ester reaction generation ether, or compound IV and aryl halides reaction generation ether, or compound IV and alcohol are reacted into ether compound, perhaps compound IV and acid anhydrides, carboxylic acid halides are reacted into ester compound, perhaps compound IV and hydroxyl protecting group reacting generating compound I; Perhaps compound IV obtains 5,6-dihalo-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester cpds II through halogenating reaction.Reaction formula is as follows:
Reaction obtains compound IV through bishydroxy from compound III, and used oxygenant is Trimethylamine 99 oxynitride (Me
3NO), potassium permanganate (KMnO
4),, perosmic anhydride (OsO
4), Potcrate (KClO
3), in the N-methylmorpholine oxynitride (N-methylmorphiline-N-oxide) one or more, solvent is a kind of in methylene dichloride, acetone, second eyeball, ethyl acetate, the trimethyl carbinol, water, methyl alcohol, ethanol, Virahol, the benzene,toluene,xylene.
Described compound IV becomes the ether reaction with halogenated alkane, used halogenated alkane is iodide R
3I, R
4I, bromide R
3Br, R
4Br, muriate R
3Cl, R
4A kind of among the Br, described compound IV becomes the ether reaction with halogenated alkane, and used halogenated alkane is iodide R
3I, R
4I, bromide R
3Br, R
4Br, muriate R
3Cl, R
4A kind of among the Br; R3 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, 4-dimethoxy-benzyl, trimethyl silicon based (TMS), tertiary butyl dimethyl silica-based (TDBMS), phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl, furyl a kind of; R4 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, the 4-dimethoxy-benzyl, a kind of in trimethyl silicon based (TMS), tertiary butyl dimethyl silica-based (TDBMS), phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl, the furyl; Be reflected at non-protonic solvent: methylene dichloride, trichloromethane, N, N dimethyl formamide (DMF), N, N diethylformamide (DEF) is carried out in one or more mixed solvents in tetrahydrofuran (THF) (THF), dioxane, the ether; Reaction needed adds alkali, and used alkali is NaH, KOH, NaOH, t-BuOK, BuLi or Me
3N, Et
3N, Bu
3N, 4-N, N-Dimethylamino pyridine, N, accelerine, N, a kind of in the N-Diethyl Aniline, preferred NaH.Compound IV becomes the ether reaction with the alkane sulfonic acid ester, used alkane sulfonic acid ester is R
3Ms, R
4Ms,, R
3Ts,, R
4A kind of among the Ts, wherein R3, R4 are with foregoing identical, be reflected at non-protonic solvent: methylene dichloride, trichloromethane, N, N dimethyl formamide (DMF), N, N diethylformamide (DEF) is carried out in one or more mixed solvents in tetrahydrofuran (THF) (THF), dioxane, the ether; Reaction needed adds alkali, and used alkali is NaH, KOH, NaOH, t-BuOK, BuLi or Me
3N, Et
3N, Bu
3N, 4-N, N-Dimethylamino pyridine, N, accelerine, N, N-Diethyl Aniline, N, N-dimethyl-α-naphthalene ethylamine, N, N-dimethyl benzylamine, N, N-dimethylcyclohexylamine, a kind of in the pyridine.
Compound IV and acid anhydrides, carboxylic acid halides are reacted into ester compound, and used acid anhydrides is a kind of in diacetyl oxide, propionic anhydride, butyryl acid anhydrides, isobutyric anhydride, trimethylacetic acid acid anhydride, benzoyl oxide, p-nitrobenzoic acid acid anhydride, Tetra hydro Phthalic anhydride, the maleic acid anhydride; Carboxylic acid halides is a kind of in Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, isobutyryl chloride, pivaloyl chloride, benzoyl chlorination, the paranitrobenzoyl chloride; Be reflected at non-protonic solvent, methylene dichloride, trichloromethane, N, N dimethyl formamide (DMF), N, N diethylformamide (DEF) is carried out in one or more mixed solvents in tetrahydrofuran (THF) (THF), dioxane, the ether; Reaction needed adds alkali, and used alkali is Trimethylamine 99 (Me
3N), triethylamine (Et
3N), Tributylamine (Bu
3N), 4-N, N-Dimethylamino pyridine, N, accelerine, N, N-Diethyl Aniline, N, N-dimethyl-α-naphthalene ethylamine, N, N-dimethyl benzylamine, N, N-dimethylcyclohexylamine, a kind of in the pyridine.Temperature of reaction is from-20 ℃ to 100 ℃.
Compound IV and aryl halides are reacted into ether, used aryl halides is aromatic bromide, aryl iodide or aryl muriate, be reflected at non-protonic solvent: N, N dimethyl formamide (DMF), N, N diethylformamide (DEF) is carried out in one or more mixed solvents in tetrahydrofuran (THF) (THF), dioxane, the ether, perhaps is reflected at methyl-sulphoxide, the trimethyl carbinol carries out in the Virahol equal solvent; Reaction needed adds alkali, and used alkali is a kind of among NaH, KOH, NaOH, t-BuOK, the BuLi.
Compound IV and hydroxyl protection reagent react generate Compound I; indication hydroxyl protection reagent is triphenylmethyl chloride; methoxychlor methane; dihydropyrane; TERT-BUTYL DIMETHYL CHLORO SILANE; a kind of in the trimethylchlorosilane; be reflected at non-protonic solvent: methylene dichloride; trichloromethane; N; N dimethyl formamide (DMF); N; N diethylformamide (DEF); tetrahydrofuran (THF) (THF); dioxane; ongoingly in one or more mixed solvents in the ether carry out in a kind of; reaction needed adds alkali; used alkali is triethylamine; N; accelerine; tri-n-butylamine; N; N-dimethyl-α-naphthalene ethylamine; N, the N-dimethyl benzylamine; N, one or more in the N-dimethylcyclohexylamine pyridine.
Compound IV is meant through bromo-reaction that through halogenating reaction chlorination or fluoro-reaction generate Compound I I, bromo-reaction phosphorus tribromide (PBr
3), carry out to 50 ℃ at-10 ℃ among a kind of in ether, tetrahydrofuran (THF), dioxane, methylene dichloride or chloroform of a kind of in the carbon tetrabromide/triphenyl phosphorus (CBr4/PPh3), Hydrogen bromide (HBr); Chlorination phosphorus trichloride (PCl3), sulfur oxychloride (SOCl
2), phosphorus oxychloride (POCl
3), phosphorus pentachloride (PCl
5) in a kind of a kind of in ether, tetrahydrofuran (THF), dioxane, methylene dichloride or chloroform in or severally carry out to 50 ℃ at-10 ℃; Fluoro-reaction refers among a kind of in anhydrous diethyl ether, tetrahydrofuran (THF), dioxane, methylene dichloride or chloroform of a kind of in diethylin sulfur trifluoride (DAST), 4-morpholine sulfur trifluoride (4-morpholinosulfur trifluoride), two (4-morpholinyl) the bifluoride sulphur (difluoro-di-morpholin-4-yl-4-sulfane) or severally reacts to 50 ℃ at-78 ℃.
Said process can be further explained above-mentioned reaction by following reaction formula:
((R)-1-styroyl-2-azabicyclo [2.2.2] octane-5-alkene-3-carboxylic acid, ethyl ester (15) is a raw material from known (3S)-2-for we; through the bishydroxy reaction; obtain (1R, 3S, 4S; 5S; 6R)-5,6-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (16), this compound BOC on over hydrogenation just obtains (3S; 5S; 6R)-5,6-dihydroxyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (17), this compound can pass through alkylation; acylations; perhaps go up the protecting group of hydroxyl, such as TBS, TDBMS obtains compound 18; through the ester hydrolysis; obtain compound 19, can perhaps become acyl ammonia through alkylation; go the Boc protecting group, loading onto R through reaction
2Group can obtain different compound 25.Also can be by an other approach, styroyl is taken off in promptly first hydrogenation, obtains compound 20, goes up R again
2Group, hydrolysis obtains compound 22 then, goes up R then
1Group passes through alkylation again, and acylations perhaps goes up the protecting group of hydroxyl, and such as TBS, TDBMS obtains compound 25.
In addition, by to compound 24 process halogenating reactions, can obtain compound 26.
Beneficial effect of the present invention: we have not only improved the water-soluble of template greatly at two hydroxyls of 5,6 introducings of 2-azabicyclo [2.2.2] octane-3-carboxyl acid, we are with 5 simultaneously, the 6-dihydroxy compound is the basis, has prepared halides by halogenating reaction, particularly fluorochemical.And the introduction of halogen has changed the ester dissolubility and the metabolism performance of this compounds.By acylation reaction, become ether reaction etc., introduced other a large amount of groups at 5,6, these compounds have not only changed solvability, biological metabolism stability etc., and change physiologically active probably, for the medicine of preparation biologically active is laid a good foundation.
Embodiment: enumerate embodiment so that the present invention is done detailed description, but the present invention is not limited to these embodiment.
Embodiment 1:(3S, 5S, 6R)-and 2-tert-butoxycarbonyl-5, the preparation of 6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
One). (1R, 3S, 4S, 5S, 6R)-5, the preparation of 6-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Reaction formula:
Operation steps:
The OsO of catalytic amount
4And N-methylmorpholine-N-oxide compound (5.8g, 46.6mmol) be dissolved in 16mL water, in the 8mL acetone and the 32mL trimethyl carbinol, then under 0 ℃, be added dropwise to (1R, 3S, 4R)-and the acetone soln (8g/20mL) of 2-((R)-1-styroyl)-2-azabicyclo [2.2.2] octane-5 alkene-3-carboxylic acid, ethyl ester, stirring is spent the night.In reaction solution, add sodium sulfite aqueous solution, stir one hour after-filtration and concentrate.The water layer dichloromethane extraction, drying obtains the 8g crude product after concentrating, with the normal hexane recrystallization get 6.8g (1R, 3S, 4S, 5S, 6R)-5,6-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester.(yield 76%)
HNMR(CDCl3)δ：1.25-1.33(m，6H)，1.50-1.61(m，4H)，2.38(m，1H)，2.67(m，1H)，3.10(d，1H)，3.25(m，1H)，3.5(m，1H)，4.08(q，1H)，4.15(q，2H)，7.0-7.5(m，5H)
MASS：320.2
Two) (3S, 5S, 6R)-and 2-tertbutyloxycarbonyl-5, the preparation of 6-dihydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Reaction formula:
Operation steps: adding Boc acid anhydrides in 75mL hydrogenation bottle (2.2g, 10mmol), (1R, 3S, 4S, 5S, 6R)-5,6-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (3.2g, 10mmol), Pd (OH)
2-C (500mg) and 40mL methyl alcohol, the air with in the hydrogen exchange hydrogenation bottle is forced into 45psi then, and reaction solution stirred 8 hours under the room temperature nitrogen atmosphere, and filtering and concentrating obtains the 3.2g product.(yield 100%)
HNMR(CDCl3)δ：1.29(t，3H)，1.38(s，9H)，1.53(m，2H)，1.74(m，2H)，2.77(m，1H)，3.2-3.8(m，3H)，4.15-4.23(m，3H)4.81(b，2H).
MASS：316.7
Embodiment 2:(3S, 5R, 6S)-and 2-tert-butoxycarbonyl-5, the preparation of 6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters
Operation steps: in an exsiccant three-necked bottle, add (3S, 5S, 6R)-5,6-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (3.15g, 10mmol), the 50mL anhydrous methylene chloride, be cooled to-78 ℃ then, (3.84g 24mmol) is dissolved in the anhydrous methylene chloride of 20mL DAST, slowly is added drop-wise in the three-necked bottle.Reaction solution stirred 3 hours at-78 ℃, slowly was warming up to stirred overnight at room temperature.In reaction system, add NaHCO
3Aqueous solution cancellation reaction, layering, organic phase saturated common salt water washing, drying, concentrate thick product, slightly the product column chromatography obtain 2.2g (3S, 5R, 6S)-2-tert-butoxycarbonyl-5,6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters.(yield 70%)
MASS：320.3
Embodiment 3:(3S, 5S, 6R)-and 2-tert-butoxycarbonyl-5, the preparation of 6-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Operation steps: the first step: in an exsiccant three-necked bottle, add (1R, 3S, 4S, 5S, 6R)-5,6-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (3.2g, 10mmol), the 50mL anhydrous methylene chloride, be cooled to-78 ℃ then, (3.84g 24mmol) is dissolved in the anhydrous methylene chloride of 20mL DAST, slowly is added drop-wise in the three-necked bottle.Reaction solution stirred 3 hours at-78 ℃, slowly was warming up to stirred overnight at room temperature.In reaction system, add NaHCO
3Aqueous solution cancellation reaction, layering, organic phase saturated common salt water washing, drying, concentrate thick product, slightly the product column chromatography obtains 2.5g compound 7.(yield 77%)
Second step: adding Boc acid anhydrides in 75mL hydrogenation bottle (1.74g, 8mmol), compound 7 (2.5g, 7.7mmol), Pd (OH)
2-C (400mg) and 40mL methyl alcohol, the air with in the hydrogen exchange hydrogenation bottle is forced into 45psi then, and reaction solution stirred 8 hours under the room temperature nitrogen atmosphere, and filtering and concentrating obtains the 2.5g product.The total recovery of (yield 100%) two-step reaction is 77%.
Embodiment 4:(3S, 5S, 6R)-and 2-tert-butoxycarbonyl-5, the preparation of 6-dimethoxy-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Operation steps: in an exsiccant three-necked bottle, add (3S, 5S, 6R)-2-tert-butoxycarbonyl-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (3.15g, 10mmol), the 50mL anhydrous tetrahydro furan, be cooled to-10 ℃ then, add 60% sodium hydride 0.5g, stirred 10 minutes, be added dropwise to the solution of the 10mL of methyl iodide 2ml.Reaction solution stirred 3 hours at-10 ℃, slowly was warming up to stirred overnight at room temperature.In reaction system, add NH
4Cl
3Aqueous solution cancellation reaction, layering, organic phase saturated common salt water washing, drying, concentrate thick product, thick product column chromatography obtains 2.7g (3S, 5S, 6R)-2-tert-butoxycarbonyl-5,6-dimethoxy-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester .MS:344.3 (M+1)
Embodiment 5:(3S, 5S, 6R)-and 2-tert-butoxycarbonyl 5, the preparation of 6-diformazan sulfo group-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Operation steps: in an exsiccant three-necked bottle, add (3S, 5S, 6R)-2-tert-butoxycarbonyl-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (3.15g, 10mmol), the 50mL anhydrous tetrahydro furan, be cooled to-20 ℃ then, add 2.1gN, accelerine, stirred 10 minutes, and be added dropwise to the solution of the 10mL of methane sulfonyl chloride 2ml.Reaction solution stirred 3 hours at-20 ℃, slowly being warming up to 0 ℃ of stirring spends the night, in reaction system, add sodium bicarbonate aqueous solution cancellation reaction, layering, organic phase saturated common salt water washing, dry, concentrate thick product, thick product column chromatography obtains 3.1g (3S, 5S, 6R)-and 2-tert-butoxycarbonyl 5,6-diformazan sulfo group-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester .MS:472.6 (M+1)
Embodiment 6:(3S, 5S, 6R)-5, the preparation of 6-dimethoxy-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Operation steps: 0.343g (3S, 5S, 6R)-and 2-tert-butoxycarbonyl-5,6-dimethoxy-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester is dissolved in the anhydrous methylene chloride of 10ml, adds the anhydrous trifluoroacetic acid of 1.5ml.Reaction mixture is in stirred overnight at room temperature.In reaction system, add NaHCO
3Aqueous solution cancellation reaction, layering, organic phase saturated common salt water washing, drying, concentrated obtain 0.243g (3S, 5S, 6R)-5,6-dimethoxy-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, yield 100%, MS:244.3 (M+1).
Embodiment 7:
(3S, 5S, 6R)-preparation of 2-tert-butoxycarbonyl 6-isopropoxy-5-(pyridine-2-oxygen)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Operation steps: in an exsiccant three-necked bottle, add (3S, 5S, 6R)-2-tert-butoxycarbonyl-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (3.15g, 10mmol), the 50mL anhydrous tetrahydro furan, be cooled to-20 ℃ then, add 1.21gN, accelerine, stirred 10 minutes, and be added dropwise to the anhydrous tetrahydrofuran solution of the 10mL of 1.80g Iso-Propyl iodide.Reaction solution stirred 5 hours at-20 ℃, added 60% sodium hydride, slowly was warming up to 0 ℃, add the 2-chloropyridine, at room temperature stir and spend the night, in reaction system, add sodium bicarbonate aqueous solution cancellation reaction, layering, organic phase saturated common salt water washing, drying, concentrate thick product, thick product column chromatography obtains 1.96g (3S, 5S, 6R)-2-tert-butoxycarbonyl 6-isopropoxy-5-(pyridine-2-oxygen)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, yield 45%.MS：435.6(M+1)
Embodiment 8:(3S, 5S, 6R)-and 2-benzyl-5, the preparation of 6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid benzyl ester
Operation steps:
The first step: in an exsiccant three-necked bottle, add (3S, 5S, 6R)-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (2.15g, 10mmol), 50mL ethanol, phenyl aldehyde 1.6g (15mmol) stirs and adds sodium cyanoborohydride (NaBH after two hours
3CN) 0.6g, stirring is spent the night, and concentrates, and at the resistates acetic acid ethyl dissolution, uses the NH4Cl solution washing, and dry concentrating is directly used in next step reaction.
In second step, the compound dissolution of previous step in 50ml methyl alcohol, is added the Powdered K of 5g
2CO
3, at room temperature stirred 6 hours, filter unnecessary salt of wormwood, methyl alcohol concentrates to be done, use acetic acid ethyl dissolution, add dilute hydrochloric acid, tell ethyl acetate layer, concentrate and obtain (3S, 5S, 6R)-2-benzyl-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid.
The 3rd step: with 3S, 5S, 6R)-and 2-benzyl-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid is dissolved in the ethanol, adds the Powdered K of 3g
2CO
3The potassiumiodide that adds 1.8g benzyl bromine and catalytic amount again, stirred overnight at room temperature, solids removed by filtration, add ethyl acetate, with the saturated common salt washing, concentrate dried back and use column chromatography, obtain 1.8 gram (3S, 5S, 6R)-and 2-benzyl-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid benzyl ester, yield 48% (three steps).MS：368.3(M+1)
Embodiment 9:(3S, 5R, 6S)-and 2-carbobenzoxy-(Cbz)-5, the preparation of 6-two chloro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters
Operation steps:
The first step: in an exsiccant reaction flask, add (3S, 5S, 6R)-5, (2.15g 10mmol), adds each 50ml of entry and tetrahydrofuran (THF) to 6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, add salt of wormwood 6g again, under vigorous stirring, add Carbobenzoxy Chloride 1.80 grams (10mmol), finish and stirred 3 hours, add 0.5 gram triethylamine again and stirred 18 hours.Add methylene dichloride 100ml, layering, the water dichloromethane extraction, the dichloromethane layer drying concentrates, and analyses separation with post, obtain (3S, 5S, 6R)-and 2-carbobenzoxy-(Cbz)-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester.
Second step: in an exsiccant reaction flask, add (3S, 5S, 6R)-2-carbobenzoxy-(Cbz)-5,6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, add methylene dichloride 100ml, be cooled to-20 ℃, slowly the dichloromethane solution of 1.2g sulfur oxychloride, the N that adds catalytic amount, dinethylformamide remains under this temperature and to stir 1 hour, after slowly be warming up to 0 ℃ of stirring and spend the night, in reaction system, add sodium bicarbonate aqueous solution cancellation reaction, layering, organic phase saturated common salt water washing, drying, concentrate thick product, thick product column chromatography obtains 2.2g3S, 5R, 6S)-2-carbobenzoxy-(Cbz)-5,6-two chloro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters, yield 57% (two steps).MS：386.1(M+1)
Embodiment 10:(3S, 5S, 6R)-2-(2-tert-butoxycarbonyl-5, the preparation of 6-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid
Operation steps: compound 5 (1.56g, 5mmol) and LiOH (300mg, 7.5mmol) be dissolved in MeOH (10mL) and the water (10mL), reaction solution stirred 3 hours down at 50 ℃, with the dilute hydrochloric acid PH=3 that neutralizes, concentrate the 1.7g crude product, this crude product obtains the 1.2g product through treatment on ion exchange columns.(yield 83.6%)
Embodiment 11:(3S, 5R, 6S)-5, the preparation of 6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid carbethoxy hydrochlorides
Operation steps: (3.2g 10mmol) is dissolved in the 3mL methyl alcohol compound 6, slowly joins in the saturated ether solution of hydrogen chloride of 20mL.Stir to concentrate after 1 hour and obtain 2.6g compound 9.(yield 100%)
Embodiment 12:(3S, 5R, 6S)-and 2-ethanoyl-5, the preparation of 6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters
Operation steps: (3S, 5R, 6S)-5,6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (2.19g, 10mmol) be dissolved in (40mL) in the chloroform, add triethylamine 1ml, aceticanhydride 2g is dissolved in the 10ml chloroform under 0 ℃, is added drop-wise in the reaction solution then, stirred 12 hours, reaction finishes, and washs in the dilute hydrochloric acid, uses the saturated common salt water washing then, the chloroform layer drying, filter, concentrate the 3.0g crude product, this crude product is handled through column chromatography and is obtained the 2.0g product, yield 76.6%, MS:262.3 (M+1)
Embodiment 13:(3S, 5R, 6S)-and 2-(2-pyridyl)-5, the preparation of 6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters
Operation steps: (3S, 5R, 6S)-5; (2.4g 11mmol) is dissolved in 1 to 6-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters, in the 2-glycol dimethyl ether (40mL); add potassium tert.-butoxide 1.2 grams; 2-chloropyridine 1.15 grams add palladium 0.1 gram, tri-tert phosphorus 0.1 gram; the reaction mixture deoxidation; be heated to 80 ℃ under nitrogen protection, reacted 12 hours, reaction finishes; add ethyl acetate; filter, use the saturated common salt water washing then, the ethyl acetate layer drying; filter; concentrate the 2.7g crude product, this crude product is handled through column chromatography and is obtained 2.01 gram products, yield 68.1%.
MS：297.3(M+1)。
HNMR(CDCl3)δ：1.29(t，3H)，1.46(m，2H)，1.53(m，2H)，2.57(m，1H)，2.90(m，1H)，3.3-3.8(m，3H)，4.18(q，2H)，6.6-6.9(m，2H)，7.60(dd，1H)，8.01(d，1H)。
Claims (10)
1,2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that: chemical structural formula is as follows:
Wherein R1 is selected from alkyl, the benzyl or 2 of H, C1～C6 for replacing functional group, a kind of in the 4-dimethoxy-benzyl; R2 is selected from alkyl, the benzyl, 2 of H, C1～C6 for replacing functional group or amino protecting group, 4-dimethoxy-benzyl, 4-methoxy-benzyl, a kind of in tertbutyloxycarbonyl, carbobenzoxy-(Cbz), alkyloyl or the aroyl; R3 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, the 4-dimethoxy-benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, a kind of in phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl, furyl, alkyloyl or the aroyl; R4 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, the 4-dimethoxy-benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, a kind of in phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl, furyl, alkyloyl or the aroyl; Wherein X is a halogen.
2, the preparation method of the described 2-azabicyclo of claim 1 [2.2.2] octane-3-carboxyl acid derivative; it is characterized in that; alkyl is the alkyl of H or C1～C6 in the alkyloyl, and aromatic base is selected from a kind of in benzene, substituted benzene, pyridine, pyrimidine, thiophene or the furans in the aroyl.
3, the preparation method of the described 2-azabicyclo of claim 1 [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that, suffering-5-alkene-3-carboxylic acid esters III is a raw material to adopt 2-azabicyclo [2.2.2], through the bishydroxy reaction, obtain 5,6-dihydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester cpds IV, and then generate ether with halogenated alkane reaction, or compound IV and alkane sulfonic acid ester reaction generation ether, or compound IV and aryl halides reaction generation ether, or compound IV and alcohol are reacted into ether compound, perhaps compound IV and acid anhydrides, carboxylic acid halides is reacted into ester compound, perhaps compound IV and hydroxyl protecting group reacting generating compound I; Perhaps compound IV obtains 5 through halogenating reaction, 6-dihalo-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester cpds II, and the principal reaction formula is as follows:
4, the preparation method of 2-azabicyclo according to claim 3 [2.2.2] octane-3-carboxyl acid derivative is characterized in that, described compound IV becomes the ether reaction with halogenated alkane, and used halogenated alkane is iodide R
3I, R
4I, bromide R
3Br, R
4Br or muriate R
3Cl, R
4A kind of among the Br, R3 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, the 4-dimethoxy-benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl or furyl a kind of; R4 is for replacing the protecting group of functional group or hydroxyl, be selected from H, C1～C10 straight chain or contain alkyl, the benzyl, 2 of substituting group side chain, the 4-dimethoxy-benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, a kind of in phenyl, substituted-phenyl, pyridyl, pyrimidyl, thienyl or the furyl; Be reflected at non-protonic solvent: methylene dichloride, trichloromethane, N, N dimethyl formamide, N carry out in one or more mixed solvents in N diethylformamide, tetrahydrofuran (THF), dioxane and the ether; Reaction needed adds alkali, and used alkali is NaH, KOH, NaOH, t-BuOK, BuLi, Me3N, Et3N, Bu3N, 4-N, N-Dimethylamino pyridine, N, accelerine or N, a kind of in the N-Diethyl Aniline.
5. the preparation method of 2-azabicyclo according to claim 3 [2.2.2] octane-3-carboxyl acid derivative is characterized in that, compound IV becomes the ether reaction with the alkane sulfonic acid ester, and used alkane sulfonic acid ester is R
3Ms, R
4Ms,, R
3Ts, or R
4A kind of among the Ts, wherein R3, R4 are identical with claim 1, be reflected at non-protonic solvent: methylene dichloride, trichloromethane, N, N dimethyl formamide, N carry out in one or more mixed solvents in N diethylformamide, tetrahydrofuran (THF), dioxane and the ether; Reaction needed adds alkali, and used alkali is NaH, KOH, NaOH, t-BuOK, BuLi, Me
3N, Et
3N, Bu
3N, 4-N, N-Dimethylamino pyridine, N, accelerine, N, N-Diethyl Aniline, N, N-dimethyl-α-naphthalene ethylamine, N, N-dimethyl benzylamine, N, a kind of in N-dimethylcyclohexylamine or the pyridine.
6. the preparation method of 2-azabicyclo according to claim 3 [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that, described compound IV and acid anhydrides or carboxylic acid halides are reacted into ester compound, and used acid anhydrides is a kind of in diacetyl oxide, propionic anhydride, butyryl acid anhydrides, isobutyric anhydride, trimethylacetic acid acid anhydride, benzoyl oxide, p-nitrobenzoic acid acid anhydride, Tetra hydro Phthalic anhydride or the maleic acid anhydride; Carboxylic acid halides is a kind of in Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, isobutyryl chloride, pivaloyl chloride, Benzoyl chloride or the paranitrobenzoyl chloride; Be reflected at non-protonic solvent: methylene dichloride, trichloromethane, N, N dimethyl formamide, N carry out in one or more mixed solvents in N diethylformamide, tetrahydrofuran (THF), dioxane and the ether; Reaction needed adds alkali, used alkali is Trimethylamine 99, triethylamine, Tributylamine, 4-N, N-Dimethylamino pyridine, N, accelerine, N, N-Diethyl Aniline, N, N-dimethyl-α-naphthalene ethylamine, N, N-dimethyl benzylamine, N, a kind of in N-dimethylcyclohexylamine or the pyridine, temperature of reaction is from-20 ℃ to 100 ℃.
7. the preparation method of 2-azabicyclo according to claim 3 [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that, described compound IV and aryl halides are reacted into ether, used aryl halides is a kind of in aromatic bromide, aryl iodide or the aryl muriate, be reflected at non-protonic solvent: N, N dimethyl formamide, N, carry out in one or more mixed solvents in N diethylformamide, tetrahydrofuran (THF), dioxane and the ether, perhaps be reflected among a kind of in methyl-sulphoxide, the trimethyl carbinol or the isopropanol solvent and carry out; Reaction needed adds alkali, and used alkali is a kind of among NaH, KOH, NaOH, t-BuOK or the BuLi.
8. the preparation method of 2-azabicyclo according to claim 3 [2.2.2] octane-3-carboxyl acid derivative; it is characterized in that; described compound IV and hydroxyl protection reagent react generate Compound I; indication hydroxyl protection reagent is triphenylmethyl chloride; methoxychlor methane; dihydropyrane; a kind of in TERT-BUTYL DIMETHYL CHLORO SILANE or the trimethylchlorosilane; be reflected at non-protonic solvent: methylene dichloride; trichloromethane; N; the N dimethyl formamide; N; the N diethylformamide; tetrahydrofuran (THF); ongoingly in one or more mixed solvents in dioxane and the ether carry out in a kind of; reaction needed adds alkali; used alkali is triethylamine; N; accelerine; tri-n-butylamine; N; N-dimethyl-α-naphthalene ethylamine; N; the N-dimethyl benzylamine; N, one or more in N-dimethylcyclohexylamine and the pyridine.
9. the preparation method of 2-azabicyclo according to claim 3 [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that, described compound IV is through halogenating reaction, be meant a kind of generation Compound I I in bromo-reaction, chlorination or fluoro-reaction, bromo-reaction is with carrying out to 50 ℃ at-10 ℃ among a kind of in ether, tetrahydrofuran (THF), dioxane, methylene dichloride or chloroform of a kind of in phosphorus tribromide, carbon tetrabromide/triphenyl phosphorus or the Hydrogen bromide; Chlorination is with among a kind of in ether, tetrahydrofuran (THF), dioxane, methylene dichloride and chloroform of a kind of in phosphorus trichloride, sulfur oxychloride, phosphorus oxychloride or the phosphorus pentachloride or severally carry out to 50 ℃ at-10 ℃; Fluoro-reaction refers among a kind of in anhydrous diethyl ether, tetrahydrofuran (THF), dioxane, methylene dichloride and chloroform of a kind of in diethylin sulfur trifluoride, 4-morpholine sulfur trifluoride, two (4-morpholinyl) bifluoride sulphur or two (methoxy ethyl) the amido sulfur trifluoride or severally reacts to 50 ℃ at-78 ℃.
10. the intermediate during the described 2-azabicyclo of claim 1 [2.2.2] octane-3-carboxyl acid derivative synthesizes as medicine or the application of structure fragment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100946032A CN101463006A (en) | 2007-12-21 | 2007-12-21 | 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100946032A CN101463006A (en) | 2007-12-21 | 2007-12-21 | 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101463006A true CN101463006A (en) | 2009-06-24 |
Family
ID=40803826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100946032A Pending CN101463006A (en) | 2007-12-21 | 2007-12-21 | 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101463006A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417513A (en) * | 2010-09-27 | 2012-04-18 | 上海药明康德新药开发有限公司 | 4-cyano-6-substituted-2-oxabicyclo[2,2,2]octane derivate and preparation method thereof |
| CN107586272A (en) * | 2016-07-06 | 2018-01-16 | 浙江圣效化学品有限公司 | A kind of bicyclic [2.2.2] Octane derivatives of polysubstituted benzo and preparation method thereof |
-
2007
- 2007-12-21 CN CNA2007100946032A patent/CN101463006A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417513A (en) * | 2010-09-27 | 2012-04-18 | 上海药明康德新药开发有限公司 | 4-cyano-6-substituted-2-oxabicyclo[2,2,2]octane derivate and preparation method thereof |
| CN102417513B (en) * | 2010-09-27 | 2015-05-27 | 上海合全药物研发有限公司 | 4-cyano-6-substituted-2-oxabicyclo[2,2,2]octane derivate and preparation method thereof |
| CN107586272A (en) * | 2016-07-06 | 2018-01-16 | 浙江圣效化学品有限公司 | A kind of bicyclic [2.2.2] Octane derivatives of polysubstituted benzo and preparation method thereof |
| CN107586272B (en) * | 2016-07-06 | 2020-09-01 | 浙江圣效化学品有限公司 | Polysubstituted benzo-bicyclo [2.2.2] octane derivative and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3464245B1 (en) | Benzazepine dicarboxamide compounds with tertiary amide function | |
| CN109311854B (en) | Benzazepine dicarboxamide compounds having secondary amide functionality | |
| EP3350168B1 (en) | Sulfinylphenyl or sulfonimidoylphenyl benzazepines | |
| CN101351466B (en) | Heterocyclic Janus kinase 3 inhibitors | |
| BR112017013806B1 (en) | COMPOUND, PHARMACEUTICAL COMPOSITION, USE OF A COMPOUND OF FORMULA (I) AND PROCESS FOR MANUFACTURING A COMPOUND | |
| CN102089307A (en) | Pyrrolopyridines as kinase inhibitors | |
| CA3054324C (en) | Tri-cycle compound and applications thereof | |
| Ouyang et al. | Selective bone targeting 5-fluorouracil prodrugs: synthesis and preliminary biological evaluation | |
| CN1982315A (en) | Synthesis of cefaclor | |
| CN101679418A (en) | [2,6] naphthyridines compounds as protein kinase inhibitors | |
| KR101107336B1 (en) | Macrolide-conjugates with anti-inflammatorory activity | |
| WO2022112345A1 (en) | Aryl derivatives for treating trpm3 mediated disorders | |
| CN101463006A (en) | 2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation | |
| JP7398137B2 (en) | Isoquinoline derivatives and their use as ROCK protein kinase inhibitors | |
| CN108239089B (en) | Method for synthesizing avibactam sodium | |
| CN113929676A (en) | Pyridino-heterocyclic derivative and preparation method and application thereof | |
| JPH045289A (en) | Amide compound | |
| CN101462999A (en) | Fluoro or difluoro-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof | |
| EP2672821B9 (en) | Cathepsin c inhibitors | |
| CN101463000A (en) | 5-amino-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof | |
| CN113173877A (en) | Indole acetyl imino sulfone series compound and preparation method thereof | |
| CN101463007A (en) | Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation | |
| CN101580490A (en) | 3-azabicyclo (3.3.1) nonane-9-substituted derivative and preparation method thereof | |
| CN101001854A (en) | Highly selective novel amidation method | |
| JPH05255313A (en) | N,n'-disubstituted amide derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20090624 |