CN101463007A - Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation - Google Patents

Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation Download PDF

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CN101463007A
CN101463007A CNA2007100946066A CN200710094606A CN101463007A CN 101463007 A CN101463007 A CN 101463007A CN A2007100946066 A CNA2007100946066 A CN A2007100946066A CN 200710094606 A CN200710094606 A CN 200710094606A CN 101463007 A CN101463007 A CN 101463007A
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fluoro
octane
azabicyclo
carboxyl acid
benzyl
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曹茉莉
郑明伟
杜峰
胡斌
吴颢
董径超
马汝建
陈曙辉
李革
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Wuxi Apptec Co Ltd
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Abstract

The invention relates to a fluoro or difluoro-2-diazabicyclo (2.2.2) octane-3-carboxylic acid derivative and a preparing method thereof. The derivative is mainly used as an intermediate or a structural fragment during the drug synthesis. A chemical structural formula is as shown in the right formula. 5-hydroxyl group-2-diazabicyclo (2.2.2) octane-3-carboxylic ester or 5-carbonyl-2-diazabicyclo (2.2.2) octane-3-carboxylic ester is adopted for obtaining 5-fluorine-2-diazabicyclo (2.2.2) octane-3-carboxylic ester or 5, 5-difluoro-2-diazabicyclo (2.2.2) octane-3-carboxylic ester by fluorination. And then carboxylic acid is obtained by hydrolysis. When the protection is removed, free amino compound is obtained. By the transformation of changing protecting groups or ester groups, an object product is obtained.

Description

Fluoro or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation method
Technical field:
The present invention relates to fluoro or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation method, 5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and 5 particularly, 5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and their preparation method.
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.
Figure A200710094606D00041
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.
Figure A200710094606D00051
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.
Figure A200710094606D00052
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 Chemistry Letters 11 (2001) 2597-2602. have reported that structural formula 9 is gonadotropin releasing hormone (GnRH; Or LHRH) non-peptide receptoroid antagonist is expected to be used for the treatment of the cancer that hormone relies on, endometriosis, fibroma uteri etc.
Figure A200710094606D00053
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.
Figure A200710094606D00061
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, all have only hydrophobic groups such as carbon atom and hydrogen atom in the structure of present dicyclic compound, and because the rigidity of structure, make these compounds that certain limitation be arranged as the drug research template time, need specific structural modification further to improve its quasi-medicated property matter.Given this, we introduce fluorine element and have prepared the azabicyclo structural compounds of new class in template.Because the introduction of fluorine atom, not only changed the physicals of compound, the more important thing is the internal metabolism that has changed this series compound, performance such as distribute in the body and stable, simultaneously, because fluorine atom can also form hydrogen bond with the intravital amino acid of biology, thereby may change the mechanism of action of biomacromolecule in compound and the body or act on performance.
Summary of the invention:
The purpose of this invention is to provide a kind of fluoro or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation method thereof, mainly be 5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative or 5,5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation method thereof.Mainly solve the technical problem of the metabolic stability difference of existing azabicyclo structure existence.
Technical scheme: the chemical structural formula of fluoro or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative is as follows:
Figure A200710094606D00071
R 1For replacing functional group or amino protecting group, as hydrogen (H), 2,4-dimethoxy-benzyl, benzyl, tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz).
R2 is for replacing functional group, as hydrogen (H), methyl, and ethyl, benzyl, 2, a kind of in the 4-dimethoxy-benzyl;
X is fluorine atom (F) or hydrogen (H).
The present invention relates to the 5-amino shown in the above-claimed cpd formula I-2-azabicyclo [2.2.2] octane-3-carboxyl acid and derivative or 5,5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid and derivative includes but not limited to:
(A-1) (1R, 3S, 4S)-5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester;
(A-2) (1R, 3S, 4S)-5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid; ,
(A-3) (1R, 3S, 4S, 5S)-5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester;
(A-4) (1R, 3S, 4S)-5-fluoro-2-carbobenzoxy-(Cbz)-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters;
(A-5) (1R, 3S, 4S)-5-fluoro-2-carbobenzoxy-(Cbz)-2-azabicyclo [2.2.2] octane-3-carboxyl acid benzyl ester;
(A-6) (1R, 3S, 4S)-5-fluoro-2-carbobenzoxy-(Cbz)-2-azabicyclo [2.2.2] octane-3-carboxyl acid;
(A-7) (1R, 3S, 4S)-5-fluoro-2-(2, the 4-dimethoxy-benzyl)-2-azabicyclo [2.2.2] octane-3-carboxyl acid benzyl ester;
(A-8) (1R, 3S, 4S)-5-fluoro-2-benzyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester;
(B-1) (1R, 3S, 4S)-5,5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester;
(B-2) (1R, 3S, 4S)-5,5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid;
(B-3) (1R, 3S, 4S)-5,5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters,
(B-4) (1R, 3S, 4S)-5-fluoro-2-benzyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid;
(B-5) (1R, 3S, 4S)-5,5-two fluoro-2-benzyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters;
(B-6) (1R, 3S, 4S)-5,5-two fluoro-2-benzyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid;
(B-7) (1R, 3S, 4S)-5,5-two fluoro-2-benzyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester;
(B-8) (1R, 3S, 4S)-5,5-two fluoro-2-carbobenzoxy-(Cbz)s-2-azabicyclo [2.2.2] octane-3-carboxyl acid benzyl ester;
The above-mentioned structural formula of compound of mentioning is as follows:
Figure A200710094606D00081
Above-claimed cpd is the endocyclic compound of a class formation novelty, does not all have its structure of any bibliographical information and synthetic method at present.
5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid and derivative, 5, the preparation method of 5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid and derivative, step is as follows:
Figure A200710094606D00082
In above-mentioned technology; 5-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester or 5-carbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester are obtained 5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester or 5 through fluoridation; 5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid esters; obtain carboxylic acid through hydrolysis again; if slough protection, just can obtain the free aminocompound.Some known chemical processes of process just can realize changing the conversion of protecting group or ester group, obtain target product.
PG represents protecting group in the formula, as 2, and 4-dimethoxy-benzyl, benzyl, tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz).R is a methyl, ethyl, benzyl.
Fluoridation wherein, the solvent of its reaction usefulness is an aprotic solvent, comprises ether, propyl ether, butyl ether, dioxane, 1,2 dimethoxy ether, methylene dichloride, 1,2 ethylene dichloride, chloroform, tetrahydrofuran (THF), benzene, one or more in the toluene, preferred methylene dichloride, ether; Temperature of reaction is from-78 ℃ to 120 ℃; Reaction reagent is diethylin sulfur trifluoride (DAST), two (methoxy ethyl) amido sulfur trifluoride (Deoxofluor (CH3OCH2CH2) 2N-SF3), 4-morpholine sulfur trifluoride (4-morpholinosulfur trifluoride), two (4-morpholinyl) bifluoride sulphur (difluoro-di-morpholin-4-yl-4-sulfane), triphenyl phosphorus/Potassium monofluoride (PPh 3/ a kind of in KF), or two kinds used with.Preferred methylene dichloride is a solvent, and diethylin sulfur trifluoride (DAST) is a fluorination reagent, stirred overnight at room temperature.
The used method that removes protecting group is an ordinary method; remove 2 as the method with catalytic hydrogenation, three kinds of 4-dimethoxy-benzyls, benzyl, uncle's carbobenzoxy-(Cbz) (Cbz) are with acid (hydrochloric acid; trifluoracetic acid etc.) remove 2,4-dimethoxy-benzyl, two kinds of protecting groups of tertbutyloxycarbonyl (Boc).
And for hydrolysis reaction, its solvent is a methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, the trimethyl carbinol, various alcohols such as methyl cellosolve, acetone, butanone, ether, dioxane, tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, one or both mixtures in the various polar solvents such as water, the used alkali of hydrolysis is NaOH, KOH, LiOH, Na 2CO 3, K 2CO 3, Li 2CO 3In a kind of.The temperature of hydrolysis reaction is from room temperature to 100 ℃, preferred room temperature to 60 ℃.
Beneficial effect of the present invention: 5-position fluoro or the two fluoric compound for preparing 2-azabicyclo [2.2.2] octane-3-carboxyl acid first of the present invention, because the introduction of fluorine atom, not only changed the physicals of compound, the more important thing is the internal metabolism that has changed this series compound, distribute and stability, simultaneously, because fluorine atom can also form hydrogen bond with the amino-acid residue in the intravital biomacromolecule of biology, thereby may change effect performance or the mechanism of biomacromolecule in compound and the body.
Embodiment: enumerate embodiment so that the present invention is done detailed description, but the present invention is not limited to these embodiment.
Embodiment 1
(1R, 3S, 4S, 5S)-preparation of 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Reaction formula:
Figure A200710094606D00091
Operation steps :-78 ℃, with (1R, 3S, 4S, 5R)-5-hydroxyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (1.49g, 5mmol) be dissolved in the dichloromethane solution that the 10mL methylene dichloride is added drop-wise to 1mL diethylin sulfur trifluoride (DAST), stirred 6 hours, be raised to ambient temperature overnight at-78 ℃.After reaction finishes, saturated sodium bicarbonate solution is added in the reaction solution, organic phase is washed with saturated common salt, and anhydrous sodium sulfate drying concentrates, cross post, get product (1R, 3S, 4S, 5S)-and 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester 0.78g, productive rate is 52.0%.
HNMR(CDCl3)δ：5.02-4.81(m，1H)；4.46(m，1H)；4.30-4.18(m，3H)；2.55(m，1H)；2.07-1.85(m3H)；1.65(m，2H)；1.45(m，9H)；1.27(m，4H).
MASS：302.2(M+1)
Embodiment 2
((1R, 3S, 4S, 5S)-preparation of 5-fluoro-2-carbobenzoxy-(Cbz)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Reaction formula:
Figure A200710094606D00101
Operation steps: at-78 ℃, with (1R, 3S, 4S, 5R)-5-hydroxyl-2-carbobenzoxy-(Cbz)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (1.68g, 5mmol) be dissolved in the dichloromethane solution that the 10mL methylene dichloride is added drop-wise to 1.2g two (methoxy ethyl) amido sulfur trifluoride (Deoxofluor), stirred 6 hours, be raised to ambient temperature overnight at-78 ℃.Reaction is added to saturated sodium bicarbonate solution in the reaction solution after finishing, and organic phase is washed with saturated common salt, anhydrous sodium sulfate drying, concentrate, cross post, get product (1R, 3S, 4S, 5S)-5-fluoro-2-carbobenzoxy-(Cbz)-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester 0.91g, productive rate is 54.5%.
MASS：336.2(M+1)
Embodiment 3
((1R, 3S, 4S, 5S)-preparation of 5-fluoro-2-carbobenzoxy-(Cbz)-2-azabicyclo [2.2.2] octane-3-carboxyl acid benzyl ester
Reaction formula:
Figure A200710094606D00102
Specifically with reference to embodiment 1, reaction solvent ether, fluorination reagent are with diethylin sulfur trifluoride (DAST), and productive rate is 47.3%.
MASS：398.2(M+1)
Embodiment 4
((1R, 3S, 4S, 5S)-preparation of 5-fluoro-2-benzyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters
Reaction formula:
Figure A200710094606D00111
Specifically with reference to embodiment 1, reaction solvent methylene dichloride, fluorination reagent are with 4-morpholine sulfur trifluoride (4-morpholinosulfur trifluoride), and productive rate is 40.8%.
MASS：278.2(M+1)
Embodiment 5
(1R, 3S, 4S)-preparation of 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters
Reaction formula:
Figure A200710094606D00112
Specifically with reference to embodiment 2, the reaction solvent methylene dichloride, fluorination reagent is 50.5% with two (methoxy ethyl) amido sulfur trifluoride (Deoxofluor), productive rate.
MASS：288.2(M+1)
Embodiment 6
(1R, 3S, 4S)-5, the preparation the first step of 5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters reaction: (1R, 3S, 4S)-preparation of 5-carbonyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters
Reaction formula:
Figure A200710094606D00113
Operation steps: at-78 ℃; nitrogen protection; the dichloromethane solution (0.9mL/5mL) of dimethyl sulfoxide (DMSO) was joined in 20 minutes in the dichloromethane solution (0.52/10) of oxalyl chloride; mixed solution stirred after 20 minutes, added (1R, 3S again; 4S; 5R)-and the dichloromethane solution (1.4g is dissolved in the 5mL methylene dichloride) of 5-hydroxyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters, after reaction solution stirs half an hour, the 3.5mL triethylamine is dripped wherein.Reaction solution is raised to room temperature, continues reaction 2 hours, reaction finishes, after the water cancellation, organic phase washing 3 times, dry concentrating crossed post and obtained (1R, 3S, 4S)-5-carbonyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters 0.72g, productive rate is 51%.
HNMR(CDCl3)δ::4.43-4.52(m，1H)；4.25(m，2H)；2.84-2.76(m，1H)；2.63-2.49(m，1H)；2.44-2.30(m，2H)；1.93-1.79(m，2H)；1.62(s，2H)；1.42(m，9H)；1.30-1.21(m，3H).
MASS：284.1
The reaction of second step: (1R, 3S, 4S)-5, the preparation of 5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters
Reaction formula:
Figure A200710094606D00121
Operation steps: at-78 ℃, with compound (1R, 3S, 4S, 5R)-5-hydroxyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters (1.42g, 5mmol) be dissolved in the dichloromethane solution that the 10mL methylene dichloride is added drop-wise to 1mLDAST, stirred 6 hours, be raised to ambient temperature overnight at-78 ℃.In reaction solution, add the 1mL dehydrated alcohol again, continue to stir 16 hours.After reaction finishes, saturated sodium bicarbonate solution is added in the reaction solution, organic phase is washed with saturated common salt, and anhydrous sodium sulfate drying concentrates, cross post, product (1R, 3S, 4S)-5,5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters 0.8g, productive rate is 53.3%.
HNMR(CDCl3)δ：4.55-4.41(m，1H)；4.36-4.18(m，2H)；2.86-2.75(m，1H)；2.40-2.32(m，1H)；1.81-1.69(m，6H)；1.54-1.42(m，9H)；138-1.23(m，3H).
MASS：306.1
Embodiment 7
(1R, 3S, 4S)-5, the preparation of 5-two fluoro-2-benzyl carbonyl 2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters
Reaction formula:
Figure A200710094606D00122
Specifically with reference to embodiment 2, the reaction solvent methylene dichloride, fluorination reagent is 57.8% with two (methoxy ethyl) amido sulfur trifluoride (Deoxofluor), productive rate.
MASS：340.1
Embodiment 8
(1R, 3S, 4S, 5S)-preparation of 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid
Reaction formula:
Operation steps: with compound (1R, 3S, 4S, 5S)-and 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (0.3,1mmol) be dissolved in 10mL methyl alcohol and the 2mL water, add sodium hydroxide (0.08g again, 2mmol), reaction solution at room temperature stirs and spends the night.After reaction is finished, revolve to steam and remove methyl alcohol, use ethyl acetate extraction, water is transferred pH to 7 with the hydrochloric acid soln of 1mol/L, and lyophilize gets product 0.24g, and productive rate is 88.9%.
HNMR(CDCl3)δ：5.05(s，1H)；4.39(s，1H)；4.17(s，1H)；2.50(d，1H，J＝21Hz)；2.08-1.94(m，3H)；1.76(m，2H)；1.48(m，9H).
MASS：272.1(M-1)
Embodiment 9
(1R, 3S, 4S, 5S)-preparation of 5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Reaction formula:
Figure A200710094606D00132
Operation steps: with compound (1R, 3S, 4S, 5S)-5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (0.30,1mmol) be dissolved in the 20mL salt acid ether, stirred 2 hours.Add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction, reaction solution be spin-dried for (1R, 3S, 4S, 5S)-5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester 0.18g, productive rate is 90.1%.
HNMR(CDCl3)δ：4.37-4.55(m，3H)；3.86(s，1H)；3.21(m，1H)，2.91-2.69(m，1H)；2.65-2.37(m，2H)；2.2-1.94(m，2H)；1.95-1.56(m，2H)；1.47-1.25(m，4H).
MASS：202.1
Embodiment 10
(1R, 3S, 4S)-5, the preparation of 5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl esters
Figure A200710094606D00133
Operation steps: with compound (1R, 3S, 4S)-5, (0.71g 2mmol) is dissolved in the 20mL dehydrated alcohol 5-two fluoro-2-carbobenzoxy-(Cbz)s-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, adds 10% palladium/carbon of 0.1g, reaction is spent the night under 40 ℃ in 0.5 atmospheric hydrogen, reacted after-filtration and removed catalyzer, revolve inspissation contract product 0.40g, productive rate is 90.9%.
MASS：220.1(M+1)
Embodiment 11
((1R, 3S, 4S, 5S)-preparation of 5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid methyl esters
Reaction formula:
Figure A200710094606D00141
Specifically with reference to embodiment 10, reaction solvent methyl alcohol, catalyzer is with 10% palladium hydroxide/carbon, 30 ℃ of temperature of reaction, and productive rate is 89.3%.
MASS：188.1(M+1)
Embodiment 12
(1R, 3S, 4S)-5, the preparation of 5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid carbethoxy hydrochlorides
Reaction formula:
Operation steps: with compound (1R, 3S, 4S)-5, (0.32g 1mmol) is dissolved in the 20mL salt acid ether 5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, stirs 2 hours.Reaction solution be spin-dried for product (1R, 3S, 4S)-5,5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid carbethoxy hydrochloride 0.26g, productive rate is 100%.
HNMR(CDCl3)δ：4.37-4.55(m，3H)；3.86(s，1H)；2.91-2.69(m，1H)；2.65-2.38(m，2H)；2.19-1.95(m，2H)；1.95-1.57(m，2H)；1.48-1.26(m，4H).
MASS：220.1(M+1)
Embodiment 13
(1R, 3S, 4S)-5, the preparation of 5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid
Reaction formula:
Operation steps: with compound (1R, 3S, 4S)-5, (0.32g 1mmol) is dissolved in 10mL methyl alcohol and the 2mL water 5-two fluoro-2-tertbutyloxycarbonyls-2-azabicyclo [2.2.2] octane-3-carboxyl acid, adds sodium hydroxide (0.08g again, 2mmol), reaction solution at room temperature stirs and spends the night.After reaction is finished, revolve to steam and remove methyl alcohol, use ethyl acetate extraction, water is transferred pH to 7 with the hydrochloric acid soln of 1mol/L, and lyophilize gets product 0.23g, and productive rate is 79.0%.
HNMR(CDCl3)δ：4.52(s，1H)；4.18(m，1H)；2.77(d，1H，J＝20.4Hz)；2.42-2.29(m，4H)；2.07(m，1H)；1.62-1.81(m，2H)；1.45(m，9H).
MASS：290.1(M-1)
Embodiment 14
(1R, 3S, 4S, 5R)-preparation of 5-fluoro-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
The first step reaction: (1R, 3S, 4S, 5S)-preparation of 5-hydroxyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester.
Reaction formula:
Figure A200710094606D00151
Operation steps: with compound (1R, 3S, 4S)-2-tertbutyloxycarbonyl-5-carbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester (1.49g, 5mmol) be dissolved in the 50mL dehydrated alcohol, be cooled to 0 ℃, again to the sodium borohydride that wherein adds 0.4g, stir half an hour, reaction finishes.Add saturated ammonium chloride solution stopped reaction, add the methylene dichloride of 30mL again, the extraction separatory.The organic phase anhydrous sodium sulfate drying revolves inspissation and contracts, obtain product (1R, 3S, 4S, 5S)-5-hydroxyl-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester 1.2g, productive rate is 80.0%.
The second step reaction: (1R, 3S, 4S, 5R)-preparation of 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Reaction formula:
Operation steps: at-78 ℃, with (1R, 3S, 4S, 5S)-(1.2g 4mmol) is dissolved in the dichloromethane solution that the 10mL methylene dichloride is added drop-wise to 1mLDAST 5-hydroxyl-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, stirred 6 hours at-78 ℃, be raised to ambient temperature overnight.After reaction finishes, saturated sodium bicarbonate solution is added in the reaction solution, organic phase is washed with saturated common salt, and anhydrous sodium sulfate drying concentrates, cross post, get product (1R, 3S, 4S, 5R)-and 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester 0.72g, productive rate is 60.1%.
HNMR(CDCl3)δ：5.02-4.81(m，1H)；4.46(m，1H)；4.30-4.18(m，3H)；2.55(m，1H)；2.07-1.85(m3H)；1.65(m，2H)；1.45(m，9H)；1.27(m，4H).
MASS：302.2
Embodiment 15
(1R, 3S, 4S, 5R)-preparation of 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid
Reaction formula:
Figure A200710094606D00161
Operation steps: with compound (1R, 3S, 4S, 5R)-(0.3g 1mmol) is dissolved in 15mL methyl alcohol and the 0.5mL water 5-fluoro-2-tertbutyloxycarbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester, adds powder salt of wormwood 2 gram again, at room temperature stirs and spends the night.After reaction is finished, remove by filter salt of wormwood, revolve to steam and remove methyl alcohol, add 20ml water, transfer pH to 3, use ethyl acetate extraction with the hydrochloric acid soln of 0.5mol/L, the dry product 0.23g that gets of cryoconcentration, productive rate is 84%.
HNMR(CDCl3)δ：5.05(s，1H)；4.39(s，1H)；4.17(s，1H)；2.50(d，1H，J＝21Hz)；2.08-1.94(m，3H)；1.76(m，2H)；1.48(m，9H).
MS：272.1(M-1)
Embodiment 16
(1R, 3S, 4S, 5R)-preparation of 5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ethyl ester
Reaction formula:
Figure A200710094606D00162
Specifically with reference to embodiment 10, reaction solvent ethanol, catalyzer is with 10% palladium hydroxide/carbon, 30 ℃ of temperature of reaction, and productive rate is 90.3%.
MASS：202.1.

Claims (10)

1, fluoro or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that: chemical structural formula is as follows:
Figure A200710094606C00021
R 1For replacing functional group or amino protecting group, be selected from hydrogen, 2, a kind of in 4-dimethoxy-benzyl, benzyl, tertbutyloxycarbonyl or the carbobenzoxy-(Cbz);
R2 is selected from hydrogen, methyl for replacing functional group, ethyl, benzyl or 2, a kind of in the 4-dimethoxy-benzyl;
X is fluorine atom or hydrogen.
2, the preparation method of described fluoro of claim 1 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that: reactions steps is as follows:
In above-mentioned technology, 5-hydroxyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester or 5-carbonyl-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester are obtained 5-fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid ester or 5 through fluoridation, 5-two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid esters, obtain carboxylic acid through hydrolysis again, slough protection, obtain the free aminocompound,, obtain target product through changing the conversion of protecting group or ester group;
PG represents protecting group in the formula, is 2, a kind of in 4-dimethoxy-benzyl, benzyl, tertbutyloxycarbonyl or the carbobenzoxy-(Cbz);
Rn is a kind of in methyl, ethyl or the benzyl.
3, the preparation method of fluoro according to claim 2 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that: described fluoridation, the solvent of its reaction usefulness is an aprotic solvent, be selected from ether, propyl ether, butyl ether, dioxane, 1, in 2 dimethoxy ether, methylene dichloride, 1,2 ethylene dichloride, chloroform, tetrahydrofuran (THF), benzene and the toluene one or more; Temperature of reaction is from-78 ℃ to 120 ℃; Reaction reagent is one or both in diethylin sulfur trifluoride, two (methoxy ethyl) amido sulfur trifluoride, 4-morpholine sulfur trifluoride, two (4-morpholinyl) bifluoride sulphur and the triphenyl phosphorus/Potassium monofluoride.
4, the preparation method of fluoro according to claim 3 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that: the reaction solvent of fluoridation is methylene dichloride or ether.
5, the preparation method of fluoro according to claim 3 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that: the reagent of fluoridation is the diethylin sulfur trifluoride.
6, the preparation method of fluoro according to claim 2 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative; it is characterized in that: wherein the protecting group of indication is 2, a kind of in 4-dimethoxy-benzyl, benzyl, tertbutyloxycarbonyl or the carbobenzoxy-(Cbz).
7, the preparation method of fluoro according to claim 2 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative; it is characterized in that: the deprotection base of indication wherein; method with catalytic hydrogenation removes 2; a kind of protecting group in 4-dimethoxy-benzyl, benzyl or the uncle's carbobenzoxy-(Cbz); remove 2 with hydrochloric acid or trifluoracetic acid, two kinds of protecting groups of 4-dimethoxy-benzyl and tertbutyloxycarbonyl.
8, the preparation method of fluoro according to claim 2 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative, it is characterized in that: described hydrolysis reaction, its solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, the trimethyl carbinol, methyl cellosolve, acetone, butanone, ether, dioxane, tetrahydrofuran (THF), N, one or both mixtures in dinethylformamide, methyl-sulphoxide and the water, the used alkali of hydrolysis is NaOH, KOH, LiOH, Na 2CO 3, K 2CO 3Or Li 2CO 3In a kind of, the temperature of hydrolysis reaction is from room temperature to 100 ℃.
9, the preparation method of fluoro according to claim 8 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative is characterized in that: the temperature of hydrolysis reaction is a room temperature to 60 ℃.
10, the intermediate during described fluoro of claim 1 or two fluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative synthesizes as medicine or the application of structure fragment.
CNA2007100946066A 2007-12-21 2007-12-21 Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation Pending CN101463007A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103420952A (en) * 2013-09-03 2013-12-04 天津全和诚科技有限责任公司 Method for synthesizing 3-fluoro-3-phenyloxetane
CN105384673A (en) * 2015-11-09 2016-03-09 南京富润凯德生物医药有限公司 Synthetic method of 3-fluoro-azetidine derivative

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103420952A (en) * 2013-09-03 2013-12-04 天津全和诚科技有限责任公司 Method for synthesizing 3-fluoro-3-phenyloxetane
CN105384673A (en) * 2015-11-09 2016-03-09 南京富润凯德生物医药有限公司 Synthetic method of 3-fluoro-azetidine derivative
CN105384673B (en) * 2015-11-09 2017-11-14 南京富润凯德生物医药有限公司 The synthetic method of 3 fluoro azetidine derivatives

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