CN101463002A - Dihydroxy-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivative and preparation - Google Patents
Dihydroxy-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivative and preparation Download PDFInfo
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- CN101463002A CN101463002A CNA2007100946085A CN200710094608A CN101463002A CN 101463002 A CN101463002 A CN 101463002A CN A2007100946085 A CNA2007100946085 A CN A2007100946085A CN 200710094608 A CN200710094608 A CN 200710094608A CN 101463002 A CN101463002 A CN 101463002A
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- heptane
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- 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
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Abstract
The invention relates to a dihydroxy-2-diazabicyclo (2.2.1) heptane-3-carboxylic acid derivative and a preparing method thereof, mainly solving the technical problems of poor water solubility and low bioavailability of a large number of current azabicyclo. A chemical structural formula is shown in the right formula. In the formula, R1 represents a substituted functional group which is selected from one of H, alkyls of C1 to C6, benzyl, 2,4-dimethoxyphenyl, tert-butyl and substituted benzene. R2 represents a substituted functional group or a protecting group of amino which is selected from one of H, alkyls of C1 to C6, benzyl, 2,4-dimethoxyphenyl, 4-methoxybenzyl, tertbutyloxycarbonyl, benzyloxycarbonyl, alkanoyl and aroyl. (1R, 3S, 4S, 5S, 6R)-5, 6-dihydroxy-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester is used as raw material. After the substitution reaction between the (1R, 3S, 4S, 5S, 6R)-5, 6-dihydroxy-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester and carboxylic acid under the function of an azo compound condensing agent and triarylated phosphate or trialkyl phosphate, rearrangement products are obtained. And final products are obtained after the hydrolysis.
Description
Technical field:
The present invention relates to a kind of dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative and preparation method, particularly 6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid and derivative and 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 A 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, the muscarinic acetylcholine acceptor that pyridazine, the azabicyclic derivatives formula B of pyrimidine can the excitomotor center nerves, 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 C 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 D as figure is the antagonist 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 E as figure is the 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 F is the 5-HT3 receptor antagonist, 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.
J.Med.Chem.; EN; 40; 12; 1997; 1906-1918., report that this a series of Azabicyclic compounds formula G 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 H arrhythmia activity is that potassium and calcium channel stop characteristic simultaneously.Bioorganic ﹠amp; Medicinal Chemistry Letters 11 (2001) 2597-2602. have reported that structural formula I 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.
Bioorg.Med.Chem.Lett.; EN; 14; 3; 2004; 591-596. azabicyclo amino acid sulphur county amide compound formula J is the antagonist 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 compound formula K is melanocortin-4 receptor (MC4R) selective agonist, is expected to be used for the treatment of obesity or sexual dysfunction.
Report that in patent WO2003/006490 compound formula L can be used as the HCV proteinase inhibitor, has the physiologically active of anti-hepatitis.Bioorg.Med, Chem.Lett.2003,13,3867 report compound M are parts of FKBP, such part takes off in the capable property disease at neuroprotective and nerve enormous function.Bioorg.Med, Chem.Lett.2004,14,6107 report endocyclic compound formula N are Androgen acceptor and Bioorg.Med, Chem.Lett.2004,14,6107 report endocyclic compound formula O are Vasopressin receptor antagonists etc.
This compound formula P of WO2005/85236 report is the Caspase enzyme inhibitors, the Caspase enzyme belongs to L-Cysteine HCL Anhydrous family, being the key factor of regulating apoptosis and other function, belonging to proteolytic enzyme simultaneously again, is the fabulous target spot of drug development therefore.Suppressing or inducing the Caspase enzymic activity all is to regulate this family of apoptotic way to comprise 12 members, can cut precursor protein by enzyme and produce generation and the inflammatory reaction that cytokine is regulated antibody.The septicemia that lethality rate is very high is used for treating rheumatoid arthritis, and HIV infects, anti-tumor activity etc.The antagonist that the compound formula Q of 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 R of report, Bioorg.Med.Chem.; EN; 14; 12; 2006; 4208-4216. the compound formula S 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 need carry out specific structural modification with further its quasi-medicated property matter of improving.Given this; we introduce two hydroxyls at 6,7 of 2-azabicyclo [2.2.1] heptane-3-carboxylic acid first, have not only improved the water-soluble of template greatly; we pass through acylation reaction simultaneously; 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.
Summary of the invention:
The objective of the invention is to be to provide a kind of dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative and preparation method.The endocyclic compound that mainly solves present 2-azabicyclo [2.2.1] heptane 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 [2.2.1] heptane-3-carboxylic acid derivative, and can better meet organism, various enzyme, acceptor diversity structurally.
Technical scheme of the present invention: a kind of dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid and derivative, its chemical structure of general formula is:
R1 is for replacing functional group in the formula, as alkyl, the benzyl, 2 of H, C1～C6, and a kind of in 4-dimethoxy-benzyl, the tertiary butyl, the substituted benzene
R2 is for replacing functional group or amino protecting group, as alkyl, the benzyl, 2 of H, C1～C6, and 4-dimethoxy-benzyl, 4-methoxy-benzyl, a kind of in tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), alkyloyl (RCO-), the aroyl (ArCO);
A kind of dihydroxyl involved in the present invention-2-azabicyclo [2.2.1] heptane-3-carboxylic acid and derivative includes but not limited to:
(a) (3S, 6R)-6,7-dihydroxyl-2-((R)-1-phenylethyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester,
(b) (3S, 6R)-2-tertbutyloxycarbonyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester.
(c) (3S, 6R)-2-tertbutyloxycarbonyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid.
(d) (3S, 6R)-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester hydrochloride.
(e) (3S, 6R) 6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid.
F) (3S, 6R)-2-benzyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester.
G) (3S, 6R)-2-benzyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid
H) (3S, 6R) 2-ethanoyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-benzyl carboxylate
I) (3S, 6R) 2-ethanoyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid
J) (3S, 6R) 2-sec.-propyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylate methyl ester
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 all have its structure of any bibliographical information and synthetic method at present.
The synthetic method of a kind of dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid and derivative is summarized as follows:
With (1R, 3S, 4S, 5S, 6R)-5,6-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylicesters (II) is a raw material, through with carboxylic acid substitution reaction (Mitusnobu reaction) takes place under the effect of azo condensing agent and triaryl phosphorus or trialkyl phosphorus, (3S 6R)-7-hydroxyl-6-(carboxylic acid group)-2-azabicyclo [2.2.1] heptane-3-carboxylicesters (III), gets through hydrolysis to obtain rearrangement product, (3S, 6R)-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylicesters or acid (I) is derived.
Wherein the used carboxylic acid of substitution reaction is aryl acid and alkyl acid, preferred p-nitrobenzoic acid, phenylformic acid, pyridine carboxylic acid, naphthyl formic acid, a kind of azo condensing agent in the acetate, a kind of in diethyl azodiformate (DEAD), azoformic acid two p-chlorobenzyl esters (DCAD), diisopropyl azodiformate (DIAD), azoformic acid two piperidines (ADDP), used phosphorus compound is triaryl phosphorus or trialkyl phosphorus, preferred triphenyl phosphorus (PPh3) and tri-tert phosphorus; Solvent is one or more in methylene dichloride, acetone, second eyeball, ethyl acetate, tetrahydrofuran (THF), dioxane, ether, butyl ether, the benzene,toluene,xylene aprotic solvent.Reacting selected temperature is :-40-100 ℃.
And in the 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 ℃.
Beneficial effect of the present invention: the present invention uses the carboxylic acid-substituted rearrangement reaction to be prepared into 6 first, 7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylicesters, because 6, introduced hydroxyl simultaneously for 7, extending for the space of different directions provides condition, for the physiologically active compound for preparing different types of structure provides the foundation, also improved greatly the water-soluble of this compounds and and activity in vivo and metabolism, distribute, performances such as absorption, 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:(1S, 3S, 4R)-6, the preparation of 7-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester
Operation steps: with (1R, 3S, 4S, 5S, 6R)-5, and 6-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester (3.05g, 10mmol), nitro-4 benzoic acid (2g, 12mmol), (3.14g 12mmol) is dissolved in the 40mL anhydrous tetrahydro furan triphenyl phosphorus, 2.08g diethyl azodiformate is dissolved in the anhydrous tetrahydro furan of 10mL, slowly is added dropwise in the reaction system under 0 ℃.Reaction was at room temperature stirred 48 hours, concentrated, and column chromatography gets 1.9g:(1R, 3S, and 4R, 6R, 7R)-7-hydroxyl-6-(4 p-nitrobenzoic acid-base)-2-((R)-1-styroyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester.(yield 42%)
HNMR(CDCl3)δ：8.25-8.30(m，2H)，8.12-8.15(m，2H)，7.31-7.38(m，2H)，7.28-7.30(m，2H)，7.21-7.24(m，2H)，5.26-5.30(m，1H)，4.13(br，1H)，3.95-4.03(m，2H)，3.83-3.88(m，1H)，3.50(d，1H，J＝3.2Hz)，3.42(br，1H)，2.62(br，1H)，2.30-2.36(m，1H)，1.92-1.98(m，2H)，1.43-1.45(m，3H)，1.13-1.17(m，3H)
MS：455.2
Second step: (1R, 3S, 4R, 6R, 7R)-(1.9g 4.2mmol) is dissolved in the 20mL methyl alcohol 7-hydroxyl-6-(4 p-nitrobenzoic acid-base)-2-((R)-1-styroyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester, adds K inward
2CO
3Water (6.9g) (20mL) solution, 50 ℃ of following stirrings are spent the night.Concentrate methyl alcohol, aqueous phase extracted gets the 1.1g crude product, crude product through column chromatography obtain 0.9g (1R, 3S, 4R, 6R, 7R)-6,7-dihydroxyl-2-((R)-1-styroyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester.Yield 70.2%.
HNMR(CDCl3)δ：7.38(m，2H)，7.29(m，2H)，7.21(m，1H)，4.09-4.15(m，2H)，3.96-4.03(m，2H)，3.78-3.83(m，1H)，3.43(d，1H，J＝2.8Hz)，3.21(d，1H，J＝6.4Hz)，2.11-2.16(m，1H)，1.55-1.71(m，3H)，1.40-1.47(m，3H)，1.13-1.19(m，3H)
MS：306.2(M+1)
Embodiment 2:(1S, 3S, 4R)-6, the preparation of 7-dihydroxyl-2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester
Operation steps: the first step: (1R, 3S, 4S, 5S, 6R)-5, and 6-dihydroxyl-2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester (2.91g, 10mmol), nitro-4 benzoic acid (2g, 12mmol), (2.4g 12mmol) is dissolved in the 40mL anhydrous tetrahydro furan tri-tert phosphorus, 2.4g diisopropyl azodiformate (DIAD) is dissolved in the anhydrous tetrahydro furan of 10mL, slowly is added dropwise in the reaction system under 0 ℃.Under nitrogen protection, stirred under the room temperature 40 hours, concentrate, column chromatography get 2.19g (1R, 3S, 4R, 6R, 7R)-7-hydroxyl-6-(4 p-nitrobenzoic acid-base)-2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester, yield 50%.
HNMR(CDCl3)δ：8.25-8.30(m，2H)，8.12-8.15(m，2H)，7.31-7.38(m，2H)，7.28-7.30(m，2H)，7.21-7.24(m，2H)，5.26-5.30(m，1H)，4.13(br，1H)，3.95-4.03(m，2H)，3.83-3.88(m，1H)，3.60(s，2H)，3.42(br，1H)，2.62(br，1H)，2.30-2.36(m，1H)，1.92-1.98(m，2H)，1.43-1.45(m，3H)，MS：441.2(M+1)
Second step: (1R, 3S, 4R, 6R, 7R)-(1.1g 2.5mmol) is dissolved in the 15mL alcohol 7-hydroxyl-6-(4 p-nitrobenzoic acid-base)-2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester, adds Na inward
2CO
3(5g) and water (2mL), 40 ℃ were stirred 20 hours down.Concentrate ethanol, add entry 15ml, get the 0.9g crude product with ethyl acetate extraction, crude product through column chromatography obtain 0.6g (1R, 3S, 4R, 6R, 7R)-6,7-dihydroxyl-2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester, yield 70.2%.
HNMR(CDCl3)δ：7.39(m，2H)，7.28(m，2H)，7.21(m，1H)，4.10-4.17(m，2H)，3.92-4.05(m，2H)，3.79-3.84(m，1H)，3.60(s，2H)，3.21(d，1H，J＝6.4Hz)，2.11-2.16(m，1H)，1.56-1.75(m，3H)，1.38-1.48(m，3H).MS：292.2(M+1)
Embodiment 3:(1S, 3S, 4R)-6, the preparation of 7-dihydroxyl-2-sec.-propyl-2-azabicyclo [2.2.1] heptane-3-carboxylate methyl ester
Operation steps: the first step: (1R, 3S, 4S, 5S, 6R)-5, and 6-dihydroxyl-2-sec.-propyl-2-azabicyclo [2.2.1] heptane-3-carboxylate methyl ester (2.29g, 10mmol), phenylformic acid (1.4g, 12mmol), (3.14g 12mmol) is dissolved in the 35mL anhydrous tetrahydro furan triphenyl phosphorus, 2.4g diisopropyl azodiformate (DIAD) is dissolved in the anhydrous tetrahydro furan of 10mL, slowly is added dropwise in the reaction system under 0 ℃.Under nitrogen protection, stirred under the room temperature 40 hours, concentrate, column chromatography get 1.56g (1R, 3S, 4R, 6R, 7R)-7-hydroxyl-6-benzoyloxy-2-sec.-propyl-2-azabicyclo [2.2.1] heptane-3-carboxylate methyl ester product, yield 47%.
MS：334.4(M+1)
Second step: (1R, 3S, 4R, 6R, 7R)-(1.2g 3.6mmol) is dissolved in the 15mL methyl alcohol 7-hydroxyl-6-benzoyloxy-2-sec.-propyl-2-azabicyclo [2.2.1] heptane-3-carboxylate methyl ester, adds K inward
2CO
3(5g) and water (1mL), 60 ℃ were stirred 20 hours down.Concentrate methyl alcohol, add entry 15ml, get crude product with ethyl acetate extraction, crude product through column chromatography obtain 0.54g (1R, 3S, 4R, 6R, 7R)-6,7-dihydroxyl-2-sec.-propyl-2-azabicyclo [2.2.1] heptane-3-carboxylate methyl ester.(yield 64.8%)
MS：230.2(M+1)
Embodiment 4:(1S, 3S, 4R, 6R, 7R)-and 2-tertbutyloxycarbonyl-6, the preparation of 7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic 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 [2.2.1] heptane-3-carboxylic acid, ethyl ester (3.1g, 10mmol), Pd (OH)
2-C (500mg) and 40mL methyl alcohol, the air with in the hydrogen exchange hydrogenation bottle is forced into 0.3 normal atmosphere then, and reaction solution stirred 8 hours under the room temperature nitrogen atmosphere, and filtering and concentrating obtains the 3.1g product.(yield 100%)
HNMR(CDCl3)δ：4.34(br，1H)，4.11-4.25(m，6H)，2.71(s，1H)，2.03-2.12(m，1H)，1.78-1.82(m，1H)，1.36(s，2.8H)，1.44(s，6.2H)，1.26-1.26(m，3H)
MS：302.5
Embodiment 5:(1S, 3S, 4R, 6R, 7R)-and 2-tertbutyloxycarbonyl-6, the preparation of 7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid
Reaction formula:
Operation steps: compound (1S, 3S, 4R, 6R, 7R)-2-tertbutyloxycarbonyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester (1.5g, 5mmol) and LiOH (300mg 7.5mmol) is 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 84%)
HNMR(CDCl3)δ：4.01-4.16(m，2H)，3.83-3.97(m，2H)，2.52-2.64(m，1H)，2.13-2.24(m，1H)，1.70-1.74(m，1H)，1.32-1.48(s，9H)
MS：274.1(M+1)
Embodiment 6:
8:(1S, 3S, 4R, 6R, 7R)-6, the preparation of 7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester hydrochloride.
Reaction formula:
Operation steps: will (1S, 3S, 4R, 6R, 7R)-and 2-tertbutyloxycarbonyl-6, (3.1g 10mmol) is dissolved in the 3mL methyl alcohol 7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester, slowly joins in the saturated ether solution of hydrogen chloride of 20mL.Stir to concentrate after 1 hour and obtain the 2.6g product.(yield 100%)
HNMR(CDCl3)δ：4.24-4.32(m，13H)，4.00-4.03(m，1H)，3.50-3.63(m，1H)，3.22-3.26(m，1H)，2.75(m，1H)，1.69-2.07(m，2H)，1.17-1.26(m，3H)
MS：202.5(M+1)
Embodiment 7:(1S, 3S, 4R, 6R, 7R)-and 2-benzyl-6, the preparation of 7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid
Reaction formula:
Operation steps: (1S, 3S, 4R, 6R, 7R)-2-benzyl-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid, ethyl ester (0.29g, 1mmol) and NaOH (80mg, 2mmol) be dissolved in tetrahydrofuran (THF) (10mL) and the water (10mL), reaction solution at room temperature stirred 8 hours, with the dilute hydrochloric acid PH=5 that neutralizes, used ethyl acetate extraction, concentrate 0.21g, yield 80%.
HNMR(CDCl3)δ：7.0-7.5(m，5H)，4.00-4.16(m，2H)，3.83-3.97(m，2H)，3.60(s，2H)，2.52-2.64(m，1H)，2.13-2.24(m，1H)，1.70-1.74(m，1H)，1.30-1.49(s，9H)
MS：262.1(M-1).
Claims (8)
1, a kind of dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid and derivative is characterized in that chemical structural formula is as follows
R1 is selected from alkyl, the benzyl, 2 of H, C1～C6 for replacing functional group among the formula I, a kind of in 4-dimethoxy-benzyl, the tertiary butyl or the substituted benzene;
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.
2, the preparation method of the described a kind of dihydroxyl of claim 1-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative, it is characterized in that, with (1R, 3S, 4S, 5S, 6R)-5,6-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylicesters is a raw material, through under the effect of azo condensing agent and triaryl phosphorus or trialkyl phosphorus substitution reaction taking place with carboxylic acid, obtains rearrangement product (3S, 6R)-7-hydroxyl-6-(carboxylic acid group)-2-azabicyclo [2.2.1] heptane-3-carboxylicesters, through hydrolysis get (3S, 6R)-6,7-dihydroxyl-2-azabicyclo [2.2.1] heptane-3-carboxylicesters or acid and derivative; Reaction formula is as follows:
3, the preparation method of a kind of dihydroxyl according to claim 2-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative, it is characterized in that: the used carboxylic acid of its substitution reaction is aryl acid and alkyl acid, used azo condensing agent, be diethyl azodiformate, azoformic acid two p-chlorobenzyl esters, a kind of in diisopropyl azodiformate or azoformic acid two piperidines, used phosphorus compound is triaryl phosphorus or trialkyl phosphorus, solvent is an aprotic solvent, be selected from methylene dichloride, acetone, the second eyeball, ethyl acetate, tetrahydrofuran (THF), dioxane, ether, butyl ether, benzene, in toluene and the dimethylbenzene one or more, temperature of reaction is :-40～100 ℃.
4, the preparation method of a kind of dihydroxyl according to claim 3-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative is characterized in that: the used carboxylic acid of its substitution reaction is selected from a kind of in p-nitrobenzoic acid, phenylformic acid, pyridine carboxylic acid, naphthyl formic acid or the acetate.
5, the preparation method of a kind of dihydroxyl according to claim 3-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative, it is characterized in that: used phosphorus compound is triphenyl phosphorus or tri-tert phosphorus.
6, the preparation method of a kind of dihydroxyl according to claim 2-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative, it is characterized in that: in the hydrolysis reaction of its indication, 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.
7, the preparation method of a kind of dihydroxyl according to claim 2-2-azabicyclo [2.2.1] heptane-3-carboxylic acid derivative is characterized in that: in the hydrolysis reaction of its indication, 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 ℃.
8. the intermediate during the described a kind of dihydroxyl of claim 1-2-azabicyclo [2.2.1] heptane-3-carboxylic acid and derivative synthesize as medicine or the application of structure fragment.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105848A (en) * | 2021-11-24 | 2022-03-01 | 四川同晟生物医药有限公司 | Preparation method of cis-D-hydroxyproline derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105848A (en) * | 2021-11-24 | 2022-03-01 | 四川同晟生物医药有限公司 | Preparation method of cis-D-hydroxyproline derivative |
| CN114105848B (en) * | 2021-11-24 | 2024-01-12 | 四川同晟生物医药有限公司 | Preparation method of cis-D-hydroxyproline derivative |
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