CN102452981B - 1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives and preparation method - Google Patents
1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives and preparation method Download PDFInfo
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Abstract
The present invention relates to 1,3-bis-replaces-3-azabicyclo [3,2,1] octane substitutive derivative and preparation method, mainly solve current 3-azabicyclo [3,2,1] endocyclic compound of octane structure is restricted in space structure extension the technical problem being unfavorable for rapid screening compound activity and carrying out SAR analysis.Chemical structural formula is as follows:
wherein R
1for replacing the protecting group of functional group or amino, be selected from the one in H, C1 ~ C10 straight chain or the alkyl containing substituting group side chain, benzyl, tertbutyloxycarbonyl, alkyloyl, alkylsulfonyl, urea, thiocarbamide; G is the one of hydroxyl, C1 ~ C10 straight chain or the alkoxyl group containing substituting group side chain, methylamino, dimethylin.
Description
Technical field
The present invention relates to 1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives and preparation method, particularly 1-carboxyl-3-replaces-3-azabicyclo [3,2,1] octane analog derivative and 1-replacement-3-azabicyclo [3.2.1] octane analog derivative and preparation method thereof.
Background technology
Bridged ring compounds is the more special molecule of a class formation, the pharmacophore unit of key effectively can be connected is incorporated in its rigid structure, form the molecule with special space configuration/conformation, thus the space structure of different biomacromolecule in organism can be mated, produce corresponding biological activity or effectiveness, a lot of endocyclic compound all has different biological activity, so have wide using value, particularly in drug research process as template compound.Endocyclic compound containing 3-azabicyclo structure is proved to have various biological activity by a lot of experiments, be below in partial monopoly and document disclosed in and examples more closely-related with the technology of the present invention.
Document Chem. Pharm. Bull.:EN:52:2004:675-687 reports the compound containing 3-azabicyclo [3,2,1] octane fragment
1, can to reduce inflammation reaction as a kind of anti-adhesion molecule antibody, in the test to animal model small white mouse, have good pharmacokinetic data, showing it has good therapeutic action to by collagen-induced rheumatoid arthritis.This compounds can develop into the drug candidate for the treatment of human autoimmune's property disease (as rheumatoid arthritis).
Document J. Med. Chem.:EN:46:2003:1456-1464 also reports the compound of a series of 3-azabicyclo [3.2.1] octane fragment
2, this compound is a kind of effectively Dopamine uptake inhibitor, has good biological activity as lead compound, and what can be developed as cocaines drugs gives up medicine.
Document HYPOTENSIVE AGENTS. VI11:EN:22:1957:1223-1225 also reports the compound of a series of 3-azabicyclo [3.2.1] octane fragment
3there is good antihypertensive effect.This compounds uses comparatively low dosage, can obtain satisfied antihypertensive effect.
The compound of patent US4261892 a series of 3-azabicyclo [3.2.1] octane fragment
4there is anti-inflammatory efficacy, particularly significant role is played to the arthritic treatment of chronic progressive.
The compound of patent US6468998 report
5to serum plain-2 acceptor, there is antagonistic action, can hematoblastic congregation, peripheral circulation and lacrimation be improved simultaneously.Therefore, this compound is expected to become one and offsets removing thrombus embolism, the medicine that alleviation and treatment dry eyes etc. are useful.
Patent US2002137766 reports compound
6there is antiarrhythmic effect, be the effective especially lead compound of prevention and therapy heart disorder, and the ionic current of sodium and calcium is not affected substantially.
Although we can see that azabicyclo structure finds in a large amount of active compounds from example above, but, current caged scaffold mostly depends on the group that nitrogen-atoms goes to carry out modifying or connecting other on space structure extends, thus space extension is restricted, and cannot meet the various enzyme of organism, acceptor diversity structurally.Also be unfavorable for rapid screening compound activity and carry out SAR analysis.Therefore, we need to expand its structural modification space to improve its quasi-medicated property matter further.
Summary of the invention
The object of the invention is to be to provide a kind of 1,3-bis-to replace-3-azabicyclo [3.2.1] Octane derivatives and preparation method.The endocyclic compound mainly solving current azabicyclo [3.2.1] octane structure is restricted in space structure extension the technical problem being unfavorable for rapid screening compound activity and carrying out SAR analysis.Change polarity or the biological metabolism performance of existing 1-replacement-azabicyclo [3.2.1] Octane derivatives, and organism, various enzyme, acceptor diversity structurally can be better met.
Technical scheme is: a kind of 1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives and pharmaceutical salts thereof or solvate, it is characterized in that: general structure is shown in following formula:
Formula 1
Wherein R
1for replacing the protecting group of functional group or amino, be selected from the one in H, C1 ~ C10 straight chain or the alkyl containing substituting group side chain, benzyl, tertbutyloxycarbonyl, alkyloyl, alkylsulfonyl, urea, thiocarbamide; G is hydroxyl, C1 ~ C10 straight chain or the one containing the alkoxyl group of substituting group side chain, methylamino, dimethylin.
According to the present invention, 1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives and pharmaceutical salts thereof or solvate, and preferred compound is: when G is hydroxyl, is that the 1-carboxyl-3-shown in formula I replaces-3-azabicyclo [3.2.1] Octane derivatives;
Wherein R
1for replacing the protecting group of functional group or amino, be selected from the one in H, C1 ~ C10 straight chain or the alkyl containing substituting group side chain, benzyl, tertbutyloxycarbonyl, alkyloyl, alkylsulfonyl, urea, thiocarbamide;
On this basis, the further preferred compound of the present invention includes but not limited to:
I-a:1-carboxyl-3-benzyl 3-azabicyclo [3.2.1] octane;
I-b:1-carboxyl-3-methyl-3-azabicyclo [3.2.1] octane;
I-c:1-carboxyl-3-ethanoyl-3-azabicyclo [3.2.1] octane;
I-d:1-carboxyl-3-methylsulfonyl-3-azabicyclo [3.2.1] octane;
I-e:1-carboxyl-3-benzoyl-3-azabicyclo [3.2.1] octane;
I-f:1-carboxyl-3-methylaminocarbonyl-3-azabicyclo [3.2.1] octane;
I-g:1-carboxyl-3-methoxycarbonyl-3-azabicyclo [3.2.1] octane;
I-h:1-carboxyl-3-methylamine thiocarbonyl-3-azabicyclo [3.2.1] octane.
According to the present invention, 1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives and pharmaceutical salts thereof or solvate, and preferred compound is: work as R
1during for hydrogen, for the 1-shown in formula II replaces-3-azabicyclo [3.2.1] Octane derivatives:
G is C1 ~ C10 straight chain or the one containing the alkoxyl group of substituting group side chain, methylamino, dimethylin;
On this basis, the further preferred compound of the present invention includes but not limited to:
II-a:1-carboxyl-3-azabicyclo [3.2.1] octane;
II-b:1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane;
II-c:1-methylaminocarbonyl-3-azabicyclo [3.2.1] octane;
II-d:1-dimethylaminocarbonyl-3-azabicyclo [3.2.1] octane.
The above-mentioned structural formula of compound mentioned is as follows:
Above-claimed cpd is the endocyclic compound of a class formation novelty, at present without its structure of any bibliographical information and synthetic method.
Such as formula 1 shown in I, 3-bis-replaces the preparation method of-3-azabicyclo [3.2.1] Octane derivatives, it is characterized in that: the G in formula 1 is hydroxyl, 1, it is that 1-carboxyl-3-replaces-3-azabicyclo [3.2.1] octane, preparation process that 3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives: adopt 2-cyclopentanone ethyl formate
1for raw material, through twice Mannich reaction, obtain 1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo [3.2.1] octane
2, compound
2with to Methyl benzenesulfonyl hydrazine reaction, obtain compound 1-ethoxycarbonyl-3-benzyl-8-Tosylhydrazone-3-azabicyclo [3.2.1] octane
3; Compound
3compound 1-ethoxycarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane is generated under sodium cyanoborohydride and tosic acid effect
4; Then compound
4compound 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane is obtained through catalytic hydrogenation debenzylation
iI-b; Compound
iI-bbe obtained by reacting 1-ethoxycarbonyl-3-from different alkylations, acylting agent and replace-3-azabicyclo [3.2.1] octane
i-b - h-1; Compound
i-b - h-1obtain compound 1-carboxyl-3-through lithium hydrate and replace-3-azabicyclo [3.2.1] Octane derivatives
i-b - h, reaction formula is as follows:
Wherein R
1be selected from H, C1 ~ C10 straight chain or containing the one in the alkyl of substituting group side chain, benzyl, tertbutyloxycarbonyl, alkyloyl, alkylsulfonyl, urea, thiocarbamide.
Replace the preparation method of-3-azabicyclo [3.2.1] Octane derivatives such as formula 1,3-shown in II bis-, it is characterized in that: R in formula 1
1for H, it is that 1-replaces-3-azabicyclo [3.2.1] octane, preparation process that 1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives: adopt compound
4for raw material, obtain compound through alkaline hydrolysis
i-a, then acid amide condensation obtains compound
iI-a, c, d-1, last hydrogenation takes off benzyl and obtains target compound
iI-a, c, d, reaction formula is as follows:
G is C1 ~ C10 straight chain or the one containing the alkoxyl group of substituting group side chain, methylamino, dimethylin.
Beneficial effect of the present invention
:we are in 1 carbonylate class functional group of 3-azabicyclo [3.2.1] octane compound, not only improve the polarity of template, we are based on 1-ethoxycarbonyl compound simultaneously, and by hydrolysis reaction, acid amide condensation reaction introduces other group at 1; New group is introduced further by 3 alkylations or acylation reaction; greatly increasing substrate molecule multifarious while; also the object changing the fat-soluble of this compounds and metabolism performance is reached; and probably change physiologically active; biological metabolism stability etc., to finding the compound with new physiologically active, are laid a good foundation for preparation has bioactive medicine.
Embodiment
Enumerate embodiment to be described in detail the present invention, but the present invention is not limited to these embodiments.
embodiment 1: the preparation of 1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
Cyclopentanone-2-carboxylates is added in the there-necked flask of 1 liter
1(20 grams, 0.13 mole), N, N-diethoxy methyl-benzyl amine (58 grams, 0.26 mole) and anhydrous acetonitrile (400 milliliters), drip trichloromethyl silane (39 grams, 0.26 mole), stirring at room temperature 20 hours under nitrogen protection at 0 DEG C.Reaction solution regulates pH to 7 with saturated sodium bicarbonate solution at 0 DEG C, extraction into ethyl acetate, and organic phase is concentrated obtains 22 grams of 1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo [3.2.1] octanes
2, be directly used in next step reaction, yield 58%.
HNMR (CDCl
3) d: 7.28-7.19（m，5H），4.14-4.09（m，2H），3.62-3.56（m，2H），3.06（d，
J= 10.8 Hz，1H），2.90（d，
J= 10.8 Hz，1H），2.70（d，
J= 11.2 Hz，1H），2.50（d，
J= 10.4 Hz，1H），2.38-2.21（m，3H），1.98-1.88（m，2H），1.24（t，
J= 7.2 Hz, 3H）。
embodiment 2: the preparation of 1-ethoxycarbonyl-3-benzyl-8-Tosylhydrazone-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo [3.2.1] octane is added in the there-necked flask of 500 milliliters
2(22 grams, 0.08 mole) and anhydrous methanol (200 milliliters), drip p-toluene sulfonyl hydrazide (37 grams, 0.2 mole), stirring at room temperature 36 hours under nitrogen protection at 0 DEG C.Reaction solution directly concentrates under 50 degree celsius temperature at 40 degrees Celsius, crosses column purification by the elutriant system of sherwood oil and ethyl acetate, obtains 10 grams of 1-ethoxycarbonyl-3-benzyl-8-Tosylhydrazone-3-azabicyclo [3.2.1] octanes
3, be directly used in next step reaction, yield 31%.
HNMR (CDCl
3) d: 7.79-7.75（m，2H），7.36-7.23（m，8H），4.18-4.11（m，2H），3.54-3.46（m，2H），2.97（d，
J= 10.4 Hz，1H），2.90（d，
J= 10.8 Hz，1H），2.76（d，
J = 11.2 Hz，1H），2.52（d，
J= 10.4 Hz，1H），2.47（s，3H），2.28-2.20（m，1H），2.14-2.09（m，2H），1.95-1.90（m，1H），1.89-1.70（m，1H），1.25（t，
J= 7.2 Hz, 3H）。
embodiment 3: the preparation of 1-ethoxycarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-benzyl-8-Tosylhydrazone-3-azabicyclo [3.2.1] octane is added in the there-necked flask of 500 milliliters
3(10 grams; 0.022 mole), methyl alcohol (100 milliliters) and tetrahydrofuran (THF) (100 milliliters), add sodium cyanoborohydride (1.6 grams, 0.026 mole) at 0 DEG C; regulate the pH value of reaction system about 4 with the dilute hydrochloric acid of 1N, under nitrogen protection stirring at room temperature 2 hours.Reaction solution is used water quenched dilution, ethyl acetate (3 × 100 milliliters) extracts, and organic phase is concentrated is dissolved in ethanol (100 milliliters), adds a hydrated sodium acetate (28 grams, 0.22 mole).Under nitrogen protection, stirring reaction is continued 2 hours.Reaction solution dilute with water, ethyl acetate (3 × 100 milliliters) extracts, and organic phase concentrates, and crosses column purification by the elutriant system of sherwood oil and ethyl acetate, obtains 2 grams of 1-ethoxycarbonyl-3-benzyl-3-azabicyclo [3.2.1] octanes
4, yield 33%.
HNMR (CDCl
3) d: 7.36-7.23（m，5H），4.06-4.00（m，2H），3.52-3.40（m，2H），2.86（d，
J= 10.4 Hz，1H），2.52（d，
J= 10.4 Hz，1H），2.16-2.14（m，2H），1.95-1.88（m，4H），1.85-1.81（m，2H），1.66（d，
J= 10.8 Hz，1H），1.42（t，
J= 7.8 Hz, 3H）。
embodiment 4: the preparation of 1-carboxyl-3-benzyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 10 milliliters
4(0.15 gram, 0.42 mmole) and methyl alcohol (2 milliliters), drip lithium hydroxide aqueous solution (1 milliliter, 1N) at 0 DEG C, this reaction mixture stirring at room temperature 2 hours under nitrogen protection.Reaction solution 10 ml waters dilute, and regulate pH to 3, extraction into ethyl acetate at 0 DEG C with the dilute hydrochloric acid of 1 mol/L, and organic phase is concentrated obtains 0.13 gram of 1-carboxyl-3-benzyl-3-azabicyclo [3.2.1] octane
i-a, yield 90%.
HNMR (CDCl
3) d: 7.35-7.27（m，5H），3.53-3.39（m，2H），2.87（d，
J= 9.6 Hz，1H），2.58（d，
J= 10.6 Hz，1H），2.19-2.17（m，2H），1.96-1.89（m，4H），1.87-1.84（m，2H），1.69（d，
J= 12.8 Hz，1H）。
embodiment 5: the preparation of 1-carboxyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-carboxyl-3-benzyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
i-a(130 milligrams, 0.53 mmole), palladium carbon (50 milligrams, mass percent 10%) and methyl alcohol (5 milliliters), in 50 DEG C of stirring reactions 12 hours in three atmospheric hydrogen environments.By reacting liquid filtering, concentrate and obtain 73 milligrams of 1-carboxyl-3-azabicyclo [3.2.1] octanes
iI-a, yield 89%.
HNMR (CDCl
3) d: 2.87（d，
J= 9.8 Hz，1H），2.60（d，
J= 11.4 Hz，1H），2.20-2.18（m，2H），1.93-1.88（m，4H），1.86-1.84（m，2H），1.69（d，
J= 12.0 Hz，1H）。
embodiment 6: the preparation of 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
4(500 milligrams, 1.83 mmoles), palladium carbon (50 milligrams, mass percent 10%) and methyl alcohol (5 milliliters), stir 12 hours in 50 DEG C in three atmospheric hydrogen environments.By reacting liquid filtering, concentrate and obtain 300 milligrams of 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octanes
iI-b, yield 89%.
HNMR (CDCl
3) d: 4.07-4.01（m，2H），2.93（d，
J= 10.6 Hz，1H），2.50（d，
J= 9.8 Hz，1H），2.18-2.16（m，2H），1.94-1.89（m，4H），1.85-1.83（m，2H），1.69（d，
J= 10.2 Hz，1H），1.40（t，
J= 8.0 Hz, 3H）。
embodiment 7: the preparation of 1-ethoxycarbonyl-3-methyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
iI-b(40 milligrams, 0.22 mmole) and DMF (2 milliliters); sodium hydride (9 milligrams, 0.22 mmole, 60%) stirring reaction is added 0.5 hour at 0 DEG C; drip methyl iodide (31 milligrams, 0.22 mmole), stirring at room temperature 2 hours under nitrogen protection.Concentrated by reaction solution, thick product is separated through silica-gel plate and obtains 36 milligrams of 1-ethoxycarbonyl-3-methyl-3-azabicyclo [3.2.1] octanes
i-b-1, yield 84%.
HNMR (CDCl
3) d: 4.06-4.00（m，2H），2.96（d，
J= 10.2 Hz，1H），2.55（d，
J= 8.6 Hz，1H），2.30（s，3H），2.15-2.13（m，2H），1.92-1.89（m，4H），1.87-1.85（m，2H），1.72（d，
J= 9.8 Hz，1H），1.44（t，
J= 8.8 Hz, 3H）。
embodiment 8: the preparation of 1-carboxyl-3-methyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-methyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
i-b-1(36 milligrams, 0.18 mmole) and methyl alcohol (2 milliliters), add lithium hydroxide (43 milligrams, 1.80 mmoles) at 0 DEG C, stirring at room temperature reacts 2 hours under nitrogen protection.Reaction solution is concentrated, being dissolved in water (10 milliliters) dilute hydrochloric acid regulates the pH of reaction solution to be less than 4, with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying is concentrated obtains 20 milligrams of 1-carboxyl-3-methyl-3,8-diazabicyclo [3.2.1] octanes
i-b, yield 65%.
HNMR (CDCl
3) d: 2.96（d，
J= 10.6 Hz，1H），2.58（d，
J= 8.0 Hz，1H），2.37（s，3H），2.13-2.10（m，2H），1.95-1.90（m，4H），1.88-1.84（m，2H），1.79（d，
J= 9.6 Hz，1H）。
embodiment 9: the preparation of the preparation of 1-carboxyl-3-ethanoyl-3-azabicyclo [3.2.1] octane
Operation steps:
By 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane
iI-a(40 milligrams, 0.22 mmole), Acetyl Chloride 98Min. (25.4 milligrams, 0.27 mmole), triethylamine (0.2 milliliter) is dissolved in tetrahydrofuran (THF) (4 milliliters), and this mixed solution at room temperature stirs and spends the night.Concentration of reaction solution, is dissolved in water (10 milliliters), and with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying concentrates to obtain thick product.Thick product is separated through silica-gel plate and obtains 1-carboxyl-3-ethanoyl-3-azabicyclo [3,2,1] octane
i-c, 35 milligrams, yield 70%.
HNMR (CDCl
3) d: 2.98（d，
J= 9.8 Hz，1H），2.60（d，
J= 8.4 Hz，1H），2.24（s，3H），2.18-2.14（m，2H），1.98-1.95（m，4H），1.90-1.85（m，2H），1.77（d，
J= 7.8 Hz，1H）。
embodiment 10: the preparation of 1-ethoxycarbonyl-3-methylsulfonyl-3-azabicyclo [3.2.1] octane
Operation steps:
By 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane
iI-b(40 milligrams, 0.22 mmole), methane sulfonyl chloride (30 milligrams, 0.26 mmole), triethylamine (0.2 milliliter) is dissolved in tetrahydrofuran (THF) (4 milliliters), and this mixed solution at room temperature stirring reaction spends the night.Concentration of reaction solution, is dissolved in water (10 milliliters), and ethyl acetate (3 × 5 milliliters) extracts, and organic phase drying concentrates to obtain thick product.Thick product is separated through silica-gel plate and obtains 1-ethoxycarbonyl-3-methylsulfonyl-3-azabicyclo [3.2.1] octane
i-d-1, 37 milligrams, yield 65%.
HNMR (CDCl
3) d: 4.06-4.00（m，2H），3.08（s，3H），3.00（d，
J= 10.0 Hz，1H），2.56（d，
J= 8.8 Hz，1H），2.18-2.16（m，2H），1.90-1.87（m，4H），1.89-1.86（m，2H），1.77（d，
J= 8.6 Hz，1H），1.42（t，
J= 6.8 Hz, 3H）。
embodiment 11: the preparation of 1-carboxyl-3-methylsulfonyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-methylsulfonyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
i-d-1(37 milligrams, 0.14 mmole) and methyl alcohol (2 milliliters), add lithium hydroxide (34 milligrams, 1.40 mmoles) at 0 DEG C, under nitrogen protection, stirring at room temperature reacts 2 hours.Reaction solution is concentrated; being dissolved in after water (10 milliliters) dilute hydrochloric acid regulates the pH of reaction solution to be less than 7 values uses ethyl acetate (3 × 5 milliliters) to extract; organic phase drying is concentrated obtains 21 milligrams of 1-carboxyl-3-methylsulfonyl-3,8-diazabicyclo [3.2.1] octanes
i-d, yield 65%.
HNMR (CDCl
3) d: 3.11（s，3H），3.00（d，
J= 9.6 Hz，1H），2.58（d，
J= 8.4 Hz，1H），2.15-2.13（m，2H），1.93-1.89（m，4H），1.86-1.83（m，2H），1.81（d，
J= 8.2 Hz，1H）。
embodiment 12:the preparation of 1-carboxyl-3-benzoyl-3-azabicyclo [3.2.1] octane
Operation steps:
By 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane
iI-a(40 milligrams, 0.22 mmole), Benzoyl chloride (36 milligrams, 0.26 mmole), triethylamine (0.2 milliliter) is dissolved in tetrahydrofuran (THF) (4 milliliters), and this mixed solution at room temperature stirring reaction spends the night.Concentration of reaction solution, is dissolved in water (10 milliliters), and with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying concentrates to obtain thick product.Thick product is separated through silica-gel plate and obtains 1-carboxyl-3-benzoyl-3-azabicyclo [3.2.1] octane
i-e, 47 milligrams, yield 76%.
HNMR (CDCl
3) d: 7.68-7.54（m，5H），2.97（d，
J= 9.8 Hz，1H），2.60（d，
J= 8.8 Hz，1H），2.16-2.14（m，2H），1.95-1.90（m，4H），1.85-1.82（m，2H），1.89（d，
J= 7.6 Hz，1H）。
embodiment 13:the preparation of 1-ethoxycarbonyl-3-methylaminocarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
By 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane
iI-b(40 milligrams, 0.22 mmole), N-METHYLFORMAMIDE (24 milligrams, 0.26 mmole), triethylamine (0.2 milliliter) is dissolved in tetrahydrofuran (THF) (4 milliliters), and at room temperature stirring reaction spends the night.Concentration of reaction solution, is dissolved in water (10 milliliters), and with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying concentrates to obtain thick product.Thick product is separated through silica-gel plate and obtains 1-ethoxycarbonyl-3-methylaminocarbonyl-3-azabicyclo [3.2.1] octane
i-f-1, 38 milligrams, yield 73%.
HNMR (CDCl
3) d: 4.08-4.02（m，2H），3.00（d，
J= 9.8 Hz，1H），2.98（d，
J= 5.4 Hz，1H），2.89（s，3H），2.18-2.16（m，2H），1.93-1.89（m，4H），1.87-1.85（m，2H），1.83（d，
J= 8.4 Hz，1H），1.48（t，
J= 6.6 Hz, 3H）。
embodiment 14: the preparation of 1-carboxyl-3-methylaminocarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-methylaminocarbonyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
i-f-1(38 milligrams, 0.16 mmole) and methyl alcohol (2 milliliters), add lithium hydroxide (38 milligrams, 1.60 mmoles) at 0 DEG C, stirring at room temperature reacts 2 hours under nitrogen protection.Reaction solution is concentrated, be dissolved in after water (10 milliliters) dilute hydrochloric acid regulates the pH of reaction solution to be less than 7, with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying is concentrated obtains 28 milligrams of 1-carboxyl-3-methylaminocarbonyl-3-azabicyclo [3.2.1] octanes
i-f, yield 84%.
HNMR (CDCl
3) d: 2.96（d，
J= 9.6 Hz，1H），2.94（d，
J= 6.2 Hz，1H），2.87（s，3H），2.18-2.14（m，2H），1.96-1.92（m，4H），1.89-1.84（m，2H），1.80（d，
J= 8.2 Hz，1H）。
embodiment 15:the preparation of 1-ethoxycarbonyl-3-methoxycarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
By 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane
iI-b(40 milligrams, 0.22 mmole), methyl-chloroformate (25 milligrams, 0.26 mmole), triethylamine (0.2 milliliter) is dissolved in tetrahydrofuran (THF) (4 milliliters), and this mixed solution at room temperature stirring reaction spends the night.Concentration of reaction solution, is dissolved in water (10 milliliters), and with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying concentrates to obtain thick product.Thick product is separated through silica-gel plate and obtains 1-ethoxycarbonyl-3-methoxycarbonyl-3-azabicyclo [3.2.1] octane
i-g-1, 37 milligrams, yield 71%.
HNMR (CDCl
3) d: 4.23（s，3H），4.06-4.00（m，2H），2.99（d，
J= 9.6 Hz，1H），2.97（d，
J= 5.8 Hz，1H），2.19-2.17（m，2H），1.92-1.87（m，4H），1.84-1.80（m，2H），1.76（d，
J= 8.0 Hz，1H），1.55（t，
J= 6.8 Hz, 3H）。
embodiment 16:the preparation of 1-carboxyl-3-methoxycarbonyl-3-azabicyclo [3,2,1] octane
Operation steps:
1-ethoxycarbonyl-3-methoxycarbonyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
i-g-1(37 milligrams, 0.15 mmole) and methyl alcohol (2 milliliters), add lithium hydroxide (36 milligrams, 1.50 mmoles) at 0 DEG C, under nitrogen protection, and room temperature reaction 2 hours.Reaction solution is concentrated, be dissolved in after water (10 milliliters) dilute hydrochloric acid regulates the pH of reaction solution to be less than 5, with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying is concentrated obtains 28 milligrams of 1-carboxyl-3-methoxycarbonyl-3-azabicyclo [3.2.1] octanes
i-g, yield 67%.
HNMR (CDCl
3) d: 4.24（s，3H），2.99（d，
J= 9.0 Hz，1H），2.98（d，
J= 5.4 Hz，1H），2.20-2.18（m，2H），1.96-1.92（m，4H），1.90-1.84（m，2H），1.70（d，
J= 7.6 Hz，1H）。
embodiment 17:the preparation of 1-ethoxycarbonyl-3-methylamine thiocarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
By 1-ethoxycarbonyl-3-azabicyclo [3.2.1] octane
iI-b(40 milligrams, 0.22 mmole), Trapex (19 milligrams, 0.26 mmole), triethylamine (0.2 milliliter) is dissolved in tetrahydrofuran (THF) (4 milliliters), and this mixed solution at room temperature stirring reaction spends the night.Concentration of reaction solution, is dissolved in water (10 milliliters), and with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying concentrates to obtain thick product.Thick product is separated through silica-gel plate and obtains 1-ethoxycarbonyl-3-methylamine thiocarbonyl-3-azabicyclo [3.2.1] octane
i-h-1, 38 milligrams, yield 68%.
HNMR (CDCl
3) d: 4.07-4.01（m，2H），3.88（s，3H），3.01（d，
J= 9.8 Hz，1H），2.99（d，
J= 6.0 Hz，1H），2.17-2.15（m，2H），1.94-1.89（m，4H），1.87-1.84（m，2H），1.79（d，
J= 7.8 Hz，1H），1.53（t，
J= 12.2 Hz, 3H）。
embodiment 18:the preparation of 1-carboxyl-3-methylamine thiocarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-ethoxycarbonyl-3-methylamine thiocarbonyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
i-h-1(38 milligrams, 0.15 mmole) and methyl alcohol (2 milliliters), add lithium hydroxide (36 milligrams, 1.50 mmoles) at 0 DEG C, under nitrogen protection, and room temperature reaction 2 hours.Reaction solution is concentrated, be dissolved in after water (10 milliliters) dilute hydrochloric acid regulates the pH of reaction solution to be less than 5, with ethyl acetate (3 × 5 milliliters) extraction, organic phase drying is concentrated obtains 27 milligrams of 1-carboxyl-3-methylamine thiocarbonyl-3-azabicyclo [3.2.1] octanes
i-h, yield 81%.
HNMR (CDCl
3) d: 3.89（s，3H），3.02（d，
J= 9.6 Hz，1H），3.00（d，
J= 6.4 Hz，1H），2.19-2.17（m，2H），1.97-1.94（m，4H），1.89-1.85（m，2H），1.83（d，
J= 7.4 Hz，1H）。
embodiment 19: the preparation of 1-methylaminocarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane
Operation steps:
Under nitrogen protection, in a dry three-necked bottle, add 1-carboxyl-3-benzyl-3-azabicyclo [3.2.1] octane
i-a(100 milligrams, 0.41 mmole), I-hydroxybenzotriazole (HOBT) (83 milligrams, 0.61 mmole), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (117 milligrams, 0.61 mmole) and 5 milliliters of dry DMF, then after this reaction solution at room temperature stirs 5-6 hour, add triethylamine (202 milligrams, 2.0 mmoles) and methylamine hydrochloride (60 milligrams, 0.82 mmole).Reaction solution continues stirring in room temperature and spends the night, and after waiting reaction to complete, concentration of reaction solution obtains resistates, with acetic acid ethyl dissolution, washes two to three times with water, after merging organic phase anhydrous sodium sulfate drying, filters, concentrates to obtain the thick product of yellow oily.Thick product is separated through silica-gel plate and obtains 60 milligrams of 1-methylaminocarbonyl-3-benzyl-3-azabicyclo [3.2.1] octanes
iI-c-1, yield 57%.
HNMR (CDCl
3) d: 7.46-7.25（m，5H），3.50-3.47（m，2H），3.13（s，3H），2.88（d，
J= 10.8 Hz，1H），2.57（d，
J= 9.6 Hz，1H），2.18-2.15（m，2H），1.96-1.89（m，4H），1.85-1.81（m，2H），1.77（d，
J= 10.6 Hz，1H）。
embodiment 20: the preparation of 1-methylaminocarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-methylaminocarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
iI-c-1(50 milligrams, 0.20 mmole), palladium carbon (20 milligrams, mass percent 10%) and methyl alcohol (10 milliliters), in 50 DEG C of stirring reactions 12 hours in three atmospheric hydrogen environments.By reacting liquid filtering, concentrate and obtain 28 milligrams of 1-methylaminocarbonyl-3-azabicyclo [3.2.1] octanes
iI-c, yield 86%.
HNMR (CDCl
3) d: 3.15（s，3H），2.89（d，
J= 9.8 Hz，1H），2.56（d，
J= 9.4 Hz，1H），2.09-2.06（m，2H），1.93-1.90（m，4H），1.83-1.81（m，2H），1.69（d，
J= 6.6 Hz，1H）。
embodiment 21: the preparation of 1-dimethylaminocarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane
Operation steps:
Under nitrogen protection, in a dry three-necked bottle, add 1-carboxyl-3-benzyl-3-azabicyclo [3.2.1] octane
i-a(100 milligrams, 0.41 mmole), I-hydroxybenzotriazole (HOBT) (83 milligrams, 0.61 mmole), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (117 milligrams, 0.61 mmole) and 5 milliliters of dry DMF, then after this reaction solution at room temperature stirs 5-6 hour, add triethylamine (202 milligrams, 2.0 mmoles) and dimethylamine hydrochloride (72 milligrams, 0.82 mmole).Reaction solution continues stirring in room temperature and spends the night, and after waiting reaction to complete, concentration of reaction solution obtains resistates, with acetic acid ethyl dissolution, washes two to three times with water, after merging organic phase anhydrous sodium sulfate drying, filters, concentrates to obtain the thick product of yellow oily.Thick product is separated through silica-gel plate and obtains 70 milligrams of 1-dimethylaminocarbonyl-3-benzyl-3-azabicyclo [3.2.1] octanes
iI-d-1, yield 63%.
HNMR (CDCl
3) d: 7.45-7.40（m，5H），3.53-3.49（m，2H），3.10（s，6H），2.86（d，
J= 10.8 Hz，1H），2.54（d，
J= 9.8 Hz，1H），2.16-2.14（m，2H），1.87-1.85（m，4H），1.83-1.81（m，2H），1.65（d，
J= 10.6 Hz，1H）。
embodiment 22: the preparation of 1-dimethylaminocarbonyl-3-azabicyclo [3.2.1] octane
Operation steps:
1-dimethylaminocarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane is added in the single port flask of 50 milliliters
iI-d-1(50 milligrams, 0.18 mmole), palladium carbon (20 milligrams, mass percent 10%) and methyl alcohol (10 milliliters), 50 DEG C of stirring reactions 12 hours in three atmospheric hydrogen environments.By reacting liquid filtering, concentrate and obtain 28 milligrams of 1-dimethylaminocarbonyl-3-azabicyclo [3.2.1] octanes
iI-d, yield 85%.
HNMR (CDCl
3) d: 3.14（s，6H），2.79（d，
J= 9.4 Hz，1H），2.59（d，
J= 9.6 Hz，1H），2.18-2.15（m，2H），1.90-1.87（m，4H），1.85-1.82（m，2H），1.69（d，
J= 10.2 Hz，1H）。
In order to understand essence of the present invention better, use compound below
4to the inhibiting the pharmacological results that tumor cell line A549 grows, its novelty teabag in pharmacy field is described.
embodiment 23:compound
4cytotoxic activity to A549 cell:
A549 cell RPMI 1640 culture medium culturing, containing the foetal calf serum of mass percentage 10% in substratum, the Streptomycin sulphate of 100 U/ml penicillin and 100 U/milliliter.Cell joins in 96 orifice plates with 2500, every hole cell, cultivates 24 hours in 37 DEG C of incubators containing the damp atmosphere of volume percent 5% carbonic acid gas.
The mensuration MTS method of cell survival rate: cell after 24 hours hatch, by the compound of newly joining
iI-bdimethyl sulfoxide solution join in hole, concentration from 10 micromoles per liter, with the extent of dilution of three times be diluted to respectively 1.5 nmoles/liter, 9 concentration altogether.Cultivate 72 hours in 37 DEG C of incubators containing the damp atmosphere of volume percent 5% carbonic acid gas after, add 20 mL mono-solution 96 porocyte propagation detection kit (CellTiter 96 Aquenous One Solution Reagent), after continuing to cultivate 4 hours at 37 DEG C again, formazan (formazan) surveying biochemistry light instrument (Spectra Max) colorimetric under 590 nm wavelength formed, cell survival rate is by the ratio calculation of sample relative to reference substance.
Compound
4be 331 nM to 50% inhibition concentration of A549 cell, its maximal percentage inhibition is: 51%.
Experiment conclusion: this experiment shows that the growth of this compounds to human lung cancer cell A549's cell has certain restraining effect, likely develops into the new medicine with antitumor action.
Claims (2)
1. one kind 1,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives, it is characterized in that: general structure is shown in following formula:
。
2. prepare the method that according to claim 11,3-bis-replaces-3-azabicyclo [3.2.1] Octane derivatives for one kind, it is characterized in that: preparation process: adopt 2-cyclopentanone ethyl formate
1for raw material, through twice Mannich reaction, obtain 1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo [3.2.1] octane
2, compound
2with to Methyl benzenesulfonyl hydrazine reaction, obtain compound 1-ethoxycarbonyl-3-benzyl-8-Tosylhydrazone-3-azabicyclo [3.2.1] octane
3; Compound
3compound 1-ethoxycarbonyl-3-benzyl-3-azabicyclo [3.2.1] octane is generated under sodium cyanoborohydride and tosic acid effect
4; Reaction formula is as follows:
。
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