CN102875556B - (4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative and preparation method - Google Patents

(4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative and preparation method Download PDF

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CN102875556B
CN102875556B CN201110193552.5A CN201110193552A CN102875556B CN 102875556 B CN102875556 B CN 102875556B CN 201110193552 A CN201110193552 A CN 201110193552A CN 102875556 B CN102875556 B CN 102875556B
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heptane
benzyl
methoxy
diazabicyclo
tertbutyloxycarbonyl
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CN102875556A (en
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尤佳
彭宣嘉
胡利红
沙爽
蔡兰兰
沈余红
董径超
吴颢
马汝建
陈曙辉
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Wuxi Apptec Tianjin Co Ltd
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Abstract

The present invention relates to (4S)-1-and replace-2,5-diazabicyclo [2,2,1] heptane derivative and preparation method, mainly solves 2,5-current diazabicyclos [2,2,1] endocyclic compound of heptane structure depends on 2 mostly, and the group that the nitrogen of 5 goes to carry out modifying or connecting other thus space extends and is restricted, and cannot meet the technical problem such as the various enzyme of organism, acceptor diversity structurally.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, tertbutyloxycarbonyl, alkyloyl, methylsulfonyl, urea; G is hydroxyl, C1-C10 straight chain or containing the alkoxyl group of substituting group side chain, the one of alkylamino radical.

Description

(4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative and preparation method
Technical field
The present invention relates to (4S)-1-and replace-2,5-diazabicyclo [2,2,1] heptane derivative and preparation method, particularly (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-replaces-2,5-diazabicyclo [2,2,1] iieptanes derivative, 1-methoxycarbonyl-5-replace-2,5-diazabicyclos [2,2,1] iieptanes derivative and (4S)-1-replace-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] iieptanes 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 2,5-diazabicyclo 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 j.Med.Chem.: EN:53,2010:7874-7878 have reported for work the compound containing 2,5-diazabicyclo [2,2,1] heptane fragment 1, as a kind of B-Raf kinase inhibitor, there is specific inhibitory activity, manifest it and there is good antitumor potential applicability in clinical practice.
Patent WO2009050236 reports the compound of 2,5-diazabicyclo [2,2,1] heptane fragment 2there is anti-inflammatory efficacy, also have certain therapeutic action to periphery and central nervous system disease.
Patent WO2009137503 reports the compound of 2,5-diazabicyclo [2,2,1] heptane fragment 3be class I histone deacetylase inhibitors, as the novel effective antitumour medicine of a class, can acetylation of histone be promoted, realize some specific gene transcription regulation.Also there is certain anti inflammatory immunity active simultaneously, show while anti-inflammatory inflammation inducing action in various degree.
Patent 2010061329 reports the compound of a series of 2,5-diazabicyclos [2,2,1] heptane fragment, as compound 4.It has anti-human immunodeficiency virus (HIV) effect as a kind of CCR5 antagonist, and meanwhile, this compounds also has resisting rheumatoid arthritis, analgesia, the effects such as diabetes.
Patent WO2011000845 reports the effect that compound 5 has the disorder of the anti-nervus centralis decorum, as treatment inflammation of the central nervous system, and the effects such as demyelination disease and central nervous system degenerative disease.Therefore, this compound is expected the medicine becoming a treatment alzheimer's disease.
Patent WO2011030139 reports compound 6 to be only used for the treatment of as a class G-protein-coupled receptor conditioning agent, to prevent, to slow down the disease needing GPR119G protein-coupled receptor modulators for treatment, is especially applied to the treatment of obesity and 2-patients with type Ⅰ DM.
Although we can see that azabicyclo structure finds in a large amount of active compounds from example above, but, current endocyclic compound 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, the various enzyme of organism, acceptor diversity structurally cannot be met, be also unfavorable for that rapid screening compound activity is analyzed.Therefore, we need to expand its structural modification and improve its quasi-medicated property matter further.
Summary of the invention
The object of the invention is to be to provide a kind of (4S)-1-to replace-2,5-diazabicyclos [2,2,1] heptane derivative and preparation method.Mainly solve current diazabicyclo [2,2,1] endocyclic compound of heptane structure depends on 2 mostly, and the group that the nitrogen of 5 carries out modifying or connect other thus space extends and is restricted, and cannot meet the technical problem such as the various enzyme of organism, acceptor diversity structurally.The invention provides and change the synthetic method that existing (4S)-1-replacement-2,5-diazabicyclos [2,2,1] heptane derivative 1 introduces carboxy derivatives.
Technical scheme is: a kind of (4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative, it is characterized in that: general structure is shown in following formula:
Wherein R 1for replacing the protecting group of functional group or amino, be selected from the one in H, tertbutyloxycarbonyl, alkyloyl, methylsulfonyl, urea; G is hydroxyl, amino, C1-C10 straight chain or containing the alkoxyl group of substituting group side chain, the one of alkylamino radical; PMB is to methoxy-benzyl.
According to the present invention, (4S)-1-replaces-2,5-diazabicyclos [2,2,1] the preferred compound of heptane derivative is: when G is hydroxyl, for (the 4S)-1-formic acid-5-shown in formula I replaces-2,5-diazabicyclo [2,2,1] heptane derivative:
Wherein R 1for replacing the protecting group of functional group or amino, be selected from the one of H, tertbutyloxycarbonyl, alkyloyl, methylsulfonyl.
On this basis, the further preferred compound of the present invention includes but not limited to:
I-a:(4S)-1-formic acid-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane;
I-b:(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane;
I-c:(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane;
I-d:(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane.
According to the present invention, (4S)-1-replaces-2,5-diazabicyclos [2,2,1] the preferred compound of heptane derivative is: when G is methoxyl group, for (the 4S)-1-methoxycarbonyl-5-shown in formula II replaces-2,5-diazabicyclo [2,2,1] heptane derivative:
Wherein R 1for the one in H, alkyloyl, methylsulfonyl.
On this basis, the further preferred compound of the present invention includes but not limited to:
II-a:(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane;
II-b:(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane;
II-c:(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane.
According to the present invention, (4S)-1-replaces the preferred compound of-2,5-diazabicyclos [2,2,1] heptane derivative and is: work as R 1during for tertbutyloxycarbonyl, for (the 4S)-1-shown in formula III replaces-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane derivative:
Wherein G is amino or alkylamino radical.
On this basis, the further preferred compound of the present invention includes but not limited to:
III-a:(4S)-1-aminocarboxyl-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane;
III-b:(4S)-1-formyl radical-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane;
III-c:(4S)-1-p-fluorin benzyl amine group carbonyl-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane.
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.
-2 are replaced such as formula (the 4S)-1-shown in I, 5-diazabicyclo [2,2,1] preparation method of heptane derivative, it is characterized in that: the G in formula 1 is hydroxyl, (4S)-1-replaces-2,5-diazabicyclo [2,2,1] heptane derivative is that (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-replaces-2,5-diazabicyclos [2,2,1] heptane, preparation process: adopt (2S)-1-tertbutyloxycarbonyl-2-methoxycarbonyl-4-hydroxyl azepine penta ring 1for raw material, obtain (2S)-1-tertbutyloxycarbonyl-2-(methylol through reduction)-4-hydroxyl-azepine penta ring 2; Compound 2react with Tosyl chloride, obtain (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl)-4-hydroxyl-azepine penta ring 3; Compound 3under the effect of Dai Si-Martin reagent, oxidation obtains (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl)-4-carbonyl-azepine penta ring 4; Compound 4(4S)-1-cyano group-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane is obtained under the effect of acetone cyanohydrin and 4-Methoxybenzylamine 5; Compound 5obtain through sodium hydroxide hydrolysis i-b; Compound i-bremove tertbutyloxycarbonyl through hydrochloric acid dioxane to obtain i-a; i-aobtain (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-respectively at methylsulfonyl chloride and excess acetyl chloride and replace-2,5-diazabicyclos [2,2,1] heptane derivative i-c, i-d, reaction formula is as follows:
Wherein R 1for replacing the protecting group of functional group or amino, be selected from the one of tertbutyloxycarbonyl, alkyloyl, methylsulfonyl, THF is tetrahydrofuran (THF), and TsCl is Tosyl chloride, and TEA is triethylamine, and DMP is Dai Si-Martin reagent, and DCM is methylene dichloride.
-2,5-diazabicyclos [2,2 are replaced such as formula (the 4S)-1-shown in II, 1] preparation method of heptane derivative, it is characterized in that: when G is methoxyl group, (4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative is that 1-methoxycarbonyl-5-replaces-2,5-diazabicyclos [2,2,1] heptane, preparation process: adopt compound i-bfor raw material, be obtained by reacting compound with under hydrochloric acid methanol effect iI-a, compound iI-aobtain (4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-respectively at methylsulfonyl chloride and excess acetyl chloride and replace-2,5-diazabicyclos [2,2,1] heptane derivative iI-b, iI-c, reaction formula is as follows:
Wherein R 1for the one in alkyloyl, methylsulfonyl.
(4S)-1-as shown in formula III replaces the method for-2,5-diazabicyclos [2,2,1] heptane derivative, it is characterized in that: work as R 1during for tertbutyloxycarbonyl, it is that (4S)-1-replaces-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane, preparation process that (4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative: adopt compound 5(4S)-1-cyano group-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane is raw material, obtains through alkaline hydrolysis iII-a; Adopt compound i-bfor raw material, obtain compound with methylamine hydrochloride and 4-Methoxybenzylamine condensation respectively iII-b, iII-c, reaction formula is as follows:
Wherein R 2for methyl or to luorobenzyl.HATU is 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester.
Beneficial effect of the present invention :we replace-2,5-diazabicyclos [2,2 at (4S)-1-, 1] 1 carbonylate class functional group of heptane derivative, not only improve the polarity of template, we are based on 1-formic acid cpds simultaneously, and 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; and find that the growth of the compounds of this invention to human lung cancer cell A549's cell has faint restraining effect, lay 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:(2S)-1-tertbutyloxycarbonyl-2-(methylol) preparation of-4-hydroxyl-azepine penta ring
Operation steps:
Lithium Aluminium Hydride (20 grams is added in the there-necked flask of 2 liters; 0.51 mole) and anhydrous tetrahydro furan (1000 milliliters); (50 grams, (2S)-1-tertbutyloxycarbonyl-2-methoxycarbonyl-4-hydroxyl azepine penta ring is dripped under 0 degree Celsius; 0.20 mole), stirring at room temperature 20 hours under nitrogen protection.Reaction solution goes out with shrend under 0 degree Celsius, extraction into ethyl acetate, dry, and organic phase is concentrated obtains 35 grams of (2S)-1-tertbutyloxycarbonyl-2-(methylols)-4-hydroxyl-azepine penta ring 2, be directly used in next step reaction, yield 79%.
HNMR(CDCl 3)d:5.26（s，1H），4.30（s，1H），4.07-4.09（m，1H），3.96-4.00（m，1H），3.37-3.56（m，4H），2.01-2.03（m，1H），1.65（s，1H），1.43（s，9H）。
embodiment 2: (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl) preparation of-4-hydroxyl-azepine penta ring
Operation steps:
(2S)-1-tertbutyloxycarbonyl-2-(methylol is added in the there-necked flask of 1000 milliliters)-4-hydroxyl-azepine penta ring 2(35 grams, 0.16 mole), triethylamine (48.9 grams, 0.48 mole) and anhydrous methylene chloride (500 milliliters), drip Tosyl chloride (92 grams, 0.48 mole), stirring at room temperature 24 hours under nitrogen protection under 0 degree Celsius.Reaction solution washes with water, dichloromethane extraction, and then organic phase uses saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated.Thick product obtains 20 grams of (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyls through column chromatography)-4-hydroxyl-azepine penta ring 3, yield 33%.
HNMR(CDCl 3)d:7.75（d， J=8.0Hz，2H），7.34（s，2H），4.33-4.44（m，1H），4.08-4.14（m，3H），3.22-3.53（m，2H），2.43（s，3H），2.05-2.10（m，2H），1.36（d， J=22.4Hz，9H）。
embodiment 3: (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl) preparation of-4-carbonyl-azepine penta ring
Operation steps:
In the single port flask of 500 milliliters, add Dai Si-Martin reagent (57 grams, 0.13 mole) and methylene dichloride (200 milliliters), under 0 degree Celsius, add (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl)-4-hydroxyl-azepine penta ring 3(20 grams, 0.05 mole), stirred overnight at room temperature under nitrogen protection.Reaction solution is used water quenched dilution, methylene dichloride (3 × 100 milliliters) extracts, and then organic phase uses saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated.Thick product obtains 5 grams of (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyls through column chromatography)-4-carbonyl-azepine penta ring 4, yield 25%.
HNMR(CDCl 3)d:7.76（d， J=8.0Hz，2H），7.35（d， J=8.0Hz，2H），4.45-4.47（m，2H），3.51-4.22（m，4H），2.74-2.77（m，1H），2.45（s，3H），1.44（s，9H）。
embodiment 4: the preparation of (4S)-1-cyano group-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl is added in 100 milliliters of vexed tanks of tetrafluoro) (5 grams ,-4-carbonyl-azepine penta ring; 0.01 mole); 4-Methoxybenzylamine (2 grams; 0.01 mole) and acetone cyanohydrin (3.46 grams; 0.04 mole); then in mixture, 50 milliliters of anhydrous methanols are added, airtight vexed tank.Mixture is slowly heated to 100 C overnight.Reaction solution pours 100 milliliters of saturated sodium bicarbonate solution washings into, and mixture is extracted with ethyl acetate, and then organic phase uses saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated.Thick product obtains 2 grams of (4S)-1-cyano group-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane through column chromatography 5, yield 43%.
HNMR(CDCl 3)d:7.23（d， J=8.8Hz，2H），6.84（d， J=8.8Hz，2H），4.25-4.39（m，1H），3.93-4.06（m，2H），3.78（s，3H），3.46-3.56（m，2H），3.03（brs，1H）,2.33-2.47(m，2H)，2.19（dd， J=22.6Hz，1H），1.43-1.47（m，9H）。
embodiment 5: the preparation of (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-cyano group-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2 is added in the single port flask of 100 milliliters, 5-diazabicyclo [2,2,1] heptane (1.8 grams, 5.2 mmoles), the sodium hydroxide solution (15 milliliters) of 1 mole often liter and anhydrous methanol (20 milliliters), and in 70 degrees Celsius of stirring reactions 5 hours.Reaction solution adds water washing, dichloromethane extraction, and gained organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, concentrates and obtains 1.2 grams of (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclos [2,2,1] heptane i-b, yield 63%.
HNMR(CD 3OD)d:7.51（d， J=8.0Hz，2H），7.01（d， J=8.0Hz，2H），4.65-4.68（m，2H），4.10-4.23（m，2H），3.92-3.95（m，1H），3.82（s，3H），3.48-3.51（m，2H），2.31-2.52(m，2H)，1.52（s，9H）。
embodiment 6: the preparation of (4S)-1-formic acid-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane
Operation steps:
(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2,2,1] heptane (300 milligrams, 0.83 mmole) and hydrochloric acid dioxane (20 milliliters), mixed solution at room temperature stirs 2 hours.Concentration of reaction solution, thick product obtains 120 milligrams of (4S)-1-formic acid-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane through high performance liquid phase preparative separation i-a, yield 55%.
HNMR(CDCl 3)d:7.35（d， J=8.8Hz，2H），6.90（d， J=8.8Hz，2H），4.40（s，1H），3.92-4.08（m，2H），3.80（s，3H），3.53-3.69（m，2H），2.85-3.30（m，2H），2.30-2.51(m，2H)。
embodiment 7:(4S) preparation of-1-formic acid-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-formic acid-2-(4-methoxy-benzyl)-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2,2,1] heptane (50 milligrams, 0.19 mmole), triethylamine (109 milligrams, 0.54 mmole), methane sulfonyl chloride (55 milligrams, 0.54 mmole) and methylene dichloride (3 milliliters).This mixed solution at room temperature stirring reaction 2 hours.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 obtains 10 milligrams of (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane through high performance liquid phase preparative separation i-c, yield 15%.
HNMR(CDCl 3)d:7.49（d， J=8.8Hz，2H），7.01（d， J=8.8Hz，2H），4.46-4.63（m，2H），4.22-4.28（m，2H），3.97-4.00（m，1H），3.84（s，3H），3.45-3.54（m，2H），2.72（s，3H），2.40-2.55(m，2H)。
embodiment 8:(4S) preparation of-1-formic acid-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2,2,1] heptane (50 milligrams, 0.19 mmole), triethylamine (109 milligrams, 0.54 mmole), Acetyl Chloride 98Min. (55 milligrams, 0.54 mmole) and methylene dichloride (3 milliliters).This mixed solution at room temperature stirring reaction 2 hours.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 obtains 10 milligrams of (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane through high performance liquid phase preparative separation i-d, yield 17%.
HNMR(CDCl 3)d:7.55（d， J=8.8Hz，2H），7.03（d， J=8.8Hz，2H），4.84（s，1H），4.67-4.70（m，1H），3.99-4.39（m，3H），3.84(s，3H)，3.45-3.68（m，2H），2.37-2.64（m，2H），2.14（s，3H）。
embodiment 9: the preparation of (4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane
Operation steps:
(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2,2,1] heptane (100 milligrams, 0.27 mmole) and methanol hydrochloride solution (20 milliliters, 4 moles often liter), mixed solution at room temperature stirs 2 hours.Concentration of reaction solution, thick product obtains 20 milligrams of (4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane through high performance liquid phase preparative separation iI-a, yield 26%.
HNMR(CD 3OD)d:7.30（d， J=8.8Hz，2H），6.89（d， J=8.8Hz，2H），4.32（s，1H）,3.97-4.04（m，2H），3.78(s，6H)，3.61-3.71（m，2H），3.26-3.29（m，1H），2.78-2.81（m，1H），2.48-2.50(m，1H)，2.28(d， J=8.0Hz，1H)。
embodiment 10:(4S) preparation of-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2,2,1] heptane (50 milligrams, 0.18 mmole), triethylamine (109 milligrams, 0.54 mmole), methane sulfonyl chloride (55 milligrams, 0.54 mmole) and at methylene dichloride (3 milliliters).This mixed solution at room temperature stirring reaction 2 hours.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 obtains 20 milligrams of (4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane through high performance liquid phase preparative separation iI-b, yield 32%.
HNMR(CDCl 3)d:7.50（d， J=8.8Hz，2H），7.02（d， J=8.8Hz，2H），4.42-4.65（m，2H），4.23-4.29（m，2H），3.97-4.00（m，1H），3.97（s，3H），3.83（s，3H），3.49-3.54（m，2H），2.71（s，3H），2.41-2.54(m，2H)。
embodiment 11:(4S) preparation of-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2,2,1] heptane (50 milligrams, 0.18 mmole), triethylamine (109 milligrams, 0.54 mmole), Acetyl Chloride 98Min. (55 milligrams, 0.54 mmole) and methylene dichloride (3 milliliters).This mixed solution at room temperature stirring reaction 2 hours.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 obtains 10 milligrams of (4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane through high performance liquid phase preparative separation iI-c, yield 17%.
HNMR(CDCl 3)d:7.33（d， J=8.8Hz，2H），6.83（d， J=8.8Hz，2H），4.45-4.48（s，2H），4.17-4.22（m，2H），4.06-4.10（m，1H），3.88(s，3H)，3.78(s，3H)，3.41-3.65（m，2H），2.32-2.60（m，2H），2.12（s，3H）。
embodiment 12: the preparation of (4S)-1-aminocarboxyl-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2,2,1] heptane (100 milligrams, 0.3 mmole), the sodium hydroxide solution (10 milliliters) of 1 mole often liter and anhydrous methanol (10 milliliters) were in 45 degrees Celsius of stirring reactions 3 hours.Reaction solution adds water washing, dichloromethane extraction, and gained organic phase is through saturated common salt water washing, and anhydrous sodium sulfate drying, concentrates.Thick product obtains 50 milligrams of (4S)-1-aminocarboxyl-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane through high performance liquid phase preparative separation iII-a, yield 47%.
HNMR(CD 3OD)d:7.51（d， J=8.8Hz，2H），7.00（d， J=8.8Hz，2H），4.57-4.67（m，2H），3.93-4.25（m，3H），3.81（s，3H），3.37-3.48（m，2H），2.28-2.51(m，2H)，1.52（s，9H）。
embodiment 13: the preparation of (4S)-1-formyl radical-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-acyl group-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2 is added in the single port flask of 50 milliliters; 5-diazabicyclo [2; 2; 1] heptane (100 milligrams; 0.27 mmole) and 2-(7-azo benzotriazole)-N; N; N '; N '-tetramethyl-urea phosphofluoric acid ester (209 milligrams, 0.55 mmole), triethylamine (139 milligrams; 1.38 mmoles) and dimethyl formamide (2 milliliters); after this reaction solution at room temperature stirs 10 minutes, add methylamine hydrochloride (37 milligrams, 0.55 mmole).Reaction solution is stirred overnight at room temperature under nitrogen protection.After having reacted, reaction solution adds water washing, extraction into ethyl acetate, and gained organic phase is through saturated common salt water washing, and anhydrous sodium sulfate drying, concentrates to obtain the thick product of yellow oily.Thick product obtains 20 milligrams of (4S)-1-formyl radical-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane through high performance liquid phase preparative separation iII-b, yield 19%.
HNMR(CDCl 3)d:7.51（d， J=8.0Hz，2H），7.01（d， J=8.0Hz，2H），4.57-4.67（m，2H），3.86-4.27（m，3H），3.82（s，3H），3.39-3.50（m，2H），2.85（s，3H），2.34-2.54(m，2H)，1.51（s，9H）。
embodiment 14: the preparation of (4S)-1-p-fluorin benzyl amine group carbonyl-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane
Operation steps:
(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2 is added in the single port flask of 50 milliliters, 5-diazabicyclo [2, 2, 1] heptane (100 milligrams, 0.27 mmole) and 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (209 milligrams, 0.55 mmole), triethylamine (84 milligrams, 0.83 mmole) and dimethyl formamide (2 milliliters), after this reaction solution at room temperature stirs 10 minutes, add NSC 158269 (69 milligrams, 0.55 mmole), reaction solution is stirred overnight at room temperature under nitrogen protection.After question response completes, reaction solution adds water washing, extraction into ethyl acetate, and gained organic phase is through saturated common salt water washing, and anhydrous sodium sulfate drying, concentrates.Thick product obtains 20 milligrams of (4S)-1-p-fluorin benzyl amine group carbonyl-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane through high performance liquid phase preparative separation iII-c, yield 15%.
HNMR(CDCl 3)d:7.29-7.33（m，2H），7.15（d， J=7.6Hz，2H），6.97-7.01（m，2H），6.86（d， J=8.4Hz，2H），4.35-4.50（m，3H），3.89-4.09（m，2H），3.80（s，3H），3.36-3.54（m，2H），2.88-3.25(m，2H)，2.22-2.58(m，2H)，1.45（s，9H）。
In order to understand essence of the present invention better, here is compound i-bto the inhibiting the pharmacological results that tumor cell line A549 grows, its novelty teabag in pharmacy field is described.
embodiment 15:compound i-bto the cytotoxic activity of human lung cancer cell A549's cell
A549(people's lung cancer) cell RPMI1640 culture medium culturing, containing the foetal calf serum of 10% in substratum, the Streptomycin sulphate of 100U/ ml penicillin and 100U/ milliliter.Cell joins in 96 orifice plates with 2500, every hole cell, at 37 degrees Celsius containing volume percent 5%CO 2cultivate 24 hours in the incubator of damp atmosphere.
The mensuration MTS method of cell survival rate.Cell after 24 hours hatch, by the compound of newly joining 1dimethyl sulfoxide solution join in hole, concentration, from 10 micromoles, is diluted to 1.5 nmoles respectively with the extent of dilution of three times, altogether 9 concentration.At 37 degrees Celsius containing volume percent 5%CO 2cultivate in the incubator of damp atmosphere after 72 hours, add 20 microlitre list solution 96 porocytes propagation detection kit (CellTiter96AquenousOneSolutionReagent), after continuing to cultivate 4 hours at 37 degrees Celsius again, formazan (formazan) surveying biochemistry light instrument (SpectraMax) colorimetric under 590 nmole wavelength formed, cell survival rate is by the ratio calculation of sample relative to reference substance.
Compound i-bto the maximal percentage inhibition of A549 cell be: 2.4%.
Experiment conclusion: this experiment shows that the growth of this compounds to human lung cancer cell A549's cell has faint restraining effect, by further texture improvement and modification, potentially develops into the new medicine with antitumor action.

Claims (4)

1. (4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative, and its general structure is shown in following formula:
Wherein R 1be selected from the one in H, tertbutyloxycarbonyl, ethanoyl, methylsulfonyl; G is the one of hydroxyl, amino or methoxyl group; For one of following compound:
I-a:(4S)-1-formic acid-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane;
I-b:(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane;
I-c:(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane;
I-d:(4S)-1-formic acid-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane;
II-a:(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-2,5-diazabicyclos [2,2,1] heptane;
II-b:(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-methylsulfonyl-2,5-diazabicyclo [2,2,1] heptane;
II-c:(4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-ethanoyl-2,5-diazabicyclo [2,2,1] heptane;
III-a:(4S)-1-aminocarboxyl-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane.
2. prepare (4S) according to claim 1-1-replacement-2 for one kind, 5-diazabicyclo [2,2,1] method of heptane derivative, it is characterized in that: the G in formula 1 is hydroxyl, (4S)-1-replaces-2,5-diazabicyclo [2,2,1] heptane derivative is that (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-replaces-2,5-diazabicyclos [2,2,1] heptane, preparation process: adopt (2S)-1-tertbutyloxycarbonyl-2-methoxycarbonyl-4-hydroxyl azepine penta ring 1for raw material, obtain (2S)-1-tertbutyloxycarbonyl-2-(methylol through reduction)-4-hydroxyl-azepine penta ring 2; Compound 2react with Tosyl chloride, obtain (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl)-4-hydroxyl-azepine penta ring 3; Compound 3under the effect of Dai Si-Martin reagent, oxidation obtains (2S)-1-tertbutyloxycarbonyl-2-(tolysulfonyl ylmethyl)-4-carbonyl-azepine penta ring 4; Compound 4(4S)-1-cyano group-2-(4-methoxy-benzyl)-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2,2,1] heptane is obtained under the effect of acetone cyanohydrin and 4-Methoxybenzylamine 5; Compound 5obtain through sodium hydroxide hydrolysis i-b; Compound i-bremove tertbutyloxycarbonyl through hydrochloric acid dioxane to obtain i-a; i-aobtain (4S)-1-formic acid-2-(4-methoxy-benzyl)-5-respectively at methylsulfonyl chloride and excess acetyl chloride and replace-2,5-diazabicyclos [2,2,1] heptane derivative i-c, i-d, reaction formula is as follows:
Wherein R 1be selected from ethanoyl or methylsulfonyl.
3. prepare (4S) according to claim 1-1-replacement-2,5-diazabicyclos [2,2 for one kind, 1] method of heptane derivative, it is characterized in that: when G is methoxyl group, (4S)-1-replaces-2,5-diazabicyclos [2,2,1] heptane derivative is that 1-methoxycarbonyl-5-replaces-2,5-diazabicyclos [2,2,1] heptane, preparation process: adopt compound i-bfor raw material, be obtained by reacting compound with under hydrochloric acid methanol effect iI-a, compound iI-aobtain (4S)-1-methoxycarbonyl-2-(4-methoxy-benzyl)-5-respectively at methylsulfonyl chloride and excess acetyl chloride and replace-2,5-diazabicyclos [2,2,1] heptane derivative iI-b, iI-c, reaction formula is as follows:
Wherein R 1for ethanoyl or methylsulfonyl.
4. the method prepared (4S) according to claim 1-1-and replace-2,5-diazabicyclos [2,2,1] heptane derivative, is characterized in that: compound iII-abe prepared as follows: adopt compound 5for raw material, obtain through sodium hydroxide hydrolysis iII-a;
。
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