Embodiment:
Following example helps to understand content of the present invention, but the present invention includes but be not limited to following related content.
Embodiment 1
Spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
The first step: spiral shell [1,3-dihydro indenes-1,2-two bromo-4 '-tertiary butyl oxygen carbonyl piperidines] B synthetic
(A, 100g 0.35mol) are dissolved in through anhydrous Na with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines]
2SO
4Among the dried THF (1500mL), ice bath is cooled to 0 ℃, and (68.2g 0.43mol), added in about 30 minutes to drip bromine in about 5 ℃.Drip off the back 0~5 ℃ of reaction 1.5 hours.Thereafter reaction solution is contained NaHCO in stirring slowly to pour into down
3(20g) and NaHSO
3In the aqueous solution (5g) (400mL), add ethyl acetate (700mL) after 30 minutes.After separating organic layer, water layer ethyl acetate extraction (400mL * 2).Merge organic layer and extraction liquid, with saturated common salt water washing secondary, anhydrous MgSO
4Be directly used in next step reaction after dry, concentrated the doing.
Second step: spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines] C's is synthetic
The thick product of the first step gained is dissolved in ethanol (1600mL), add under stirring KOH (56g, 1mol), reflux 3 hours.Cooled and filtered, filter cake CH
2Cl
2Wash twice.Filtrate concentrates the back column chromatography purification.Get white solid 99.6g (two step yields 78%).
The 3rd step: spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] D's is synthetic
(C, 60g 0.17mol) are dissolved among the exsiccant THF (600mL) with spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines].Under the nitrogen protection, be cooled to-78 ℃ with dry ice-propanone, in 30 minutes, (2.5Min hexane, 72mL 0.18mol), add back insulation 1 hour to drip n-Butyl Lithium then.The dry ice-propanone cooling is transferred to previously prepared CO with above-mentioned reaction solution with communicating vessels down
2(600mL exsiccant THF feeds CO down in the cooling of dry ice one acetone to-THF solution
2Gas 1 hour, flow velocity 0.1m
3/ h) in, Yi Bian feed stingy amount CO
2, drip on one side, added in about 90 minutes, being incubated heats up after 2 hours naturally spends the night.Add entry (300mL) next day, and (1M, 250mL) solution stir evenly the back and remove THF on Rotary Evaporators NaOH.The residue water layer is transferred pH9~10, and with ether (150mL * 3) washing, water layer is transferred pH4~5 with 10% citric acid down in ice-water bath, uses CH then
2Cl
2Extraction (150mL * 4).Combining extraction liquid is with saturated aqueous common salt (150mL * 2) washing, anhydrous MgSO
4Get product 46g, productive rate 85% after dry, concentrated.
The 4th step: spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
(D, 50g 0.152mol) are dissolved in the methyl alcohol (600mL), add 10%Pd/C (3g), and hydrogenation is 16 hours under room temperature, 85Psi pressure with spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid].Remove by filter Pd/C, get the 49.5g product after filtrate concentrates, productive rate is 99%.
Embodiment 2
Spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
The first step: spiral shell [1,3-dihydro indenes-1,2-two bromo-4 '-tertiary butyl oxygen carbonyl piperidines] B synthetic
(A, 100g 0.35mol) are dissolved in through anhydrous Na with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines]
2SO
4Among the dried THF (1500mL), ice bath is cooled to 0 ℃, and (68.2g 0.43mol), added in about 30 minutes to drip bromine in about 5 ℃.Drip off the back 0~5 ℃ of reaction 1.5 hours.Thereafter reaction solution is contained NaHCO in stirring slowly to pour into down
3(20g) and NaHSO
3In the aqueous solution (5g) (400mL), add ethyl acetate (700mL) after 30 minutes.After separating organic layer, water layer ethyl acetate extraction (400mL * 2).Merge organic layer and extraction liquid, with saturated common salt water washing secondary, anhydrous MgSO
4Be directly used in next step reaction after dry, concentrated the doing.
Second step: spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines] C's is synthetic
The thick product of the first step gained is dissolved in ethanol (1600mL), add under stirring KOH (56g, 1mol), reflux 3 hours.Cooled and filtered, filter cake CH
2Cl
2Wash twice.Filtrate concentrates the back column chromatography purification.Get white solid 99.6g (two step yields 78%).
The 3rd step: spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester] E's is synthetic
Palladium (0.225g, 1mmol) with 1, two (diphenylphosphino) propane (0.83g of 3-, 2mmol) join spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines] (C, 18.4g, 50mmol) and triethylamine (24.2g .70 ℃ of dimethyl formamide 0.22mol) (400mL)-methyl alcohol (100mL) solution, reaction two days under the carbon monoxide atmosphere under the normal pressure.Catalyzer is gone out in filtration, concentrates the back column chromatography and obtains 13.8g (yield: 80.5%).
The 4th step: spiral shell [1,3-dihydro indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester] F's is synthetic
With spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester](E, 7g 20mmol) are dissolved in the methyl alcohol (100mL), add 10%Pd/C (0.5g), and hydrogenation is 16 hours under room temperature, 85Psi pressure.Remove by filter Pd/C, get the 6.9g product after filtrate concentrates, productive rate is 98%.
The 5th step: spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
Spiral shell [1,3-dihydro indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester] (15mmol), (1.26g 30mmol) is dissolved in methyl alcohol (50mL)-water (30mL) lithium hydroxide list hydrate for F, 5.2g.After stirring is spent the night, pressure reducing and steaming methyl alcohol, the residual aqueous solution washs with ether (20mL * 2).Water is under 0 ℃, with about 10% citric acid adjust pH to 4.The solid filtering of separating out, washing, airing gets 4.6g product (yield: 92%).
Embodiment 3
Spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
The first step: spiral shell [1,3-dihydro indenes-1,2-two bromo-4 '-tertiary butyl oxygen carbonyl piperidines] B synthetic
(A, 100g 0.35mol) are dissolved in through anhydrous Na with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines]
2SO
4Among the dried THF (1500mL), ice bath is cooled to 0 ℃, and (68.2g 0.43mol), added in about 30 minutes to drip bromine in about 5 ℃.Drip off the back 0~5 ℃ of reaction 1.5 hours.Thereafter reaction solution is contained NaHCO in stirring slowly to pour into down
3(20g) and NaHSO
3In the aqueous solution (5g) (400mL), add ethyl acetate (700mL) after 30 minutes.After separating organic layer, water layer ethyl acetate extraction (400mL * 2).Merge organic layer and extraction liquid, with saturated common salt water washing secondary, anhydrous MgSO
4Be directly used in next step reaction after dry, concentrated the doing.
Second step: spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines] C's is synthetic
The thick product of the first step gained is dissolved in ethanol (1600mL), add under stirring KOH (56g, 1mol), reflux 3 hours.Cooled and filtered, filter cake CH
2Cl
2Wash twice.Filtrate concentrates the back column chromatography purification.Get white solid 99.6g (two step yields 78%).
The 3rd step: spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester] D's is synthetic
(C, 5.47g 15mmol) are dissolved among the exsiccant THF (60mL) with spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines].Under the nitrogen protection, be cooled to-78 ℃ with dry ice-propanone, in 30 minutes, (1M in THF, 18mL 18mmol), were warming up to stirring at room 1 hour after adding to drip sec.-propyl bromination magnesium then.Mixture is cooled to-78 ℃ with dry ice-propanone again, and the dry ice-propanone cooling is transferred to previously prepared CO with above-mentioned reaction solution with communicating vessels down
2(60mL exsiccant THF feeds CO down in the cooling of dry ice one acetone to-THF solution
2Gas 1 hour, flow velocity 0.1m
3/ h) in, Yi Bian feed stingy amount CO
2, drip on one side, added in about 30 minutes, being incubated heats up after 2 hours naturally spends the night.Add entry (30mL) next day, and (1M, 25mL) solution stir evenly the back and remove THF on Rotary Evaporators NaOH.The residue water layer is transferred pH9~10, and with ether (20mL * 3) washing, water layer is transferred pH4~5 with 10% citric acid down in ice-water bath, uses CH then
2Cl
2Extraction (30mL * 4).Combining extraction liquid is with saturated aqueous common salt (20mL * 2) washing, anhydrous MgSO
4Get product 4g, productive rate 81% after dry, concentrated.
The 4th step: spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
(D, 50g 0.152mol) are dissolved in the methyl alcohol (600mL), add 10%Pd/C (3g), and hydrogenation is 16 hours under room temperature, 85psi pressure with spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid].Remove by filter Pd/C, get the 49.5g product after filtrate concentrates, productive rate is 99%
Embodiment 4
Spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
The first step: spiral shell [1,3-dihydro indenes-1,2-two bromo-4 '-tertiary butyl oxygen carbonyl piperidines] B synthetic
(A, 100g 0.35mol) are dissolved in through anhydrous Na with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines]
2SO
4Among the dried THF (1500mL), ice bath is cooled to 0 ℃, and (68.2g 0.43mol), added in about 30 minutes to drip bromine in about 5 ℃.Drip off the back 0~5 ℃ of reaction 1.5 hours.Thereafter reaction solution is contained NaHCO in stirring slowly to pour into down
3(20g) and NaHSO
3In the aqueous solution (5g) (400mL), add ethyl acetate (700mL) after 30 minutes.After separating organic layer, water layer ethyl acetate extraction (400mL * 2).Merge organic layer and extraction liquid, with saturated common salt water washing secondary, anhydrous MgSO
4Be directly used in next step reaction after dry, concentrated the doing.
Second step: spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines] C's is synthetic
The thick product of the first step gained is dissolved in ethanol (1600mL), add under stirring KOH (56g, 1mol), reflux 3 hours.Cooled and filtered, filter cake CH
2Cl
2Wash twice.Filtrate concentrates the back column chromatography purification.Get white solid 99.6g (two step yields 78%).
The 3rd step: spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester] E's is synthetic
Under the nitrogen protection, spiral shell [indenes-1-bromo-4 '-tertiary butyl oxygen carbonyl piperidines] (C, 5.47g, 15mmol), triethylamine (3.03g, 30mmol), four triphenyl phosphorus palladiums (0.87g, 0.75mmol), the mixing solutions of methyl alcohol (60mL), in 80-85 ℃, reaction is 14 hours under 5 normal atmosphere carbon monoxide atmosphere, is cooled to room temperature then, after concentrated the doing, add water (40mL) and ethyl acetate (90mL) again, be stirred to molten entirely, standing demix, organic layer is with 2N hydrochloric acid (30mL), 5% sodium bicarbonate (30mL), each washing of water (30mL) is once; Concentrate the back column chromatography and get product 3.9g, yield 76%.
The 4th step: spiral shell [1,3-dihydro indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester] F's is synthetic
With spiral shell [indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester](E, 7g 20mmol) are dissolved in the methyl alcohol (100mL), add 10%Pd/C (0.5g), and hydrogenation is 16 hours under room temperature, 85Psi pressure.Remove by filter Pd/C, get the 6.9g product after filtrate concentrates, productive rate is 98%.
The 5th step: spiral shell [1,3-dihydro indenes-4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylic acid] synthetic
Spiral shell [1,3-dihydro indenes 4 '-tertiary butyl oxygen carbonyl piperidines-1-carboxylate methyl ester] (15mmol), (1.26g 30mmol) is dissolved in methyl alcohol (50mL)-water (30mL) lithium hydroxide list hydrate for F, 5.2g.After stirring is spent the night, pressure reducing and steaming methyl alcohol, the residual aqueous solution washs with ether (20mL * 2).Water is under 0 ℃, with about 10% citric acid adjust pH to 4.The solid filtering of separating out, washing, airing gets 4.6g product (yield: 92%).