CN101092396B - Method for preparing template compound of ancylus fluviatilis [1,3 dihydro indene - 4'- piperidine 1 - carboxylic acid] - Google Patents
Method for preparing template compound of ancylus fluviatilis [1,3 dihydro indene - 4'- piperidine 1 - carboxylic acid] Download PDFInfo
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- CN101092396B CN101092396B CN2006100278794A CN200610027879A CN101092396B CN 101092396 B CN101092396 B CN 101092396B CN 2006100278794 A CN2006100278794 A CN 2006100278794A CN 200610027879 A CN200610027879 A CN 200610027879A CN 101092396 B CN101092396 B CN 101092396B
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Abstract
This invention relates to a method for synthesizing spiro compound, i.e., spiro [1, 3-dihydrolindane-4'-piperidine-1-carboxylic acid] template compound. The method comprises: performing addition reaction between spiro[lindane-4'-tert-butoxycarbonyl piperidine] and bromine to obtain dibromide, eliminating HBr from the dibromide in the presence of alkali to obtain olefin bromide, treating with lithium compound, introducing CO2 to obtain alpha,beta-unsaturated acid, and hydrogenating to obtain the target compound, or performing carbonylation reaction to obtain alpha,beta-unsaturated ester from olefin bromide C, hydrogenating, and hydrolyzing to obtain the target compound. The method overcomes the problems of long synthesis route, low yield, expensive reagents and unable mass production faced by the present synthesis method. The method has such advantages as short synthesis route, no need for expensive reagents, mild reaction conditions and low cost, and is suitable for mass production.
Description
Technical field:
The present invention relates to the preparation method of a class spirocyclic compound, particularly relate to the preparation method of a kind of spiral shell [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] template compound.
Background technology:
Contain spiral shell [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] spirocyclic compound of structure has been proved to be has various physiologically actives, once reported among patent US5578593 and the US6420376 with structure 1 compounds (deriving) and had interior life or the excretory physiologically active that stimulates the body inner growth hormone from above-mentioned volution template, can be used to treat the very few relative disease of body inner growth hormone, as nanism etc., and can stimulate the growth of some animal targetedly, thereby obtain animal that meat is many, fine hair is plentiful etc.
Document Bioorg.Med.Chem.Lett1997, also report once in 7 (17), 2319 is that the compound 2 of division center also has the organism of promotion inner growth hormone excretory function with this template compound.
About the synthetic method of spiral shell [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] class template compound, bibliographical information sees (Bioorg.Med.Chem.Lett1997,7 (17), 2319-2324; US6420376).This method is after obtaining alcohol with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines] by hydroboration; oxidation obtains corresponding ketone; ketone under the effect of alkali with N; N-two (fluoroform acyl group) aniline reaction generates triflate; under palladium catalysis, insert the carbonyl esterification then and obtain third rare ester; hydrogenation synthesizes target compound after the hydrolysis.Shown in Scheme1:
Scheme1
There is following deficiency in this synthetic method: route is very long, causes total recovery very low.Used 9-BBN, PhN (Tf)
2, the costing an arm and a leg of reagent such as KHMDS.This synthetic method of bibliographical information does not possess the feasibility of mass preparation.
Summary of the invention:
The technical issues that need to address of the present invention are: the synthetic method to a kind of spiral shell [indenes-4 '-piperidines-1-carboxylic acid] class template compound is improved, in the hope of a kind of efficient, mild condition being provided, possessing the synthetic method of spiral shell [indenes-4 '-piperidines-1-carboxylic acid] template compound that mass preparation is worth.
Technical scheme of the present invention:
Spiral shell of the present invention [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] template compound synthesis technique is as follows:
The present invention is a starting raw material with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines] A equally, to get two bromo-derivative B after the bromine addition, cancellation a part hydrogen bromide obtains alkene bromine C under the effect of alkali then, handle back feeding carbonic acid gas with metal lithiumation thing and obtain α, beta-unsaturated acid D, last hydrogenation gets target compound.Simultaneously also can obtain alpha, beta-unsaturated esters E by alkene bromine C by carbonylation reaction, hydrogenation then, hydrolysis obtain target compound.
In the above-mentioned technology, it is NaOH, KOH, Ba (OH) that second step was eliminated used alkali
2, a kind of among the DBU (1,5-diazabicylo [5.4.0] hendecene-5).Used metal reagent is a kind of in lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, the sec.-propyl bromination magnesium from C to D.Temperature of reaction from-78 ℃ to room temperature; Catalyzer from C to the E carbonylation reaction is Pd (OAc)
2, Pd (PPh
3)
4, Pd (dppf)
2In a kind of.In the technology of the present invention, shorten document technology, avoided using expensive reagent and harsh reaction conditions, greatly reduced the synthetic cost of product.
The invention has the beneficial effects as follows: the synthetic method that the present invention relates to a kind of spiral shell [indenes-4 '-piperidines-1-carboxylic acid] class template compound is improved, and provides a kind of reaction scheme short, avoids using expensive reagent, scalable scale production, synthetic method with low cost.Spiral shell [indenes-4 '-piperidines-1-carboxylic acid] compounds can be in conjunction with " combinatorial chemistry " technology platform, synthesize at short notice in a large number at known spiral shell [indenes-4 '-piperidines-1-carboxylic acid] the structurally-modified compound library of compounds, further screening helps to obtain biological activity better medicament precursor compound.
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%).
Claims (5)
1. spiral shell [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] preparation method of template compound, it is characterized in that, A is a starting raw material with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines], with after the bromine addition two bromo-derivative B, cancellation a part hydrogen bromide obtains alkene bromine C under the effect of alkali then, handle back feeding carbonic acid gas with metal lithiumation thing and obtain α, beta-unsaturated acid D, last hydrogenation gets target compound, and reaction formula is as follows:
2. spiral shell [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] preparation method of template compound, it is characterized in that, A is a starting raw material with spiral shell [indenes-4 '-tertiary butyl oxygen carbonyl piperidines], with after the bromine addition two bromo-derivative B, cancellation a part hydrogen bromide obtains alkene bromine C under the effect of alkali then, obtain α by carbonylation reaction by alkene bromine C, beta-unsaturated esters E, hydrogenation then, hydrolysis obtain target compound, and reaction formula is as follows:
3. according to claim 1 or 2 described a kind of spiral shells [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] preparation method of template compound, it is characterized in that two bromo-derivative B cancellation a part hydrogen bromide under the effect of alkali obtains in the process of alkene bromine C, used alkali is NaOH, KOH, Ba (OH)
2Or a kind of among the DBU.
4. according to the described a kind of spiral shell [1 of claim 1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] preparation method of template compound, it is characterized in that, handle the used metal lithiumation thing of alkene bromine C and be a kind of in lithium methide, n-Butyl Lithium, s-butyl lithium or the tert-butyl lithium, temperature of reaction is to room temperature from-78 ℃.
According to the described a kind of spiral shell of claim 2 [1,3-dihydro indenes-4 '-piperidines-1-carboxylic acid] preparation method of template compound, it is characterized in that in the carbonylation processes of alpha, beta-unsaturated esters E, the catalyzer that is adopted is Pd (OAc) at alkene bromine C
2, Pd (PPh
3)
4Or Pd (dppf) Cl
2In a kind of.
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| CN2006100278794A CN101092396B (en) | 2006-06-20 | 2006-06-20 | Method for preparing template compound of ancylus fluviatilis [1,3 dihydro indene - 4'- piperidine 1 - carboxylic acid] |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578593A (en) * | 1992-12-11 | 1996-11-26 | Merck & Co., Inc. | Spiro piperidines and homologs promote release of growth hormone |
| US6420376B1 (en) * | 1999-07-13 | 2002-07-16 | Merck & Co., Inc. | Amido spiropiperidines promote the release of growth hormone |
-
2006
- 2006-06-20 CN CN2006100278794A patent/CN101092396B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578593A (en) * | 1992-12-11 | 1996-11-26 | Merck & Co., Inc. | Spiro piperidines and homologs promote release of growth hormone |
| US6420376B1 (en) * | 1999-07-13 | 2002-07-16 | Merck & Co., Inc. | Amido spiropiperidines promote the release of growth hormone |
Non-Patent Citations (2)
| Title |
|---|
| James R. Tata et.al..The design and synthesis of orally active short durationspiroindane growth hormone secretagogues.Bioorganic & Medicinal Chemistry Letters7 17.1997,7(17),2319-2344. |
| James R. Tata et.al..The design and synthesis of orally active short durationspiroindane growth hormone secretagogues.Bioorganic & Medicinal Chemistry Letters7 17.1997,7(17),2319-2344. * |
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Assignee: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Assignor: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Contract record no.: 2011310000011 Denomination of invention: Process for the preparation of spiro [1,3- two hydrogen -4 '- piperidine -1- carboxylic acid] template compounds Granted publication date: 20100915 License type: Exclusive License Open date: 20071226 Record date: 20110221 |
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