CN1640876A - Spiro dihydroindole template compound and its preparing method - Google Patents
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Abstract
The present invention relates to one kind of spirodihydro indole template compounds with spiro [2m 3-dihydro-indolyl-3, 4'-piperidyl]-5-formic acid as kernel and its preparation process. The compounds have the chemical structure as shown. The compounds may be screened to obtain medicine precursor with high bioactivity.
Description
Technical field: the present invention relates to class spirocyclic compound and preparation method thereof, particularly a kind of is the spiral shell dihydroindolines template compound of core and the preparation method of related derivatives with " spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid ".
Background technology: contain spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] spirocyclic compound of structure has various physiologically actives by extensive proof, below be in partial monopoly or the document open and with the example of the closely-related several compounds of the technology of the present invention, its chemical structural formula is as follows:
Once reported among the patent WO9413696, contain said medicine template 1 and have interior life or the excretory physiologically active that stimulates the body inner growth hormone for the compound of core texture, 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.
Report among the patent WO9964002, the compound that contains 2 core textures can be used as novel melanocortin receptor agonists, play a very important role in the treatment of diseases relevant with the novel melanocortin receptor excitement, prevention, this class disease comprises obesity, diabetes, sexual dysfunction etc.
Once reported with drug template 3 to be that the compound of parent nucleus can be developed into antihypertensive vasopressin antagonists, diuresis temper palace relaxant among the EP636609.
At J.Med.Chem.1997,40, disclose among the 3905-3914, with compound 4 is that the compound of template can have higher affinity with vagusstoff transhipment part in the vesica, thereby can intervene with the storage of phatidylcholine and then influence the function of cholinergic nerve system, so may prevent with treat with the relevant disease of first choline, for example dysthymia disorders or irritated disease etc.
J.Med.Chem.1983,26, disclosing among the 981-986 with compound 5 is that the compound of template has the effect of depression.
J.Heterocyclic Chem.1981 announces in 18,815 and can be developed into psychotolytic medicine with compound 6.
Reported among the patent WO9413696 that compound 7 can be used as preferred non-peptide class tethelin succagoga, can treat the disease relevant with growth hormone secretion.
Tetrahedron Lett.1997; all reported in 1497-1500 and the WO9633189 document; the preparation method (shown in following reaction formula I) of relevant " spiral shell [2; 3-dihydro-indoles-3; 4 '-piperidines] "; mainly piperidines-4-the formaldehyde reaction by phenyl hydrazine and N-protected obtains corresponding spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] compound (PG is an amino protecting group).
Reaction formula I
In patent WO9413696, the several different methods of these spirocyclic compounds of preparation was also disclosed.
Summary of the invention: the technical issues that need to address of the present invention are: to known spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] carry out modification, optimization for " drug template " of main structure, obtaining " spiral shell [2; 3-dihydro-indoles-3,4 '-piperidines]-5-formic acid " is the spiral shell indoline template compound of core.Further optimize, modify at the active group on these template compounds, can obtain a series of have dependency structure, similar active spiral shell indoline analog derivatives.
Technical solution of the present invention is: spiral shell dihydroindolines template compound and related derivatives, with spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid " and be core, its chemical structure of general formula is as follows:
Compound 1
In the following formula, R
1, R
2For H or amino protecting group (are called PG in the following technology
1, PG
2Or PG
3), as tertbutyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), carbobenzoxy-(Cbz) (Cbz), allyloxycarbonyl (Alloc) etc.
This compounds novel structure does not have bibliographical information.This compounds can cooperate the synthetic relevant compound library of combinatorial chemistry technique, and further screening will help to obtain biological activity better medicament precursor compound.
With spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid " be the synthesis technique of the spiral shell dihydroindolines template compound of core, specifically be summarized as follows:
This technology thinking: adopting the spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] of the 4 '-amido protecting that is produced on a large scale is raw material; obtain a behind the halo; can obtain spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid template compound c of 4 '-amido protecting by two kinds of different approach.The spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] of 4 '-amido protecting is carried out halo behind the amido protecting, or behind the first halo again amido protecting obtain d, insert carbonyl reaction posthydrolysis through catalysis then and obtain spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid template compound e; The different substituted radical of the also replaceable one-tenth of amino protecting group on the Verbindung.
In the above-mentioned technology, halide reagent is liquid bromine, chlorine, iodine, bromo-succinimide (NBS), chlorosuccinimide, iodo succimide etc.; Solvent is chosen ethanol, acetonitrile, Virahol, tetracol phenixin etc.; Temperature of reaction is 0～20 ℃.
A can obtain compound c by two kinds of different approach: (1. a inserts the carbonyl reaction through catalysis and obtains the corresponding carboxylic acid ester, and basic hydrolysis obtains c then.Catalyzer is four (triphenyl is seen) palladium, Palladous chloride, dichloro two (triphenyl see palladium) etc.; Reaction pressure is a 2-100 normal atmosphere; Solvent is methyl alcohol, ethanol, methyl alcohol-acetonitrile, methyl alcohol-acetonitrile-triethylamine etc.; Temperature of reaction is room temperature～80 ℃; The hydrolysis mineral alkali is potassium hydroxide, lithium hydroxide, sodium hydroxide, and solvent is methyl alcohol, ethanol, water etc.2. a after metalized directly and CO
2Reaction obtains c.Metallization reagent is n-Butyl Lithium, s-butyl lithium etc., and solvent is a tetrahydrofuran (THF), ether etc., temperature is-78～0 ℃).1. d can prepare e by similar above-mentioned technology.
Alkaline assistant is selected in the amido protecting reaction for use, as sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine etc.; Organic solvent is methylene dichloride, acetonitrile, chloroform, dioxane, ethyl acetate, ether, tetrahydrofuran (THF) etc.In deprotection reaction, adopt methods such as acidolysis, hydrogenation deprotection, temperature is that room temperature is to refluxing.Wherein, the used acid of acidolysis is trifluoroacetic acid, hydrochloric acid, sulfuric acid, perchloric acid etc.; Organic solvent is methyl alcohol, ethanol, dioxane, ethyl acetate, ether, tetrahydrofuran (THF) etc.The hydrogenation catalyst system therefor is palladium carbon, platinum carbon etc., and solvent is methyl alcohol, ethanol, ethyl acetate etc.
Through above-mentioned technological process, we can prepare a series of is the template compound 1 of core with " spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid ".
The invention has the beneficial effects as follows: to known spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] center " drug template " structure is modified, modification, mainly introduce a carboxyl at its 5, obtain spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid " be the spiral shell dihydroindolines template compound of core.This compounds can cooperate combinatorial chemistry technique, can synthesize in a large number the compound library at known spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] composition optimizes at short notice, and further screening can help to obtain biological activity better medicament precursor.
Embodiment:
Following examples can help to understand the present invention, but content of the present invention is including, but not limited to the following example content.
Embodiment 1
Synthesizing of N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
The first step: 5-bromo-N's '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] is synthetic
With N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] (25g 0.077mol) is dissolved in the acetonitrile (300mL), be cooled to 0 ℃ after, drip NBS (15g, 0,084mol) in the solution of acetonitrile (50mL), react after 3 hours, rise to ambient temperature overnight naturally.There is solid to separate out.Filter out product (26g), productive rate: 84%.
1H?NMR(400Mz，CDCl
3)：7.41-7.30(m，5H)，7.13(dd，J＝8，0?and2.0Hz，1H)，7.08(d，J＝2.0Hz，1H)，6.51(d，J＝8.0Hz，1?H)，5.16(s，2H)，4.12(m，2H)，3.49(s，2H)，2.97(m，2H)，1.58(m，4H).
Second step: N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid synthetic
(26g 0.065mol) is dissolved in CH with 5-bromo-N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]
3OH (400mL) adds triethylamine (10g) and four (triphenyl is seen) palladium (3g) under the carbon monoxide atmosphere, in 60 ℃, 80 normal atmosphere react after 12 hours down, cooling, remove by filter catalyzer after, add the 2M LiOH aqueous solution (100mL), after stirring is spent the night, concentrate and remove methyl alcohol, regulate PH and be about 5, use dichloromethane extraction, extracting solution saturated common salt water washing, anhydrous Na
2SO
4Dry concentrating.Behind recrystallization, get faint yellow N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid solid (18g), productive rate 75%.
1H?NMR(400Mz，CDCl
3)：7.80(d，J＝7.6Hz，1H)，7.65(s，1H)，6.55(d，J＝8.0Hz，1H)，5.18(s，2H)，4.08(m，2H)，3.52(s，2H)，2.85(m，2H)，1.86-1.60(m，2H)；MS(m/z)：367(M
++1)。
Embodiment 2
Synthesizing of N '-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
Method 1: with embodiment 1, productive rate 72%.
1H?NMR(400Mz，CDCl
3)：7.80(d，J＝8.0Hz，1H)，7.71(s，1H)，6.54(d，J＝8.0Hz，1H)，4.04
*M，2H)，3.54(s，1H)，3.41(s，1H)，2.88(m，2H)，1.90-1.61(m，2H)，1.47(s，9H)；MS(m/z)：355(M
++Na)。
2: the second steps of method are adopted metallization back and CO
2The method of reaction:
Under the nitrogen protection, in reaction flask A, with 5-bromo-N '-Cbz-spiral shell [2,3-dihydro-indoles-3; 4 '-piperidines] (26g 0.065mol) is dissolved in anhydrous THF (200mL), is cooled to-78 ℃; (26mL2.5M, 0.054mol), reaction is 1 hour under this temperature slowly to add n-BuLi.In another reaction flask B, add anhydrous THF (200mL), be cooled to-78 ℃, the logical dry CO that crosses
2In solution one hour.To the lithium reagent that prepare slowly be pressed in the A bottle with nitrogen then, be incubated 2 hours; Continue logical CO
2Spend the night; Splash into water (200mL) then, stirred 30 minutes.THF is removed in decompression, and with the impurity of dichloromethane extraction water layer, water is cooled to 0 ℃, regulates pH=4-5 with citric acid, again with dichloromethane extraction three times.Merge organic phase, anhydrous sodium sulfate drying after concentrating, gets straight product (32g), productive rate 62% behind the thick product recrystallization of gained.
Embodiment 3
Synthesizing of N '-Cbz-N-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
The first step: N-Boc-N's '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] is synthetic
To N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] (100g, 0.31mol) and triethylamine (47g in methylene dichloride 0.46mol) (800mL) solution, drips (BOC)
2(66g, the 0.31mol) solution of methylene dichloride (100mL) reflux after 2 hours O.Reaction solution is used 0.5M HCl, 5%NaHCO successively
3, water and saturated common salt water washing; After concentrating, through getting colorless solid (116g) behind the recrystallization. productive rate 90%.
1H?NMR(400Mz，CDCl
3)：7.75(d，J＝7.6Hz，1H)，7.32(m，5H)，7.22(d，J＝8.0Hz，1H)，7.14(m，1H)，6.99(m，1H)，5.17(s，2H)，4.22(m，2H)，3.86(m，2H)，2.96(m，2H)，1.80(m，2H)，1.70(m，2H)，1.65(s，9H)。
Second step: the N-Boc-N's '-Cbz-5-bromo-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] is synthetic
Method is made solvent with the first step of embodiment 1 with Virahol, yield: 99%.
The 3rd step: N-Boc-N '-Cbz-5-bromo-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid synthetic
With N-Boc-N '-Cbz-2,3-dihydro-5-bromo-spiral shell [indoles-3,4 '-piperidines] is a raw material, and method is with second step of embodiment 1, with the solvent of the slotting carbonyl of ethanol work, yield: 88%.
1H?NMR(400Mz，CDCl
3)：8.05(d，J＝7.6Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.81(s，1H)，7.30(m，5H)，5.18(s，2H)，4.10(m，2H)，3.89(s，2H)，2.95(m，2H)，1.92-1.65(m，4H)，1.49(s，9H)；MS(m/z)：467(M
++1)。
Embodiment 4
Synthesizing of N '-Cbz-N-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
(12g in acetonitrile 32.8mmol) (120mL) solution, adds (BOC) to N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
2(N dimethylamine yl pyridines (0.5g) after the stirred overnight at room temperature, concentrates O, gets colorless solid (13.9g), productive rate 91% behind the thick product recrystallization for 7.2g, 32.8mmol) triethylamine (5mL) and 4-N.
Embodiment 5
Synthesizing of N '-Fmoc-N-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
To N-Boc-N '-Cbz-5-bromo-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid (5g, 10.7mmol) methanol solution (1.2L) in add 5%Pd-C catalyzer (0.2g), 2 hours after-filtration of hydrogenation are removed catalyzer under atmospheric pressure at room, after concentrating, reaction solution is dissolved in the solution (30mL) of THF (30mL) and 5% sodium bicarbonate, the ice bath cooling drips FmocCl (3.6g down, 13.9mmol) THF (20mL) solution, after room temperature reaction spends the night, concentrate, transfer to PH=5～6 with citric acid, with dichloromethane extraction three times, combining extraction liquid, saturated common salt water washing; Concentrate behind the anhydrous sodium sulfate drying, get product (3.9g), productive rate 65% behind the thick product column chromatography purification of gained.
1H?NMR(400Mz，CDCl
3)：8.03(d，J＝8.0Hz，1H)，7.98(d，J＝8.0Hz，1H)，7.78(s，1H)，7.75-7.25(m，9H)，4.51(d，J＝6.4Hz，2H)，4.32(d，J＝6.4Hz，2H)，4.15(m，2H)，3.05(m，2H)，1.92-1.65(m，4H)，1.49(s，9H)；MS(m/z)：467(M
++1)。MS(m/z)：555(M
++1)。
Embodiment 6
Synthesizing of N-Alloc-N '-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
To N '-Boc-5-bromo-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid (15g, 46.6mmol) dichloromethane solution (250mL) in add triethylamine (10mL) and 4-N, N dimethylamine yl pyridines (1g), ice bath cooling drip AllocCl (7.2g, methylene dichloride 60.0mmol) (20mL) solution down, after room temperature reaction spends the night, concentrate, transfer to PH=5～6, use dichloromethane extraction three times with citric acid, combining extraction liquid, the saturated common salt water washing; Concentrate behind the anhydrous sodium sulfate drying, get product (15.4g), productive rate 82% behind the recrystallization.
1H?NMR(400Mz，CDCl
3)：8.01(d，J＝8.0Hz，1H)，7.95(d，J＝8.0Hz，1H)，7.81(s，1H)，5.87(m，2H)，5.17(m，2H)，4.51(d，J＝5.2Hz，2H)，4.11(m，2H)，3.01(m，2H)，1.90-1.65(m，4H)，1.48(s，9H)；MS(m/z)：417(M
++1)。
Embodiment 7
Synthesizing of N '-Cbz-N-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
(12g in dioxane 32.8mmol) (120mL) solution, adds (BOC) to N '-Cbz-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
2(N dimethylamine yl pyridines (0.5g) after the stirred overnight at room temperature, concentrates O, gets colorless solid (13.9g), productive rate 91% behind the thick product recrystallization for 7.2g, 32.8mmol) triethylamine (5mL) and 4-N.
Embodiment 8
Synthesizing of N '-Fmoc-N-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
To N-Boc-N '-Cbz-5-bromo-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid (5g, 10.7mmol) methanol solution (1.2L) in add 5%Pd-C catalyzer (0.2g), 2 hours after-filtration of hydrogenation are removed catalyzer under atmospheric pressure at room, after concentrating, reaction solution is dissolved in the solution (30mL) of THF (30mL) and 5% sodium bicarbonate, the ice bath cooling drips FmocCl (3.6g down, 13.9mmol) THF (20mL) solution, after room temperature reaction spends the night, concentrate, transfer to PH=5～6 with citric acid, with dichloromethane extraction three times, combining extraction liquid, saturated common salt water washing; Concentrate behind the anhydrous sodium sulfate drying, get product (3.9g), productive rate 65% behind the thick product column chromatography purification of gained.
1H?NMR(400Mz，CDCl
3)：7.75(d，J＝7.6Hz，1H)，7.32(m，5H)，7.22(d，J＝8.0Hz，1H)，7.14(m，1H)，6.99(m，1H)，5.17(s，2H)，4.22(m，2H)，3.86(m，2H)，2.96(m，2H)，1.80(m，2H)，1.70(m，2H)，1.65(s，9H)；MS(m/z)：455(M
++1)。
Embodiment 9
Synthesizing of N-Alloc-N '-Boc-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid
To N '-Boc-5-bromo-spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid (15g, 46.6mmol) dichloromethane solution (250mL) in add triethylamine (10mL) and 4-N, N dimethylamine yl pyridines (1g), ice bath cooling drip AllocCl (7.2g, methylene dichloride 60.0mmol) (20mL) solution down, after room temperature reaction spends the night, concentrate, transfer to PH=5～6, use dichloromethane extraction three times with citric acid, combining extraction liquid, the saturated common salt water washing; Concentrate behind the anhydrous sodium sulfate drying, get product (15.4g), productive rate 82% behind the recrystallization.
1H?NMR(400MHz，CDCl
3)：7.75(d，J＝7.6Hz，1H)，7.32(m，5H)，7.22(d，J＝8.0Hz，1H)，7.14(m，1H)，6.99(m，1H)，5.17(s，2H)，4.22(m，2H)，3.86(m，2H)，2.96(m，2H)，1.80(m，2H)，1.70(m，2H)，1.65(s，9H)；MS(m/z)：417(M
++1)。
Claims (9)
1, spiral shell dihydroindolines template compound, relating to a class is the volution template compound of core with " spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid ", its chemical structure of general formula is as follows:
In the following formula, R
1, R
2Be H or amino protecting group, amino protecting group is called PG in following claim
1, PG
2Or PG
3, as tertbutyloxycarbonyl Boc, fluorenylmethoxycarbonyl Fmoc, carbobenzoxy-(Cbz) Cbz, allyloxycarbonyl Alloc.
2, the preparation method of spiral shell dihydroindolines template compound is characterized in that, its reaction process is as follows:
3, the preparation method of spiral shell dihydroindolines template compound according to claim 2, it is characterized in that, the spiral shell [2 of 4 '-amido protecting that employing is produced on a large scale, 3-dihydro-indoles-3,4 '-piperidines] be raw material, obtain a behind the halo, can obtain the spiral shell [2 of 4 '-amido protecting by two kinds of approach, 3-dihydro-indoles-3,4 '-piperidines]-5-formic acid template compound c; The spiral shell [2,3-dihydro-indoles-3,4 '-piperidines] of 4 '-amido protecting is carried out halo behind the amido protecting, or behind the first halo again amido protecting obtain d, obtain spiral shell [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid template compound e through inserting carbonyl reaction posthydrolysis then; The different substituted radical of the also replaceable one-tenth of amino protecting group on the Verbindung, obtaining a series of " spiral shells [2,3-dihydro-indoles-3,4 '-piperidines]-5-formic acid " is the spiral shell dihydroindolines template compound I of core.
According to the preparation method of claim 2 or 3 described spiral shell dihydroindolines template compounds, it is characterized in that 4, in halogenating reaction, halide reagent adopts a kind of in liquid bromine, chlorine, iodine, bromo-succinimide, the chlorosuccinimide; Reaction solvent is chosen a kind of in ethanol, acetonitrile, the Virahol; Temperature of reaction is 0～20 ℃.
5, according to the preparation method of claim 2 or 3 described spiral shell dihydroindolines template compounds, it is characterized in that, feed carbon dioxide or catalysis pressurization after in preparation c and e process, can adopting metalized and feed a kind of in two kinds of approach such as CO gas.
6, the preparation method of spiral shell dihydroindolines template compound according to claim 5 is characterized in that, uses the catalyzing carbon monoxide pressurization in preparation c and e process; Reaction solvent is a kind of in methyl alcohol, methyl alcohol-acetonitrile, the methyl alcohol-acetonitrile-triethyl ammonia, and catalyzer is a kind of in four (triphenyl is seen) palladium, Palladous chloride, dichloro two (triphenyl see palladium); Reaction pressure 2-100 normal atmosphere, temperature of reaction are 50～80 ℃.
7, the preparation method of spiral shell dihydroindolines template compound according to claim 5 is characterized in that, feeds carbon dioxide process after with metalized in preparation c process; Metallization reagent is n-Butyl Lithium, s-butyl lithium; Reaction process needs low temperature, protection of inert gas, and temperature of reaction is-78～0 ℃.
According to the preparation method of claim 2 or 3 described spiral shell indoline class templates and derivative, it is characterized in that 8, used alkali is a kind of in sodium bicarbonate, sodium hydroxide, potassium hydroxide, the triethylamine in the amido protecting reaction; Organic solvent is a kind of in methylene dichloride, acetonitrile, chloroform, dioxane, ethyl acetate, ether, the tetrahydrofuran (THF).
9, according to the preparation method of claim 2 or 3 described spiral shell indoline class templates and derivative, it is characterized in that, in deprotection reaction, adopt methods such as acidolysis, hydrogenation deprotection, temperature is that room temperature is to refluxing; Wherein, the used acid of acidolysis is a kind of in trifluoroacetic acid, hydrochloric acid, sulfuric acid, the perchloric acid, and organic solvent is a kind of in methyl alcohol, ethanol, dioxane, ethyl acetate, ether, the tetrahydrofuran (THF); The hydrogenation catalyst system therefor is palladium carbon, platinum carbon, and solvent is a kind of in methyl alcohol, ethanol, the ethyl acetate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875448A (en) * | 2012-11-05 | 2013-01-16 | 中国药科大学 | Synthetic method for preparing indole spiral cyclopentane derivant |
| CN109503582A (en) * | 2018-12-17 | 2019-03-22 | 上海合全药物研发有限公司 | The synthetic method of cis- spiral shell [piperidines simultaneously -4,1 '-pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate |
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| CZ151495A3 (en) * | 1992-12-11 | 1995-12-13 | Merck & Co Inc | Spiropiperidine derivatives, process of their preparation and a pharmaceutical composition containing thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875448A (en) * | 2012-11-05 | 2013-01-16 | 中国药科大学 | Synthetic method for preparing indole spiral cyclopentane derivant |
| CN109503582A (en) * | 2018-12-17 | 2019-03-22 | 上海合全药物研发有限公司 | The synthetic method of cis- spiral shell [piperidines simultaneously -4,1 '-pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate |
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