CN102086202A - Method for quickly preparing cis-octahydropyrrolo[3,2-b]pyrrole - Google Patents
Method for quickly preparing cis-octahydropyrrolo[3,2-b]pyrrole Download PDFInfo
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- CN102086202A CN102086202A CN200910201887XA CN200910201887A CN102086202A CN 102086202 A CN102086202 A CN 102086202A CN 200910201887X A CN200910201887X A CN 200910201887XA CN 200910201887 A CN200910201887 A CN 200910201887A CN 102086202 A CN102086202 A CN 102086202A
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Abstract
The invention relates to a novel synthesis method for cis-octahydropyrrolo[3,2-b]pyrrole, and mainly solves the technical problems that raw materials are expensive, reaction conditions are harsh, a reaction route is long, the reaction operation is inconvenient, and a large number of isomers are generated through ring closure in the conventional cis-octahydropyrrolo[3,2-b]pyrrole preparation process. The method comprises the following steps of: performing alkylation reaction of industrially available 3-pyrrolidone serving as an initiative raw material and an allyl compound directly under the action of acid to obtain a 3-tetrahydro-pyrrolidone substitute; performing reductive amination reaction to obtain a 3-aminopyrrolidine derivative; performing protective group adding reaction; and performing ozonization reduction ring-closing reaction and dehydroxylation reaction on the 3-aminopyrrolidine derivative added with the protective group to obtain a corresponding cis-octahydropyrrolo[3,2-b]pyrrole derivative. The target product and important intermediates can be widely applied to synthesizing various pyrrole derivatives.
Description
Technical field
A kind of novel synthesis of the cis that the present invention relates to-octahydro pyrrolo-[3,2-b] pyrroles.
Background technology
Cis octahydro pyrrolo-[3,4-b] the pyrrole ring compounds with and corresponding derivative be widely used as the important intermediate of synthesizing adenosine enzyme inhibitors class 4-quinolizidine morpholine carboxylic acid, and synthetic be foundation structure with the uridylic, selectivity suppresses III type archaeal dna polymerase and II type topoisomerase class antiseptic-germicide compound.For example: current research finds that the novel basic 2-aryl-7-ammonia of a class replaces an also very effective precursor structure adenosinase inhibitor of [5,4-b] pyrimidine of-oxazoles.As shown in Equation 1, discover from the X-ray of molecular structure, the space geometry structure that its active size and its 7 ammonia replace the appropriate molecule of two Pyrrolidine ring structures in the group has confidential relation, this compound can have certain space active structure, and the ductility of good active group can be provided.
Formula 1
The method of synthetic this compound of document is as follows at present:
The synthetic route that document provided, step is long, the starting raw material costliness, severe reaction conditions when carrying out ring closure reaction, has a large amount of isomer to produce, and multistep needs column chromatography purification, and total recovery is lower, carries out difficulty of technology amplification ratio.
Summary of the invention:
The object of the present invention is to provide a kind of quick preparation cis-octahydro pyrrolo-[3,2-b] pyrroles's method, mainly solve existing cis-octahydro pyrrolo-[3,2-b] raw material costliness among the pyrroles preparation technology, severe reaction conditions, reaction scheme is long, operation inconvenience, and close the technical problem that ring produces a large amount of isomer.
Technical scheme of the present invention: the 3-pyrrolidone that the present invention can get with industrialization is a starting raw material; directly under the acid effect, obtain 3-tetrahydro pyrrolidine ketone substituent with allylic cpd generation alkylated reaction; obtain the amino Pyrrolidine alkane derivatives of 3-through reduction amination again; be to add the protecting group reaction then; the amino Pyrrolidine alkane derivatives of 3-that adds protecting group reduces ring closure reaction through ozonize; obtain corresponding cis-octahydro pyrrolo-[3 behind the decarboxylation reaction; 2-b] pyrrole derivative, technological reaction formula of the present invention is as follows:
In the above-mentioned technology, X is a chlorine, bromine or hydroxyl etc., and R is a carbonyl ester class protecting group, alkyl protecting group, aryl protecting group etc.; In the first step alkylated reaction, allylic cpd is halides such as allyl bromide 98, chlorallylene, vinyl carbinol and derivative thereof etc., reaction solvent is a toluene, dimethylbenzene, acetonitrile etc., can be at phenylformic acid, under the organic acid catalysis effects such as Phenylsulfonic acid, temperature of reaction is 100-130 ℃; Second step was classical reduction amination, and solvent is selected methyl alcohol usually for use, ethanol, tetrahydrofuran (THF) etc.Reductive agent adopts sodium cyanoborohydride usually, the boron acetate sodium hydride, and sodium borohydride etc., temperature of reaction is room temperature (10-30 a ℃), can add the tart reaction promoter in the reaction: tosic acid, phenylformic acid etc.The 3rd step added the protecting group reaction, the optional carbonyl ester of protecting group class protecting group and aryl, and the alkyls protection is selected from carbonyl ester class protecting group and aryl, alkyls protecting group, preferred CbzCl, Boc
2O, BnBr etc., reaction solvent are tetrahydrofuran (THF), sodium hydroxide solution etc.; Temperature of reaction is-10 ℃ and arrives room temperature (10-30 ℃); Liquid etc.; The 4th step was ozonize reduction ring closure reaction, and post-treatment reagents can be dimethyl sulphide, triphenyl phosphorus etc., solvent is generally methyl alcohol, ethanol, methylene dichloride etc., reductive agent adopts sodium cyanoborohydride usually, boron acetate sodium hydride etc., and temperature of reaction is room temperature (10-30 a ℃).The 5th step was decarboxylation reaction, can adopt triethyl silicon hydrogen, sodium borohydride-trifluoroacetic acid, trimethylchlorosilane-sodium iodide, thiocarbonic ester or N-(triethyl ammonium sulphonyl) Urethylane (burgess (burgess) reagent) reacts, and reaction solvent is a methyl alcohol usually, tetrahydrofuran (THF), methylene dichloride or their mixed solvent etc., temperature of reaction is that room temperature (10-30 ℃) is to 80 ℃
Beneficial effect of the present invention: the invention solves the difficult acquisition of raw material in the present synthetic method, route is longer, and yield is low, operation inconvenience, the preparation method does not have shortcomings such as general applicability to different cis cis-octahydro pyrrolo-[3,2-b] pyrrole derivative.Reaction process of the present invention is selected rationally, it has adopted the raw material 3-pyrrolidone that is easy to get to be, shortened reaction scheme, yield is than the height of bibliographical information, and polystep reaction is classical reaction, strong operability, and the reaction times is short, the reaction conditions gentleness can obtain the target compound that needs apace.Helping technology amplifies.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention
Embodiment 1
With compound 1 (10.0g, 45.6mmol), allyl bromide 98 (7.9g, 137mmol), tosic acid (11.8g, 68.4mmol) and anhydrous sodium sulphate (25.1g) join in the dimethylbenzene (200mL).The reaction mixture reflux stirred 20 hours.The reactant cooled and filtered.Filtrate obtains yellow oily compound 2 (6.1g) after concentrating, and yield is 53.2%.
To compound 2 (10.5g, add in methyl alcohol 40.6mmol) (100mL) solution amine acetate (31.2g, 405mmol).After the reaction mixture reflux 1 hour, be cooled to 30 ℃.Add in batches sodium cyanoborohydride (10.2g, 162mmol).Reaction mixture reflux 1 hour, reactant cooling back adds frozen water (50mL) cancellation reaction.Extract with ethyl acetate (3x50mL).Organic phase adds sodium bicarbonate and regulates pH=8～9 after washing with ether (100mL) with 4N hydrochloric acid soln (3x50mL) extraction, water, adds Boc
2O (3.5g, 15.4mmol).Stir under the reaction mixture room temperature and spend the night.Reaction solution is with extracting with ethyl acetate (3x50mL), and organic phase is washed with 1N citric acid solution (100mL), saturated aqueous common salt (100mL), the anhydrous sodium sulfate drying after-filtration, and filtrate obtains brown oily compound 5 (7.6g) after concentrating, and yield is 59.6%.
(5.0g 14mmol) is dissolved in the mixing solutions of anhydrous methylene chloride (50mL) and methyl alcohol (50mL) with compound 5.Reaction mixture is bathed and is cooled to-78 ℃, slowly feeds ozone then in solution.Behind the color transition of reaction mixture, stop in reactant, to feed ozone, with nitrogen redundant ozone is displaced, until the blueness disappearance of reaction mixture.After dimethyl sulphide (5mL) slowly was added dropwise to reaction solution, reaction solution stirred 1 hour, and reaction solution obtains yellow oily compound 6 (3.4g) after concentrating, and yield is 68%.
With compound 6 (1.4g, anhydrous methylene chloride 3.9mmol) (20mL) solution is cooled to-78 ℃, add then triethyl silicane (0.9g, 7.7mmol) and boron trifluoride diethyl etherate (1.4g, 8.5mmol).Behind reinforced the finishing, reaction mixture slowly gos up to room temperature, and stirring is spent the night.In reactant, add entry (40mL) cancellation reaction.Use sodium bicarbonate conditioned reaction thing pH=7 then.Reaction solution extracts with methylene dichloride (3x50mL).Organic phase drip to add 1M TFA/THF solution (10mL), obtains faint yellow compound 6 (0.85g) after stirring filtration in 10 minutes.Yield 61.3%
Embodiment 2
With compound 1 (10.0g, 45.6mmol), chlorallylene (7.9g, 137mmol), Phenylsulfonic acid (11.8g, 68.4mmol) and anhydrous magnesium sulfate (25.1g) join in the toluene (200mL).The reaction mixture reflux stirred 20 hours.The reactant cooled and filtered.Filtrate obtains yellow oily compound 2 (5.83g) after concentrating, and yield is 50.2%.
To compound 2 (10.5g, add in ethanol 40.6mmol) (100mL) solution amine acetate (31.2g, 405mmol).After the reaction mixture reflux 1 hour, be cooled to 30 ℃.Add in batches the acetoxyl sodium borohydride (10.2g, 162mmol).Reaction mixture reflux 1 hour, reactant cooling back adds frozen water (50mL) cancellation reaction.Extract with ethyl acetate (3x50mL).Organic phase adds sodium bicarbonate and regulates pH=8～9 after washing with ether (100mL) with 4N hydrochloric acid soln (3x50mL) extraction, water, adds Boc
2O (3.5g, 15.4mmol).Stir under the reaction mixture room temperature and spend the night.Reaction solution is with extracting with ethyl acetate (3x50mL), and organic phase is washed with 1N citric acid solution (100mL), saturated aqueous common salt (100mL), the anhydrous sodium sulfate drying after-filtration, and filtrate obtains brown oily compound 5 (7.53g) after concentrating, and yield is 58.6%.
(5.0g 14mmol) is dissolved in the mixing solutions of anhydrous methylene chloride (50mL) and methyl alcohol (50mL) with compound 5.Reaction mixture is bathed and is cooled to-78 ℃, slowly feeds ozone then in solution.Behind the color transition of reaction mixture, stop in reactant, to feed ozone, with nitrogen redundant ozone is displaced, until the blueness disappearance of reaction mixture.After triphenyl phosphorus (6g) slowly added reaction solution, reaction was heated to 50 ℃ and stirred 1 hour, and reaction solution obtains yellow oily compound 6 (3.43g) after concentrating, and yield is 68.5%.With compound 6 (1.4g, anhydrous methanol 3.9mmol) (20mL) solution is cooled to-30 ℃, add then trimethylchlorosilane (1.19g, 7.7mmol) and sodium iodide (2.4g, 8.5mmol).Behind reinforced the finishing, reaction mixture slowly gos up to room temperature, and stirring is spent the night.In reactant, add entry (40mL) cancellation reaction.Use sodium bicarbonate conditioned reaction thing pH=7 then.Reaction solution extracts with methylene dichloride (3x50mL).Organic phase drip to add 1M TFA/THF solution (10mL), obtains faint yellow compound 6 (0.75g) after stirring filtration in 10 minutes.Yield 55.3%.
Claims (10)
1. one kind prepares cis-octahydro pyrrolo-[3 fast; 2-b] pyrroles's method; it is characterized in that; the 3-pyrrolidone is a starting raw material; directly under the acid effect, obtain 3-tetrahydro pyrrolidine ketone substituent with allylic cpd generation alkylated reaction; obtain the amino Pyrrolidine alkane derivatives of 3-through reduction amination again; be to add the protecting group reaction then; the amino Pyrrolidine alkane derivatives of 3-that adds protecting group reduces ring closure reaction through ozonize; obtain corresponding cis-octahydro pyrrolo-[3,2-b] pyrrole derivative behind the decarboxylation reaction.
2. a kind of quick preparation cis according to claim 1-octahydro pyrrolo-[3,2-b] pyrroles's method, it is characterized in that: described allylic cpd is selected from allyl group halides or vinyl carbinol and derivative thereof.
3. a kind of quick preparation cis according to claim 1-octahydro pyrrolo-[3,2-b] pyrroles's method, it is characterized in that: described alkylated reaction carries out in solvent, reaction solvent is a kind of in toluene, dimethylbenzene or the acetonitrile, described acid is Phenylsulfonic acid or phenylformic acid, the alkylated reaction heating is carried out, and Heating temperature is 100～130 ℃.
4. a kind of quick preparation cis according to claim 1-octahydro pyrrolo-[3,2-b] pyrroles's method, it is characterized in that: described reduction amination is the carbonyl and the amine acetate reaction of 3-tetrahydro pyrrolidine ketone substituent, obtain amino through reduction reaction, reduction amination carries out in solvent, described solvent is a kind of in methyl alcohol, ethanol or the tetrahydrofuran (THF), and the reduction agents useful for same is a kind of of sodium cyanoborohydride, boron acetate sodium hydride or sodium borohydride.
5. a kind of quick preparation cis according to claim 4-octahydro pyrrolo-[3,2-b] pyrroles's method is characterized in that: add the acid-reaction auxiliary agent in reduction amination, be toluenesulphonic acids or phenylformic acid.
6. a kind of quick preparation cis according to claim 1-octahydro pyrrolo-[3,2-b] pyrroles's method is characterized in that: described protecting group is a kind of in carbonyl ester class protecting group, aryl protecting group or the alkyls protecting group.
7. a kind of quick preparation cis according to claim 6-octahydro pyrrolo-[3,2-b] pyrroles's method, it is characterized in that: described protecting group is CbzCl, Boc
2A kind of among O or the BnBr.
8. a kind of quick preparation cis according to claim 1-octahydro pyrrolo-[3; 2-b] pyrroles's method; it is characterized in that: the described protecting group that adds is reflected in the solvent and carries out, and described solvent is tetrahydrofuran (THF) or sodium hydroxide, adds the protecting group temperature of reaction and is-10～30 ℃.
9. a kind of quick preparation cis according to claim 1-octahydro pyrrolo-[3,2-b] pyrroles's method, it is characterized in that: the ozone of described ozonize reduction ring closure reaction turns to the thiazolinyl and the ozone reaction of the amino Pyrrolidine alkane derivatives of 3-of band protecting group, and post-treatment reagents is dimethyl sulphide or triphenyl phosphorus; It is wherein a kind of of sodium cyanoborohydride, boron acetate sodium hydride or sodium borohydride that reductive agent that ring adopts is closed in the reduction of described ozonize reduction ring closure reaction; The solvent of ozonize reduction ring closure reaction is a kind of of methyl alcohol, ethanol or methylene dichloride, and temperature of reaction is 10-30 ℃.
10. a kind of quick preparation cis according to claim 1-octahydro pyrrolo-[3,2-b] pyrroles's method, it is characterized in that: described decarboxylation reaction, adopt a kind of in triethyl silicon hydrogen, sodium borohydride-trifluoroacetic acid, trimethylchlorosilane-sodium iodide, thiocarbonic ester or N-(triethyl ammonium sulphonyl) Urethylane as reaction reagent, decarboxylation reaction carries out in solvent, reaction solvent is one or more of methyl alcohol, tetrahydrofuran (THF) or methylene dichloride, and temperature of reaction is 10-80 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299438A (en) * | 2017-01-13 | 2018-07-20 | 国家纳米科学中心 | PH response near infrared fluorescent probe compounds and its preparation method and application |
| CN112225700A (en) * | 2020-11-12 | 2021-01-15 | 湖南新合新生物医药有限公司 | Preparation method of altimezole |
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2009
- 2009-12-02 CN CN200910201887XA patent/CN102086202A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299438A (en) * | 2017-01-13 | 2018-07-20 | 国家纳米科学中心 | PH response near infrared fluorescent probe compounds and its preparation method and application |
| CN108299438B (en) * | 2017-01-13 | 2022-05-17 | 国家纳米科学中心 | PH-responsive near-infrared fluorescent probe compound and preparation method and application thereof |
| CN112225700A (en) * | 2020-11-12 | 2021-01-15 | 湖南新合新生物医药有限公司 | Preparation method of altimezole |
| CN112225700B (en) * | 2020-11-12 | 2023-11-17 | 湖南新合新生物医药有限公司 | Preparation method of atemezole |
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Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Hequan Pharmaceutical Co., Ltd., Shanghai |
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Application publication date: 20110608 |