CN103601666B - The preparation method of octahydro pentamethylene [C] pyrroles - Google Patents
The preparation method of octahydro pentamethylene [C] pyrroles Download PDFInfo
- Publication number
- CN103601666B CN103601666B CN201310627653.8A CN201310627653A CN103601666B CN 103601666 B CN103601666 B CN 103601666B CN 201310627653 A CN201310627653 A CN 201310627653A CN 103601666 B CN103601666 B CN 103601666B
- Authority
- CN
- China
- Prior art keywords
- pyrroles
- preparation technology
- octahydro pentamethylene
- reductive agent
- thf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- UZHVXJZEHGSWQV-UHFFFAOYSA-N C(C1)CC2C1CNC2 Chemical compound C(C1)CC2C1CNC2 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 description 2
- QCWDCTDYSDJKTP-UHFFFAOYSA-N O=C(C1C2CCC1)NC2=O Chemical compound O=C(C1C2CCC1)NC2=O QCWDCTDYSDJKTP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a kind of preparation method of octahydro pentamethylene [C] pyrroles (I); The method, by under Lewis acid promotion, obtains octahydro pentamethylene [C] pyrroles (I) by boron reductive agent reduction ring valeryl group with imine moiety (II) single stage method.
Description
Technical field
The invention belongs to chemical pharmacy field, relate to the preparation method of crucial synthetic intermediate octahydro pentamethylene [C] pyrroles (octahydrocyclopenta [c] pyrrole, CAS No. is 5661-03-0) of medicine particularly.
Background technology
Hepatitis C virus is the linear positive chain RNA virus of a kind of sub-thread, and due to various chronic hepatopathy can be caused to occur, hepatitis C virus is one of primary killers of mankind's death because of disease up to now.2011 FDA (Food and Drug Adminstration) (FDA) have approved VX-960 (Telaprevir) and uncle match a Wei (Boceprevir) two small-molecule drugs go on the market in the U.S..The listing of these two proteinase inhibitor, changes the result for the treatment of of the third liver during the last ten years in the past; This is larger breakthrough in the third liver treatment field.
Octahydro pentamethylene [C] pyrroles (or its salt) is a kind of medicine intermediate very useful in pharmaceutical synthesis.It is not only the key intermediate of synthesis VX-960 (Telaprevir), but also is the synthetic intermediate of diabetes medicament gliclazide (gliclazide).Therefore, for its large-scale industrial production, there is very important marketable value.Octahydro pentamethylene [C] pyrroles is following structural formula (I):
The preparation method of octahydro pentamethylene [C] pyrroles has bibliographical information very early: R.Griot at Helv.Chim.Acta., 1959,67-72 magazine proposes first a direct synthetic method in nineteen fifty-nine; Griot adopts LiAlH
4in tetrahydrofuran solution, reduce ring valeryl imines (II), obtain target compound octahydro pentamethylene [C] pyrroles (I) with 51% yield.
WO2009/55467 reports another synthetic method: N-benzyl rings valeryl imines is first through LiAlH
4after reduction, re-use 10% palladium carbon (Pd/C) hydrogenating reduction with 55% total recovery two step obtain target compound octahydro pentamethylene [C] pyrroles (I).The method flow process is as follows:
In the industrialization research and development of the pharmaceutical intermediate to octahydro pentamethylene [C] pyrroles, contriver finds that the yield that above two kinds of methods one side obtains the finished product is not high, lower than 55%; All need in addition to use a large amount of lithium aluminum hydride (LiAlH
4), and LiAlH
4be the highstrung chemical reagent of a kind of chance water, laboratory is when applying, because usage quantity is little, risk level can also be tolerated; But in suitability for industrialized production, because usage quantity is large, its danger is very large, in reduction reaction process and the excessive reductive agent LiAlH of aftertreatment
4time can very exothermic, when localized heat is uneven, be very easy to security incidents such as blasting.Generally speaking, during chemical industryization is produced, should avoid using as LiAlH
4so highstrung chemical reagent of chance water.
Up to now, also not reporting the industrialized preparing process of octahydro pentamethylene [C] pyrroles, quantizing production method in the urgent need to finding a kind of effective industry of safe and high yield.
Summary of the invention
The object of this invention is to provide a kind of preparation method meeting octahydro pentamethylene [C] pyrroles (I) of suitability for industrialized production.
For achieving the above object, the present invention after extensive studies it, devise and prepare the new method being different from prior art of octahydro pentamethylene [C] pyrroles, namely under suitable reductive agent and suitable promotor act on, obtain target compound octahydro pentamethylene [C] pyrroles (I) by " single stage method " direct-reduction by ring valeryl imines (II).
Specifically, the preparation method of octahydro pentamethylene [C] pyrroles (I) provided by the invention, comprise reaction substrate ring valeryl imines (II) under boron reductive agent and lewis promoters effect, in appropriate solvent, react at moderate temperatures, obtain target compound octahydro pentamethylene [C] pyrroles (I).
In a kind of embodiment, described suitable reductive agent is selected from sodium borohydride or POTASSIUM BOROHYDRIDE; Preferred sodium borohydride.
In a kind of embodiment, described lewis promoters is selected from zinc chloride, calcium chloride, iron(ic) chloride, iron protochloride, magnesium chloride etc.; More preferably, described lewis promoters is zinc chloride.
In a kind of embodiment, described appropriate solvent is inert solvent; Described inert solvent is selected from tetrahydrofuran (THF), acetonitrile, 1,4-dioxane, toluene, dimethylbenzene, benzene, glycol dimethyl ether, ethylene glycol monomethyl ether, DMF, methyl-sulphoxide, chloroform single solvent or wherein two or more mixed solvent.Preferably, solvent is tetrahydrofuran (THF) or toluene, or both mixed solvents.
In a kind of embodiment, reaction uses single solvent, and temperature of reaction is the reflux temperature of solvent for use.
In a kind of embodiment, reaction uses mixed solvent, and temperature of reaction is arbitrary temp between the boiling point of each solvent used or the azeotropic temperature of this mixed solvent.
In a kind of embodiment, the mol ratio of described reductive agent and reaction substrate (II) is 1:1 to 10:1; Preferred 1.1:1 to 5:1.
In a kind of embodiment, the mol ratio of described promotor and reaction substrate (II) is 0.5:1 to 10:1; Preferred 1.1:1 to 5:1.
Compared with current published technology, novel preparation method of the present invention is by reduction ring valeryl group with imine moiety (II), single stage method prepares octahydro pentamethylene [C] pyrroles (I), advantage is, have employed low price on the one hand, and reaction temperature and, operational safety go back original reagent, on the other hand improve the reactive behavior of going back original reagent by suitable Lewis acid, the higher and purity of product yield is also high (>97%).Therefore this novel method adopt reagent safety, reaction conditions is gentle, product yield is high; Suitability for industrialized production can be met well.
Following examples are only illustrate the present invention further, there is no the intention limiting the invention to this specific embodiment.One skilled in the art would recognize that and present invention encompasses all possible alternatives, improvement project and equivalents in Claims scope.
Embodiment
Raw material and reagent:
Ring valeryl imines (II) (self-control is formed by 1,2-ring penta dioctyl phthalate and urine dehydrating condensation according to existing document);
Sodium borohydride, POTASSIUM BOROHYDRIDE, zinc chloride, iron(ic) chloride and other solvent used and reagent are Chemical Reagent Co., Ltd., Sinopharm Group to be provided.
Embodiment 1
Under nitrogen atmosphere, be equipped with in the there-necked flask of the 5L of mechanical stirrer toward one and add tetrahydrofuran (THF) (500mL), toluene (1.5L), sodium borohydride (68.40g successively, 2.5eq.) with zinc chloride (125.0g, 1.3eq.).Gained suspended substance is heated to backflow.Slowly steam tetrahydrofuran (THF), temperature is controlled at 90 ± 5 DEG C, until there is black solid to generate.Drip tetrahydrofuran (THF) (500mL) solution of ring valeryl imines (100g, 0.72mol), and backflow is spent the night at this temperature.Cooling, is neutralized to pH=2-3 with dilute hydrochloric acid, and divide and go organic phase, aqueous phase ethyl acetate (1L x3) extracts three times, divides and goes organic phase.After being with acid water layer saturated solution of sodium carbonate to be neutralized to pH=8-9, extract by ethyl acetate (1L x3).The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Obtain white solid octahydro pentamethylene [C] pyrroles (72.8g, 90.9%), HPLC purity is 97%.
Embodiment 2
Under nitrogen atmosphere, be equipped with in the there-necked flask of the 500mL of mechanical stirrer toward one and add tetrahydrofuran (THF) (50mL), toluene (150mL), sodium borohydride (6.84g successively, 2.5eq.) with zinc chloride (12.5g, 1.3eq.).Gained suspended substance is heated to backflow.Slowly steam tetrahydrofuran (THF), temperature is controlled at 90 ± 5 DEG C, until there is black solid to generate.Drip tetrahydrofuran (THF) (50mL) solution of ring valeryl imines (10g, 72mmol), and backflow is spent the night at this temperature.Cooling, is neutralized to pH=2-3 with dilute hydrochloric acid, and divide and go organic phase, aqueous phase ethyl acetate (100mL x3) extracts three times, divides and goes organic phase.After being with acid water layer saturated solution of sodium carbonate to be neutralized to pH=8-9, extract by ethyl acetate (100mL x3).The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Obtain white solid octahydro pentamethylene [C] pyrroles (7.35g, 91.8%), HPLC purity is 97%.
Embodiment 3
Under nitrogen atmosphere, be equipped with in the there-necked flask of the 500mL of mechanical stirrer toward one and add tetrahydrofuran (THF) (50mL), toluene (150mL), POTASSIUM BOROHYDRIDE (9.76g successively, 2.5eq.) with zinc chloride (14.4g, 1.5eq.).Gained suspended substance is heated to backflow.Slowly steam tetrahydrofuran (THF), temperature is controlled at 90 ± 5 DEG C, until there is black solid to generate.Drip tetrahydrofuran (THF) (50mL) solution of ring valeryl imines (10g, 72mmol), and backflow is spent the night at this temperature.Cooling, is neutralized to pH=2-3 with dilute hydrochloric acid, and divide and go organic phase, aqueous phase ethyl acetate (100mL x3) extracts three times, divides and goes organic phase.After being with acid water layer saturated solution of sodium carbonate to be neutralized to pH=8-9, extract by ethyl acetate (100mL x3).The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Obtain white solid octahydro pentamethylene [C] pyrroles (7.33g, 91.6%), HPLC purity is 97%.
Embodiment 4
Under nitrogen atmosphere, be equipped with in the there-necked flask of the 250mL of mechanical stirrer toward one and add acetonitrile (25mL), dimethylbenzene (75mL), sodium borohydride (4.93g successively, 3.0eq.) with iron(ic) chloride (11.5g, 2.0eq.).Gained suspended substance is heated to 90 ± 5.Slowly steam tetrahydrofuran (THF), temperature is controlled at 90 ± 5 DEG C, until there is black solid to generate.Drip tetrahydrofuran (THF) (50mL) solution of ring valeryl imines (5g, 36mmol), and spend the night at this temperature.Cooling, is neutralized to pH=2-3 with dilute hydrochloric acid, and divide and go organic phase, aqueous phase ethyl acetate (100mL x3) extracts three times, divides and goes organic phase.After being with acid water layer saturated solution of sodium carbonate to be neutralized to pH=8-9, extract by ethyl acetate (100mL x3).The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Obtain white solid octahydro pentamethylene [C] pyrroles (3.26g, 81.4%), HPLC purity is 95%.
Embodiment 5
Under nitrogen atmosphere, be equipped with in the there-necked flask of the 250mL of mechanical stirrer toward one and add tetrahydrofuran (THF) (25mL), dimethylbenzene (75mL), POTASSIUM BOROHYDRIDE (11.22g successively, 5.0eq.) with zinc chloride (19.32g, 4.0eq.).Gained suspended substance is heated to 90 ± 5 DEG C.Slowly steam tetrahydrofuran (THF), temperature is controlled at 90 ± 5 DEG C, until there is black solid to generate.Drip tetrahydrofuran (THF) (50mL) solution of ring valeryl imines (5g, 36mmol), and spend the night at this temperature.Cooling, is neutralized to pH=2-3 with dilute hydrochloric acid, and divide and go organic phase, aqueous phase ethyl acetate (50mL x3) extracts three times, divides and goes organic phase.After being with acid water layer saturated solution of sodium carbonate to be neutralized to pH=8-9, extract by ethyl acetate (50mL x3).The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Obtain white solid octahydro pentamethylene [C] pyrroles (3.65g, 91.2%), HPLC purity is 96%.
Claims (6)
1. the preparation technology of octahydro pentamethylene [C] pyrroles I, it is characterized in that, by reaction substrate ring valeryl imines II under boron reductive agent, lewis promoters effect, react in appropriate solvent, under proper temperature, obtain target compound octahydro pentamethylene [C] pyrroles I; Chemical reaction is shown in following formula:
Described boron reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE, and described lewis promoters is zinc chloride,
Described appropriate solvent is selected from two or more the mixed solvent in tetrahydrofuran (THF), toluene, dimethylbenzene,
Described proper temperature is arbitrary temp between the boiling point of each solvent used or the azeotropic temperature of this mixed solvent.
2. preparation technology as claimed in claim 1, it is characterized in that, described appropriate solvent is selected from the mixed solvent of tetrahydrofuran (THF) and toluene.
3. preparation technology as claimed in claim 1, it is characterized in that, the mol ratio of described reductive agent and reaction substrate ring valeryl imines II is 1:1 to 10:1.
4. preparation technology as claimed in claim 3, it is characterized in that, the mol ratio of described reductive agent and reaction substrate ring valeryl imines II is 1.1:1 to 5:1.
5. preparation technology as claimed in claim 1, it is characterized in that, the mol ratio of described promotor and reaction substrate ring valeryl imines II is 0.5:1 to 10:1.
6. preparation technology as claimed in claim 5, it is characterized in that, the mol ratio of described promotor and reaction substrate ring valeryl imines II is 1:1 to 5:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310627653.8A CN103601666B (en) | 2013-11-28 | 2013-11-28 | The preparation method of octahydro pentamethylene [C] pyrroles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310627653.8A CN103601666B (en) | 2013-11-28 | 2013-11-28 | The preparation method of octahydro pentamethylene [C] pyrroles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103601666A CN103601666A (en) | 2014-02-26 |
| CN103601666B true CN103601666B (en) | 2015-09-02 |
Family
ID=50119950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310627653.8A Expired - Fee Related CN103601666B (en) | 2013-11-28 | 2013-11-28 | The preparation method of octahydro pentamethylene [C] pyrroles |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103601666B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206357A (en) * | 2017-07-04 | 2019-01-15 | 浙江九洲药业股份有限公司 | A kind of general formula compound and its preparation method and application of gliclazide intermediate |
| CN109438325A (en) * | 2018-12-05 | 2019-03-08 | 兰州大学 | A kind of method of ring valeryl imines catalytic hydrogenation synthesis octahydro pentamethylene [C] pyrroles |
| CN116283719B (en) * | 2023-03-28 | 2023-09-08 | 安徽金鼎医药股份有限公司 | Preparation process and preparation system of gliclazide intermediate amino heterocyclic hydrochloride |
| CN117510394A (en) * | 2023-11-08 | 2024-02-06 | 内蒙古源宏精细化工有限公司 | Preparation method of N-amino-3-azabicyclo [3, 0] octane hydrochloride |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235011A (en) * | 2008-03-11 | 2008-08-06 | 浙江大学 | N-amino-1,2-cyclopentanediformylimine and preparation method thereof |
| CN101381338A (en) * | 2007-09-03 | 2009-03-11 | 上海医药工业研究院 | Method for preparing cis-hexahydroisoindoline |
| WO2009140279A2 (en) * | 2008-05-12 | 2009-11-19 | Concert Pharmaceuticals, Inc. | Sulfonyl urea compounds |
| CN102816102A (en) * | 2011-06-08 | 2012-12-12 | 瑟维尔实验室 | Synthesis process, and crystalline form of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy} benzamide hydrochloride and pharmaceutical compositions containing it |
| CN102924362A (en) * | 2012-10-26 | 2013-02-13 | 浙江工业大学 | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride |
| WO2013050301A1 (en) * | 2011-10-03 | 2013-04-11 | Syngenta Participations Ag | Enantionselective processes to insecticidal 3-aryl-3-trifluoromethyl-substituted pyrrolidines |
| TW201341358A (en) * | 2012-01-06 | 2013-10-16 | Lonza Ag | Method for preparation of octahydrocyclopenta[c] pyrrole |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004131399A (en) * | 2002-10-08 | 2004-04-30 | Ihara Chem Ind Co Ltd | Method for producing cis-hexahydroisoindoline |
-
2013
- 2013-11-28 CN CN201310627653.8A patent/CN103601666B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101381338A (en) * | 2007-09-03 | 2009-03-11 | 上海医药工业研究院 | Method for preparing cis-hexahydroisoindoline |
| CN101235011A (en) * | 2008-03-11 | 2008-08-06 | 浙江大学 | N-amino-1,2-cyclopentanediformylimine and preparation method thereof |
| WO2009140279A2 (en) * | 2008-05-12 | 2009-11-19 | Concert Pharmaceuticals, Inc. | Sulfonyl urea compounds |
| CN102816102A (en) * | 2011-06-08 | 2012-12-12 | 瑟维尔实验室 | Synthesis process, and crystalline form of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy} benzamide hydrochloride and pharmaceutical compositions containing it |
| WO2013050301A1 (en) * | 2011-10-03 | 2013-04-11 | Syngenta Participations Ag | Enantionselective processes to insecticidal 3-aryl-3-trifluoromethyl-substituted pyrrolidines |
| TW201341358A (en) * | 2012-01-06 | 2013-10-16 | Lonza Ag | Method for preparation of octahydrocyclopenta[c] pyrrole |
| CN102924362A (en) * | 2012-10-26 | 2013-02-13 | 浙江工业大学 | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| A practical and efficient procedure for reduction of carboxylic acids and their derivatives: use of KBH4–MgCl2;You-Chun Qiu,等;《Tetrahedron Letters》;20070904;第48卷(第43期);第7595-7598页 * |
| 硼氢化钠在有机合成中的新应用;车荣睿;《化学试剂》;19861231;第8卷(第02期);第94-98页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103601666A (en) | 2014-02-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103601666B (en) | The preparation method of octahydro pentamethylene [C] pyrroles | |
| Huang et al. | Construction of optically active quaternary propargyl amines by highly enantioselective zinc/BINOL‐catalyzed alkynylation of ketoimines | |
| An et al. | N-Phosphonyl/phosphinyl imines and group-assisted purification (GAP) chemistry/technology | |
| Luo et al. | Asymmetric ring-opening of oxabenzonorbornadiene with amines promoted by a chiral iridium-monophosphine catalyst | |
| CN103864885B (en) | The application of 1-hydroxyl-1,2,3-phentriazine-4 (3H)-one in Peptide systhesis | |
| CN103553857A (en) | Method for preparing o-trifluoromethyl phenylamine and derivatives thereof | |
| CN105541714A (en) | Preparation methods of papaverine and papaverine hydrochloride | |
| Jia et al. | Visible Light Induced Copper‐Catalyzed Enantioselective Deaminative Arylation of Amino Acid Derivatives Assisted by Phenol | |
| CN103012268B (en) | Novel preparation method for ivabradine | |
| CN102731333A (en) | Method for preparing tetracaine | |
| CN103588750B (en) | Method for preparing ticagrelor intermediate | |
| CN106892826B (en) | A kind of preparation method and application of amine and imines N-methyl | |
| CN102010317B (en) | Method for synthesizing felbinac and derivatives thereof | |
| CN104478746A (en) | Preparation method of DL-lysine | |
| CN106518747A (en) | New method for preparing gliclazide intermediate | |
| CN105622583A (en) | Novel preparation method for novel anti-hepatitis C drug-daklinza | |
| CN102304102B (en) | Preparation method of 1-methyl piperazine | |
| CN107344944A (en) | A kind of method for preparing DRV intermediate | |
| Kaldun et al. | Enantioselective borane reduction of ketones catalyzed by tricyclic 1, 3, 2-oxazaborolidines | |
| CN102702196B (en) | Method for synthesizing 3-methyl-7-diazaindene | |
| CN102766072B (en) | Method for preparing atorvastatin calcium chiral side chain | |
| CN104592309A (en) | Preparation method of chiral amino acid | |
| CN104356073A (en) | Microwave-assisted high-efficiency method for synthesizing 5-cyanouracil | |
| Chen et al. | Palladium catalyzed cross-dimerization of terminal acetylenes and acrylates | |
| CN109336832A (en) | A kind of polypeptide condensing agent and preparation method thereof for polypeptide drug synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150902 Termination date: 20201128 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |