CN102030658A - Methods for preparing 3-cyclopentamine and slats thereof - Google Patents
Methods for preparing 3-cyclopentamine and slats thereof Download PDFInfo
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- CN102030658A CN102030658A CN201110005559XA CN201110005559A CN102030658A CN 102030658 A CN102030658 A CN 102030658A CN 201110005559X A CN201110005559X A CN 201110005559XA CN 201110005559 A CN201110005559 A CN 201110005559A CN 102030658 A CN102030658 A CN 102030658A
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- cyclopentamine
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Abstract
The invention discloses methods for preparing 3-cyclopentamine and slats thereof. The method for preparing the 3-cyclopentamine comprises the following steps of: adding cis-1,4-dichloro-2-butene and nitromethane serving as initial raw materials into a solvent to perform a reaction in the presence of an alkaline catalyst and at the temperature of 25 to 80 DEG C to obtain 4-nitro-cyclopentyl-1-alkenyl; and reducing the 4-nitro-cyclopentyl-1-alkenyl in a reduction system to obtain the 3-cyclopentamine. The new process provided by the invention reduces the course for synthesizing the target product to a relatively large extent, successfully solves the problems of high-price, rareness and the like of the raw materials of the target product and avoids a diazotization reaction at the same time. The new process greatly reduces production cost, improves yield and product purity and is simple in operation and convenient for mass production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, relate in particular to the preparation method of 3-cyclopentamine and salt thereof.
Background technology
[0002], is widely used as the intermediate of medication chemistry and fine chemistry industry owing to the singularity of compound 3-cyclopentamine structure.
Conventional, 3-is adopted in the preparation of this compound, and cyclopentenes-1-alcohol is raw material, and through the methylsulfonic acid protection, sodium azide diazotization obtains the 3-cyclopentamine through hydrolysis again, and its reaction scheme is:
Because this synthetic route is long, yield is low, and starting raw material is not easy to obtain and costs an arm and a leg, and causes the cost of this compound of preparation very high.
Summary of the invention
One of technical problem to be solved by this invention just provides the preparation method of 3-cyclopentamine, and synthetic route is short, and preparation cost is low.
Two the preparation method who provides 3-cyclopentenes amine salt of technical problem to be solved of the present invention.
The present invention seeks to by following realization:
The preparation method of 3-cyclopentamine, be made up of following step:
Step 1: with cis-1,4-two chloro-2-butylene and Nitromethane 99Min. are starting raw material, add solvent, under the base catalysis condition, in 25 ~ 80 ℃ of temperature ranges, obtain 4-nitro-ring penta-1-alkene;
Described solvent is selected from ether, tetrahydrofuran (THF), toluene or DMF;
Described alkali is selected from NaH, LiH or potassium tert.-butoxide;
Described cis-1, the mol ratio of 4-two chloro-2-butylene and Nitromethane 99Min. is 1:1 ~ 1:3;
Step 2:4-nitro-ring penta-1-alkene reduces in reduction system and makes the 3-cyclopentamine,
Described reduction system is the reduction system of metal with acid;
Further, described metal is selected from Fe, Zn or Sn etc. than the active metal;
Described acid is selected from hydrochloric acid, acetate, ammonium chloride or ammonium formiate;
Further again, described reduction system is Fe/HCl/H
2O/C
2H
5OH system, Fe/5%CH
3COOH/H
2O system or Zn/NH
4Cl/CH
3The OH system;
The concrete reaction scheme of above-mentioned preparation is:
In the above-mentioned reaction equation, solvent is a solvent, and base is an alkali, and described solvent is ether, tetrahydrofuran (THF), toluene or DMF, and described alkali is NaH, LiH or potassium tert.-butoxide.
The invention also discloses the preparation method of 3-cyclopentenes amine salt, on the basis of above-mentioned preparation 3-cyclopentamine, also comprise the steps:
Step 3:3-cyclopentamine and acid-respons behind the purifying, make 3-cyclopentenes amine salt;
Described acid is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid or tosic acid.
The concrete reaction scheme of above-mentioned preparation is:
In the above-mentioned reaction equation, HA is acid, and described acid is hydrochloric acid, sulfuric acid, methylsulfonic acid or tosic acid.
It is short that preparation method of the present invention has synthetic route, the characteristics that preparation cost is low.Novel process of the present invention has shortened the route of synthetic target product to a great extent, has successfully solved synthetic target product raw material costliness, problem such as rare, has avoided diazotization reaction simultaneously again.Novel process greatly reduces production cost, has improved yield and product purity, easy and simple to handle, is convenient to large-scale production.
Embodiment
Embodiment 1
In the there-necked flask of 2L, add Nitromethane 99Min. 61g(1mol), THF610ml, LiH20g(2.5mol), be heated to 50 ~ 55 ℃, insulation 1h, drip cis-1,4-two chloro-2-butylene 125g(1mol), dropwise, between 70 ~ 75 ℃, be incubated 24h, be cooled to room temperature, filter, filtrate is concentrated into dried, get thick oily matter 108g, obtain 4-nitro-ring penta-1-alkene.
Embodiment 2
In the there-necked flask of 2L, add Nitromethane 99Min. 61g(1.0mol), THF610ml, NaH60g(2.5mol), be heated to 50 ~ 55 ℃, insulation 1h, drip cis-1,4-two chloro-2-butylene 125g(1.0mol), dropwise, between 70 ~ 75 ℃, be incubated 24h, be cooled to room temperature, filter, filtrate is concentrated into dried, get thick oily matter 110g, obtain 4-nitro-ring penta-1-alkene.
Embodiment 3
In the there-necked flask of 2L, add Nitromethane 99Min. 61g(1.0mol), THF610ml, potassium tert.-butoxide 336g(3.0mol), is heated to 50 ~ 55 ℃, insulation 1h, drip cis-1,4-two chloro-2-butylene 125g(1.0mol), dropwise, backflow 24h, be cooled to room temperature, filter, filtrate is concentrated into dried, get thick oily matter 106g, obtain 4-nitro-ring penta-1-alkene.
Embodiment 4
In the four-necked bottle of 5L, add methyl alcohol 1.3L, 4-nitro-ring penta-1-alkene 108g that embodiment 1 is prepared is stirred to moltenly entirely, and adding contains the aqueous solution (540g ammonium formiate+water 1L) of 540g ammonium formiate, adds zinc powder 250g (0min:100g in batches; 30min:50g; 60min:50g; 90min:50g), temperature is no more than 45 ℃, finishes, stir 3h under room temperature, reacting liquid filtering is removed zinc powder, and filtrate decompression concentrates, remove most methyl alcohol (the about 1.2L of the amount of steaming), residuum extracts with ethyl acetate (250ml X 3), merges organic layer, anhydrous sodium sulfate drying, filter, obtain filtrate, i.e. 3-cyclopentamine solution
Further drying makes 3-cyclopentamine pressed powder.
Embodiment 5
In the four-necked bottle of 5L, add ethanol 1.3L, 4-nitro-ring penta-1-alkene 110g that embodiment 3 is prepared, acetate 60g, Fe 200g is heated to backflow, reaction 4h, reacting liquid filtering is removed iron powder, and filtrate decompression concentrates, remove ethanol, add ethyl acetate 750ml in the resistates, filter, remove insolubles, filtrate is used anhydrous sodium sulfate drying, filters, obtain filtrate, i.e. 3-cyclopentamine solution
Further drying makes 3-cyclopentamine pressed powder.
Embodiment 6
Filtrate with embodiment 4 makes promptly feeds HCl gas in the 3-cyclopentamine solution, spend the night crystallization.Filter, filter cake washs with ethyl acetate, the dry off-white color solid 3-cyclopentamine hydrochloride 97g that gets; 211 ~ 212 ℃ of fusing points.
Embodiment 7
Filtrate with embodiment 5 makes promptly feeds HCl gas in the 3-cyclopentamine solution, spend the night crystallization.Filter, filter cake washs with ethyl acetate, the dry off-white color solid 3-cyclopentamine hydrochloride 91g that gets; 211 ~ 212 ℃ of fusing points.
It is short that preparation method of the present invention has synthetic route, the characteristics that preparation cost is low. New technology of the present invention has shortened the route of synthetic target product to a great extent, has successfully solved synthetic target product raw material costliness, the problem such as rare, has avoided again diazo-reaction simultaneously. New technology greatly reduces production cost, has improved yield and product purity, easy and simple to handle, is convenient to large-scale production.
Claims (9)
1.3-the preparation method of cyclopentamine is characterized in that, is made up of following step:
Step 1: with cis-1,4-two chloro-2-butylene and Nitromethane 99Min. are starting raw material, add solvent, under the base catalysis condition, in 25 ~ 80 ℃ of temperature ranges, obtain 4-nitro-ring penta-1-alkene;
Step 2:4-nitro-ring penta-1-alkene reduces in reduction system and makes the 3-cyclopentamine.
2. the preparation method of 3-cyclopentamine as claimed in claim 1 is characterized in that: solvent described in the step 1 is ether, tetrahydrofuran (THF), toluene or DMF.
3. the preparation method of 3-cyclopentamine as claimed in claim 1 is characterized in that: alkali described in the step 1 is NaH, LiH or potassium tert.-butoxide.
4. the preparation method of 3-cyclopentamine as claimed in claim 1 is characterized in that: cis described in the step 1-1, the mol ratio of 4-two chloro-2-butylene and Nitromethane 99Min. is 1:1 ~ 1:3.
5. the preparation method of 3-cyclopentamine as claimed in claim 1 is characterized in that: reduction system described in the step 2 is metal and sour reduction system.
6. the preparation method of 3-cyclopentamine as claimed in claim 5 is characterized in that: metal described in the step 2 is Fe, Zn or Sn, and described acid is hydrochloric acid, acetate, ammonium chloride or ammonium formiate.
7. the preparation method of 3-cyclopentamine as claimed in claim 6 is characterized in that: in the step 2, described reduction system is Fe/HCl/H
2O/C
2H
5OH system, Fe/5%CH
3COOH/H
2O system or Zn/NH
4Cl/CH
3The OH system.
8.3-the preparation method of cyclopentenes amine salt is characterized in that, on the basis of each preparation 3-cyclopentamine, also comprises the steps: in claim 1 ~ 7
Step 3:3-cyclopentamine and acid-respons behind the purifying, make 3-cyclopentenes amine salt.
9. the preparation method of 3-cyclopentenes amine salt as claimed in claim 8 is characterized in that: in the step 3, described acid is hydrochloric acid, sulfuric acid, methylsulfonic acid or tosic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 201110005559 CN102030658B (en) | 2011-01-12 | 2011-01-12 | Methods for preparing 3-cyclopentamine and slats thereof |
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|---|---|---|---|
| CN 201110005559 CN102030658B (en) | 2011-01-12 | 2011-01-12 | Methods for preparing 3-cyclopentamine and slats thereof |
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| CN102030658A true CN102030658A (en) | 2011-04-27 |
| CN102030658B CN102030658B (en) | 2013-07-24 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187781A (en) * | 2016-07-11 | 2016-12-07 | 江苏红豆杉药业有限公司 | A kind of preparation method of memantine |
-
2011
- 2011-01-12 CN CN 201110005559 patent/CN102030658B/en not_active Expired - Fee Related
Non-Patent Citations (5)
| Title |
|---|
| A. A. BORISENKO ET AL.: "Reaction of Cyclic Olefins with Acetyl Nitrate. [2 + 2] Cycloaddition of the Nitryl Cation?", 《J. AM. CHEM. SOC.》 * |
| DAVID M. HODGSON ET AL.: "On the Possibility of Carbamate-directed Hydroboration.An Approach to the Asymmetric Synthesis of 1-Aminocy clopentane-1,3-dicarboxylic Acid", 《TETRAHEDRON》 * |
| PETER OBRIEN ET AL.: "Synthesis and Enantioselective Rearrangement of 4-Amino-substituted Cyclopentene Oxides", 《TETRAHEDRON LETTERS》 * |
| ROBERT D. ELLIOTT ET AL.: "Phosphonate Analogs of Carbocyclic Nucleotides", 《J. MED. CHEM》 * |
| STEPHEN BARRETT ET AL.: "New Route to 4-Aminocyclopent-2-en-1-ols: Synthesis and Enantioselective Rearrangement of 4-Amino-substituted Cyclopentene Oxides", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187781A (en) * | 2016-07-11 | 2016-12-07 | 江苏红豆杉药业有限公司 | A kind of preparation method of memantine |
| CN106187781B (en) * | 2016-07-11 | 2018-07-13 | 江苏红豆杉药业有限公司 | A kind of preparation method of memantine |
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| CN102030658B (en) | 2013-07-24 |
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