CN106397216A - Method for synthesizing medical intermediates - Google Patents
Method for synthesizing medical intermediates Download PDFInfo
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- CN106397216A CN106397216A CN201610813978.9A CN201610813978A CN106397216A CN 106397216 A CN106397216 A CN 106397216A CN 201610813978 A CN201610813978 A CN 201610813978A CN 106397216 A CN106397216 A CN 106397216A
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- phenyl
- methylamine
- cyclopenta
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
- C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing medical intermediates R-alpha-cyclopentyl (phenyl) methylamine. The particular method includes generating racemization alpha-cyclopentyl (phenyl) methylamine from phenyl cyclopentanone by means of reductive amination under the effects of catalysts; combining the alpha-cyclopentyl (phenyl) methylamine, lipase and racemization catalysts with one another and carrying out dynamic kinetic resolution to obtain the R-alpha-cyclopentyl (phenyl) methylamine. The method has the advantages that the method is easy to implement, raw materials can come from wide sources, products are high in yield, resolution products are high in optical purity, and the like.
Description
Technical field
The present invention relates to a kind of synthesis of Chiral Amine and method for splitting, more particularly, to a kind of medicine intermediate R- α-cyclopenta
（Phenyl）The synthetic method of methylamine.
Background technology
α-the cyclopenta of current report（Phenyl）The synthetic method of methylamine has with phenyl cyclopentanone as raw material, in metatitanic acid
Carry out reductive amination process with ammonia under the catalysis of four isopropyl esters and obtain α-cyclopenta（Phenyl）Methylamine, yield is 25%
（Preparation of aminoquinazolinone derivatives and analogs for use as GPR119
Modulators, PCT Int. Appl., 2009143049,26 Nov 2009）；Or phenyl cyclopentanone and formic acid first
Sour ammonium reaction, reduction amination obtains α-cyclopenta（Phenyl）Methylamine, the yield of this method is 44%（Synthesis and
structure-activity relationships of potential anticonvulsants based on 2-
Piperidinecarboxylic acid and related pharmacophores, European Journal of
Medicinal Chemistry, 36(3), 265-286; 2001）.
R- α-cyclopenta in its isomers（Phenyl）The synthetic method of methylamine then has no report.
Content of the invention
The present invention is intended to provide a kind of R- α-cyclopenta（Phenyl）The synthetic method of methylamine.In order to realize this target, specifically
Operation is as follows：1）In autoclave, with methyl alcohol or ethanol as solvent, phenyl cyclopentanone is raw material, divides by phenyl cyclopentanone quality
The ratio of number 5%-20% adds catalyst；Sealing autoclave, after nitrogen displacement, with mol ratio 1:The ratio of 5-10 be passed through liquefied ammonia or
Ammonia, is finally passed through hydrogen to pressure 3-5MPa, is warmed up to 70-100 DEG C of reaction, observes and stops reaction after no longer inhaling hydrogen；Terminate
After reaction, through filtering, concentration operation obtains α-cyclopenta（Phenyl）Methylamine crude product；Crude product through acid, can purify after alkali process obtain pure
Spend the α-cyclopenta for 99%（Phenyl）Methylamine；2）Step 1）Gained α-cyclopenta（Phenyl）Methylamine is dissolved in toluene solvant, by α-
Cyclopenta（Phenyl）The ratio of methylamine 1.0-2.0 equivalent adds acry radical donor, by α-cyclopenta（Phenyl）Methylamine mass fraction 5%-
10% ratio adds lipase, by α-cyclopenta（Phenyl）The ratio of methylamine mass fraction 5%-20% adds racemization catalyst, rises
Temperature is to 40-60 DEG C of reaction 6-14 hour, you can by α-cyclopenta（Phenyl）Methylamine is fully converted to R- α-cyclopenta（Phenyl）First
The amide compound of amine；Stop reaction, filter, concentration steams toluene and must split crude product；3）By step 2）Gained crude product is used
Dimethylbenzene recrystallizes, and can obtain R- α-cyclopenta（Phenyl）Methylamine acyl compounds sterling, purity>99%；Acyl compounds are again through acid
Solution, alkali process etc. operate, and can obtain R- α-cyclopenta（Phenyl）Methylamine；And product ee value is up to more than 99%.Step 1 in the present invention）
In reducing catalyst be nickel/alumina load catalyst SN-6000P；Step 2）In acyl compounds can for (-)-newly thin
Lotus alcohol acetic ester；Step 2）In lipase used be Pseudomonas fluorecens lipase Lipase AK；Step 2）In used disappearing
Rotation catalyst is nickel/alumina load catalyst SN-6000P, and this catalyst is the industrial catalyst bought from fast triumphant catalysis work.
The method that the present invention is announced is successfully prepared α-cyclopenta（Phenyl）Methylamine, and fractionation prepares R- further
α-cyclopenta（Phenyl）Methylamine.The present invention is also equipped with the features such as simple to operate, product yield is good, purity is high simultaneously.In α-ring penta
Base（Phenyl）In the production of methylamine and fractionation research, there is great guidance and using value.
Specific embodiment
Embodiment 1
1）α-cyclopenta（Phenyl）The preparation of methylamine
In autoclave, add 87g phenyl cyclopentanone, 500ml absolute ethyl alcohol, 13g catalyst SN-6000P, sealed reactor, use
Vacuum pumping pump extracts the air in kettle, is re-filled with nitrogen and vacuumizes to 0.5MPa, then with vacuum pumping pump；It is filled with condition of negative pressure
40g ammonia, fills ammonia and finishes, and is filled with hydrogen to 4MPa in autoclave, and is warming up to 100 DEG C and is reacted.React to no longer inhaling
Receive hydrogen, then stop reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give α-cyclopenta（Phenyl）Methylamine is thick
Product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow its reaction generate α-cyclopenta（Phenyl）Methylamine salt,
And be dissolved in the aqueous solution, and remove organic impurities with ethyl acetate essence aqueous, after point liquid, retain aqueous phase, aqueous phase is used again
After ethyl acetate essence takes twice, adjust pH value to alkalescence with NaOH, then taken 3 times with ethyl acetate essence, now collect and adjust
After section pH value, the ethyl acetate phase of extraction, concentrates after being dried, obtains α-cyclopenta（Phenyl）Methylamine sterling 80.76g, yield is
92.3%, and HPLC detects that its purity is 99.5%.
2）α-cyclopenta（Phenyl）The Dynamic Kinetic Resolution of methylamine
In autoclave, add step 1) gained 35g α-cyclopenta（Phenyl）Methylamine sterling, 40g (-)-neomenthol acetic acid esters is molten
In 500ml toluene, add 6g racemization catalyst SN-6000P, 3g Pseudomonas fluorecens lipase Lipase AK, sealing is anti-
Answer kettle, extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen and vacuumize to 0.5MPa, then with vacuum pumping pump；It is replaced,
It is filled with hydrogen in autoclave to 1.0MPa, and is warming up to 45 DEG C and reacted；After 14 hours of reaction, stop reacting, detection α-
Cyclopenta（Phenyl）Methylamine is wholly absent, and is converted into R- α-cyclopenta（Phenyl）Methylamine acetyl compounds.After stopping reaction, mistake
Filter, be concentrated to give R- α-cyclopenta（Phenyl）Methylamine acetyl compounds with (-)-neomenthol, (-)-neomenthol acetic acid esters mix
The crude product of compound.
3）R- α-cyclopenta（Phenyl）The preparation of methylamine
By step 2）Gained crude product dimethylbenzene recrystallizes to obtain R- α-cyclopenta（Phenyl）Methylamine acetyl compounds sterling；To weigh
Crystallization sterling is dissolved in hydrochloric acid and the mixed solution of methyl alcohol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, etc.
R- α-cyclopenta（Phenyl）Methylamine acetyl compounds complete hydrolysis become R- α-cyclopenta（Phenyl）After methylamine, cooling, first is evaporated off
Alcohol, adjust pH value to alkalescence, taken 3 times with ethyl acetate essence, merge organic phase, be dried, concentrate after obtain R- α-cyclopenta（Phenyl）
Methylamine 32.10g, yield is 91.7%, and HPLC detects that its ee value is 99.5%.
Embodiment 2
1）α-cyclopenta（Phenyl）The preparation of methylamine
In autoclave, addition 174g phenyl cyclopentanone, 1200ml absolute ethyl alcohol, 30g catalyst SN-6000P, sealed reactor,
Extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen and vacuumize to 0.5MPa, then with vacuum pumping pump；It is filled with condition of negative pressure
90g ammonia, fills ammonia and finishes, and is filled with hydrogen to 4MPa in autoclave, and is warming up to 100 DEG C and is reacted.Discovery system is no longer
When absorbing hydrogen, then stop reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give α-cyclopenta（Phenyl）First
Amine crude product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow its reaction generate α-cyclopenta（Phenyl）Methylamine
Salt, and be dissolved in the aqueous solution, and remove organic impurities with ethyl acetate essence aqueous, after point liquid, retain aqueous phase, aqueous phase is again
After being taken twice with ethyl acetate essence, adjust pH value to alkalescence with NaOH, then taken 3 times with ethyl acetate essence, now collect
The ethyl acetate phase extracting after adjusting pH value, concentrates after being dried, obtains α-cyclopenta（Phenyl）Methylamine sterling 162.23g, yield is
92.7%, and HPLC detects that its purity is 99.4%.
2）α-cyclopenta（Phenyl）The Dynamic Kinetic Resolution of methylamine
In autoclave, add step 1) gained 105g α-cyclopenta（Phenyl）Methylamine sterling, 120g (-)-neomenthol acetic acid esters
It is dissolved in 800ml toluene, adds 20g catalyst SN-6000P, 8g Pseudomonas fluorecens lipase Lipase AK, sealing is anti-
Answer kettle, extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen and vacuumize to 0.5MPa, then with vacuum pumping pump；It is replaced,
It is filled with hydrogen in autoclave to 1.0MPa, and is warming up to 45 DEG C and reacted；After 14 hours of reaction, stop reacting, detection α-
Cyclopenta（Phenyl）Methylamine is wholly absent, and is converted into R- α-cyclopenta（Phenyl）Methylamine acetyl compounds.After stopping reaction, mistake
Filter, be concentrated to give R- α-cyclopenta（Phenyl）Methylamine acetyl compounds with (-)-neomenthol, (-)-neomenthol acetic acid esters mix
The crude product of compound.
3）R- α-cyclopenta（Phenyl）The preparation of methylamine
By step 2）Gained crude product dimethylbenzene recrystallizes to obtain R- α-cyclopenta（Phenyl）Methylamine acetyl compounds sterling；To weigh
Crystallization sterling is dissolved in hydrochloric acid and the mixed solution of methyl alcohol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, etc.
R- α-cyclopenta（Phenyl）Methylamine acetyl compounds complete hydrolysis become R- α-cyclopenta（Phenyl）After methylamine, cooling, first is evaporated off
Alcohol, adjust pH value to alkalescence, taken 3 times with ethyl acetate essence, merge organic phase, be dried, concentrate after obtain R- α-cyclopenta（Phenyl）
Methylamine 97.13g, yield is 92.5%, and HPLC detects that its ee value is 99.4%.
Claims (5)
1. a kind of medicine intermediate R- α-cyclopenta (phenyl) methylamine synthetic method it is characterised in that：1) in autoclave, with
Methyl alcohol or ethanol are solvent, and phenyl cyclopentanone is raw material, add catalysis in the ratio of phenyl cyclopentanone mass fraction 5%-20%
Agent；Sealing autoclave, after nitrogen displacement, with mol ratio 1:The ratio of 5-10 is passed through liquefied ammonia or ammonia, is finally passed through hydrogen to pressure
Power 3-5MPa, is warmed up to 70-100 DEG C of reaction, observes and stops reaction after no longer inhaling hydrogen；After terminating reaction, through filtration, concentration operation
Obtain α-cyclopenta (phenyl) methylamine crude product；Crude product can purify, after acid, alkali process, the α-cyclopenta (benzene obtaining that purity is 99%
Base) methylamine；2) step 1) gained α-cyclopenta (phenyl) methylamine is dissolved in toluene solvant, by α-cyclopenta (phenyl) methylamine 1.0-
The ratio of 2.0 equivalents adds acry radical donor, adds fat in the ratio of α-cyclopenta (phenyl) methylamine mass fraction 5%-10%
Enzyme, adds racemization catalyst in the ratio of α-cyclopenta (phenyl) methylamine mass fraction 5%-20%, is warming up to 40-60 DEG C of reaction
6-14 hour, you can α-cyclopenta (phenyl) methylamine is fully converted to the amide compound of R- α-cyclopenta (phenyl) methylamine；
Stop reaction, filter, concentration steams toluene and must split crude product；3) by step 2) gained crude product dimethylbenzene recrystallization, can
Obtain R- α-cyclopenta (phenyl) methylamine acyl compounds sterling, purity>99%；Acyl compounds are grasped through acidolysis, alkali process etc. again
Make, R- α-cyclopenta (phenyl) methylamine can be obtained；And product ee value is up to more than 99%；In sum, the synthesis of the present invention and tearing open
Divide reaction equation as follows：
2. the synthetic method of a kind of medicine intermediate R- α-cyclopenta (phenyl) methylamine according to claim 1, its feature exists
In：Step 1 described in claim 1) in reducing catalyst be nickel/alumina load catalyst SN-6000P.
3. the synthetic method of a kind of medicine intermediate R- α-cyclopenta (phenyl) methylamine according to claim 1, its feature exists
In：Step 2 described in claim 1) in acyl compounds can for (-)-neomenthol acetic acid esters.
4. the synthetic method of a kind of medicine intermediate R- α-cyclopenta (phenyl) methylamine according to claim 1, its feature exists
In：Step 2 described in claim 1) in lipase used be Pseudomonas fluorecens lipase Lipase AK.
5. the synthetic method of a kind of medicine intermediate R- α-cyclopenta (phenyl) methylamine according to claim 1, its feature exists
Step 2 described in claim 1) in racemization catalyst used be nickel/alumina load catalyst SN-6000P.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610813978.9A CN106397216A (en) | 2016-09-10 | 2016-09-10 | Method for synthesizing medical intermediates |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610813978.9A CN106397216A (en) | 2016-09-10 | 2016-09-10 | Method for synthesizing medical intermediates |
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| Publication Number | Publication Date |
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| CN106397216A true CN106397216A (en) | 2017-02-15 |
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| CN201610813978.9A Pending CN106397216A (en) | 2016-09-10 | 2016-09-10 | Method for synthesizing medical intermediates |
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| CN (1) | CN106397216A (en) |
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2016
- 2016-09-10 CN CN201610813978.9A patent/CN106397216A/en active Pending
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Application publication date: 20170215 |