CN106431934A - Method for synthesizing S-shaped amino compound - Google Patents
Method for synthesizing S-shaped amino compound Download PDFInfo
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- CN106431934A CN106431934A CN201610813885.6A CN201610813885A CN106431934A CN 106431934 A CN106431934 A CN 106431934A CN 201610813885 A CN201610813885 A CN 201610813885A CN 106431934 A CN106431934 A CN 106431934A
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- phenyl
- methylamine
- cyclopenta
- cyclopentyl
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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
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/40—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of hydroxylamino or oxyimino groups
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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
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
- C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
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Abstract
The invention discloses a method for synthesizing S-shaped amino compound, namely, S-alpha-cyclopentyl(phenyl)methylamine. The method includes the steps of using cyclopentyl phenyl ketone as a raw material, allowing cyclopentyl phenyl ketone to react with hydroxylamine hydrochloride to obtain oxime, conducting catalytic reduction on the oxime by a nickel/alumina supported catalyst SN-6000P to obtain alpha-cyclopentyl(phenyl)methylamine; conducting dynamic kinetic separation on the alpha-cyclopentyl(phenyl)methylamine by using fluorescent pseudomonas lipase Lipase AK as a biological resolution catalyst, the nickel/alumina supported catalyst SN-6000P as a racemization catalyst and (+)-D-menthol organic fatty acid ester as an acyl donor to obtain an acyl compound of S-cyclopentyl phenyl ketone, and after the acyl compound is hydrolyzed, obtaining S-alpha-cyclopentyl(phenyl)methylamine. The method has the advantages of being easy to operate, good in product yield, high in separation product optical purity and the like.
Description
Technical field
The present invention relates to a kind of fractionation preparation method of optical homochiral amines, more particularly, to a kind of left-handed Chiral Amine
Based compound S- α-cyclopenta（Phenyl）The method of the preparation 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）.
S- α-cyclopenta in its two kinds of isomers（Phenyl）The synthetic method of methylamine, existing is by asymmetric addition
Reaction obtains（Isoquinolinone derivatives as NK3 antagonists and their preparation,
pharmaceutical compositions and use in the treatment of psychosis and
Schizophrenia, U.S. Pat. Appl. Publ., 20090143402,04 Jun 2009）, some steps of this method
Rapid with raw materials used costly, and the optical purity of final products yield and product is all extremely difficult to preferable degree.
Content of the invention
The present invention is intended to provide one kind is with phenyl cyclopentanone as raw material, prepare S configuration amine compound S- α-cyclopenta
（Phenyl）The preparation method of methylamine.In order to realize this target, concrete operations are as follows： 1）With methyl alcohol as solvent, phenyl cyclopentanone is
Raw material and hydroxylamine hydrochloride, sodium hydroxide solution react to obtain phenyl cyclopentanone oxime；2）Step 1）Gained ketoxime is raw material, is being connected with ammonia
α-cyclopenta is obtained through reducing catalyst catalytic hydrogenation in the methanol solution of gas（Phenyl）Methylamine, amine can be dissociated with acid neutralization, alkali
Method process successively and purified；3）In autoclave, by step 2）Gained α-cyclopenta（Phenyl）Methylamine is dissolved into
In toluene, then press α-cyclopenta（Phenyl）Methylamine and acry radical donor mol ratio are 1：The ratio of 1.0-2.0 adds acry radical donor, presses
α-cyclopenta（Phenyl）The ratio of methylamine mass fraction 2%-10% adds lipase, by raw material α-cyclopenta（Phenyl）Methylamine quality
The ratio of fraction 5%-20% adds racemization catalyst, is warming up to 35-60 DEG C of reaction 12-14 hour, you can by α-cyclopenta（Benzene
Base）Methylamine is fully converted to S- α-cyclopenta（Phenyl）The acyl compounds of methylamine；Stop reaction, filter, concentration steams toluene
Crude product must be split；4）By step 3）Gained crude product is recrystallized with dimethylbenzene, can obtain S- α-cyclopenta（Phenyl）Methylamine acyl group
Pure compounds；Acyl compounds are operated through hydrolysis, alkali process etc., S- α-cyclopenta can be obtained（Phenyl）Methylamine；Final products
Purity>99%, product ee value is up to more than 99%.Step 2）In reducing catalyst used be nickel/alumina load catalyst SN-
6000P；Step 3）In acry radical donor used be (+)-D- peppermint alcohol acetic ester；Step 3）Described in lipase be that fluorescence is false
Fluorecens lipase Lipase AK；Step 3）Described in racemization catalyst be nickel/alumina load catalyst SN-6000P.
The present invention, with phenyl cyclopentanone as raw material, is successfully prepared left-handed chiral amino compound S- α-cyclopenta（Phenyl）
Methylamine.And the present invention possesses the features such as simple to operate, product yield is good, purity is high.
Specific embodiment
Embodiment 1
1）The synthesis of phenyl cyclopentanone oxime
In there-necked flask, add 800ml methyl alcohol as solvent, add 174g raw material benzyl ring pentanone, 75g hydroxylamine hydrochloride, normal temperature
Drip the sodium hydroxide solution that concentration is 40% under conditions of stirring to system pH value is alkalescent in batches, continues stirring after adding
Reaction 3 hours, when point plate detection raw material benzyl ring pentanone point disappears, stops reaction；Under stirring condition, add toward in system
The water of 4000ml, has a large amount of white solids to separate out；Suction filtration, gained filter cake is cleaned to neutrality with water again, dry for standby, and this walks
Phenyl cyclopentanone oxime 185.98g, yield is 98.4%.
2）The reduction amination of phenyl cyclopentanone oxime
In autoclave, 1100ml absolute methanol is added to be to make solvent, phenyl cyclopentanone oxime 185.98g is as raw material, 35g catalyst
SN-6000P, sealing autoclave, displaces the air of kettle, is passed through ammonia 18g, then is passed through and keeps Hydrogen Vapor Pressure to enter to 3.5MPa
Row reaction, etc. system not re-absorption hydrogen when, stop reaction；Filter, be concentrated to give α-cyclopenta（Phenyl）Methylamine crude product；By crude product
First become salt with hydrochloric acid reaction, and wash away impurity, then the α-cyclopenta dissociated after purification with NaOH with ethyl acetate（Phenyl）
Methylamine hydrochloride, ethyl acetate extracts, is dried, is concentrated to give α-cyclopenta（Phenyl）Methylamine sterling 165.66g, this walks yield
96.3%.
3）α-cyclopenta（Phenyl）The Dynamic Kinetic Resolution of methylamine
In autoclave, add 35g α-cyclopenta（Phenyl）Methylamine sterling, 45g (+)-D- peppermint alcohol acetic ester is dissolved in 400ml toluene
In, add 6g catalyst SN-6000P, 3g Pseudomonas fluorecens lipase Lipase AK, sealed reactor, use vacuum pumping pump
Extract the air in kettle, be re-filled with nitrogen and vacuumize to 0.5MPa, then with vacuum pumping pump；It is replaced, in autoclave, be filled with hydrogen
Gas is to 1.5MPa, and is warming up to 45 DEG C and is reacted；After 14 hours of reaction, stop reaction, detect α-cyclopenta（Phenyl）First
Amine is wholly absent, and is converted into S- α-cyclopenta（Phenyl）Methylamine acetyl compounds.After stopping reaction, filter, be concentrated to give containing S-
The crude product of α-cyclohexyl benzene methylamine acetyl compounds.
4）S- α-cyclopenta（Phenyl）The preparation of methylamine
By step 3）Gained crude product dimethylbenzene recrystallizes to obtain S- 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.
α-cyclopenta（Phenyl）Methylamine acetyl compounds complete hydrolysis become S- α-cyclopenta（Phenyl）After methylamine, cooling, adjust pH value
To alkalescence, methyl alcohol is evaporated off, is taken 3 times with dichloromethane essence, merge organic phase, be dried, concentrate after S- α-cyclopenta（Phenyl）First
Amine 32.87g, yield is 93.9%, and HPLC detects that its ee value is 99.4%.
Claims (5)
1. a kind of synthetic method of S configuration amine compound S- α-cyclopenta (phenyl) methylamine it is characterised in that：1) with methyl alcohol it is
Solvent, phenyl cyclopentanone is that raw material reacts to obtain phenyl cyclopentanone oxime with hydroxylamine hydrochloride, sodium hydroxide solution；2) step 1) gained ketone
Oxime is raw material, obtains α-cyclopenta (phenyl) methylamine through reducing catalyst catalytic hydrogenation, amine can in the methanol solution be connected with ammonia
Purified with being processed successively with the method that acid neutralization, alkali dissociate；3) in autoclave, by step 2) gained α-cyclopenta
(phenyl) methylamine is dissolved in toluene, then presses α-cyclopenta (phenyl) methylamine and acry radical donor mol ratio for 1：The ratio of 1.0-2.0
Example add acry radical donor, in α-cyclopenta (phenyl) methylamine mass fraction 2%-10% ratio add lipase, by raw material α-
The ratio of cyclopenta (phenyl) methylamine mass fraction 5%-20% adds racemization catalyst, is warming up to 35-60 DEG C of reaction 12-14 little
When, you can α-cyclopenta (phenyl) methylamine is fully converted to the acyl compounds of S- α-cyclopenta (phenyl) methylamine；Stop anti-
Should, filter, concentration steams toluene and must split crude product；4) by step 3) gained crude product with dimethylbenzene recrystallize, can obtain S- α-
Cyclopenta (phenyl) methylamine acyl compounds sterling；Acyl compounds are operated through hydrolysis, alkali process etc., S- α-cyclopenta can be obtained
(phenyl) methylamine；Final products purity>99%, product ee value is up to more than 99%；In sum, the reaction equation of the present invention
As follows：
2. a kind of synthetic method of S configuration amine compound S- α-cyclopenta (phenyl) methylamine according to claim 1, it is special
Levy and be：Step 2 described in claim 1) in reducing catalyst used be nickel/alumina load catalyst SN-6000P.
3. a kind of synthetic method of S configuration amine compound S- α-cyclopenta (phenyl) methylamine according to claim 1, it is special
Levy and be：Step 3 described in claim 1) in acry radical donor used be (+)-D- peppermint alcohol acetic ester.
4. a kind of synthetic method of S configuration amine compound S- α-cyclopenta (phenyl) methylamine according to claim 1, it is special
Levy and be：Step 3 described in claim 1) described in lipase be Pseudomonas fluorecens lipase Lipase AK.
5. a kind of synthetic method of S configuration amine compound S- α-cyclopenta (phenyl) methylamine according to claim 1, it is special
Levy and be：Step 3 described in claim 1) described in racemization catalyst be nickel/alumina load catalyst SN-6000P.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610813885.6A CN106431934A (en) | 2016-09-10 | 2016-09-10 | Method for synthesizing S-shaped amino compound |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610813885.6A CN106431934A (en) | 2016-09-10 | 2016-09-10 | Method for synthesizing S-shaped amino compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115403500A (en) * | 2022-10-08 | 2022-11-29 | 上海壮铭生物医药有限公司 | Preparation method of levetiracetam |
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- 2016-09-10 CN CN201610813885.6A patent/CN106431934A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115403500A (en) * | 2022-10-08 | 2022-11-29 | 上海壮铭生物医药有限公司 | Preparation method of levetiracetam |
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Application publication date: 20170222 |
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