CN108017552A - A kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers - Google Patents
A kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers Download PDFInfo
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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Abstract
The present invention relates to a kind of synthetic method of α hydroxyls beta amino acids single stereoisomers.The existing chiral ligand using costliness of existing synthetic method or hypertoxic raw material are mainly solved, is not suitable for the technical problem of industrialized production.Preparation process of the present invention：（1）According to the α hydroxyl beta amino acids racemies of literature method synthesis substitution；（2）With the α hydroxyl beta amino acids individual isomers of penicillin G acylase stereoselective syntheses (S, S) configuration and（R,R）The α hydroxyl beta amino acids individual isomers of configuration.The present invention is adapted to low cost, efficiently prepares the α hydroxyl beta amino acids of individual isomer.
Description
Technical field
The invention belongs to the field of chemical synthesis, more particularly to a kind of synthesis of alpha-hydroxyl-beta-aminophenol single stereoisomers
Method.
Background technology
The alpha-hydroxyl-beta-aminophenol of individual isomer is the important building block of some medicines, such as taxol and the like,
In the synthesis of ubenimex, it is widely used in the screening of polypeptide drugs.Alpha-hydroxy-beta-amino of individual isomer
The synthetic technology of acid has document report：Such as（1）The Chiral Amine hydroxyl that document Synth. Commun. 1998,28,4463 are reported
Base method：Sharpless et al. is catalyzed lower asymmetric amine hydroxylating α with chiral ligand, and beta-unsaturated acyl amine, then passes through number
Step synthesis obtains the alpha-hydroxyl-beta-aminophenol of individual isomer.（2）Document Tetrahedron:Asymmetry, 2001,
The cyaniding of 12,347-353 reports：Jose M. Andresl et al. Cymag attack chiral amino aldehyde, then acidolysis obtain
To individual isomer alpha-hydroxyl-beta-aminophenol.Method one will use the chiral ligand of costliness, be not suitable for industrialized production；Method
The problems such as two use the cyaniding sodium raw materials of severe toxicity, there is stringent limitation to environment, unsuitable large-scale use.
The content of the invention
The object of the present invention is to provide a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers, main solution
The existing chiral ligand using costliness of certainly existing synthetic method or hypertoxic raw material, are not suitable for the technical problem of industrialized production.
Thinking of the present invention is that first choice uses literature method（Tetrahedron, 2004, 60, 9043–9048）Pass through 1 ~ 3
Three steps synthesize alpha-hydroxyl-beta-aminophenol raceme c, then with penicillin G acylase stereoselective syntheses, obtain single isomerism
The method of body alpha-hydroxyl-beta-aminophenol.
Technical solution of the present invention is as follows：A kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers, including with
Lower step：
（1）The preparation of trans-epoxide
Trans -2- olefin(e) acids ester is added into the container with reflux condensate device, solvent dichloroethanes is added into the container
In, then into the container add material amount be trans 1.3 ~ 1.5 times of -2- olefin(e) acids ester metachloroperbenzoic acid, 40 DEG C ~
3h ~ 6h is reacted at 65 DEG C, after reaction, cold filtration, filtrate is concentrated to give instead after being washed with saturated sodium sulfite aqueous solution
Formula epoxides a；
（2）It is prepared by oxazoline ring
Trans-epoxide, benzene acetonitrile and boron trifluoride ether are added in a solvent, are reacted to complete, are added water quenching to go out, You Jirong
Oxazoline ring b is obtained after agent extraction concentration；
（3）Open loop and hydrolysis
Oxazoline ring and hydrochloric acid solution are added in a solvent, and reaction to no raw material, adds sodium hydrate aqueous solution hydrolysis completely, raw
Into solid filtering, solid is suspended in ethyl acetate, adds dilute hydrochloric acid stirring, and separation organic phase is concentrated to give product c；
（4）The synthesis of penicillin G acylase stereoselectivity
Compound c is added in a certain amount of water, adjusting pH value with inorganic base stirs to dissolving, adds penicillin G acylase, control
PH value 7 ~ 9,20 ~ 40 DEG C of reaction temperature terminate to reaction, remove penicillin G acylase, filtrate tune pH to 1 ~ 2, organic solvent extraction
Take twice, spent ion exchange resin obtains the alpha-hydroxyl-beta-aminophenol d of (S, S) configuration after purification after the water after extraction mutually concentrates；Have
Machine is concentrated to give the alpha-hydroxyl-beta-aminophenol f of the phenylacetyl group protection of (R, R) configuration after mutually merging；
（5）Hydrolyze（R,R）The alpha-hydroxyl-beta-aminophenol of configuration
The alpha-hydroxyl-beta-aminophenol f of the phenylacetyl group protection of (R, R) configuration is added in 6N hydrochloric acid, is back to that the reaction was complete,
Hydrochloric acid is removed in concentration, is added water, water is mutually concentrated to give with organic solvent washing twice（R,R）The alpha-hydroxyl-beta-aminophenol salt of configuration
Hydrochlorate g.Step（1~5）Reaction scheme it is as follows：
In formula：R1=alkyl or aromatic radical.The alkyl is preferably one kind in methyl, ethyl, propyl group, butyl or benzyl.Institute
The aromatic radical stated is preferably phenyl or substituted-phenyl.
Step（4）Water used is deionized water, and solution ph preferably 7.5 ~ 8.5 is adjusted with inorganic base；Inorganic base is hydrogen
One kind in sodium oxide molybdena, lithium hydroxide, potassium hydroxide or sodium carbonate, preferably sodium hydroxide and lithium hydroxide, the acid is salt
Acid, the organic solvent are ethyl acetate.Step（4）Penicillin G acylase used be penicillin G acylase aqueous solution either
Immobilized penicillin G acylase, preferably immobilized penicillin G acylase.Step（4）Preferable reaction temperature is 35 ~ 38 DEG C.Step
（5）Hydrolysis 6N hydrochloric acid dosages are 5 ~ 30 times, preferably 8-12 times of the alpha-hydroxyl-beta-aminophenols of the phenylacetyl group protection of (R, R) configuration.
Back flow reaction temperature control is at 100 ~ 120 DEG C, preferably 105 ~ 110 DEG C.
The beneficial effects of the invention are as follows：The present invention is a kind of to be industrially commonly used to production penicillin medicine, a large amount of uses
Cost, the penicillin G acylase of low price, the alpha-hydroxyl-beta-aminophenol for carrying out stereoselective syntheses (S, S) configuration is single
Isomers and（R,R）The alpha-hydroxyl-beta-aminophenol individual isomer of configuration.Raw materials used cost is low, and penicillin G acylase can
With recovery, technique is simple, and reaction condition requirement is common, and synthesis cycle is short, is adapted to industrial mass production.
Embodiment
The present invention is further illustrated by following instance, these examples should not be construed as limitation of the present invention.
Embodiment 1：(2S, 3S) -3- amino -2- hydroxycaproic acids and (2R, 3R) -3- amino -2- hydroxycaproic acid hydrochlorides
Prepare
（1）The preparation of trans-epoxide
Trans 2- hexenes acid esters (90g, 0.70mol) is added in 1 liter of there-necked flask, dichloroethanes (500mL) is added, between addition
Chloroperoxybenzoic acid (mass percentage 85%, 142g, 0.91 mol), when heating is 50 DEG C 3 small, the reaction was complete.After cooling
Filtering, filtrate are successively washed with saturated sodium bicarbonate and saturated sodium sulfite, anhydrous sodium sulfate drying, the grease of concentration.Oil
Shape thing is evaporated under reduced pressure to trans-epoxide a (88 g, yield 88%)；
（2）It is prepared by oxazoline ring
Trans-epoxide a (88g, 0.61mol), benzene acetonitrile (254g, 2.38mol) and dichloro are added in 2 liters of there-necked flask
Methane (880 mL).Boron trifluoride ether (308 g, 2.38 mol) is added dropwise at 0 DEG C.When room temperature reaction 18 is small after adding, add
Frozen water (500 mL × 2) washs, then is washed with saturated sodium bicarbonate, it is dry be concentrated to give compound b (containing excessive benzene acetonitrile,
Directly throw in next step)；
（3）Open loop and hydrolysis
Trans-epoxide b (obtained by previous step) is added in 2 liters of there-necked flask, tetrahydrofuran (700 mL) dissolving is added, adds
Enter 6N hydrochloric acid (40 mL), when stirring 3 is small, add 6N sodium hydroxide solutions (120 mL), when reaction 16 is small, the white of precipitation
Solid filters, and white solid is suspended in ethyl acetate (500 ml), adds 1N dilute hydrochloric acid (300 mL) stirring to solid and dissolves.
Ethyl acetate phase is separated, drying is concentrated to give compound c (87 g, 54% yield)；
（4）Synthesis (2S, 3S) -3- amino -2- hydroxycaproic acids of penicillin G acylase stereoselectivity
Deionized-distilled water (300 mL) is added in 1 liter of there-necked flask, compound c (15 g) is added, with 3N lithium hydroxides
Solution tune pH to 8 ~ 9, stirs dissolved clarification.Add immobilized penicillin G acylase (3 g).35 ~ 38 DEG C, when stirring 54 is small are warming up to,
During fractionation, pH can decline, and adjusted with 3N lithium hydroxide solutions and keep pH 8 ~ 9.Sampling analysis, splitting conversion ratio is
98.8%.Room temperature is cooled to, pH to 11 ~ 12 is adjusted, is removed by filtration immobilized penicillin G acylase.Filtrate with 6N hydrochloric acid acidifying pH to 2 ~
After 3, ethyl acetate is extracted twice.Combined ethyl acetate, drying is concentrated to give compound e, and (10.1 g, contain phenylacetic acid）.Water phase
After concentration, upper cation exchange resin removes inorganic salts, then elutes amino acid with the ammonium hydroxide of mass percentage concentration 10%, concentrates ammonia
The compound d (3.5 g) of water elution.It is as follows through nuclear magnetic resonance measuring result：1H NMR (400 MHz, DMSO-d 6 ): δ
5.40 (br, 3H), 3.16 (s, 1H), 2.81 (Br s, 1H), 1.45 (m, 2H), 1.31 (m, 2H),
0.85 (t, 3H) liquid chromatograph mass spectrography measurement results are as follows：LC-MS (ESI):m/z 147.90 [M+H]+；
（5）Hydrolyze (2R, 3R) 3- amino -2- hydroxycaproic acid hydrochlorides
Compound e (10.1 g) is suspended in 6N hydrochloric acid solutions (100 mL), be heated to reflux it is 105 DEG C 16 small when after, concentration removes
Fall hydrochloric acid, be diluted with water, ethyl acetate is washed removes phenylacetic acid twice, and water mutually concentrates dry compound g (4.7 g).Through nuclear-magnetism
The measurement result that resonates is as follows：1H NMR (400 MHz, DMSO-d 6 ): δ 13.10 (br, 1H), 8.18 (br s,
3H), 4.39 (s, 1H), 3.38 (s, 1H), 1.35 (m, 4H), 0.85 (t, 3H) liquid phase chromatogram-mass spectrometry combinations
It is as follows with measurement result：LC-MS (ESI):m/z 147.70 [M+H]+。
Embodiment 2：R1For ethyl, with 3N sodium hydroxide solution tune pH to 7.5 ~ 8.5；Penicillin G acylase is benzyl penicillin
Acylated enzyme aqueous solution, filtrate are acidified pH to 1 ~ 2, step with 6N hydrochloric acid（4）Reaction temperature is 20 ~ 25 DEG C.Step（5）Hydrolyze 6N salt
Sour dosage is 8 times of the alpha-hydroxyl-beta-aminophenol of the phenylacetyl group protection of (R, R) configuration；Reaction temperature is 110 DEG C, remaining is same
Embodiment 1.
Embodiment 3：R1For benzyl, with 3N sodium carbonate liquor tune pH to 7.5 ~ 8.5；Penicillin G acylase is immobilized mould
Plain G acylases, filtrate are acidified pH to 1 ~ 2, step with 6N hydrochloric acid（4）Reaction temperature is 30 ~ 35 DEG C.Step（5）Hydrolyze 6N hydrochloric acid
Dosage is 10 times of the alpha-hydroxyl-beta-aminophenol of the phenylacetyl group protection of (R, R) configuration；Reaction temperature is 108 DEG C, remaining is the same as real
Apply example 1.
Embodiment 4：R1For phenyl, with 3N potassium hydroxide solution tune pH to 8.5 ~ 9；Penicillin G acylase is immobilized mould
Plain G acylases, filtrate are acidified pH to 1 ~ 2, step with 6N hydrochloric acid（4）Reaction temperature is 35 ~ 38 DEG C.Step（5）Hydrolyze 6N hydrochloric acid
Dosage is 12 times of the alpha-hydroxyl-beta-aminophenol of the phenylacetyl group protection of (R, R) configuration；Reaction temperature is 115 DEG C, remaining is the same as real
Apply example 1.
Embodiment 5：R1For toluene, with 3N sodium hydroxide solution tune pH to 7.5 ~ 8.5；Penicillin G acylase is immobilized green grass or young crops
Mycin G acylases, filtrate are acidified pH to 1 ~ 2, step with 6N hydrochloric acid（4）Reaction temperature is 35 ~ 40 DEG C.Step（5）Hydrolyze 6N salt
Sour dosage is 25 times of the alpha-hydroxyl-beta-aminophenol of the phenylacetyl group protection of (R, R) configuration；Reaction temperature is 100 DEG C, remaining is same
Embodiment 1.
Claims (10)
1. a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers, it is characterized in that：Comprise the following steps：
（1）Alpha-hydroxyl-beta-aminophenol raceme is added in water, is adjusted pH value of solution to 7 ~ 9 with inorganic base, is added benzyl penicillin acyl
Change enzyme, 20 ~ 40 DEG C of controlling reaction temperature, terminates to fractionation, removes penicillin G acylase, filtrate adjusts pH to 1 ~ 2 with acid, organic
Twice, the water after extraction mutually concentrates α-hydroxyl that ion-exchange resin purification obtains the individual isomer of (S, S) configuration for solvent extraction
Base-beta-amino acids；Organic phase is concentrated to give the alpha-hydroxyl-beta-aminophenol of the phenylacetyl group protection of (R, R) configuration after above-mentioned extraction；
（2）The alpha-hydroxyl-beta-aminophenol of the phenylacetyl group protection of above-mentioned (R, R) configuration is added in 6N hydrochloric acid, is back to reaction
Completely, hydrochloric acid is removed in concentration, is added water, water is mutually concentrated to give with organic solvent washing twice（R,R）Alpha-hydroxy-β-ammonia of configuration
Base acid hydrochloride, spent ion exchange resin purify the individual isomer alpha-hydroxyl-beta-aminophenol of (R, R) configuration；Reaction equation
It is as follows：
In formula：R1=alkyl or aromatic radical.
2. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 1, it is characterized in that：Step
Suddenly（1）Water used is deionized water, and solution ph control is adjusted 7.5 ~ 8.5 with inorganic base, inorganic base be sodium hydroxide,
One kind in lithium hydroxide, potassium hydroxide or sodium carbonate, the acid are hydrochloric acid, and the organic solvent is ethyl acetate.
3. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 2, it is characterized in that：Institute
It is sodium hydroxide and lithium hydroxide to state inorganic base.
4. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 1, it is characterized in that：Step
Suddenly（1）Penicillin G acylase used is penicillin G acylase aqueous solution either immobilized penicillin G acylase.
5. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 4, it is characterized in that：Step
Suddenly（1）Penicillin G acylase used is immobilized penicillin G acylase.
6. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 1, it is characterized in that：Step
Suddenly（1）Controlling reaction temperature is controlled at 35 ~ 38 DEG C.
7. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 1, it is characterized in that：Step
Suddenly（2）Hydrolyze 5 ~ 30 times of the alpha-hydroxyl-beta-aminophenol that 6N hydrochloric acid dosages are the phenylacetyl group protections of (R, R) configuration, back flow reaction
Temperature control is at 100 ~ 120 DEG C.
8. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 7, it is characterized in that：Step
Suddenly（2）Hydrolyze 8 ~ 12 times of the alpha-hydroxyl-beta-aminophenol that 6N hydrochloric acid dosages are the phenylacetyl group protections of (R, R) configuration, back flow reaction
Temperature control is at 105 ~ 110 DEG C.
9. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 1, it is characterized in that：Institute
The alkyl stated is one kind in methyl, ethyl, propyl group, butyl or benzyl.
10. according to a kind of synthetic method of alpha-hydroxyl-beta-aminophenol single stereoisomers of the requirement of right 1, it is characterized in that：Institute
The aromatic radical stated is phenyl or substituted-phenyl.
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| CN102628075A (en) * | 2012-02-24 | 2012-08-08 | 上海瀚鸿化工科技有限公司 | Method for producing chiral amino acid by penicillin acylase resolution and product thereof |
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| CN102628075A (en) * | 2012-02-24 | 2012-08-08 | 上海瀚鸿化工科技有限公司 | Method for producing chiral amino acid by penicillin acylase resolution and product thereof |
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