CN107904268A - The synthetic method of D cyclic alkylamidos acid - Google Patents
The synthetic method of D cyclic alkylamidos acid Download PDFInfo
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- CN107904268A CN107904268A CN201711135474.7A CN201711135474A CN107904268A CN 107904268 A CN107904268 A CN 107904268A CN 201711135474 A CN201711135474 A CN 201711135474A CN 107904268 A CN107904268 A CN 107904268A
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Abstract
The invention discloses a kind of synthetic method of D cyclic alkylamidos acid.The synthetic method comprises the following steps：OrThe reaction generation in the reaction system under the action of amino acid dehydrogenaseOrWherein, n1>=0, n2>=1, M1For H or monovalent cation, m1>=0, m2>=1, M2For H or monovalent cation, the amino acid sequence of amino acid dehydrogenase is selected from one of following sequence：1) such as SEQ ID NO：Amino acid sequence shown in 1；2) such as SEQ ID NO：Amino acid sequence shown in 1 is by obtained from substitution, missing or the one or more amino acid of addition there is High level of stereoselectivity selectively willOrChange intoOr
Description
Technical field
The present invention relates to chipal compounds synthesis technical field, in particular to a kind of D- cyclic alkylamidos acid
Synthetic method.
Background technology
Non-natural hand-type amino acid and its derivative are the important composition units of polypeptide, class peptide and many drug molecules,
And the key intermediate of synthesis of chiral medicine.At present, the non-natural cyclic alkylamido acid of synthesis of chiral, mainly useization
Method, includes the use of precious metal asymmetric catalytic hydrogenation to realize the conversion of single configuration to a certain key intermediate, make
With chiral reagent resolving racemic, using chiral auxiliary asymmetric syntheses, using chiral raw material controlled syntheses the methods of.But
There are following defect for these methods：1) single structure is realized to a certain key intermediate using precious metal asymmetric catalytic hydrogenation
The conversion of type, the drawback is that precious metal asymmetric catalyst is expensive, reaction needs a large amount of organic solvents, there is weight in product
Metal residual and there may be the accessory substance of over reduction, and because containing heterocycle in the raw material of synthesis, can usually disturb expensive
The combination of heavy metal and ligand, causes catalytic efficiency not high；2) traditional chiral separation method is used, obtains in raceme one
The isomers needed, can cause the wastage of material of other half；3) using the asymmetric syntheses of chiral auxiliary or chiral raw material, relate to
And to expensive chiral raw material, longer synthetic route and substantial amounts of organic solvent, and for some cyclic alkyls
The synthesis of amino acid, obtained optical purity of products is not high, or product and impurity are not readily separated.
Amino acid is divided into two kinds of D- amino acid and l-amino acid according to hand-type.Natural amino acid leads to mainly based on L-type
Cross the just relatively easy realization of enzymatic clarification L-type alpha-non-natural amino acid.Also there are some documents or patent report to use in the prior art
The method of biological enzymatic synthesis L- alpha-non-natural amino acids.There is presently no find suitable enzyme and react bar accordingly for the prior art
Part, passes through the amino acid of bioconversion anamorphic zone D- cyclic alkyl structures.
The content of the invention
The present invention is intended to provide a kind of synthetic method of D- cyclic alkylamidos acid, to solve in the prior art without suitable
Enzyme carry out the technical problem of the amino acid by bioconversion anamorphic zone D- cyclic alkyl structures.
To achieve these goals, according to an aspect of the invention, there is provided a kind of conjunction of D- cyclic alkylamidos acid
Into method.The synthetic method comprises the following steps：In the effect of amino acid dehydrogenase
Under in the reaction system reaction generationWherein, n1>=0, n2>=1, M1For H or monovalence
Cation, m1>=0, m2>=1, M2For H or monovalent cation, the amino acid sequence of amino acid dehydrogenase is selected from one of following
Sequence：1) such as SEQ ID NO：Amino acid sequence shown in 1；2) such as SEQ ID NO：Amino acid sequence shown in 1 by substitution,
Obtained from missing or the one or more amino acid of addition there is High level of stereoselectivity selectively will Change intoAmino acid dehydrogenase activity amino acid sequence.
Further, amino group donor is further included in reaction system.
Further, amino group donor is ammonium formate or ammonium chloride.
Further, coenzyme and buffer solution are further included in reaction system.
Further, coenzyme is β-NAD+Or β-NADP+。
Further, buffer solution is Tris-HCl buffer solutions or phosphate buffer.
Further, the pH value of reaction system is 8.0~9.0, and the reaction temperature of reaction system is 30~40 DEG C.
Further, state and chaotropic agent is further included in reaction system, chaotropic agent is dimethyl sulfoxide (DMSO).
Further, in reaction systemMolar concentration for 0.2mol/L~
0.5mol/L。
Further, first propylhomoserin dehydrogenase is further included in reaction system, the enzyme activity of amino acid dehydrogenase is 30U/ml, is added
Amount is respectively 400ml, and the enzyme activity of first propylhomoserin dehydrogenase is 40U/ml, addition 100ml.
Further, the addition of accelerating agent is in reaction system5w/
V%~20w/v%.
Apply the technical scheme of the present invention, ring-type ketone acid is converted into by D- cyclic alkyls by using amino acid dehydrogenase
Amino acid, can obtain higher conversion and the non-natural hand-type amino acid of higher ee, for relative chemical synthesis, synthetic method
Reaction condition is gentle, pollution is relatively low.
Embodiment
It should be noted that in the case where there is no conflict, the feature in embodiment and embodiment in the application can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
For the prior art there is presently no suitable enzyme and corresponding reaction condition is found, to be closed by bioconversion
Into the technical problem of the amino acid with D- cyclic alkyl structures, the present invention proposes technical solution.
A kind of a kind of typical embodiment according to the present invention, there is provided synthetic method of D- cyclic alkylamidos acid.The conjunction
Comprise the following steps into method：
The reaction generation in the reaction system under the action of amino acid dehydrogenase
Wherein, n1>=0, n2>=1, M1For H or monovalent cation, m1>=0, m2>=1, M2For H or monovalent cation, amino acid
The amino acid sequence of dehydrogenase is selected from one of following sequence：
1) such as SEQ ID NO：Amino acid sequence shown in 1；SEQ ID NO：1 sequence is as follows：
MSKIRIGIVGYGNLGRGVEAAIQQNPDMELVAVFTRRDPKTVAVKSNVKVLHVDDAQSYKDEIDVMILCGGSATDLP
EQGPYFAQYFNTIDSFDTHARIPDYFDAVNAAAEQSGKVAIISVGWDPGLFSLNRLLGEVVLPVGNTYTFWGKGVSQ
GHSDAIRRIQGVKNAVQYTIPIDEAVNRVRSGENPELSTREKHARECFVVLEEGADPAKVEHEIKTMPNYFDEYDTT
VHFISEEELKQNHSGMPHGGFVIRSGKSDEGHKQIIEFSLNLESNPMFTSSALVAYARAAYRLSQNGDKGAKTVFDI
PFGLLSPKSPEDLRKEL；
2) such as SEQ ID NO：Amino acid sequence shown in 1 by substitution, missing or the one or more amino acid of addition and
What is obtained there is High level of stereoselectivity selectively willChange into Amino acid dehydrogenase activity amino acid sequence.
In the present invention, High level of stereoselectivity selectively refer to byIt is big to change into e.e values
In 80%Chiral ring amino acid.
Apply the technical scheme of the present invention, ring-type ketone acid is converted into by D- cyclic alkyls by using amino acid dehydrogenase
Amino acid, can obtain higher conversion and the non-natural hand-type amino acid of higher ee, for relative chemical synthesis, synthetic method
Reaction condition is gentle, pollution is relatively low.Also, Mek-Tol Unit compoundFor in market
Upper commercialized raw material is easily prepared, and raw material is easy to get, be adapted to industrialized production.
In order to make above-mentioned reaction more smoothly carry out, amino group donor is further included in reaction system.Preferably, amino group donor
For ammonium formate or ammonium chloride, coenzyme and buffer solution are further included in reaction system.Preferably, coenzyme is β-NAD+Or β-NADP+；It is slow
Fliud flushing is Tris-HCl buffer solutions or phosphate buffer.
Preferably, the pH value of reaction system is 8.5~9.0, and the reaction temperature of reaction system is 30~40 degrees Celsius.
Chaotropic agent is further included in reaction system, chaotropic agent is dimethyl sulfoxide (DMSO).
A kind of typical embodiment according to the present invention, in reaction systemRub
Your concentration is 0.2mol/L~0.5mol/L.
The addition of amino acid dehydrogenase and first propylhomoserin dehydrogenase is respectively 400ml in the reaction system of 10g substrates, enzyme activity
For 30U/ml and 100ml, enzyme activity 40U/ml.
The addition of accelerating agent is in reaction system5w/v%~20w/
V%, such as 10g substrates, adds 0.5ml~2ml cosolvents.
Beneficial effects of the present invention are further illustrated below in conjunction with embodiment.
Embodiment 1
(1) feed intake：Into tetra- mouthfuls of round-bottomed bottles of 2L, 10g main materials are added250ml Tris-HCl buffer solutions
(100mmol/L, pH=9.0), raw material are dispersed in Tris-HCl salt fliud flushing fliud flushings；PH to 8.5 is adjusted with 10M NaOH
~9.0, the ammonium formate of 16g is sequentially added, 0.3g β-NAD+, pH to 8.5~9.0 is adjusted with 10M NaOH.Finally by 400ml,
Enzyme activity is the amino acid dehydrogenase of 30U/ml, 100ml, and the first propylhomoserin dehydrogenase that enzyme activity is 40U/ml adds above-mentioned reaction system,
And pH is adjusted to 8.5~9.0.
(2) react：And 30~40 DEG C are warming up to, reacted.
(3) post-process：System is tracked after reaction 16h, detection raw material reaction finishes, is down to room temperature, delays into four-hole boiling flask
The slow 40mL concentrated hydrochloric acids that are added dropwise terminate reaction, and system crosses diatomite, and filtrate is extracted with 300ml MTBE with 30%NaOH tune pH8~9
1 time, water mutually with 30%NaOH tune pH 9-10, adds 22g tertbutyloxycarbonyls, and 30%NaOH is added dropwise, and control pH is in 9~10, control
25~30 degrees Celsius of reaction 16h of temperature, add 300ml methyl tertiary butyl ether(MTBE)s (MTBE) and extract twice.Water is mutually with 10% hydrochloric acid tune pH
4.5~5.0, extracted 3 times with 300ml MTBE.Organic phase is washed twice with 300ml saturated common salts, and water mutually abandons it after liquid separation, has
Machine is added to the drying of 10g anhydrous magnesium sulfates, is filtered after dry, filter cake is rinsed with MTBE.Filtrate is contracted dry again, obtains 11.4g and consolidates
Body.Internal standard>98%, chiral purity>90%
Embodiment 2
(1) feed intake：Into tetra- mouthfuls of round-bottomed bottles of 2L, 10g main materials are added250ml Tris-HCl buffer solutions
(100mmol/L, pH=9.0), raw material are dispersed in Tris-HCl salt fliud flushing fliud flushings；PH to 8.5 is adjusted with 10M NaOH
~9.0, the ammonium formate of 16.2g is sequentially added, 0.3g β-NAD+, pH to 8.5~9.0 is adjusted with 10M NaOH.Finally will
400ml, enzyme activity are the amino acid dehydrogenase of 30U/ml, 100ml, and the first propylhomoserin dehydrogenase that enzyme activity is 40U/ml adds above-mentioned reaction
System, and pH is adjusted to 8.5~9.0.
(2) react：And 30~40 DEG C are warming up to, reacted.
(3) post-process：System is tracked after reaction 16h, detection raw material reaction finishes, and room temperature is down to, slowly to it under stirring
The middle concentrated hydrochloric acid that is added dropwise makes the pH value of mixed system after reaction to less than 1；System after tune acid is crossed to the Celite pad of 1~2cm, is used
200ml purified water filter washes cake 2 times aqueous solution, obtained filtrate pH value is adjusted between 5~6 with sodium hydroxide, filtering should
Mixed solution obtains filter cake and filtrate, filter cake respectively with 300ml purifying washings twice after, then with 5 times of volume pure water agitator treatings 3
It is secondary, obtain product 7.8g, nuclear-magnetism internal standard after filtered filter cake drying>98%, hand-type purity>85%.
Embodiment 3
(1) feed intake：Into tetra- mouthfuls of round-bottomed bottles of 2L, 10g main materials are added250ml Tris-HCl buffer solutions
(100mmol/L, pH=9.0), raw material are dispersed in Tris-HCl salt fliud flushing fliud flushings；PH to 8.5 is adjusted with 10M NaOH
~9.0, the ammonium formate of 14.8g is sequentially added, 0.3g β-NAD+, pH to 8.5~9.0 is adjusted with 10M NaOH.Finally will
400ml, enzyme activity are the amino acid dehydrogenase of 30U/ml, 100ml, and the first propylhomoserin dehydrogenase that enzyme activity is 40U/ml adds above-mentioned reaction
System, and pH is adjusted to 8.5~9.0.
(2) react：And 30~40 DEG C are warming up to, reacted.
(3) post-process：System is tracked after reaction 16h, detection raw material reaction finishes, is down to room temperature, delays into four-hole boiling flask
The slow 40mL concentrated hydrochloric acids that are added dropwise terminate reaction, and system crosses diatomite, and pH is adjusted with solid sodium hydroxide under obtained filtrate ice-water bath
Value filters after stirring 30min between 5~6, obtains white solid；Solid is washed with 10mL again, and drying obtains 8.5g.Internal standard>
96%, chiral purity>98%
Embodiment 4
(1) feed intake：Into tetra- mouthfuls of round-bottomed bottles of 2L, 10g main materials are added250ml Tris-HCl buffer solutions
(100mmol/L, pH=9.0), raw material are dispersed in Tris-HCl salt fliud flushing fliud flushings；PH to 8.5 is adjusted with 10M NaOH
~9.0, the ammonium formate of 17.8g is sequentially added, 0.3g β-NAD+, pH to 8.5~9.0 is adjusted with 10M NaOH.Finally will
400ml, enzyme activity are the amino acid dehydrogenase of 30U/ml, 100ml, and the first propylhomoserin dehydrogenase that enzyme activity is 40U/ml adds above-mentioned reaction
System, and pH is adjusted to 8.5~9.0.
(2) react：And 30~40 DEG C are warming up to, reaction system is reacted according to following chemical formula.
(3) post-process：System is tracked after reaction 16h, detection raw material reaction finishes, and room temperature is down to, slowly to it under stirring
The middle concentrated hydrochloric acid that is added dropwise makes the pH value of mixed system after reaction to less than 1；System after tune acid is crossed to the Celite pad of 1~2cm, is used
Sodium hydroxide adjusts obtained filtrate pH value between 5~6, obtains crude product aqueous solution.By crude product aqueous solution cross model 001 ×
7 storng-acid cation exchange resin resin column purification, gained crude product are filtered after being washed with absolute ethyl alcohol, and filter cake is dried
Solid product；The storng-acid cation exchange resin resin column purification that filtrate crosses model 001 × 7 obtains off-white powder product
5.0g, nuclear-magnetism internal standard>98%, hand-type purity>90%.
It can be seen from the above description that the above embodiments of the present invention realize following technique effect：The present invention's
Ring-type ketone acid is converted into D- cyclic alkylamidos acid by amino acid dehydrogenase, obtains the non-natural of higher conversion and higher ee
Hand-type amino acid, the stable process conditions that synthetic method uses, reaction condition is gentle, easy to operate, dirty in whole production process
Contaminate it is relatively low, for artificial synthesized D- cyclic alkylamidos acid a kind of new idea and method is provided.
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the invention, for the skill of this area
For art personnel, the invention may be variously modified and varied.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should all be included in the protection scope of the present invention.
Sequence table
<110>Kai Laiying Pharmaceutical Groups（Tianjin）Limited company
<120>The synthetic method of D- cyclic alkylamidos acid
<130> PN78834KLY
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 325
<212> PRT
<213> artifical sequence
<400> 1
Met Ser Lys Ile Arg Ile Gly Ile Val Gly Tyr Gly Asn Leu Gly Arg
1 5 10 15
Gly Val Glu Ala Ala Ile Gln Gln Asn Pro Asp Met Glu Leu Val Ala
20 25 30
Val Phe Thr Arg Arg Asp Pro Lys Thr Val Ala Val Lys Ser Asn Val
35 40 45
Lys Val Leu His Val Asp Asp Ala Gln Ser Tyr Lys Asp Glu Ile Asp
50 55 60
Val Met Ile Leu Cys Gly Gly Ser Ala Thr Asp Leu Pro Glu Gln Gly
65 70 75 80
Pro Tyr Phe Ala Gln Tyr Phe Asn Thr Ile Asp Ser Phe Asp Thr His
85 90 95
Ala Arg Ile Pro Asp Tyr Phe Asp Ala Val Asn Ala Ala Ala Glu Gln
100 105 110
Ser Gly Lys Val Ala Ile Ile Ser Val Gly Trp Asp Pro Gly Leu Phe
115 120 125
Ser Leu Asn Arg Leu Leu Gly Glu Val Val Leu Pro Val Gly Asn Thr
130 135 140
Tyr Thr Phe Trp Gly Lys Gly Val Ser Gln Gly His Ser Asp Ala Ile
145 150 155 160
Arg Arg Ile Gln Gly Val Lys Asn Ala Val Gln Tyr Thr Ile Pro Ile
165 170 175
Asp Glu Ala Val Asn Arg Val Arg Ser Gly Glu Asn Pro Glu Leu Ser
180 185 190
Thr Arg Glu Lys His Ala Arg Glu Cys Phe Val Val Leu Glu Glu Gly
195 200 205
Ala Asp Pro Ala Lys Val Glu His Glu Ile Lys Thr Met Pro Asn Tyr
210 215 220
Phe Asp Glu Tyr Asp Thr Thr Val His Phe Ile Ser Glu Glu Glu Leu
225 230 235 240
Lys Gln Asn His Ser Gly Met Pro His Gly Gly Phe Val Ile Arg Ser
245 250 255
Gly Lys Ser Asp Glu Gly His Lys Gln Ile Ile Glu Phe Ser Leu Asn
260 265 270
Leu Glu Ser Asn Pro Met Phe Thr Ser Ser Ala Leu Val Ala Tyr Ala
275 280 285
Arg Ala Ala Tyr Arg Leu Ser Gln Asn Gly Asp Lys Gly Ala Lys Thr
290 295 300
Val Phe Asp Ile Pro Phe Gly Leu Leu Ser Pro Lys Ser Pro Glu Asp
305 310 315 320
Leu Arg Lys Glu Leu
325
Claims (11)
1. a kind of synthetic method of D- cyclic alkylamidos acid, it is characterised in that comprise the following steps：
The reaction generation in the reaction system under the action of amino acid dehydrogenase
Wherein, n1>=0, n2>=1, M1For H or monovalent cation, m1>=0, m2>=1, M2For H or monovalent cation, the amino acid
The amino acid sequence of dehydrogenase is selected from one of following sequence：
1) such as SEQ ID NO：Amino acid sequence shown in 1；
2) such as SEQ ID NO：Amino acid sequence shown in 1 is one or more by substitution, missing or addition
There is High level of stereoselectivity selectively will obtained from amino acidChange intoAmino acid dehydrogenase activity amino acid sequence.
2. synthetic method according to claim 1, it is characterised in that further include amino group donor in the reaction system.
3. synthetic method according to claim 2, it is characterised in that the amino group donor is ammonium formate or ammonium chloride.
4. synthetic method according to claim 1, it is characterised in that further include coenzyme and buffering in the reaction system
Liquid.
5. synthetic method according to claim 4, it is characterised in that the coenzyme is β-NAD+Or β-NADP+。
6. synthetic method according to claim 4, it is characterised in that the buffer solution is Tris-HCl buffer solutions or phosphoric acid
Buffer solution.
7. synthetic method according to claim 1, it is characterised in that the pH value of the reaction system is 8.0~9.0, institute
The reaction temperature for stating reaction system is 30~40 DEG C.
8. synthetic method according to claim 1, it is characterised in that state and chaotropic agent is further included in reaction system, the rush
Solvent is dimethyl sulfoxide (DMSO).
9. synthetic method according to claim 1, it is characterised in that in the reaction system Molar concentration be 0.2mol/L~0.5mol/L.
10. synthetic method according to claim 1, it is characterised in that first propylhomoserin dehydrogenation is further included in the reaction system
Enzyme, the enzyme activity of amino acid dehydrogenase described in the reaction system of 10g substrates are 30U/ml, addition 400ml, the first propylhomoserin
The enzyme activity of dehydrogenase is 40U/ml, addition 100ml.
11. synthetic method according to claim 1, it is characterised in that the addition of accelerating agent is in the reaction system5w/v%~20w/v%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103194501A (en) * | 2013-03-29 | 2013-07-10 | 凯莱英医药集团（天津）股份有限公司 | Method for synthetizing chiral cyclic alkyl amino acid by amino transferase |
| CN103667380A (en) * | 2012-09-12 | 2014-03-26 | 天津工业生物技术研究所 | Novel method for synthesizing D-amino acid |
| CN106978453A (en) * | 2017-03-31 | 2017-07-25 | 浙江大学 | A kind of method that utilization amino acid dehydrogenase prepares L glufosinate-ammoniums |
-
2017
- 2017-11-16 CN CN201711135474.7A patent/CN107904268A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103667380A (en) * | 2012-09-12 | 2014-03-26 | 天津工业生物技术研究所 | Novel method for synthesizing D-amino acid |
| CN103194501A (en) * | 2013-03-29 | 2013-07-10 | 凯莱英医药集团（天津）股份有限公司 | Method for synthetizing chiral cyclic alkyl amino acid by amino transferase |
| CN106978453A (en) * | 2017-03-31 | 2017-07-25 | 浙江大学 | A kind of method that utilization amino acid dehydrogenase prepares L glufosinate-ammoniums |
Non-Patent Citations (2)
| Title |
|---|
| AKITA,H.等: "Ureibacillus thermosphaericus gene for meso-diaminopimelate dehydrogenase, partial sequence", 《GENBANK DATABASE》 * |
| HIRONAGA AKITA等: "Highly stable meso-diaminopimelate dehydrogenase from an Ureibacillus thermosphaericus strain A1 isolated from a Japanese compost: purification, characterization and sequencing", 《AMB EXPRESS》 * |
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