CN107602317A - The preparation method of the chiral Arvlacetic derivatives of 2 amino 2 - Google Patents
The preparation method of the chiral Arvlacetic derivatives of 2 amino 2 Download PDFInfo
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- CN107602317A CN107602317A CN201710655711.6A CN201710655711A CN107602317A CN 107602317 A CN107602317 A CN 107602317A CN 201710655711 A CN201710655711 A CN 201710655711A CN 107602317 A CN107602317 A CN 107602317A
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Abstract
The invention discloses a kind of preparation method of the chiral Arvlacetic derivatives of 2 amino 2.The preparation method comprises the following steps：1) Strecker reactions are carried out between raw material and amine or ammonium salt and cyanate using substituted or non-substituted aromatic aldehyde or the miscellaneous aldehyde of virtue；2) product obtained by step 1) hydrolyzes to obtain the Arvlacetic derivatives of 2 amino 2 of racemization in acid condition；3) Arvlacetic derivatives of 2 amino 2 of racemization are under the catalysis of aldehyde compound and the mixing of chiral acids resolution reagent, the chiral resolution induced by crystallization obtain the optically pure chiral Arvlacetic derivatives of 2 amino 2.Apply the technical scheme of the present invention, can synthesize the chiral amino acid building block with high economic value using initiation material cheap and easy to get, substrate adaptability is extensive, and can avoid, using expensive metallic catalyst, avoiding the metal residual of product；Improve synthesis yield.
Description
Technical field
The present invention relates to chemosynthesis technical field, derives in particular to a kind of chiral 2- amino -2- Arylacetic acids
The preparation method of thing.
Background technology
Chiral 2- amino -2- Arvlacetic derivatives are mainly used in synthetic drug intermediate, bulk drug and its related preparations.
Efficiently producing the method for such compound has very high economic value, it is possibility to have promotes to power the progress of association area.
At present, the main synthetic route of this kind of compound is to include following four：
1.Strecker methods
2. α-bromination method
3.Gabriel methods
4.Knoop-Oesterlin synthetic methods
Method more than is synthesized after obtaining the amino acid derivativges of racemization, is split by chiral reagent, or pass through life
Thing Enzymatic Resolution obtains optically pure amino acid derivativges.The theoretical yield of split process is up to 50%.
The major defect of these routes includes：Yield is low, it is necessary to Multi-step conversion and use noble metal catalyst etc..
The content of the invention
The present invention is intended to provide a kind of preparation method of chiral 2- amino -2- Arvlacetic derivatives, to solve existing skill
The low technical problem of 2- amino -2- Arvlacetic derivatives synthesis yields in art.
To achieve these goals, according to an aspect of the invention, there is provided a kind of chiral 2- amino -2- Arylacetic acids
The preparation method of derivative.The preparation method comprises the following steps：1) using substituted or non-substituted aromatic aldehyde or the miscellaneous aldehyde of virtue as original
Strecker reactions are carried out between material and amine or ammonium salt and cyanate；2) product obtained by step 1) hydrolyzes in acid condition
To the 2- amino -2- Arvlacetic derivatives of racemization；3) the 2- amino -2- Arvlacetic derivatives of racemization are in aldehyde compound
Catalysis is lower and chiral acids resolution reagent mixes, and optically pure chiral 2- amino -2- is obtained by the chiral resolution for crystallizing induction
Arvlacetic derivatives.
Further, synthetic route is as follows：
Wherein, X represents CH or N, Y represent CH or N, Z represent CH or N.
Further, in step 1), substituted or non-substituted aromatic aldehyde or the miscellaneous aldehyde of virtue are hexatomic ring or pentacyclic chemical combination
Thing.
Further, the Strecker reactions in step 1) are carried out in reaction dissolvent, and reaction dissolvent selects Free water, first
One or more in the group that alcohol, ethanol, tetrahydrofuran, ethanol and isopropanol form.
Further, amine or ammonium salt be selected from by ammoniacal liquor, ammonia or ammonia in methanol, ethanol, Isosorbide-5-Nitrae dioxane, tetrahydrochysene
One kind or more in the group of solution in furans or isopropanol, ammonium chloride and its hydrate or ammonium sulfate and its hydrate composition
Kind.
Further, cyanate is Cymag and/or potassium cyanide.
Further, the acid condition in step 2) is mixed to form for acid and solvent, and acid is by hydrochloric acid, sulfuric acid or Louis
One or more in the group of acid composition, solvent are one kind in the group being made up of water, methanol, ethanol, isopropanol and the tert-butyl alcohol
It is or a variety of.
Further, one or more of the aldehyde compound in step 3) in fatty aldehyde or aromatic aldehyde.
Further, fatty aldehyde is formaldehyde and/or butyraldehyde；Aromatic aldehyde is benzaldehyde and/or P-methoxybenzal-dehyde.
Further, chiral acids resolution reagent be by tartaric acid its derivative, its derivative of mandelic acid and malic acid and
One or more in the group of its derivative composition.
Apply the technical scheme of the present invention, can be synthesized with high economic value using initiation material cheap and easy to get
Chiral amino acid building block, substrate adaptability is extensive, and can avoid, using expensive metallic catalyst, avoiding the gold of product
Category residual；Each step reaction condition is gentle；Traditional chiral resolution strategy is avoided using crystallization induction dynamic chiral separation method
The shortcomings that yield is less than 50%, improve synthesis yield.
Embodiment
It should be noted that in the case where not conflicting, the feature in embodiment and embodiment in the application can phase
Mutually combination.The present invention is described in detail below in conjunction with embodiment.
According to a kind of typical embodiment of the present invention, there is provided a kind of system of chiral 2- amino -2- Arvlacetic derivatives
Preparation Method.The preparation method comprises the following steps：1) using substituted or non-substituted aromatic aldehyde or the miscellaneous aldehyde of virtue as raw material and amine or ammonium
Strecker reactions are carried out between salt and cyanate；2) product obtained by step 1) hydrolyzes to obtain the 2- of racemization in acid condition
Amino -2- Arvlacetic derivatives；3) the 2- amino -2- Arvlacetic derivatives of racemization are under the catalysis of aldehyde compound and hand
Property the mixing of acids resolution reagent, the chiral resolution by crystallizing induction obtains optically pure chiral 2- amino -2- Arylacetic acids and spreads out
Biology.
Apply the technical scheme of the present invention, can be synthesized with high economic value using initiation material cheap and easy to get
Chiral amino acid building block, substrate adaptability is extensive, and can avoid, using expensive metallic catalyst, avoiding the gold of product
Category residual；Each step reaction condition is gentle；Traditional chirality is avoided using crystallization induction dynamic chiral resolution (CIDR) method to tear open
The shortcomings that dividing tactful yield to be less than 50%, improve synthesis yield.
It is as follows according to a kind of typical embodiment of the present invention, synthetic route：
, wherein, X represents CH or N, Y represent CH or N, Z represent CH or N.
According to a kind of typical embodiment of the present invention, in step 1), substituted or non-substituted aromatic aldehyde or the miscellaneous aldehyde of virtue are
Hexatomic ring or pentacyclic compound.
Preferably, Strecker reactions are carried out in reaction dissolvent, and reaction dissolvent includes but is not limited to select Free water, first
One or more in the group that alcohol, ethanol, tetrahydrofuran, ethanol and isopropanol form.Imitated using the reaction of these solvent substrates
Rate and dissolubility are higher, are advantageous to the progress of reaction.Ammonium salt includes but is not limited to ammoniacal liquor, ammonia or ammonia in methanol, ethanol, 1,
Solution in other organic solvents such as 4 dioxane, tetrahydrofuran or isopropanol, ammonium chloride and its hydrate or ammonium sulfate and its
Hydrate.Preferably, cyanate is Cymag and/or potassium cyanide.Conveniently it is easy to get using both cyanates, it is cheap, fit
Together in industrialized production.
According to a kind of typical embodiment of the present invention, the acid condition in step 2) is mixed to form for acid and solvent, acid
For the one or more in the group that is made up of hydrochloric acid, sulfuric acid or lewis acid, solvent is by water, methanol, ethanol, isopropanol and uncle
One or more in the group of butanol composition.The reaction efficiency and dissolubility of substrate are higher, are advantageous to the progress of reaction.
Preferably, one or more of the aldehyde compound in step 3) in fatty aldehyde or aromatic aldehyde.Wherein, it is fatty
Aldehyde includes but is not limited to formaldehyde and/or butyraldehyde；Aromatic aldehyde includes but is not limited to benzaldehyde and/or P-methoxybenzal-dehyde.Using
Above-mentioned aldehydes, reaction efficiency are high.
Preferably, chiral acids resolution reagent be by tartaric acid its derivative, its derivative of mandelic acid and malic acid and its
One or more in the group of derivative composition.Above-mentioned chiral acids resolution reagent is conveniently easy to get, cheap, is suitable for industry
Metaplasia is produced.Beneficial effects of the present invention are further illustrated below in conjunction with embodiment.
Embodiment 1
10g benzaldehydes are dissolved in 100ml acetonitriles, 0.5g zinc iodides is added, 12g sodium hydrogensulfites, adds 12.27g cyanogen
Change potassium, 2h is stirred at 0 DEG C.4M NH are added at subzero 20 DEG C340 DEG C of methanol solution at stir 15h.TLC detection reactions are complete
Afterwards.The tertiary ether of 200ml first is added, organic phase is with 60ml water washings 3 times.After organic phase is spin-dried for, is recrystallized, obtained with 100ml normal heptanes
To 9.96g target compounds, yield 80%.
10g compounds are dissolved in 100ml 0.5M HCl methanol solutions, 5h is stirred at 60 DEG C.Reaction solution is rotated and steamed
30ml is sent to, is added into 150ml dichloromethane, 2h is stirred at 0 DEG C.Suction filtration obtains 14.5g off-white powders, yield 95%.
10g compounds are dissolved in 100ml methanol solutions, the tartaric acid of addition 0.5g benzaldehydes and 8.9gD configurations, 60 DEG C
Lower stirring 15h.Reaction solution rotary evaporation to 30ml is added into 150ml dichloromethane, 2h is stirred at 0 DEG C.It is white that suction filtration obtains class
Color solid, recrystallized in 100ml acetonitriles.After suction filtration, 11.6g white solids, yield 75% are obtained.
Embodiment 2
10g 4- aldehyde radical pyridines are dissolved in 100ml acetonitriles, 0.5g zinc iodides is added, 12g sodium hydrogensulfites, adds
12.27g potassium cyanide, 2h is stirred at 0 DEG C.4M NH are added at subzero 20 DEG C340 DEG C of methanol solution at stir 15h.TLC is detected
After reaction completely.The tertiary ether of 200ml first is added, organic phase is with 60ml water washings 3 times.After organic phase is spin-dried for, with 100ml normal heptane weights
Crystallization, obtains 10.58g target compounds, yield 85%.
10g compounds are dissolved in 100ml 0.5M HCl methanol solutions, 5h is stirred at 60 DEG C.Reaction solution is rotated and steamed
30ml is sent to, is added into 150ml dichloromethane, 2h is stirred at 0 DEG C.Suction filtration obtains the light yellow white solids of 12.08g, yield
75%.
10g compounds are dissolved in 100ml methanol solutions, the tartaric acid of addition 0.5g benzaldehydes and 8.9g D configurations, 60
15h is stirred at DEG C.Reaction solution rotary evaporation to 30ml is added into 150ml dichloromethane, 2h is stirred at 0 DEG C.Suction filtration obtains class
White solid, recrystallized in 100ml acetonitriles.After suction filtration, 12.37g white solids, yield 80% are obtained.
Embodiment 3
10g 3- aldehyde radical pyridines are dissolved in 100ml acetonitriles, 0.5g zinc iodides is added, 12g sodium hydrogensulfites, adds
12.27g potassium cyanide, 2h is stirred at 0 DEG C.4M NH are added at subzero 20 DEG C340 DEG C of methanol solution at stir 15h.TLC is detected
After reaction completely.The tertiary ether of 200ml first is added, organic phase is with 60ml water washings 3 times.After organic phase is spin-dried for, with 100ml normal heptane weights
Crystallization, obtains 9.71g target compounds, yield 78%.
10g compounds are dissolved in 100ml 0.5M HCl methanol solutions, 5h is stirred at 60 DEG C.Reaction solution is rotated and steamed
30ml is sent to, is added into 150ml dichloromethane, 2h is stirred at 0 DEG C.Suction filtration obtains 9.92g off-white powders, yield 65%.
10g compounds are dissolved in 100ml methanol solutions, the tartaric acid of addition 0.5g benzaldehydes and 8.9gD configurations, 60 DEG C
Lower stirring 15h.Reaction solution rotary evaporation to 30ml is added into 150ml dichloromethane, 2h is stirred at 0 DEG C.It is white that suction filtration obtains class
Color solid, recrystallized in 100ml acetonitriles.After suction filtration, 10.82g white solids, yield 70% are obtained.In description more than,
As can be seen that the above embodiments of the present invention realize following technique effect：
1) synthesis strategy synthesizes the chiral amino acid with high economic value using initiation material cheap and easy to get and built
Block；
2) substrate adaptability is extensive；
3) avoid, using expensive metallic catalyst, avoiding the metal residual of product；
4) each step reaction condition is gentle；
5) traditional chiral resolution strategy yield lacking less than 50% is avoided using crystallization induction dynamic chiral separation method
Point, improves synthesis yield.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should be included in the scope of the protection.
Claims (10)
1. a kind of preparation method of chiral 2- amino -2- Arvlacetic derivatives, it is characterised in that comprise the following steps：
1) Strecker is carried out between raw material and amine or ammonium salt and cyanate using substituted or non-substituted aromatic aldehyde or the miscellaneous aldehyde of virtue
Reaction；
2) product obtained by the step 1) hydrolyzes to obtain the 2- amino -2- Arvlacetic derivatives of racemization in acid condition；
3) the 2- amino -2- Arvlacetic derivatives of racemization mix under the catalysis of aldehyde compound with chiral acids resolution reagent
Close, optically pure chiral 2- amino -2- Arvlacetic derivatives are obtained by the chiral resolution for crystallizing induction.
2. preparation method according to claim 1, it is characterised in that synthetic route is as follows：
Wherein, X represents CH or N, Y represent CH or N, Z represent CH or N.
3. preparation method according to claim 1, it is characterised in that described substituted or non-substituted in the step 1)
Aromatic aldehyde or the miscellaneous aldehyde of virtue are hexatomic ring or pentacyclic compound.
4. preparation method according to claim 1, it is characterised in that the Strecker reactions in the step 1) are being reacted
Carried out in solvent, the reaction dissolvent selects one in the group of Free water, methanol, ethanol, tetrahydrofuran, ethanol and isopropanol composition
Kind is a variety of.
5. preparation method according to claim 1, it is characterised in that the amine or ammonium salt be selected from by ammoniacal liquor, ammonia or
Solution of the ammonia in methanol, ethanol, Isosorbide-5-Nitrae dioxane, tetrahydrofuran or isopropanol, ammonium chloride and its hydrate or ammonium sulfate
And its one or more in the group of hydrate composition.
6. preparation method according to claim 1, it is characterised in that the cyanate is Cymag and/or potassium cyanide.
7. preparation method according to claim 1, it is characterised in that the acid condition in the step 2) is acid and solvent
Be mixed to form, the acid is the one or more in the group being made up of hydrochloric acid, sulfuric acid or lewis acid, the solvent be by water,
One or more in the group that methanol, ethanol, isopropanol and the tert-butyl alcohol form.
8. preparation method according to claim 1, it is characterised in that the aldehyde compound in the step 3) is selected from fat
One or more in aldehyde or aromatic aldehyde.
9. preparation method according to claim 8, it is characterised in that the fatty aldehyde is formaldehyde and/or butyraldehyde；The virtue
Fragrant aldehyde is benzaldehyde and/or P-methoxybenzal-dehyde.
10. preparation method according to claim 1, it is characterised in that the chiral acids resolution reagent is by tartaric acid
One or more in the group of its derivative of its derivative, mandelic acid and malic acid and its derivative composition.
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| CN101497575A (en) * | 2008-01-28 | 2009-08-05 | 上海华理生物医药有限公司 | Method for splitting S-(+)-o-chlorobenzene glycine methyl ester |
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| CN108409589A (en) * | 2018-03-26 | 2018-08-17 | 爱斯特（成都）生物制药股份有限公司 | A kind of preparation method of the beta-amino acid esters of band chirality |
-
2017
- 2017-08-02 CN CN201710655711.6A patent/CN107602317A/en active Pending
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|---|---|---|---|---|
| JPS52139001A (en) * | 1976-05-17 | 1977-11-19 | Teijin Ltd | Resolution of racemic organic amines |
| CN1189829A (en) * | 1995-05-02 | 1998-08-05 | 先灵公司 | Piperazino derivatives as neurokinin antagonists |
| CN101186944A (en) * | 2007-12-29 | 2008-05-28 | 河北科技大学 | Biological resolution method for amino acid |
| CN101497575A (en) * | 2008-01-28 | 2009-08-05 | 上海华理生物医药有限公司 | Method for splitting S-(+)-o-chlorobenzene glycine methyl ester |
| CN101333223A (en) * | 2008-07-28 | 2008-12-31 | 台州市知青化工有限公司 | Method for preparing clopidogrel and salts thereof |
| CN103030575A (en) * | 2013-01-04 | 2013-04-10 | 中国农业大学 | Double-cyano acidamide compound, and synthetic method and application of compound |
| CN108409589A (en) * | 2018-03-26 | 2018-08-17 | 爱斯特（成都）生物制药股份有限公司 | A kind of preparation method of the beta-amino acid esters of band chirality |
Non-Patent Citations (2)
| Title |
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| 侯鹏云等: "S-邻氯苯甘氨酸制备技术的研究进展", 《精细与专用化学品》 * |
| 纵朝阳等: "不对称Strecker反应催化剂的研究进展", 《合成化学》 * |
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