CN107827845A - A kind of method of new synthesis butyrolactone derivative - Google Patents
A kind of method of new synthesis butyrolactone derivative Download PDFInfo
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- CN107827845A CN107827845A CN201711126332.4A CN201711126332A CN107827845A CN 107827845 A CN107827845 A CN 107827845A CN 201711126332 A CN201711126332 A CN 201711126332A CN 107827845 A CN107827845 A CN 107827845A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Abstract
The invention discloses a kind of method of new synthesis butyrolactone derivative, comprise the following steps：(1) it will be reacted after the chiral lithiation of valeric acid shown in formula (II) with bromoacetonitrile, obtain the compound shown in formula (III)；(2) compound shown in formula (III) is obtained into the compound shown in formula (IV) through borane reduction carboxyl；(3) compound shown in formula (IV) is hydrolyzed into cyano group in the basic conditions, obtains the carboxylic acid derivates shown in formula (V), then the butyrolactone derivative shown in acquisition formula (I) is reacted through dehydration condensation.The advantage of the invention is that：A kind of brand-new butyrolactone derivative synthetic method is provided, the cost of synthesis material valeric acid is cheap, it is only necessary to which 4 steps are reacted, and stereoselectivity is good, it is possible to substantially reduce production cost.Synthetic route is as follows：
Description
Technical field
The present invention relates to organic synthesis technical field, is more particularly to a kind of side of new synthesis butyrolactone derivative
Method.
Background technology
Butyrolactone derivative shown in lower formula (I) is new antiepileptic medicine Bu Waxitan (Brivaracetam) synthesis
Key intermediate.
At present, has the more document reports synthetic method of above-mentioned butyrolactone derivative, for example, patent document
Following synthetic method is reported in WO2016/191435, wherein using R- epoxychloropropane as raw material, is contracted with diethyl malonate
Close, then with ethyl phosphonium bromide reactive magnesium, last decarboxylation obtains key intermediate butyrolactone derivative, but its cost is costly.
And for example, document Hughes, G. et al., J.Am.Chem.Soc.2003, report is with positive penta in 125,11253-11258
Aldehyde is raw material, through cyclization, reduction, most above-mentioned butyrolactone derivative is obtained through asymmetric reduction afterwards, wherein using valuable chirality
Catalyst and part, and it is difficult to keep high chiral purity.And document Rudroff, F. et al.,
Adv.Synth.Catal.2007, report uses expensive biology enzyme using 1- amylenes as raw material after cyclization in 349,1436-1444
Catalyst, oxidation ring expansion obtain above-mentioned butyrolactone derivative.
Therefore, find that a kind of step is simple, production cost is low, regioselectivity is strong, the butyrolactone derivative of high income
Synthetic method is the current technical problem for being badly in need of solving.
The content of the invention
The technical problems to be solved by the invention are the provision of a kind of method of new synthesis butyrolactone derivative.
The present invention is that solve above-mentioned technical problem by the following technical programs：
A kind of method of new synthesis butyrolactone derivative, it is characterised in that comprise the following steps：
(1) it will be reacted after the chiral lithiation of valeric acid shown in formula (II) with bromoacetonitrile, obtain the change shown in formula (III)
Compound；
(2) compound shown in formula (III) is obtained into the compound shown in formula (IV) through borane reduction carboxyl；
(3) compound shown in formula (IV) is hydrolyzed into cyano group in the basic conditions, obtains the carboxylic acid shown in formula (V) and derive
Thing, then react the butyrolactone derivative shown in acquisition formula (I) through dehydration condensation；
Preferably, the synthetic method comprises the following steps：
(1) diisopropylamine is dissolved in ether, is cooled to -60~-90 DEG C, add the hexane solution of n-BuLi,
After being stirred at -60~-90 DEG C, chiral nitrogen-containing ligands are added, continue to stir, add the valeric acid shown in formula (II)
Diethyl ether solution, then stirred at -30~-50 DEG C, be cooled to -60~-90 DEG C, add the ether of bromoacetate
Solution, after -60~-90 DEG C stir, be warming up to 0 DEG C in 4~6 hours, terminating reaction, it is scrubbed, dry, be spin-dried for it is molten
Agent, and after column chromatography, obtain the compound shown in formula (III)；
(2) compound shown in formula (III) is dissolved in tetrahydrofuran and is cooled to 0 DEG C, addition tetrahydrofuran borine network
Compound, 20~30 DEG C be stirred overnight after be added dropwise aqueous hydrochloric acid solution, stir 0.5~2 hour, washed after dilution, dry and be spin-dried for molten
Agent, obtain the compound shown in formula (IV)；
(3) compound shown in formula (IV) is suspended in the mixture of second alcohol and water, adds NaOH, backflow 10~30 is small
Shi Hou, 0 degree Celsius is cooled to, is spin-dried for after being adjusted to neutrality, obtain the carboxylic acid derivates shown in formula (V)；By the carboxylic acid shown in formula (V)
Derivative is dissolved in toluene, adds p-methyl benzenesulfonic acid, and backflow overnight, is washed out, is spin-dried for solvent, is evaporated under reduced pressure again, obtains formula
(I) butyrolactone derivative shown in.
Preferably, in step (1), the chiral nitrogen-containing ligands are selected from the chemical combination shown in (-)-sparteine or formula (VI)
Thing
Preferably, in step (1), diisopropylamine：N-BuLi：Chiral nitrogen-containing ligands：Valeric acid：Mole of bromoacetonitrile
Equivalent proportion is 2~4:2~5:2~5:1:1.
Preferably, in step (1), the reagent of the terminating reaction is saturated aqueous ammonium chloride；And/or
The process of the washing is successively with water, saturated common salt water washing.
Preferably, in step (2), 15~40mL tetrahydrofuran borines are added in the compound shown in per 1g formulas (III)
Complex compound.
Preferably, in step (2), the process of the dilution is to be diluted with methyl tertiary butyl ether(MTBE)；And/or
The process of the washing is to use aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.
Preferably, in step (3), the mass ratio of compound and NaOH shown in formula (IV) is 4~9:1；And/or
The volume ratio of ethanol and water is 2~4 in the mixture of the second alcohol and water:1.
Preferably, in step (3), the process of the washing is to use water, saturated sodium bicarbonate aqueous solution and saturation successively
Brine It.
Purposes of the butyrolactone derivative that synthetic method of the present invention obtains in Bu Waxitan is prepared.
The present invention has advantages below compared with prior art：A kind of brand-new butyrolactone derivative synthetic method is provided, closed
Cost into raw material valeric acid is cheap, it is only necessary to which 4 steps are reacted, and stereoselectivity is good, it is possible to substantially reduce production cost.
Embodiment
Embodiments of the invention are elaborated below, the present embodiment is carried out lower premised on technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
The synthesis of compound shown in the formula of embodiment 1 (III)
Diisopropylamine (6.1g, 3 equivalents) is dissolved in 30mL ether, is cooled to -78 DEG C, adds 40mL n-BuLis
Hexane solution (1.6M hexane solutions, 3.2 equivalents), after stirring 30min at a temperature of this, add (-)-sparteine
(3.2 equivalent), stirs 30min at a temperature of this, add valeric acid shown in 20mL formulas (II) diethyl ether solution (2.0g valeric acids, 1
Equivalent), then stirred 1 hour at -40 DEG C, be cooled to -78 DEG C, add diethyl ether solution (the 2.4g bromine second of 20mL bromoacetonitriles
Nitrile, 1 equivalent), after -78 DEG C are stirred 2 hours, 0 DEG C was warming up in 5 hours, 50mL saturated aqueous ammonium chlorides are added dropwise and terminate
Reaction, successively with 75mL water, 75mL saturated common salt water washings, dry, be spin-dried for solvent, and after column chromatography, obtain shown in formula (III)
Compound (yield 56%, e.r. values be 98:2, e.r. refer to the ratio for representing two kinds of enantiomters).High resolution mass spectrum (ESI+)：C7H10NO2- theoretical values 140.0717, measured value 140.0719.
The synthesis of compound shown in the formula of embodiment 2 (III)
Diisopropylamine (6.1g, 3 equivalents) is dissolved in 30mL ether, is cooled to -78 DEG C, adds 40mL n-BuLis
Hexane solution (1.6M hexane solutions, 3.2 equivalents), after stirring 30min at a temperature of this, add the change shown in formula (VI)
Compound (3.2 equivalent), 30min is stirred at a temperature of this, add the diethyl ether solution (2.0g penta of the valeric acid shown in 20mL formulas (II)
Acid, 1 equivalent), then stirred 1 hour at -40 DEG C, be cooled to -78 DEG C, add the diethyl ether solution (2.4g of 20mL bromoacetonitriles
Bromoacetonitrile, 1 equivalent), after -78 DEG C are stirred 2 hours, 0 DEG C was warming up in 5 hours, 50mL saturated aqueous ammonium chlorides are added dropwise
Terminating reaction, successively with 75mL water, 75mL saturated common salt water washings, dry, be spin-dried for solvent, and after column chromatography, obtain formula (III)
(yield 49%, e.r. values are 96 to shown compound:4, e.r. refer to the ratio for representing two kinds of enantiomters).High resolution mass spectrum
(ESI+)：C7H10NO2- theoretical values 140.0717, measured value 140.0719.
Embodiment 3
Compound (10g, 1 equivalent) shown in formula (III) prepared by embodiment 1 is dissolved in 200mL tetrahydrofurans and cold
But to 0 DEG C, add 280mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after be added dropwise
100mL 1N (mol/L) aqueous hydrochloric acid solution, stir 1 hour, diluted with 500mL methyl tertiary butyl ether(MTBE)s, successively with 250mL 1N salt
Aqueous acid, 250mL saturated sodium bicarbonate aqueous solutions, 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain formula
(IV) compound (7.7g, yield 85%) shown in.High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, it is real
Measured value is 128.1063.
Compound (20.3g, 1 equivalent) shown in formula (IV) is suspended in the mixture of 30mL ethanol and 10mL water, added
Enter NaOH (3g), after flowing back 20 hours, be cooled to 0 degree Celsius, be spin-dried for after being adjusted to neutrality with 1N hydrochloric acid, obtain the thick of intermediate V
Product.This crude product is directly suspended in 300mL toluene, adds p-methyl benzenesulfonic acid (41.3g, 1.5 equivalents), backflow overnight, will be anti-
Answer liquid to use 100mL water, 100mL saturated sodium bicarbonate aqueous solutions and 100mL saturated common salt water washings successively, be spin-dried for solvent
Compound crude product, then it is evaporated under reduced pressure to obtain the butyrolactone derivative (12g, yield 59%) shown in formula (I).High resolution mass spectrum (ESI+)：C7H13O2+ theoretical values 129.0910, measured value 129.0903.
Embodiment 4
Compound (10g, 1 equivalent) shown in formula (III) prepared by embodiment 2 is dissolved in 200mL tetrahydrofurans and cold
But to 0 DEG C, add 280mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after be added dropwise
100mL 1N aqueous hydrochloric acid solutions, stir 1 hour, diluted with 500mL methyl tertiary butyl ether(MTBE)s, it is water-soluble with 250mL 1N hydrochloric acid successively
Liquid, 250mL saturated sodium bicarbonate aqueous solutions, 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain shown in formula (IV)
Compound (6.4g, yield 71%).High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, measured value are
128.1063。
Compound (20.3g, 1 equivalent) shown in formula (IV) is suspended in the mixture of 30mL ethanol and 10mL water, added
Enter NaOH (3g), after flowing back 20 hours, be cooled to 0 degree Celsius, be spin-dried for after being adjusted to neutrality with 1N hydrochloric acid, obtain intermediate formula (V)
The crude product of shown carboxylic acid derivates.This crude product is directly suspended in 300mL toluene, and addition p-methyl benzenesulfonic acid (41.3g, 1.5
Equivalent), reaction solution overnight, is used 100mL water, 100mL saturated sodium bicarbonate aqueous solutions and 100mL saturated aqueous common salts by backflow successively
Washing, is spin-dried for solvent and obtains crude compound, then be evaporated under reduced pressure to obtain butyrolactone derivative (12g, the yield shown in formula (I)
59%).High resolution mass spectrum (ESI+)：C7H13O2+ theoretical values 129.0910, measured value 129.0903.
The butyrolactone derivative that embodiment 3-4 is obtained can be used for preparing Bu Waxitan.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
- A kind of 1. method of new synthesis butyrolactone derivative, it is characterised in that comprise the following steps：(1) it will be reacted after the chiral lithiation of valeric acid shown in formula (II) with bromoacetonitrile, obtain the chemical combination shown in formula (III) Thing；(2) compound shown in formula (III) is obtained into the compound shown in formula (IV) through borane reduction carboxyl；(3) compound shown in formula (IV) is hydrolyzed into cyano group in the basic conditions, obtains the carboxylic acid derivates shown in formula (V), then Through the butyrolactone derivative shown in dehydration condensation reaction acquisition formula (I)；
- 2. the method for new synthesis butyrolactone derivative according to claim 1, it is characterised in that comprise the following steps：(1) diisopropylamine is dissolved in ether, is cooled to -60~-90 DEG C, the hexane solution of n-BuLi is added, in -60 After being stirred at~-90 DEG C, chiral nitrogen-containing ligands are added, continue to stir, add the second of the valeric acid shown in formula (II) Ethereal solution, then stirred at -30~-50 DEG C, be cooled to -60~-90 DEG C, add the diethyl ether solution of bromoacetonitrile, in - After 60~-90 DEG C stir, 0 DEG C was warming up in 4~6 hours, terminating reaction is scrubbed, dry, be spin-dried for solvent, and post After chromatography, the compound shown in formula (III) is obtained；(2) compound shown in formula (III) is dissolved in tetrahydrofuran and is cooled to 0 DEG C, add tetrahydrofuran borane complex, 20~30 DEG C be stirred overnight after be added dropwise aqueous hydrochloric acid solution, stir 0.5~2 hour, washed after dilution, dry and be spin-dried for solvent, obtained Obtain the compound shown in formula (IV)；(3) compound shown in formula (IV) is suspended in the mixture of second alcohol and water, adds NaOH, flowed back 10~30 hours Afterwards, 0 degree Celsius is cooled to, is spin-dried for after being adjusted to neutrality, obtains the carboxylic acid derivates shown in formula (V)；Carboxylic acid shown in formula (V) is spread out Biology is dissolved in toluene, adds p-methyl benzenesulfonic acid, and backflow overnight, is washed out, is spin-dried for solvent, is evaporated under reduced pressure again, obtains formula (I) Shown butyrolactone derivative.
- 3. the method for new synthesis butyrolactone derivative according to claim 2, it is characterised in that in step (1), institute Chiral nitrogen-containing ligands are stated selected from the compound shown in (-)-sparteine or formula (VI)
- 4. the method for new synthesis butyrolactone derivative according to claim 2, it is characterised in that in step (1), two Isopropylamine：N-BuLi：Chiral nitrogen-containing ligands：Valeric acid：The molar equivalent ratio of bromoacetonitrile is 2~4:2~5:2~5:1:1.
- 5. the method for new synthesis butyrolactone derivative according to claim 2, it is characterised in that in step (1), institute The reagent for stating terminating reaction is saturated aqueous ammonium chloride；And/orThe process of the washing is successively with water, saturated common salt water washing.
- 6. the method for new synthesis butyrolactone derivative according to claim 2, it is characterised in that in step (2), often 15~40mL tetrahydrofuran borane complexes are added in compound shown in 1g formulas (III).
- 7. the method for new synthesis butyrolactone derivative according to claim 2, it is characterised in that in step (2), institute The process for stating dilution is to be diluted with methyl tertiary butyl ether(MTBE)；And/orThe process of the washing is to use aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.
- 8. the method for new synthesis butyrolactone derivative according to claim 2, it is characterised in that in step (3), formula (IV) mass ratio of compound and NaOH shown in is 4~9:1；And/orThe volume ratio of ethanol and water is 2~4 in the mixture of the second alcohol and water:1.
- 9. the method for new synthesis butyrolactone derivative according to claim 2, it is characterised in that in step (3), institute The process for stating washing is to use water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.
- 10. the butyrolactone derivative that the synthetic method any one of claim 1 to 9 obtains is in Bu Waxitan is prepared Purposes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115197178A (en) * | 2022-08-24 | 2022-10-18 | 四川诺非特生物药业科技有限公司 | Synthesis method of brivaracetam key intermediate |
| CN115197178B (en) * | 2022-08-24 | 2024-04-26 | 四川诺非特生物药业科技有限公司 | Synthesis method of brivaracetam key intermediate |
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| JP2009155280A (en) * | 2007-12-27 | 2009-07-16 | Mitsubishi Rayon Co Ltd | METHOD FOR PRODUCING gamma-BUTYROLACTONE COMPOUND |
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| EP1940811B1 (en) * | 2005-10-21 | 2014-02-26 | Bayer Intellectual Property GmbH | Heterocyclic compounds with carboxyl isostere groups and their use for the treatment of cardiovascular diseases |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115197178A (en) * | 2022-08-24 | 2022-10-18 | 四川诺非特生物药业科技有限公司 | Synthesis method of brivaracetam key intermediate |
| CN115197178B (en) * | 2022-08-24 | 2024-04-26 | 四川诺非特生物药业科技有限公司 | Synthesis method of brivaracetam key intermediate |
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