CN107698543A - A kind of preparation method of butyrolactone derivative - Google Patents
A kind of preparation method of butyrolactone derivative Download PDFInfo
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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
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Abstract
The invention discloses a kind of preparation method of butyrolactone derivative, comprise the following steps：(1) compound of formula (II) is substituted with propyl group grignard reagent, obtains the compound of formula (III)；(2) compound of formula (III) is removed into benzyl protection, obtains the compound of formula (IV)；(3) it is cyano group by the compound substituted hydroxy of formula (IV), obtains the compound of formula (V)；(4) by the compound removing tert-butyl group protection of formula (V), the compound of acquisition formula (VI)；(5) compound of formula (VI) is reduced into carboxyl, obtains the compound of formula (VII)；(6) compound of formula (VII) is hydrolyzed into cyano group in the basic conditions, obtains the carboxylic acid derivates of formula (VIII), then the butyrolactone derivative of acquisition formula (I) is reacted through dehydration condensation.It is an advantage of the current invention that stereoselectivity is good, easy to operate, total recovery is higher, is adapted to amplification production.Synthetic route is as follows：
Description
Technical field
The present invention relates to organic synthesis technical field, is more particularly to a kind of preparation method of butyrolactone derivative.
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
Preparation 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 preparation method of new butyrolactone derivative.
The present invention is that solve above-mentioned technical problem by the following technical programs：
A kind of preparation method of butyrolactone derivative, comprises the following steps：
(1) compound shown in formula (II) is substituted with propyl group grignard reagent, obtains the compound shown in formula (III)；
(2) compound shown in formula (III) is removed into benzyl protection, obtains the compound shown in formula (IV)；
(3) it is cyano group by the compound substituted hydroxy shown in formula (IV), obtains the compound shown in formula (V)；
(4) by the compound removing tert-butyl group protection shown in formula (V), the compound shown in formula (VI) is obtained；
(5) compound shown in formula (VI) is reduced into carboxyl, obtains the compound shown in formula (VII)；
(6) compound shown in formula (VII) is hydrolyzed into cyano group in the basic conditions, obtains the carboxylic acid shown in formula (VIII) and spread out
Biology, then react the butyrolactone derivative shown in acquisition formula (I) through dehydration condensation；
Preferably, the preparation method comprises the following steps：
(1) anhydrous zinc chloride is dissolved in tetrahydrofuran, the compound shown in addition formula (II), 20~30 DEG C of stirrings 5~
0 DEG C is cooled to after 15min, adds after propyl group grignard reagent and is stirred 2~4 hours at 0 DEG C, terminating reaction, has been washed out
Machine phase, solvent is spin-dried for, obtains the compound shown in formula (III)；
(2) compound shown in formula (III) is dissolved in methanol, addition palladium carbon, normal pressure hydrogenation 2~5 hours, then mistake
Filter, be spin-dried for filtrate, again through column chromatography, obtaining the compound shown in formula (IV)；
(3) compound shown in formula (IV) is dissolved in dichloromethane, adds N, N- diisopropyl ethyl amines and methyl sulphur
Acyl chlorides, after 20~30 DEG C are stirred 1~3 hour, progress first time washing, drying are simultaneously spin-dried for solvent, are re-dissolved in dioxane, add
Enter TBAB and potassium cyanide, 20~30 DEG C are stirred 36~60 hours, and second of washing is carried out after dilution, dries and is spin-dried for
Solvent, obtain the compound shown in formula (V)；
(4) compound shown in formula (V) is dissolved in dichloromethane, then adds trifluoroacetic acid, 20~30 DEG C of stirrings 1~
4 hours, solvent is spin-dried at a temperature of no more than 40 DEG C, then through column chromatography, obtain the compound shown in formula (VI)；
(5) compound shown in formula (VI) is dissolved in tetrahydrofuran and is cooled to 0 DEG C, addition tetrahydrofuran borane
Thing, 20~30 DEG C be stirred overnight after be added dropwise aqueous hydrochloric acid solution, stir 0.5~2 hour, wash, dry after dilution and be spin-dried for solvent,
Compound shown in acquisition formula (VII)；
(6) compound shown in formula (VII) is suspended in the mixture of second alcohol and water, adds NaOH, backflow 10~30
After hour, 0 degree Celsius is cooled to, is spin-dried for after being adjusted to neutrality, obtains the carboxylic acid derivates shown in formula (VIII)；By formula (VIII) institute
The carboxylic acid derivates shown are dissolved in toluene, add p-methyl benzenesulfonic acid, and backflow overnight, is washed out, is spin-dried for solvent, depressurizes steaming again
Evaporate, obtain the butyrolactone derivative shown in formula (I).
Preferably, in step (1), propyl group grignard reagent is propyl group magnesium chloride, and/or
The molar equivalent ratio of compound and propyl group magnesium chloride shown in formula (II) is 1:1~2.
Preferably, in step (1), the reagent of terminating reaction is saturated aqueous ammonium chloride；And/or
The process of washing is successively with saturated sodium bicarbonate aqueous solution, saturated common salt water washing.
Preferably, in step (2), the mass ratio of compound and palladium carbon shown in formula (III) is 15~20:1；The palladium
Carbon is 10% palladium carbon.
Preferably, in step (3), the compound shown in formula (IV)：N, N- diisopropyl ethyl amine：Methylsufonyl chloride：
TBAB：The mass ratio of potassium cyanide is 40~55:30~45:25~35:1:15~25；And/or
The process of washing is successively with aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt washing for the first time
Wash；And/or
The process of dilution is to be diluted with methyl tertiary butyl ether(MTBE)；And/or
The process of second of washing is successively with aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt washing
Wash.
Preferably, in step (4), 1~1.5mL trifluoroacetic acids are added in the compound shown in per 1g formulas (V).
Preferably, in step (5), 15~40mL tetrahydrofuran borine networks are added in the compound shown in per 1g formulas (VI)
Compound；And/or
The process of dilution is to be diluted with methyl tertiary butyl ether(MTBE)；And/or
The process of washing is to use aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.
Preferably, in step (6), the mass ratio of compound and NaOH shown in formula (VII) is 4~9:1；And/or
The volume ratio of ethanol and water is 2~4 in the mixture of second alcohol and water:1；
The process of washing is to use water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.
Purposes of the butyrolactone derivative that preparation 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 preparation method is provided, its
Stereoselectivity is good, easy to operate, and total recovery is higher, is adapted to amplification production.
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 preparation of compound shown in the formula of embodiment 1 (II)
Synthetic route is as follows：
(1) L- glyceric acid (138g) and DMAP (10g) are dissolved in THF (2L), are cooled to 0 degree Celsius, are added portionwise
Boc2O (872g), after subsequent 0 degree Celsius is stirred 24 hours, reaction solution is spin-dried for, it is dry 3 times with toluene band.Residue is re-dissolved in
In THF (1L), potassium carbonate (276g) is added, stirring at normal temperature is after 1 hour, adds benzyl chloride (190g), then stirring at normal temperature 48 hours, adds
Enter after reaction is quenched in methanol (50mL), reaction solution is poured into 1L water, separates organic phase, then aqueous phase is extracted with the tertiary ether of first.Merge
After organic phase, with saturated common salt water washing 2 times, organic phase is spin-dried for, residue cross post obtain grease II-1 (118g,
47%).High resolution mass spectrum (ESI+)：C14H21O4+ theoretical values 253.1434, measured value 253.1428.
(2) above-mentioned oily compound II-1 (63.0g, 250mmol) is dissolved in dichloromethane (1.5L), adds 2,6- diformazans
Yl pyridines (40.0g, 375mmol), are cooled to 0 DEG C, and trifluoromethanesulfanhydride anhydride (98.7g, 350mmol) is slowly added dropwise, and are added dropwise within 1 hour
Finish, then reacted 1 hour at 0 DEG C.Reaction solution uses 1N aqueous hydrochloric acid solutions (1L × 2) and saturated sodium-chloride sodium chloride water successively
Solution washing (1L × 2) washing, anhydrous magnesium sulfate are dried, and are concentrated under reduced pressure into the dry compound (91.6g) obtained shown in formula (II),
Yield is 95%.High resolution mass spectrum (ESI+)：C15H20F3O6S+ theoretical values 385.0927, measured value 385.0921.
The synthesis of butyrolactone derivative shown in the formula of embodiment 2 (I)
Synthetic route is as follows：
(1) anhydrous zinc chloride (0.17g, 0.025 equivalent) is dissolved in 300mL tetrahydrofurans (THF), adds embodiment 1
Compound (19.2g, 1 equivalent) shown in the formula (II) of preparation, 20~30 DEG C stirring 10min after be cooled to 0 DEG C, add propyl group
Magnesium chloride (70mL, 1.4 equivalents, concentration：1M THF solutions), stirred 3 hours at 0 DEG C, 100mL saturated aqueous ammonium chlorides are added dropwise
Terminating reaction, organic phase with 150mL saturated sodium bicarbonate aqueous solutions, 150mL saturated common salt water washings, are spin-dried for solvent, obtained successively
Obtain the compound (12.4g, yield 89%) shown in formula (III).High resolution mass spectrum (ESI+)：C17H27O3+ theoretical values
279.1955 measured value 279.1949.
(2) compound (9.3g, 1 equivalent) shown in formula (III) is dissolved in 100mL methanol, adds the palladiums of 0.5g 10%
Carbon, normal pressure hydrogenation 3 hours, then filtering reacting liquid, is spin-dried for filtrate, obtains crude compound, then column chromatography obtains formula (IV) institute
The compound (5.7g, yield 90%) shown.High resolution mass spectrum (ESI+)：C10H21O3+ theoretical values 189.1485, measured value are
189.1477。
(3) compound (4.7g, 1 equivalent) shown in formula (IV) is dissolved in 80mL dichloromethane, adds N, N- diisopropyls
Base ethylamine (3.9g, 1.2 equivalents) and methylsufonyl chloride (3.1g, 1.1 equivalents), after 20~30 DEG C are stirred 2 hours, use successively
40mL 1N (mol/L) aqueous hydrochloric acid solution, 40mL saturated sodium bicarbonate aqueous solutions and 40mL saturated aqueous common salts wash for the first time
Wash, dry and be spin-dried for solvent, then residue is dissolved in 50mL dioxane, add TBAB (100mg) and cyaniding
Potassium (1.95g, 1.2 equivalents), 20~30 DEG C are stirred 48 hours, then dilute reaction solution with 100mL methyl tertiary butyl ether(MTBE)s, then according to
It is secondary to carry out second of washing with 75mL 1N aqueous hydrochloric acid solutions, 75mL saturated sodium bicarbonate aqueous solutions and 75mL saturated aqueous common salts, do
It is dry and be spin-dried for solvent, obtain the compound shown in formula (V).High resolution mass spectrum (ESI+)：C11H20NO2+ theoretical values
198.1489 measured value 198.1481.
(4) compound shown in 8g formulas (V) is dissolved in 80mL dichloromethane, addition 10mL trifluoroacetic acids, 20~30 DEG C
Stirring 2 hours, solvent is spin-dried at a temperature of no more than 40 DEG C, then residue is obtained into the change shown in formula (VI) through column chromatography
Compound (1.1g, yield 31%).High resolution mass spectrum (ESI+)：C7H10NO2- theoretical values 140.0717, measured value are
140.0719。
(5) compound (10g, 1 equivalent) shown in formula (VI) is dissolved in 200mL tetrahydrofurans and is cooled to 0 DEG C, addition
280mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after be added dropwise 100mL 1N hydrochloric acid
The aqueous solution, stir 1 hour, after being diluted with 500mL methyl tertiary butyl ether(MTBE)s, successively with 250mL 1N aqueous hydrochloric acid solutions, 250mL saturations
Sodium bicarbonate aqueous solution and 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain the compound shown in formula (VII)
(7.7g, yield 85%).High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, measured value 128.1063.
(6) compound (20.3g, 1 equivalent) shown in formula (VII) is suspended in the mixture of 30mL ethanol and 10mL water
In, NaOH (3g) is added, after flowing back 20 hours, 0 degree Celsius is cooled to, is spin-dried for after being adjusted to neutrality with 1N hydrochloric acid, obtains intermediate
The crude product of carboxylic acid derivates shown in formula (VIII).This crude product is directly suspended in 300mL toluene, adds p-methyl benzenesulfonic acid
Reaction solution overnight, is used 100mL water, 100mL saturated sodium bicarbonate aqueous solutions and 100mL by (41.3g, 1.5 equivalents), backflow successively
Saturated common salt water washing, it is spin-dried for solvent and obtains crude compound, then is evaporated under reduced pressure to obtain the butyrolactone derivative shown in formula (I)
(12g, yield 59%).High resolution mass spectrum (ESI+)：C7H13O2+ theoretical values 129.0910, measured value 129.0903.
The synthesis of butyrolactone derivative shown in the formula of embodiment 3 (I)
(1) anhydrous zinc chloride (0.17g, 0.025 equivalent) is dissolved in 300mL tetrahydrofurans (THF), adds embodiment 1
Compound (19.2g, 1 equivalent) shown in the formula (II) of preparation, 20~30 DEG C stirring 5min after be cooled to 0 DEG C, add propyl group
Magnesium chloride (70mL, 1 equivalent, concentration：1M THF solutions), stirred 2 hours at 0 DEG C, it is whole that 100mL saturated aqueous ammonium chlorides are added dropwise
Only react, organic phase with 150mL saturated sodium bicarbonate aqueous solutions, 150mL saturated common salt water washings, is spin-dried for solvent successively, obtains
Compound (9.2g, yield 78%) shown in formula (III).High resolution mass spectrum (ESI+)：C17H27O3+ theoretical values
279.1955 measured value 279.1949.
(2) compound (7.5g, 1 equivalent) shown in formula (III) is dissolved in 100mL methanol, adds the palladiums of 0.5g 10%
Carbon, normal pressure hydrogenation 2 hours, then filtering reacting liquid, is spin-dried for filtrate, obtains crude compound, then column chromatography obtains formula (IV) institute
The compound (4.1g, yield 80%) shown.High resolution mass spectrum (ESI+)：C10H21O3+ theoretical values 189.1485, measured value are
189.1477。
(3) compound (4g) shown in formula (IV) is dissolved in 80mL dichloromethane, adds N, N- diisopropyl ethyl amines
(3g) and methylsufonyl chloride (2.5g), 20~30 DEG C stirring 1 hour after, successively with 40mL 1N (mol/L) aqueous hydrochloric acid solution,
40mL saturated sodium bicarbonate aqueous solutions and 40mL saturated aqueous common salts carry out first time washing, dry and are simultaneously spin-dried for solvent, then by remnants
Thing is dissolved in 50mL dioxane, adds TBAB (100mg) and potassium cyanide (1.5g), and 20~30 DEG C of stirrings 36 are small
When, then reaction solution is diluted with 100mL methyl tertiary butyl ether(MTBE)s, then successively with 75mL 1N aqueous hydrochloric acid solutions, 75mL unsaturated carbonates
Hydrogen sodium water solution and 75mL saturated aqueous common salts carry out second and washed, and dry and are spin-dried for solvent, obtain the chemical combination shown in formula (V)
Thing.High resolution mass spectrum (ESI+)：C11H20NO2+ theoretical values 198.1489, measured value 198.1481.
(4) compound shown in 8g formulas (V) is dissolved in 80mL dichloromethane, adds 8mL trifluoroacetic acids, 20~30 DEG C are stirred
Mix 1 hour, solvent is spin-dried at a temperature of no more than 40 DEG C, then residue is obtained into the chemical combination shown in formula (VI) through column chromatography
Thing (0.8g, yield 27%).High resolution mass spectrum (ESI+)：C7H10NO2- theoretical values 140.0717, measured value are
140.0719。
(5) compound (10g, 1 equivalent) shown in formula (VI) is dissolved in 200mL tetrahydrofurans and is cooled to 0 DEG C, addition
150mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after be added dropwise 100mL 1N hydrochloric acid
The aqueous solution, stir 0.5 hour, after being diluted with 500mL methyl tertiary butyl ether(MTBE)s, satisfied successively with 250mL 1N aqueous hydrochloric acid solutions, 250mL
With sodium bicarbonate aqueous solution and 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain the compound shown in formula (VII)
(5.4g, yield 76%).High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, measured value 128.1063.
(6) compound (12g) shown in formula (VII) is suspended in the mixture of 20mL ethanol and 10mL water, added
NaOH (3g), after flowing back 10 hours, 0 degree Celsius is cooled to, is spin-dried for after being adjusted to neutrality with 1N hydrochloric acid, obtains intermediate formula (VIII)
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 (8g, the yield shown in formula (I)
43%).High resolution mass spectrum (ESI+)：C7H13O2+ theoretical values 129.0910, measured value 129.0903.
The synthesis of butyrolactone derivative shown in the formula of embodiment 4 (I)
(1) anhydrous zinc chloride (0.17g, 0.025 equivalent) is dissolved in 300mL tetrahydrofurans (THF), adds embodiment 1
Compound (19.2g, 1 equivalent) shown in the formula (II) of preparation, 20~30 DEG C stirring 15min after be cooled to 0 DEG C, add propyl group
Magnesium chloride (70mL, 2 equivalents, concentration：1M THF solutions), stirred 4 hours at 0 DEG C, it is whole that 100mL saturated aqueous ammonium chlorides are added dropwise
Only react, organic phase with 150mL saturated sodium bicarbonate aqueous solutions, 150mL saturated common salt water washings, is spin-dried for solvent successively, obtains
Compound (10.1g, yield 81%) shown in formula (III).High resolution mass spectrum (ESI+)：C17H27O3+ theoretical values
279.1955 measured value 279.1949.
(2) compound (10g, 1 equivalent) shown in formula (III) is dissolved in 100mL methanol, adds the palladiums of 0.5g 10%
Carbon, normal pressure hydrogenation 5 hours, then filtering reacting liquid, is spin-dried for filtrate, obtains crude compound, then column chromatography obtains formula (IV) institute
The compound (5.2g, yield 83%) shown.High resolution mass spectrum (ESI+)：C10H21O3+ theoretical values 189.1485, measured value are
189.1477。
(3) compound (5.5g) shown in formula (IV) is dissolved in 80mL dichloromethane, adds N, N- diisopropyl ethyls
Amine (4.5g) and methylsufonyl chloride (3.5g), it is water-soluble with 40mL 1N (mol/L) hydrochloric acid successively after 20~30 DEG C are stirred 3 hours
Liquid, 40mL saturated sodium bicarbonate aqueous solutions and 40mL saturated aqueous common salts carry out first time washing, dry and are spin-dried for solvent, then will be residual
Excess is dissolved in 50mL dioxane, adds TBAB (100mg) and potassium cyanide (2.5g), and 20~30 DEG C of stirrings 60 are small
When, then reaction solution is diluted with 100mL methyl tertiary butyl ether(MTBE)s, then successively with 75mL 1N aqueous hydrochloric acid solutions, 75mL unsaturated carbonates
Hydrogen sodium water solution and 75mL saturated aqueous common salts carry out second and washed, and dry and are spin-dried for solvent, obtain the chemical combination shown in formula (V)
Thing.High resolution mass spectrum (ESI+)：C11H20NO2+ theoretical values 198.1489, measured value 198.1481.
(4) compound shown in 8g formulas (V) is dissolved in 80mL dichloromethane, addition 12mL trifluoroacetic acids, 20~30 DEG C
Stirring 4 hours, solvent is spin-dried at a temperature of no more than 40 DEG C, then residue is obtained into the change shown in formula (VI) through column chromatography
Compound (1.0g, yield 28%).High resolution mass spectrum (ESI+)：C7H10NO2- theoretical values 140.0717, measured value are
140.0719。
(5) compound (10g, 1 equivalent) shown in formula (VI) is dissolved in 200mL tetrahydrofurans and is cooled to 0 DEG C, addition
400mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after be added dropwise 100mL 1N hydrochloric acid
The aqueous solution, stir 2 hours, after being diluted with 500mL methyl tertiary butyl ether(MTBE)s, successively with 250mL 1N aqueous hydrochloric acid solutions, 250mL saturations
Sodium bicarbonate aqueous solution and 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain the compound shown in formula (VII)
(7.1g, yield 79%).High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, measured value 128.1063.
(6) compound (27g) shown in formula (VII) is suspended in the mixture of 40mL ethanol and 10mL water, added
NaOH (3g), after flowing back 30 hours, 0 degree Celsius is cooled to, is spin-dried for after being adjusted to neutrality with 1N hydrochloric acid, obtains intermediate formula (VIII)
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 (10.5g, the yield shown in formula (I)
52%).High resolution mass spectrum (ESI+)：C7H13O2+ theoretical values 129.0910, measured value 129.0903.
The butyrolactone derivative that embodiment 2-4 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)
1. a kind of preparation method of butyrolactone derivative, it is characterised in that comprise the following steps：
(1) compound shown in formula (II) is substituted with propyl group grignard reagent, obtains the compound shown in formula (III)；
(2) compound shown in formula (III) is removed into benzyl protection, obtains the compound shown in formula (IV)；
(3) it is cyano group by the compound substituted hydroxy shown in formula (IV), obtains the compound shown in formula (V)；
(4) by the compound removing tert-butyl group protection shown in formula (V), the compound shown in formula (VI) is obtained；
(5) compound shown in formula (VI) is reduced into carboxyl, obtains the compound shown in formula (VII)；
(6) compound shown in formula (VII) is hydrolyzed into cyano group in the basic conditions, obtains the carboxylic acid shown in formula (VIII) and derive
Thing, then react the butyrolactone derivative shown in acquisition formula (I) through dehydration condensation；
2. the preparation method of butyrolactone derivative according to claim 1, it is characterised in that comprise the following steps：
(1) anhydrous zinc chloride is dissolved in tetrahydrofuran, adds the compound shown in formula (II), 20~30 DEG C of 5~15min of stirring
After be cooled to 0 DEG C, add after propyl group grignard reagent and stirred 2~4 hours at 0 DEG C, terminating reaction, be washed out organic phase,
Solvent is spin-dried for, obtains the compound shown in formula (III)；
(2) compound shown in formula (III) is dissolved in methanol, addition palladium carbon, normal pressure hydrogenation 2~5 hours, then filter,
It is spin-dried for filtrate, again through column chromatography, obtains the compound shown in formula (IV)；
(3) compound shown in formula (IV) is dissolved in dichloromethane, adds N, N- diisopropyl ethyl amines and methylsufonyl chloride,
After 20~30 DEG C are stirred 1~3 hour, progress first time washing, drying are simultaneously spin-dried for solvent, are re-dissolved in dioxane, add four
Butylammonium bromide and potassium cyanide, 20~30 DEG C are stirred 36~60 hours, and second of washing is carried out after dilution, dries and is spin-dried for molten
Agent, obtain the compound shown in formula (V)；
(4) compound shown in formula (V) is dissolved in dichloromethane, then adds trifluoroacetic acid, 20~30 DEG C of stirrings 1~4 are small
When, solvent is spin-dried at a temperature of no more than 40 DEG C, then through column chromatography, obtain the compound shown in formula (VI)；
(5) compound shown in formula (VI) 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 (VII)；
(6) compound shown in formula (VII) 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 (VIII)；By shown in formula (VIII)
Carboxylic acid derivates are dissolved in toluene, add p-methyl benzenesulfonic acid, and backflow overnight, is washed out, is spin-dried for solvent, is evaporated under reduced pressure again, obtain
Obtain the butyrolactone derivative shown in formula (I).
3. the preparation method of butyrolactone derivative according to claim 1 or 2, it is characterised in that in step (1), institute
It is propyl group magnesium chloride to state propyl group grignard reagent.
4. the preparation method of butyrolactone derivative according to claim 2, it is characterised in that in step (1), the end
The reagent only reacted is saturated aqueous ammonium chloride；And/or
The process of the washing is successively with saturated sodium bicarbonate aqueous solution, saturated common salt water washing.
5. the preparation method of butyrolactone derivative according to claim 2, it is characterised in that in step (2), formula
(III) mass ratio of compound and palladium carbon shown in is 15~20:1；The palladium carbon is 10% palladium carbon.
6. the preparation method of butyrolactone derivative according to claim 2, it is characterised in that in step (3), formula (IV)
Shown compound：N, N- diisopropyl ethyl amine：Methylsufonyl chloride：TBAB：The mass ratio of potassium cyanide be 40~
55:30~45:25~35:1:15~25；And/or
The process of the first time washing is successively with aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt washing
Wash；And/or
The process of the dilution is to be diluted with methyl tertiary butyl ether(MTBE)；And/or
The process of second of washing is successively with aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt washing
Wash.
7. the preparation method of butyrolactone derivative according to claim 2, it is characterised in that in step (4), per 1g formulas
(V) 1~1.5mL trifluoroacetic acids are added in the compound shown in.
8. the preparation method of butyrolactone derivative according to claim 2, it is characterised in that in step (5), per 1g formulas
(VI) 15~40mL tetrahydrofuran borane complexes are added in the compound shown in；And/or
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.
9. the preparation method of butyrolactone derivative according to claim 2, it is characterised in that in step (6), formula
(VII) mass ratio of compound and NaOH shown in 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；
The process of the washing is to use water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.
10. the butyrolactone derivative that the preparation method any one of claim 1 to 9 obtains is in Bu Waxitan is prepared
Purposes.
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| IT201800006320A1 (en) * | 2018-06-14 | 2019-12-14 | PROCESS FOR THE ASYMMETRIC SYNTHESIS OF (R) -4-PROPYLDIHYDROFURAN-2 (3H) -ONE | |
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| CN111675643B (en) * | 2020-06-15 | 2021-10-26 | 浙江天宇药业股份有限公司 | Preparation method of brivaracetam |
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