CN107652254A - method for preparing butyrolactone derivative - Google Patents
method for preparing butyrolactone derivative Download PDFInfo
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- CN107652254A CN107652254A CN201711126335.8A CN201711126335A CN107652254A CN 107652254 A CN107652254 A CN 107652254A CN 201711126335 A CN201711126335 A CN 201711126335A CN 107652254 A CN107652254 A CN 107652254A
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- NSXYYYUKWBLFQH-MHECFPHRSA-N methyl (2r)-4-hydroxy-2-[[(3s)-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-6-yl]methyl]-3-(4-hydroxyphenyl)-5-oxofuran-2-carboxylate Chemical compound O([C@@]1(CC=2C=C3C[C@H](O)C(C)(C)OC3=CC=2)C(=O)OC)C(=O)C(O)=C1C1=CC=C(O)C=C1 NSXYYYUKWBLFQH-MHECFPHRSA-N 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 14
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 10
- 229910000085 borane Inorganic materials 0.000 claims abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 230000018044 dehydration Effects 0.000 claims abstract description 3
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 235000002639 sodium chloride Nutrition 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- RMCYTHFAWCWRFA-UHFFFAOYSA-N borane;oxolane Chemical class B.C1CCOC1 RMCYTHFAWCWRFA-UHFFFAOYSA-N 0.000 claims 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical class O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 abstract 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 229940117803 phenethylamine Drugs 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000012043 crude product Substances 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- LRWZZZWJMFNZIK-NFJMKROFSA-N (2R)-2-chloro-3-methyloxirane Chemical compound CC1O[C@@H]1Cl LRWZZZWJMFNZIK-NFJMKROFSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 description 1
- 229960002161 brivaracetam Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- NCCOOTMRZHTROF-UHFFFAOYSA-N ethylphosphanium;bromide Chemical compound [Br-].CC[PH3+] NCCOOTMRZHTROF-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a method for preparing butyrolactone derivatives, which comprises the following steps: (1) resolving the compound shown in the formula (II) by using chiral phenethylamine to obtain a compound shown in a formula (III); (2) reducing a carboxyl group of a compound shown in a formula (III) by borane to obtain a compound shown in a formula (IV); (3) hydrolyzing a cyano group by using the compound shown in the formula (IV) under an alkaline condition to obtain a carboxylic acid derivative shown in the formula (V), and then carrying out dehydration cyclization reaction to obtain a butyrolactone derivative shown in the formula (I). The invention has the advantages that: provides a brand new method for synthesizing butyrolactone derivatives, the cost of synthetic raw materials is low, and only 5 steps of reaction are needed, so that the production cost can be obviously reduced. The synthetic route is as follows:
Description
Technical field
The present invention relates to organic synthesis technical field, is more particularly to a kind of method for preparing 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
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 new method for preparing butyrolactone derivative.
The present invention is that solve above-mentioned technical problem by the following technical programs：
A kind of method for preparing butyrolactone derivative, comprises the following steps：
(1) compound shown in formula (II) is split with chiral phenyl ethylamine, obtains 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 shown in formula (V) and derive
Thing, then react the butyrolactone derivative shown in acquisition formula (I) through dehydration condensation；
Preferably, the preparation method comprises the following steps：
(1) compound shown in formula (II) is dissolved in toluene, chiral phenyl ethylamine is added at 50~70 DEG C and is stirred, from
15~30 DEG C are so cooled to, crystallization and filtration is separated out and collects crystallization, suspension crystallization, adjust pH to 2, be sufficiently stirred rear liquid separation, wash
Wash organic phase, decompression is spin-dried for, the compound shown in acquisition 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 molar equivalent ratio of compound and chiral phenyl ethylamine shown in formula (II) is 1:0.5
~2.
Preferably, chiral phenyl ethylamine is (S)-phenyl ethylamine.
Preferably, in step (1), the reagent of the suspension crystallization is methyl tertiary butyl ether(MTBE)；And/or
The reagent of the regulation pH is sodium bisulphate solution；And/or
The reagent of the washing is saturated aqueous common salt.
Preferably, in step (2), 15~40mL tetrahydrofuran borine networks are added in the compound shown in per 1g formulas (VI)
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 (VII) 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 is cheap, and only needs 5 steps to react, it is possible to substantially reduces 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 preparation of compound shown in the formula of embodiment 1 (II)
Synthetic route is as follows：
N-BuLi (2.5mol/L hexane solution, 10mL) is added in reaction bulb, removes n-hexane under reduced pressure, nitrogen is protected
- 78 DEG C are cooled under shield, 10mL tetrahydrofurans dissolving n-BuLi is added, adds diethylamine (365mg, 5mmol).Will reaction
Liquid is warming up to 0 DEG C and stirred 15 minutes, is cooled to -78 DEG C again, positive valeric acid (1.15g, 11.3mmol) tetrahydrofuran is added dropwise
(10mL) solution, 0 DEG C is warming up to after being added dropwise and is reacted 30 minutes.Reaction solution is cooled to -78 DEG C, bromoacetonitrile is added dropwise
Tetrahydrofuran (10mL) solution of (1.34g, 11.3mmol), then heat to room temperature reaction 24 hours.Gone out instead with 80mL water quenchings
Liquid is answered, then is extracted (50mL × 3) with methyl tertiary butyl ether(MTBE).Aqueous phase adjusts pH=1 with concentrated hydrochloric acid, and (50mL is extracted with ethyl acetate
× 3), anhydrous magnesium sulfate is dried, and is concentrated under reduced pressure into dry, obtains the compound 2- cyanogen methylvaleric acid 1.24g shown in formula (II), yield
For 78%.High resolution mass spectrum (ESI+)：C7H10NO2- theoretical values 140.0717, measured value 140.0713.
The synthesis of butyrolactone derivative shown in the formula of embodiment 2 (I)
Synthetic route is as follows：
(1) compound (28.2g, 1 equivalent) shown in formula (II) is dissolved in 300mL toluene, at 60 DEG C add (S)-
Phenyl ethylamine (25.4g, 1.05 equivalents) simultaneously stirs 0.5 hour, naturally cools to 20 DEG C, separates out crystallization and filtration and collects crystallization, will
This crystallization is suspended in 500mL methyl tertiary butyl ether(MTBE)s, is added 1N (mol/L) sodium bisulphate solution regulation pH to 2, is sufficiently stirred
Liquid separation afterwards, with 250mL saturated common salt water washing organic phases, decompression is spin-dried for, and is obtained the compound shown in formula (III) and (10.7g, is received
Rate 38%).
(2) compound (10g, 1 equivalent) shown in formula (III) is dissolved in 200mL tetrahydrofurans and is cooled to 0 DEG C, added
Enter 280mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after 100mL 1N salt is added dropwise
Aqueous acid, stir 1 hour, diluted with 500mL methyl tertiary butyl ether(MTBE)s, successively with 250mL 1N aqueous hydrochloric acid solutions, 250mL saturations
Sodium bicarbonate aqueous solution, 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain the compound shown in formula (IV)
(7.7g, yield 85%).High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, measured value 128.1063.
(3) compound (20.3g, 1 equivalent) shown in formula (IV) is suspended in the mixture of 30mL ethanol and 10mL water,
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, obtain intermediate formula
(V) crude product of the carboxylic acid derivates shown in.This crude product is directly suspended in 300mL toluene, addition p-methyl benzenesulfonic acid (41.3g,
1.5 equivalents), backflow is eaten with 100mL water, 100mL saturated sodium bicarbonate aqueous solutions and 100mL saturations successively overnight, by reaction solution
Salt water washing, it is spin-dried for solvent and obtains crude compound, then the butyrolactone derivative for being evaporated under reduced pressure to obtain shown in formula (I) (12g, is received
Rate 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) compound (28.2g, 1 equivalent) shown in formula (II) is dissolved in 300mL toluene, at 50 DEG C add (S)-
Phenyl ethylamine (0.5 equivalent) simultaneously stirs 0.3 hour, naturally cools to 15 DEG C, separates out crystallization and filtration and collects crystallization, and this crystallization is outstanding
Float in 500mL methyl tertiary butyl ether(MTBE)s, add 1N (mol/L) sodium bisulphate solution regulation pH to 2, be sufficiently stirred rear liquid separation,
With 250mL saturated common salt water washing organic phases, decompression is spin-dried for, and obtains the compound (5.1g, yield 29%) shown in formula (III).
(2) compound (10g, 1 equivalent) shown in formula (III) is dissolved in 200mL tetrahydrofurans and is cooled to 0 DEG C, added
Enter 150mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after 100mL 1N salt is added dropwise
Aqueous acid, stir 0.5 hour, diluted with 500mL methyl tertiary butyl ether(MTBE)s, satisfied successively with 250mL 1N aqueous hydrochloric acid solutions, 250mL
And sodium bicarbonate aqueous solution, 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain the compound shown in formula (IV)
(4.8g, yield 76%).High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, measured value 128.1063.
(3) compound (12g) shown in formula (IV) is suspended in the mixture of 20mL ethanol and 10mL water, adds 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, is obtained shown in intermediate formula (V)
The crude product of carboxylic acid derivates.This crude product is directly suspended in 300mL toluene, adds p-methyl benzenesulfonic acid (41.3g, 1.5 equivalents),
Reaction solution overnight, is used 100mL water, 100mL saturated sodium bicarbonate aqueous solutions and 100mL saturated common salt water washings by backflow successively,
It is spin-dried for solvent and obtains crude compound, then is evaporated under reduced pressure to obtain the butyrolactone derivative (8g, yield 43%) shown in formula (I).It is high
Resolution Mass Spectrometry (ESI+)：C7H13O2+ theoretical values 129.0910, measured value 129.0903.
The synthesis of butyrolactone derivative shown in the formula of embodiment 4 (I)
(1) compound (28.2g, 1 equivalent) shown in formula (II) is dissolved in 300mL toluene, at 70 DEG C add (S)-
Phenyl ethylamine (2 equivalent) simultaneously stirs 1 hour, naturally cools to 30 DEG C, separates out crystallization and filtration and collects crystallization, this crystallization is suspended in
In 500mL methyl tertiary butyl ether(MTBE)s, 1N (mol/L) sodium bisulphate solution regulation pH to 2 is added, rear liquid separation is sufficiently stirred, uses
250mL saturated common salt water washing organic phases, decompression are spin-dried for, and obtain the compound (9.8g, yield 36%) shown in formula (III).
(2) compound (10g, 1 equivalent) shown in formula (III) is dissolved in 200mL tetrahydrofurans and is cooled to 0 DEG C, added
Enter 400mL tetrahydrofurans borane complex (1M tetrahydrofurans, 4 equivalents), 20~30 DEG C be stirred overnight after 100mL 1N salt is added dropwise
Aqueous acid, stir 2 hours, diluted with 500mL methyl tertiary butyl ether(MTBE)s, successively with 250mL 1N aqueous hydrochloric acid solutions, 250mL saturations
Sodium bicarbonate aqueous solution, 250mL saturated common salt water washings, dry and be spin-dried for solvent, obtain the compound shown in formula (IV)
(7.1g, yield 82%).High resolution mass spectrum (ESI+)：C7H14NO+ theoretical values 128.1070, measured value 128.1063.
(3) compound (27g) shown in formula (IV) is suspended in the mixture of 40mL ethanol and 10mL water, adds 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, is obtained shown in intermediate formula (V)
The crude product of carboxylic acid derivates.This crude product is directly suspended in 300mL toluene, adds p-methyl benzenesulfonic acid (41.3g, 1.5 equivalents),
Reaction solution overnight, is used 100mL water, 100mL saturated sodium bicarbonate aqueous solutions and 100mL saturated common salt water washings by backflow successively,
It is spin-dried for solvent and obtains crude compound, then is evaporated under reduced pressure to obtain the butyrolactone derivative (10.5g, yield 52%) shown in formula (I).
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)
- A kind of 1. method for preparing butyrolactone derivative, it is characterised in that comprise the following steps：(1) compound shown in formula (II) is split with chiral phenyl ethylamine, obtains 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 Through the butyrolactone derivative shown in dehydration condensation reaction acquisition formula (I)；
- 2. the method according to claim 1 for preparing butyrolactone derivative, it is characterised in that comprise the following steps：(1) compound shown in formula (II) is dissolved in toluene, chiral phenyl ethylamine is added at 50~70 DEG C and is stirred, it is naturally cold But to 15~30 DEG C, separate out crystallization and filtration and collect crystallization, suspension crystallization, adjust pH to 2, be sufficiently stirred rear liquid separation, washing has Machine phase, decompression are spin-dried for, and obtain the compound shown in formula (III)；(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 according to claim 1 or 2 for preparing butyrolactone derivative, it is characterised in that in step (1), formula (II) the molar equivalent ratio of compound and chiral phenyl ethylamine shown in is 1:0.5~2.
- 4. the method according to claim 3 for preparing butyrolactone derivative, it is characterised in that the chiral phenyl ethylamine is (S)-phenyl ethylamine.
- 5. the method according to claim 2 for preparing butyrolactone derivative, it is characterised in that described outstanding in step (1) The reagent of floating crystallization is methyl tertiary butyl ether(MTBE)；And/orThe reagent of the regulation pH is sodium bisulphate solution；And/orThe reagent of the washing is saturated aqueous common salt.
- 6. the method according to claim 2 for preparing butyrolactone derivative, it is characterised in that in step (2), per 1g formulas (VI) 15~40mL tetrahydrofuran borane complexes are added in the compound shown in.
- 7. the method according to claim 1 or 2 for preparing butyrolactone derivative, 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 according to claim 2 for preparing butyrolactone derivative, it is characterised in that in step (3), formula (VII) 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 according to claim 2 for preparing butyrolactone derivative, it is characterised in that described to wash in step (3) The process washed 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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