CN108203421B - The technique for preparing butylphenyl phthaleine - Google Patents
The technique for preparing butylphenyl phthaleine Download PDFInfo
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- CN108203421B CN108203421B CN201810176976.2A CN201810176976A CN108203421B CN 108203421 B CN108203421 B CN 108203421B CN 201810176976 A CN201810176976 A CN 201810176976A CN 108203421 B CN108203421 B CN 108203421B
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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
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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Abstract
The present invention relates to the techniques that one prepares butylphenyl phthaleine.The technique uses one kettle way, easy to operate, and industrialized production has apparent advantage.The technological operation are as follows: starting material 1,2- dibromobenzene is under n-BuLi effect, it is reacted with dry ice, generate intermediate, following reaction does not need to be quenched, and n-BuLi is directly added again into midbody solution, then reacts with valeraldehyde, finally reaction solution is handled with HCl, obtains butylphenyl phthaleine after column chromatographic purifying.
Description
Technical field
The present invention relates to the new preparation processes of butylphenyl phthaleine.
Background technique
Butylphenyl phthaleine (also known as Butylphthalide, trade name En Bipu) be Chinese third possess completely independent intellectual property right,
A kind of anti-cerebral ischemia new drug of the country of completely new chemical structure, and current first, the whole world is based on " cerebral arterial thrombosis treatment "
Want the completely new chemicals of indication.It has outstanding safety monolithic entity structure, while having multiple pharmacological effect, can
Complete treatment cerebral arterial thrombosis significantly reduces neurological deficit, improvement minimal invasive treatment's capability state after infraction.The compound
It is found from the extract of southern Chinese celery vegetable seed earliest, is mainly responsible for the fragrance and taste of celery, is synthesized by artificial chemistry,
3 carbon atoms of butylphenyl phthaleine chemical structure are asymmetric carbon atom, there is S- and R- enantiomter, artificial synthesized for its racemization
Body, dependency structure and compound name are as follows:
The synthesis of butylphenyl phthaleine at present mainly using adjacent formylbenzoate as starting material, the preparation method reported at present compared with
Few, existing some preparation processes are as described below:
Nakai Ryozo (patent JP0469325) and Zhang Yihua (" China Medicine University's journal ", 2008,39,392-
397、Bioorg.Med.Chem.Lett.,2011,21,4210-4214)、Org.Biomol.Chem.,2011,9,5670-
5681) it is raw material that report, which uses adjacent formylbenzoate, by being acidified system after carrying out addition reaction with Grignard Reagent n-BuMgBr
Standby butylphenyl phthaleine.This method is although easy to operate, but report yield difference it is big, it is particularly worth mentioning that report method with
Low-flash ether is solvent, this is difficult to realize during industrial amplification production, and this method is only for laboratory preparation research
Sample.The specific synthetic route of the technique is as follows:
Li Shaobai reports the synthetic route (orchid that butylphenyl phthaleine is prepared using phthalic anhydride and positive valeric anhydride as starting material
State college journal-natural science edition, 1990,26,118-119).Method is first by phthalic anhydride and positive valeric anhydride anhydrous
300 DEG C of high temperature preparation 3- butylidenephthalide is heated in the presence of sodium sulphate, then using Pd/C as catalyst to 3- butylidenephthalide
It is hydrogenated.Since the preparation method is related to 300 DEG C of high temperature, it is unfavorable for industrial amplification production.The technique is specific
Synthetic route is as follows:
It reports benzocyclobutane enol hypoiodite within Japanese Kobayashi et al. 1987 and butylbenzene is prepared by β-cracking process
The synthetic route (Tetrahedron Lett., 1987,28,3369-3372) of phthalein.This method carries out ring crack ring to raw material first
Change, then carry out photodestruciton reaction using optical induction performance, finally synthesizes butylphenyl phthaleine by tributyl tin hydrogen reduction.Due to rising
Beginning raw material is not easy the tributyl tin hydrogen for obtaining and using toxicity high, the equally improper carry out industrial amplification production of this method.It should
The specific synthetic route of technique is as follows:
The building et al. of king (CN101962374) is raw material using phthalic anhydride, by with butyl halide Grignard Reagent
Addition obtains adjacent valeryl benzoic acid Intermediate, and the preparation of butylphenyl phthaleine is completed in the latter's cyclization after sodium borohydride reduction.Although should
The raw material that method uses is easy to get, but numerous impurity can be generated in reaction process, thus final products butylphenyl phthaleine need high temperature,
It carries out vacuum distillation under condition of high vacuum degree (180-185 DEG C/1mmHg) to be purified, therefore industrialized production is difficult.The technique
Specific synthetic route is as follows:
Although the above-described method for preparing butylphenyl phthaleine can successfully synthesize butylphenyl phthaleine, the technique of report is not
It is appropriate for industrialization production.Therefore, the method for researching and developing new synthesis butylphenyl phthaleine pushes away the industrialization of butylphenyl phthaleine and commercial market
Extensively have a very important significance.
Summary of the invention
Technical problem to be solved by the present invention lies in provide a kind of new process for preparing butylphenyl phthaleine.
For process route using 1,2- dibromobenzene as starting material, specific synthetic route is as follows:
Technique of the invention takes one kettle way to facilitate the preparation for realizing butylphenyl phthaleine, including two specific operating units:
Operation 1 be starting material 1,2- dibromobenzene (Formulas I) 1.0-1.1 equivalent n-BuLi effect under and dry ice (CO2) anti-
It answers, generates midbody solution, the subsequent reaction does not need react to be quenched, and midbody solution directly carries out next operation；
Operation 2 for operation 1 midbody solution in be added 1.2-1.5 equivalent n-BuLi, then with valeraldehyde (CH3
(CH2)3CHO it) reacts, finally reaction solution is handled with HCL aqueous solution, column chromatographic purifying obtains butylphenyl phthaleine.
The preparation process for the butylphenyl phthaleine that the present invention describes is not related to industrial a large amount of using by the danger and play limited to
Malicious reagent, easy to operate using one kettle way, industrialized production has apparent advantage.
Specific embodiment
The present invention can be more specifically understood by the following examples, but it illustrates rather than the limitation present invention
Range.
Embodiment
1, butylphenyl phthaleine is prepared
Laboratory lab scale craft:
Under nitrogen protection, compound of formula I (5.0g, 21.2mmol, 1.0eq.) and anhydrous is sequentially added in 250mL there-necked flask
THF (60mL) is cooled to -78 DEG C under system stirring, n-BuLi then is added dropwise by dropping funel into reaction system
(1.6Min Hexane, 14.5mL, 23.2mmol, 1.09eq.), maintenance system temperature is not higher than -70 DEG C in adition process.Drop
System is 1 hour stirred below at -75 DEG C after adding, and CO is then added by several times into system2(dry ice) (3.0g).CO2(dry ice)
Maintenance system is 1 hour stirred below at -75 DEG C after addition, and system passes through to be continually fed under grass tube intercalation reaction liquid level
That has dried water removal displaces the complete CO of unreacted in nitrogen 1 hour2.Then, again into reaction system by dropping funel by
It is added dropwise to n-BuLi (1.6M in Hexane, 16.5mL, 26.4mmol, 1.25eq.), maintenance system temperature is not in adition process
Higher than -70 DEG C, system is 1 hour stirred below at -75 DEG C after addition, is then slowly added dropwise into system by dropping funel
Enter anhydrous THF (5mL) solution of valeraldehyde (2.40g, 27.8mmol, 1.3eq.), adition process maintenance system -75 DEG C with
Under, architecture heat preservation reacts 3 hours after addition.Then, 3N HCl (5mL) careful quenching reaction, body are slowly added into system
It is warmed naturally to room temperature (25 DEG C) under system's stirring, after reaction system stirs 2 hours under the conditions of 25 DEG C, reaction system is added
100mL water, stirs 30min, and subsequent system extracts 3 times (3 × 60mL) using EtOAc.Merge organic phase, organic phase uses anhydrous
Sodium sulphate dries, filters, and is removed under reduced pressure solvent, after residue column chromatographic purifying butylphenyl phthaleine product (3.18g, 78.8%
yield)。
2, butylphenyl phthaleine is prepared
Laboratory amplification technique:
Under nitrogen protection, compound of formula I (60g, 254mmol, 1.0eq.) and nothing are sequentially added into the four-hole bottle of 3L
Water THF (600mL) is cooled to -75 DEG C or less under system stirring.N-BuLi is slowly added to by dropping funel into reaction system
(1.6M in Hexane, 175mL, 280mmol, 1.1eq.), maintenance system temperature is not higher than -70 DEG C in adition process.It is added dropwise
After system it is 2 hours stirred below at -75 DEG C, CO is then added by several times into system2(dry ice) (30g).CO2(dry ice) adds
Maintenance system is 1.5 hours stirred below at -75 DEG C after entering, and system passes through to be continually fed under grass tube intercalation reaction liquid level
That has dried water removal displaces the complete CO of unreacted in nitrogen 2 hours2.Then, into reaction system again by dropping funel
It is slowly added to n-BuLi (1.6M in Hexane, 190mL, 304mmol, 1.20eq.), maintenance system temperature is not in adition process
Higher than -70 DEG C, system is 2 hours stirred below at -75 DEG C after addition, is then slowly added dropwise into system by dropping funel
Enter valeraldehyde (28.5g, 331mmol, 1.3eq.), adition process maintenance system at -75 DEG C hereinafter, be added after architecture heat preservation
Reaction 5 hours.Then, 3N HCl (50mL) quenching reaction is slowly added into system, lower reaction system is stirred and warms naturally to room
Warm (25 DEG C), after reaction system stirs 6 hours under the conditions of 25 DEG C, 1L water is added in reaction system, stirs 30min, subsequent system
3 times (3 × 800mL) is extracted using EtOAc.Merge organic phase, organic phase is dried, filtered using anhydrous sodium sulfate, is removed under reduced pressure
Solvent, after residue column chromatographic purifying butylphenyl phthaleine product (35.2g, 72.8%yield).
Claims (1)
1. a kind of preparation process of butylphenyl phthaleine, including two specific operating procedures:
First operating procedure are as follows: starting material 1,2- dibromobenzene 1.0-1.1 equivalent n-BuLi effect under and dry ice (CO2) anti-
It answers, generates reaction intermediate, the subsequent reaction does not need react to be quenched, and reaction intermediate solution directly carries out next behaviour
Make；Second operating procedure are as follows: the n- of 1.2-1.5 equivalent is added into the resulting reaction intermediate solution of first operating procedure
BuLi, then with valeraldehyde (CH3(CH2)3CHO it) reacts, finally reaction solution is handled with HCl, is obtained after column chromatographic purifying
Butylphenyl phthaleine.
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Effective date of registration: 20180914 Address after: 350003 Fuzhou Jinshan Industrial Concentration Zone, Fujian, twenty-eighth yuan, fourth level east area. Applicant after: Fujian Bao Nuo medicine research and Development Co., Ltd. Address before: 226100 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Applicant before: Wisdom Pharmaceutical Co., Ltd. Applicant before: Fujian Boro Medical Co., Ltd. |
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