CN108409543A - A kind of preparation process of 7- chloro-4-hydroxyls dihydroindene - Google Patents
A kind of preparation process of 7- chloro-4-hydroxyls dihydroindene Download PDFInfo
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- CN108409543A CN108409543A CN201810455114.3A CN201810455114A CN108409543A CN 108409543 A CN108409543 A CN 108409543A CN 201810455114 A CN201810455114 A CN 201810455114A CN 108409543 A CN108409543 A CN 108409543A
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- dihydroindene
- chloro
- preparation process
- hydroxyls
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Disclosed in the present application is the preparation process of the 4 hydroxyl dihydroindene A of 7 chlorine in organic chemical industry field a kind of, is included the following steps：1) parachlorophenol and β chlorpromazine chlorides obtain rubigan β chloropropionates B by phenolic hydroxyl group esterification at moderate temperatures; 2) compound B Fries acyl rearrangements occurs in the presence of anhydrous Aluminum chloride 7 chlorine 2 is obtained by the reaction at moderate temperatures; 3 dihydro, 4 hydroxyl indenes 1 ketone C, 3) compound C occurs reduction reaction with triethylsilane under trifluoroacetic acid solvent and obtains compound A at moderate temperatures.The preparation process of the present invention uses parachlorophenol and β chlorpromazine chlorides for raw material, and starting material and reaction reagent are to be conventionally synthesized reagent, cheap and easy to get；Each step reaction high income, post-processing is also easy to operate, and target product overall yield is high, and manufacturing cost is low, meets industrialization production requirements.
Description
Technical field
The invention belongs to organic chemical industry fields, and in particular to medicine and a kind of 7- chloro-4-hydroxyls dihydro of chemical intermediate
The preparation process of indenes.
Background technology
Indenes is important a kind of chemical constitution in medicine and chemical field, and derivative includes mainly indenes, dihydroindene, indenes
Ketone and indanol etc. are widely present in the bioactive molecules such as natural products, drug, pesticide.Multiple indene drug listings at present,
Antidepressant Indatraline, for Adult chronic obstructive disease of lung patient maintaining treatment bronchodilator indenes up to spy
Sieve is dihydroindene amine compounds；Treat donepezil and the suppression of the protease for the treatment of HIV infection and AIDS of senile dementia
Preparation indinavir is indone class drug；Indeno pyrazoles (GN39484) belongs to Antitubulin, has preferably anti-pernicious
Tumor promotion.
Nearest research finds that 7- chloro-4-hydroxyl dihydroindene I is the important feature piece for synthesizing many active drug molecules
Section.Including the compound 1 of 7- chloro-4-hydroxyl dihydroindene has cetp (CETP) inhibitory activity, inhibit
CETP albumen can inhibit cholesteryl ester and be transferred to low-density lipoprotein (LDL) and extra-low density fat from high-density lipoprotein (HDL)
Albumen (VLDL), so as to cause increasing to inhibit atherosclerosis for HDL.The benzo piperazine compounds of Pfizer report
2 there is gamma-secretase to adjust activity, can penetrate blood-brain barrier, the potential treatment for Alzheimer's disease.
Document reports that seldom Buck JS are reported using 4- hydroxyls two for the synthesis of 7- chloro-4-hydroxyl dihydroindene A
Hydrogenation indenes 3 is reacted with thionyl chloride at 55 DEG C in glacial acetic acid obtains 5- and 7- monochloro for 1 hour for mix products；And due to chlorine
For the regioselectivity at phenyl ring ortho position and contraposition and bad, 7- chloro-4-hydroxyl dihydroindene A yields are only 47% for generation reaction,
See following formulas.
AmEnde CW are reported in patent document WO2012131539A1 uses cyanogen by 1- oxo -4- hydroxyls dihydroindene 4
After being handled with trim,ethylchlorosilane after base sodium borohydride reduction, 4- hydroxyls dihydroindene 5 is obtained, then use chlorosuccinimide
(N-Chlorosuccinimide, abbreviation NCS) obtains compound A after carrying out chlorination, sees following formulas.The document is not reported
Road product yield, however generally, due to phenolic hydroxyl group is extremely strong power supplying groups, especially so that the ortho para position of phenolic hydroxyl group is easy
By electrophilic reagent attack, therefore the regioselectivity of such reaction is not high.
The synthetic method of above two document report using 4- hydroxyls indane derivatives as raw material, expensive starting materials and
It is not easy to prepare.Therefore, the present invention is intended to provide a kind of 7- chloro-4-hydroxyl dihydros that are simple and convenient, being suitble to industrialized production
Change the preparation process of indenes 1.
Invention content
The present invention is intended to provide a kind of preparation of 7- chloro-4-hydroxyls dihydroindene 1 that is simple and convenient, being suitble to industrialized production
Technique.
The preparation process of 7- chloro-4-hydroxyls dihydroindene A provided by the invention a kind of, includes the following steps：1) to chlorobenzene
Phenol and β-chlorpromazine chloride are obtained by phenolic hydroxyl group esterification to compound B (chlorphenyl β-chlorine third at a temperature of 40 DEG C~100 DEG C
Acid esters), 2) generation Fries acyl rearrangements are obtained by the reaction compound B at a temperature of 100~190 DEG C in the presence of anhydrous Aluminum chloride
Chloro- 2, the 3- dihydros -4- hydroxyl 1-Indanones (compound C) of 7-, 3) compound C and triethylsilane under trifluoroacetic acid solvent
Reduction occurs under reflux temperature, compound A is obtained by the reaction, sees following reaction route：
A kind of preferred embodiment, the temperature described in step 1) are preferably 50~100 DEG C；More preferably 85~100
℃。
A kind of preferred embodiment, the temperature described in step 2) are preferably 120~190 DEG C；More preferably 160~
190℃。
A kind of preferred embodiment, temperature described in step 1) are 85 DEG C~100 DEG C；Temperature described in step 2) is
160 DEG C~190 DEG C.
The invention has the advantages that：The present invention provides a kind of preparation processes of 7- chloro-4-hydroxyls dihydroindene A, with to chlorine
Phenol is starting material, and parental materials obtain corresponding indenes ring, ketone carbonyl after passing sequentially through phenolic hydroxyl group esterification, Fries acyl rearrangements
Three step reactions of reduction obtain target compound A.
Parachlorophenol and β-chlorpromazine chloride employed in the preparation process of 7- chloro-4-hydroxyl dihydroindene A are raw material, are risen
Beginning raw material and reaction reagent are to be conventionally synthesized reagent, cheap and easy to get；Each step reaction high income, post-processing also operation letter
Single, target product overall yield is high, and manufacturing cost is low, meets industrialization production requirements.
Specific implementation mode
Below will by specific embodiment, the present invention is further explained, but the protection domain being not intended to restrict the invention.
Without departing from the inventive concept of the premise, those skilled in the art to preparation method and can use instrument within the scope of the claims
Device makes improvements, these improvement also should be regarded as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended
Subject to claim.
In following embodiments, unless otherwise indicated, the test method is usually according to normal condition or manufacturer builds
The condition of view is implemented；Shown in raw material, reagent can be obtained by way of commercially available purchase.
The preparation of rubigan β-chloropropionate B
At 40-50 DEG C, by β-chlorpromazine chloride (63g, 0.50mol) be added dropwise under stiring parachlorophenol (64g,
0.50mol)；After being added dropwise, reaction mixture is stirred 2 hours at 40~50 DEG C, 100 DEG C is then heated to and is stirred to react
3 hours.Distillation gained reacts oily mixture, obtains compound B 101.8g, and yield 93% is colorless oil.1H NMR
(300MHz,CDCl3) δ 7.41 (d, J=8Hz, 2H), 7.12 (d, J=8Hz, 2H), 3.92 (t, 2H), 3.09 (t, 2H)；GC-
MS218[M]+。
The preparation of the chloro- 2,3- dihydros -4- hydroxyls 1-Indanone C of 7-
The mixture of compound B (138g, 0.63mol) and anhydrous Aluminum chloride (250g, 1.87mol) is stirred at 100 DEG C
It mixes 3 hours, then heats to 180~190 DEG C and continue to be stirred to react 3 hours.Gained mixture is poured into ice water, with acetic acid second
Ester extracts three times (200mL x 3).Merge organic layer, and be washed with water until pH be 6-7, with anhydrous MgSO4It is dry.Organic layer
After concentration, gained residue is yellow solid by obtaining compound C 83g, yield 72% after flash column chromatography.1H
δ=9.00 (s, 1H) NMR (300MHz, CDCl3), 7.47 (d, J=8Hz, 1H), 6.79 (d, J=8Hz, 1H), 3.14 (t,
2H),2.80(t,2H)；LC-MS 183[M+H]+.
The preparation of 7- chloro-4-hydroxyl dihydroindene A
Under nitrogen protection, triethyl group is added into trifluoroacetic acid (300mL) solution of compound C (83g, 0.45mol)
Silane (160g, 1.38mol).Then it is stirred 4 hours at a temperature of reaction solution being heated to reflux.Solvent is removed under reduced pressure in reaction solution
Afterwards, gained residue is poured into aq.NaOH (2N, 1L), 3 times (300mL x 3) is extracted with hexane.By water layer concentrated hydrochloric acid acid
Change to pH=1, is extracted with ethyl acetate 3 times (300mL x 3).Merge organic layer, and is washed with water and uses anhydrous Na2SO4It is dry
It is dry.After solvent is evaporated off in organic layer reduced pressure, crystallization, obtains compound in gained residue petroleum ether (b.p.90-120 DEG C)
A 53g, yield 69% are white solid.δ=7.03 (d, J=8Hz, 1H) 1H NMR (300MHz, CDCl3), 6.59 (d, J=
8Hz,1H),4.64(s,1H),3.00-2.89(m,4H),2.19-2.09(m,2H)；GC-MS 168[M]+；HPLC94.1%
(purity).
The present invention synthesizes in the route of chloro- 2, the 3- dihydros -4- hydroxyls 1-Indanone A of 7-, and the reduction reaction of third step is most
Important single step reaction, inventor's development test, which shows go back original reagent and reaction dissolvent all, can influence the yield of this step.Knot
Fruit finds target product A in selection (CH3)3SiH is solvent in trifluoroacetic acid, obtains product A yields and be up to as go back original reagent
69%, significantly larger than select the catalytic hydrogenation carbonyl of Pd/C, Pt/C at methylene (- CH2-).
The reduction reaction conditions of 1. third step carbonyl of table optimize
Claims (6)
1. a kind of preparation process of 7- chloro-4-hydroxyls dihydroindene A, which is characterized in that include the following steps：1) parachlorophenol and
β-chlorpromazine chloride obtains compound B at a temperature of 40~100 DEG C by phenolic hydroxyl group esterification, 2) compound B is in anhydrous chlorination
Fries acyl rearrangements occur at 100~190 DEG C in the presence of aluminium, chloro- 2, the 3- dihydros -4- hydroxyls 1-Indanone C of 7- are obtained by the reaction,
3) compound C and triethylsilane reduction reaction occur under trifluoroacetic acid solvent obtain compound A at a reflux temperature, specifically
See following reaction route：
2. the preparation process of 7- chloro-4-hydroxyls dihydroindene A according to claim 1, which is characterized in that institute in step 1)
It is 50~100 DEG C to state temperature.
3. the preparation process of 7- chloro-4-hydroxyls dihydroindene A according to claim 2, which is characterized in that institute in step 1)
It is 85~100 DEG C to state temperature.
4. the preparation process of 7- chloro-4-hydroxyls dihydroindene A according to claim 1, which is characterized in that institute in step 2)
It is 120~190 DEG C to state temperature.
5. the preparation process of 7- chloro-4-hydroxyls dihydroindene A according to claim 4, which is characterized in that institute in step 2)
It is 160~190 DEG C to state temperature.
6. the preparation process of the 7- chloro-4-hydroxyl dihydroindene A according to Claims 1 to 5 any one, feature exist
In temperature described in step 1) is 85~100 DEG C；Temperature described in step 2) is 160~190 DEG C.
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| CN201810455114.3A CN108409543A (en) | 2018-05-14 | 2018-05-14 | A kind of preparation process of 7- chloro-4-hydroxyls dihydroindene |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB770593A (en) * | 1954-07-22 | 1957-03-20 | Sterling Drug Inc | Chlorinated hydroxyindanes |
| US3097243A (en) * | 1959-07-16 | 1963-07-09 | Sterling Drug Inc | Indane compounds |
| CN101058535A (en) * | 2007-05-25 | 2007-10-24 | 复旦大学 | Di(7-hydrxyl-2,3-dihydro-1-1H-indeno)ether and the like, synthetic method and application |
-
2018
- 2018-05-14 CN CN201810455114.3A patent/CN108409543A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB770593A (en) * | 1954-07-22 | 1957-03-20 | Sterling Drug Inc | Chlorinated hydroxyindanes |
| US3097243A (en) * | 1959-07-16 | 1963-07-09 | Sterling Drug Inc | Indane compounds |
| CN101058535A (en) * | 2007-05-25 | 2007-10-24 | 复旦大学 | Di(7-hydrxyl-2,3-dihydro-1-1H-indeno)ether and the like, synthetic method and application |
Non-Patent Citations (1)
| Title |
|---|
| 靳通收: "新型还原剂-氢硅烷在有机还原反应中的应用", 《贵州化工》 * |
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