CN106854141A - A kind of synthetic method of 4- chloromethanes benzene compound - Google Patents
A kind of synthetic method of 4- chloromethanes benzene compound Download PDFInfo
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- CN106854141A CN106854141A CN201510901179.2A CN201510901179A CN106854141A CN 106854141 A CN106854141 A CN 106854141A CN 201510901179 A CN201510901179 A CN 201510901179A CN 106854141 A CN106854141 A CN 106854141A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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Abstract
The invention discloses a kind of synthetic method of 4- chloromethanes benzene compound 4- (2- chloroethoxies) benzyl chloride, with P-hydroxybenzoic acid as initiation material, target compound is obtained through over-churning, condensation, reduction, chlorination, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of synthesis technique of 4- chloromethanes benzene compound 4- (2- chloroethoxies) benzyl chloride.
Technical background
4- chloromethane benzene compounds 4- (2- chloroethoxies) benzyl chloride, structural formula is：
This compound is the side chain for being used as estrogenic agents.Estrogen is growth in humans, develops and the important conditioning agent for safeguarding secondary sex characters, into after the senescence phase, human body inner estrogen level is reduced, and shows osteoporosis, estrogen-dependent type cancer (breast cancer, the cancer of the uterus and oophoroma), angiocardiopathy etc..It is clinical to treat postmenopausal osteoporosis frequently with controversies in hormone replacement in the elderly, although determined curative effect, but side effect is obvious.
At present, post-menopause syndrome and the illness relevant with estrogen level reduction are typically clinically treated using controversies in hormone replacement in the elderly or hormone replacement therapy.But, the therapy increased the probability for suffering from carcinoma of endometrium and breast cancer in the colleague of relief of symptoms.The method of hormone replacement therapy and progestin combinations medication, although the stimulation to uterus can be reduced, but still there is uterus to begin to learn, the side effect such as breast pain.And the recovery of menstruation, the interference of central nervous system more reduce the tolerance of patient.The appearance of SERM, the side effect that controversies in hormone replacement in the elderly or hormone replacement therapy bring is reduced to a certain extent, so-called " selectivity " is exactly that they show as activator in some tissues (bone, liver, cardiovascular system), and antagonist is shown as in other tissue (brain, mammary gland), can be activator, or antagonist in uterus.
A kind of preparation method of 4- chloromethanes benzene compound 4- (2- chloroethoxies) benzyl chloride of the present invention plays an important roll for new drug development.
The content of the invention
The method that one kind prepares 4- chloromethane benzene compounds 4- (2- chloroethoxies) benzyl chloride, it is characterized in that with P-hydroxybenzoic acid as initiation material, target compound is obtained through over-churning, condensation, reduction, chlorination.Synthesis step is as follows：
(1) with P-hydroxybenzoic acid as initiation material, 2 are obtained through esterification；
(2) there is condensation reaction with bromoacetate 2, obtain 3；
(3) 4 are obtained with reducing agent reaction 3；
(4) 5 are obtained with chlorination reaction 4；
One preferred embodiment in, described esterification prepares catalyst used by ethyl-para-hydroxybenzoate and is selected from p-methyl benzenesulfonic acid；The alkali that described condensation reaction prepares used by ethyl -4- (2- ethyoxyl -2- oxoethoxies) methyl benzoate is selected from NaOH；Reducing agent used by described reduction reaction is selected from sodium borohydride；Chlorinating agent used by described chlorination reaction is selected from thionyl chloride.
One preferred embodiment in, described esterification prepares solvent used by ethyl-para-hydroxybenzoate and is selected from ethanol；The solvent that described condensation reaction prepares used by ethyl -4- (2- ethyoxyl -2- oxoethoxies) methyl benzoate is selected from tetrahydrofuran；Solvent used by described reduction reaction is selected from the mixture of one or more in methyl alcohol, ethanol, normal propyl alcohol, isopropanol；Solvent used by described chlorination reaction is selected from toluene.
One preferred embodiment in, the reaction temperature that described esterification prepares used by ethyl-para-hydroxybenzoate is room temperature；Described condensation reaction prepares the reflux temperature that the temperature used by ethyl -4- (2- ethyoxyl -2- oxoethoxies) methyl benzoate is；Temperature used by described reduction reaction is room temperature；Temperature used by described chlorination reaction is the reflux temperature of solvent.
The present invention relates to the synthesis technique of 4- (2- chloroethoxies) benzyl chloride, currently without other Patents documents report.
The present invention is further described by the following embodiment, and these descriptions are not that present invention is further limited.It should be understood by those skilled in the art that the equivalent made to technical characteristic of the invention, or be correspondingly improved, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of ethyl-para-hydroxybenzoate
25g P-hydroxybenzoic acid is added in 200m absolute ethyl alcohols, 1.2g p-methyl benzenesulfonic acids are added, is stirred overnight at room temperature, be concentrated under reduced pressure and remove ethanol, add saturated sodium bicarbonate aqueous solution and ethyl acetate is extracted, point liquid, drying, concentration obtain 27g ethyl-para-hydroxybenzoates.
(2) synthesis of ethyl -4- (2- ethyoxyl -2- oxoethoxies) methyl benzoate
20g ethyl-para-hydroxybenzoates are added in 180ml tetrahydrofurans, 4.8g sodium hydrides are added, half an hour is stirred, then bromoacetate is added dropwise, it is heated to reflux 3 hours, room temperature is cooled to, reaction solution is poured slowly into frozen water, add ethyl acetate, extraction point liquid, organic phase is collected, point liquid, drying, concentration, silica gel post separation obtains 16.8g ethyls -4- (2- ethyoxyl -2- oxoethoxies) methyl benzoate on residue.
The synthesis of (3) 2-(4-(hydroxymethyl) phenoxy group) ethanol
15g ethyls-4- (2- ethyoxyl-2- oxoethoxies) methyl benzoate is added in 120ml absolute ethyl alcohols, add 5.4g sodium borohydrides, it is stirred at room temperature 6 hours, add 1N hydrochloric acid, ethyl acetate is added, extraction point liquid collects organic phase, divide liquid, drying, concentration, silica gel post separation obtains 10.2g 2-(4-(hydroxymethyl) phenoxy group) ethanol on residue.
(4) synthesis of 4- (2- chloroethoxies) benzyl chloride
10g 2-(4-(hydroxymethyl) phenoxy group) ethanol is added in 70ml thionyl chlorides, it is heated to reflux 4 hours, unnecessary thionyl chloride is removed under reduced pressure, residue ethyl acetate is recrystallized with petroleum ether, obtains 6.5g 4- (2- chloroethoxies) benzyl chloride for white solid.
Claims (6)
1. the method that one kind prepares 4- chloromethane benzene compounds 4- (2- chloroethoxies) benzyl chloride, it is characterized in that with P-hydroxybenzoic acid
It is initiation material, target compound is obtained through over-churning, condensation, reduction, chlorination, synthetic route is as follows：
2. method according to claim 1, it is characterized by described 4 steps reaction is,
(1) with P-hydroxybenzoic acid as initiation material, 2 are obtained through esterification；
(2) there is condensation reaction with bromoacetate 2, obtain 3；
(3) 4 are obtained with reducing agent reaction 3；
(4) 5 are obtained with chlorination reaction 4；
3. method according to claim 1, it is characterised in that described esterification is prepared used by ethyl-para-hydroxybenzoate
Catalyst be selected from p-methyl benzenesulfonic acid, DMAP, hydrogen chloride, sulfuric acid in the mixture of one or more；
Described condensation reaction prepare alkali used by ethyl -4- (2- ethyoxyl -2- oxoethoxies) methyl benzoate be selected from NaOH,
Potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, triethylamine, sodium acid carbonate, pyridine, triisopropylamine,
The mixture of one or more in saleratus；Reducing agent used by described reduction reaction be selected from sodium borohydride, potassium borohydride,
The mixture of one or more in lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine；Used by described chlorination reaction
Chlorinating agent be selected from thionyl chloride, chlorine, POCl3, phosphorus trichloride, phosphorus pentachloride in the mixture of one or more.
4. method according to claim 1, it is characterised in that described esterification is prepared used by ethyl-para-hydroxybenzoate
Solvent be selected from ethanol, tetrahydrofuran, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide,
The mixture of one or more in DMAC N,N' dimethyl acetamide；Described condensation reaction prepares ethyl -4- (2- ethyoxyl -2- oxygen
For ethyoxyl) solvent used by methyl benzoate is selected from dichloromethane, chloroform, toluene, tetrahydrofuran, toluene, adjacent two
One or more mixed in toluene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide
Compound；Solvent used by described reduction reaction is selected from the mixed of one or more in methyl alcohol, ethanol, normal propyl alcohol, isopropanol
Compound；Solvent used by described chlorination reaction is selected from tetrahydrofuran, toluene, ortho-xylene, paraxylene, meta-xylene
The mixture of one or more.
5. method according to claim 1, it is characterised in that described esterification is prepared used by ethyl-para-hydroxybenzoate
Reaction temperature be 0 DEG C~solvent reflux temperature；Described condensation reaction prepares ethyl -4- (2- ethyoxyl -2- oxoethoxies)
Temperature used by methyl benzoate is the reflux temperature of 0 DEG C-solvent；Temperature used by described reduction reaction is returning for 0 DEG C-solvent
Stream temperature；Temperature used by described chlorination reaction is the reflux temperature of room temperature-solvent.
6. method according to claim 1, it is characterised in that described esterification is prepared used by ethyl-para-hydroxybenzoate
Reaction temperature be room temperature；Described condensation reaction prepares ethyl -4- (2- ethyoxyl -2- oxoethoxies) methyl benzoate institute
Temperature is room temperature；Temperature used by described reduction reaction is room temperature；Temperature used by described chlorination reaction is that solvent is returned
Stream temperature.
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| CN201510901179.2A CN106854141A (en) | 2015-12-08 | 2015-12-08 | A kind of synthetic method of 4- chloromethanes benzene compound |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4634701A (en) * | 1984-06-06 | 1987-01-06 | Ausonia Farmaceutici S.R.L. | Furan derivatives having anti-ulcer activity |
| CN1111247A (en) * | 1993-12-07 | 1995-11-08 | 伊莱利利公司 | Protein kinase C inhibitors |
| CN103804187A (en) * | 2014-01-23 | 2014-05-21 | 苏州美诺医药科技有限公司 | Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A |
-
2015
- 2015-12-08 CN CN201510901179.2A patent/CN106854141A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4634701A (en) * | 1984-06-06 | 1987-01-06 | Ausonia Farmaceutici S.R.L. | Furan derivatives having anti-ulcer activity |
| CN1111247A (en) * | 1993-12-07 | 1995-11-08 | 伊莱利利公司 | Protein kinase C inhibitors |
| CN103804187A (en) * | 2014-01-23 | 2014-05-21 | 苏州美诺医药科技有限公司 | Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A |
Non-Patent Citations (1)
| Title |
|---|
| YOSHIHIKO KOTAKE等: "Novel 6-5 Fused Ring Heterocycle Antifolates with Potent Antitumor Activity: Bridge Modifications and Heterocyclic Benzoyl Isosters of 2,4-Diamino-6,7-dihydro-5H- cyclopenta[d]pyrimidine Antifolate", 《CHEM.PHARM.BULL.》 * |
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