CN102617537A - Preparation method of flocoumafen - Google Patents
Preparation method of flocoumafen Download PDFInfo
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- CN102617537A CN102617537A CN2011100328775A CN201110032877A CN102617537A CN 102617537 A CN102617537 A CN 102617537A CN 2011100328775 A CN2011100328775 A CN 2011100328775A CN 201110032877 A CN201110032877 A CN 201110032877A CN 102617537 A CN102617537 A CN 102617537A
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Abstract
The invention discloses a preparation method of flocoumafen, which treats anisole and phenylacetyl chloride as initial raw materials to sequentially obtain a white crystal 4-methoxyphenylacetophenone, 4-phenyl-3-(4-methoxyphenyl)-3-ethylhydroxybutyrate, 4-phenyl-3-(4-methoxyphenyl)ethyl butyrate, a white solid 4-phenyl-3-(4-methoxyphenyl)butyric acid, a light yellow solid 3-(4-methoxyphenyl)-1-tetralone, 3-(4-methoxyphenyl)-1-tetrahydronaphthol, 4-hydroxy-3-{1,2,3,4-tetrahydro-3-(4-methoxyphenyl)-1-naphthalene}coumarin, 4-hydroxy-3-{1,2,3,4-tetrahydro-3-(4-hydroxyphenyl)-1-naphthalene}coumarin, and 4-hydroxy-3-[1,2,3,4-tetrahydro-3-{4-(4-trifluoromethylbenzyloxy)phenyl}-1-naphthalene]coumarin. The preparation method of the invention has the advantages of cheap and easily available raw materials, simple and easily carried out reactions, and simple post-processing operation; and boron trifluoride is used as a Lewis acid to substitute iodine to solve a problem of low conversion rate formerly existing in a second step of OeeSookPark and BongSuekJang, so the total reaction yield is improved, and the industrial production of flocoumafen has a meaning.
Description
Technical field
The invention belongs to field of fine chemical, be specifically related to the synthetic of a kind of s-generation anticoagulant property rodenticide fluorine mouse ketone.
Background technology
Fluorine mouse ketone (flocoumafen) claims to kill its battle again, is the s-generation coumarins anti-coagulant that Britain Shell Co. Ltd obtained patent in 1984.Its feature is efficient, good palatability, have highly select the property killed, to various rodents, comprise the muroid that first-generation anti-coagulant is developed immunity to drugs, good killing effect is arranged, and has effective toxinicide vitamin K1.With fluorine mouse ketone is that this s-generation anti-coagulant that has acute rodenticide and chronic rodenticide advantage concurrently of representative is a rodenticide development recent progress, has theory and practical significance for the exploration of its preparation method.
At present, the report on fluorine mouse ketone compound direction is very few both at home and abroad.The raw material Witting reagent that is used for synthetic fluorine mouse ketone among the patent GB2126578 is difficult for buying, and needs preparation voluntarily, makes cost increase." efficient rodenticide kills the synthetic of its battle " literary composition improved on the basis of this patent in 2000; Substitute Witting reagent as starting raw material with ETHYLE ACETATE; But still be in use to the Grignard reagent of cylite and the reaction of carbon-carbon double bond addition; The difficult point of this reaction has two places: the one, and dimerization takes place in the Grignard reagent of cylite easily, generates 1, the 2-diphenylethane; The 2nd, Grignard reagent is a nucleophilic reagent, is not easy the attack carbon-carbon double bond.Nineteen ninety-five Oee Sook Park, Bong Suek Jang have reported the novel method of synthetic fluorine mouse ketone of nine steps; Wherein the second step Refortmasky is reflected at after reactant ratio, catalyst levels, temperature of reaction, reaction times, these influence factor experiments of order of addition(of ingredients), finds that the transformation efficiency of substrate p-methoxyphenyl benzyl ketone is all lower.Both at home and abroad the report about the Refortmasky reaction is a lot, but majority is the research to aldehyde, and to the exploration of ketone seldom, and the Refortmasky reaction substrate structure influence of originally experiencing is bigger, does not also have the method for the sophisticated regularization of ten minutes at present.Therefore the effective preparation method who expands fluorine mouse ketone becomes a problem that waits to solve.
Summary of the invention
The object of the present invention is to provide a kind of effective ways of synthetic fluorine mouse ketone, make it can be applicable to industrial production.
The technical solution that realizes the object of the invention is: a kind of preparation method of fluorine mouse ketone may further comprise the steps:
The first step; Phenyllacetyl chloride, methyl-phenoxide are dissolved in the methylene dichloride by a certain percentage, under optimal temperature, add aluminum chloride, stir; After the end with in the reaction solution impouring hydrochloric acid; Phase-splitting, organic phase obtains bullion through saturated common salt washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtains white crystal 4-p-methoxy-phenyl phenylethylketone through recrystallizing methanol again;
Second step; Be dissolved in the first step product, metal reagent, METHYL BROMOACETATE in the organic solvent by a certain percentage; Drip a certain amount of boron trifluoride complex under vigorous stirring, the optimal temperature, dropwise the back and stir, finish after-filtration; ETHYLE ACETATE washing filter residue, filtrating obtains 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate through salt pickling, washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure;
The 3rd step; The second step product is dissolved in the methylene dichloride, adds triethyl silicane, trifluoroacetic acid, boron trifluoride complex by a certain percentage under stirring, reflux; After the end reaction solution is chilled to room temperature; Add wet chemical, tell organic phase, wash again, anhydrous magnesium sulfate drying, concentrating under reduced pressure can obtain 4-phenyl-3-(4-p-methoxy-phenyl) ethyl n-butyrate;
In the 4th step, it is soluble in water to get a certain amount of sodium hydroxide, stirs down in certain three step of flow control product, to add the above-mentioned aqueous sodium hydroxide solution for preparing, and refluxes; After the end reaction solution is chilled to room temperature, to wherein adding ETHYLE ACETATE, tells water, can obtain faint yellow solid with hcl acidifying, filtration, washing obtain bullion; This bullion is carried out recrystallization, obtain white solid 4-phenyl-3-(4-p-methoxy-phenyl) butyric acid;
The 5th step, under the optimal temperature in PPA gradation add a certain proportion of the 4th step product, stir the reinforced back that finishes; Be chilled to room temperature then, with the excessive PPA of aqueous sodium carbonate flush away, filter, the filter cake washing promptly gets bullion, with methyl alcohol it is carried out recrystallization, obtains faint yellow solid 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline;
In the 6th step, gradation adds a certain amount of Peng Qinghuana in ethanol or the methanol solution of the 5th step product, under optimal temperature, stirs; Finish the back thin up, add hcl acidifying again, methylene dichloride comes together and organic phase, washes successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 3-(4-p-methoxy-phenyl)-1-tetralol;
The 7th step was dissolved in 1 by a certain percentage with the 6th step product and 4 hydroxy coumarin, and in the 2-ethylene dichloride, gradation adds an amount of tosic acid under stirring, and refluxed in the reinforced back that finishes; Finish the dilution of post-heating water, add methylene dichloride again and come together and organic phase, carry out hot water wash, anhydrous magnesium sulfate drying, concentrating under reduced pressure successively and obtain 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } tonka bean camphor;
The 8th step added Hydrogen bromide, acetic acid in the 7th step product, reflux; After the end reaction solution is chilled to room temperature; To wherein adding aqueous sodium hydroxide solution alkalization, use methylene dichloride flush away unreacting substance again, tell water with hcl acidifying, use dichloromethane extraction again; Come together organic phase obtain 4-hydroxyl-3-{1 through washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure; 2,3,4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } tonka bean camphor;
In the 9th step, the 8th step product and certain proportion acid binding agent are dissolved in the acetonitrile, to wherein adding to the trifluoromethyl bromobenzyl; After stirring under the certain temperature, removal of solvent under reduced pressure, thin up; Use dichloromethane extraction again, organic phase is washed successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 4-hydroxyl-3-[1,2; 3,4-tetrahydrochysene-3-{4-(4-trifluoromethyl benzyloxy) phenyl }-the 1-naphthalene] tonka bean camphor.
The present invention compared with prior art, its remarkable advantage:, use low in raw material cost to be easy to get, avoided using Witting reagent etc. to need the complicated raw material of preparation in addition;
Two, reaction is simple and easy to carry out, and avoided the addition reaction of the Grignard reagent and the carbon-carbon double bond of non-incident cylite, and post-processing operation is easy;
Three, substitute iodine as Lewis acid with boron trifluoride, captured Oee Sook Park, the low problem of the Bong Suek Jang second former transformation efficiency that pre-exists of step, thereby improved the total reaction yield, make that its industrial production is meaningful.
Description of drawings
Fig. 1 is the schema that the first step reaction proposes according to the present invention, and all the other steps can the rest may be inferred.
Fig. 2 is the nuclear-magnetism figure of 4-p-methoxy-phenyl phenylethylketone.
Fig. 3 is the butyro-nuclear-magnetism figure of 4-phenyl-3-(4-p-methoxy-phenyl).
Fig. 4 is the nuclear-magnetism figure of 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline.
Fig. 5 is the nuclear-magnetism figure of 3-(4-p-methoxy-phenyl)-1-tetralol.
Fig. 6 is 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } mass spectrum of tonka bean camphor.
Fig. 7 is the mass spectrum of 4-hydroxyl-3-[1,2,3,4-tetrahydrochysene-3-{4-(4-trifluoromethyl benzyloxy) phenyl }-1-naphthalene] tonka bean camphor.
Embodiment
Below in conjunction with accompanying drawing the present invention is described in further detail.
The structural formula of fluorine mouse ketone does
Its preparation process is following:
The first step; Phenyllacetyl chloride, methyl-phenoxide are dissolved in the methylene dichloride by a certain percentage, under optimal temperature, add an amount of aluminum chloride, stir 16h; In the hydrochloric acid with reaction solution impouring 10% after the end; Phase-splitting, organic phase obtains bullion through saturated common salt washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtains white crystal 4-p-methoxy-phenyl phenylethylketone through recrystallizing methanol again.
Second step was dissolved in the first step product, metal reagent, METHYL BROMOACETATE in the organic solvent by a certain percentage, dripped a certain amount of boron trifluoride complex under vigorous stirring, the optimal temperature, dropwised the back and stirred 2.5～4h.Finish after-filtration, ETHYLE ACETATE washing filter residue, filtrating obtains 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate through 5% salt pickling, washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure.
The 3rd step was dissolved in the second step product in the methylene dichloride, stirred to add triethyl silicane, trifluoroacetic acid, boron trifluoride complex, backflow 8h down by a certain percentage.After the end reaction solution is chilled to room temperature, adds 30% wet chemical, tell organic phase, wash again, anhydrous magnesium sulfate drying, concentrating under reduced pressure can obtain 4-phenyl-3-(4-p-methoxy-phenyl) ethyl n-butyrate.
In the 4th step, it is soluble in water to get a certain amount of sodium hydroxide, stirs down in certain three step of flow control product, to add the above-mentioned aqueous sodium hydroxide solution for preparing, and 6～8h refluxes.After the end reaction solution is chilled to room temperature, to wherein adding ETHYLE ACETATE, tells water, the hcl acidifying with 20% can obtain faint yellow solid, and filtration, washing obtain bullion.This bullion is carried out recrystallization, obtain white solid 4-phenyl-3-(4-p-methoxy-phenyl) butyric acid.
The 5th step, under the optimal temperature in PPA gradation add a certain proportion of the 4th step product, certain hour is stirred in the reinforced back that finishes.Be chilled to room temperature then, with the excessive PPA of 10% aqueous sodium carbonate flush away, filter, the filter cake washing promptly gets bullion, with methyl alcohol it is carried out recrystallization, obtains faint yellow solid 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline.
In the 6th step, gradation adds a certain amount of Peng Qinghuana in ethanol or the methanol solution of the 5th step product, under optimal temperature, stirs 2h.Finish the back thin up, add 20% hcl acidifying again, methylene dichloride comes together and organic phase, washes successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 3-(4-p-methoxy-phenyl)-1-tetralol.
The 7th step was dissolved in 1 by a certain percentage with the 6th step product and 4 hydroxy coumarin, and in the 2-ethylene dichloride, gradation adds an amount of tosic acid under stirring, and refluxed for some time in the reinforced back that finishes.Finish the dilution of post-heating water, add methylene dichloride again and come together and organic phase, carry out hot water wash, anhydrous magnesium sulfate drying, concentrating under reduced pressure successively and obtain 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } tonka bean camphor.
The 8th step added a certain amount of Hydrogen bromide, acetic acid in the 7th step product, 6～8h refluxes.After the end reaction solution is chilled to room temperature; To wherein adding the alkalization of 10% aqueous sodium hydroxide solution, use methylene dichloride flush away unreacting substance again, tell water with 10% hcl acidifying, use dichloromethane extraction again; Come together organic phase obtain 4-hydroxyl-3-{1 through washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure; 2,3,4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } tonka bean camphor.
The 9th step was dissolved in the 8th step product and certain proportion acid binding agent in the acetonitrile, to wherein adding in right amount to the trifluoromethyl bromobenzyl; After stirring 16h under the certain temperature, removal of solvent under reduced pressure, thin up; Use dichloromethane extraction again, organic phase is washed successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 4-hydroxyl-3-[1,2; 3,4-tetrahydrochysene-3-{4-(4-trifluoromethyl benzyloxy) phenyl }-the 1-naphthalene] tonka bean camphor.
In the above-mentioned the first step, the mol ratio of phenyllacetyl chloride and methyl-phenoxide is 1:1～1:2, and the mol ratio of phenyllacetyl chloride and aluminum chloride is 1:1～1:2; Temperature of reaction is-20～15 ℃.
In above-mentioned second step; Metal reagent is magnesium powder, zinc powder, iron powder or copper powder; The mol ratio of 4-p-methoxy-phenyl phenylethylketone and metal reagent is 1:1～1:4; The mol ratio of 4-p-methoxy-phenyl phenylethylketone and METHYL BROMOACETATE is 1:1～1:4, and the mol ratio of 4-p-methoxy-phenyl phenylethylketone and boron trifluoride complex is 1:1～1:3; Organic solvent is toluene, benzene, THF, ETHYLE ACETATE; Temperature is 25～55 ℃; The boron trifluoride complex ligand can be ether, THF, acetonitrile, methyl ether, butyl ether.
In above-mentioned the 3rd step; The mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate and triethyl silicane is 1:1～1:4; The mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate and trifluoroacetic acid is 1:1～1:6, and the mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate and boron trifluoride complex is 1:0.5～1:2; The boron trifluoride complex ligand can be ether, THF, acetonitrile, methyl ether, butyl ether.
In above-mentioned the 4th step, the mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl) ethyl n-butyrate and sodium hydroxide is 1:1～1:8; Recrystallization reagent can be ETHYLE ACETATE, acetone, chloroform, acetonitrile, methyl alcohol, ethanol.
In above-mentioned the 5th step, the mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl) butyric acid and PPA is 1:1～1:5; Temperature is 60～120 ℃; Reaction times is 1～6h.
In above-mentioned the 6th step, the mol ratio of 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline and Peng Qinghuana is 1:1～1:4; Temperature of reaction is 25～55 ℃.
In above-mentioned the 7th step, the mol ratio of 3-(4-p-methoxy-phenyl)-1-tetralol and 4 hydroxy coumarin is 1:1～1:4, and the mol ratio of 3-(4-p-methoxy-phenyl)-1-tetralol and tosic acid is 1:0.5～1:2; Reaction times is 4～24h.
In above-mentioned the 8th step, 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } tonka bean camphor and hydrobromic mol ratio be 1:1～1:8.
In above-mentioned the 9th step, acid binding agent is potassium tert.-butoxide, sodium hydrogencarbonate or triethylamine; 4-hydroxyl-3-{1,2,3; 4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } mol ratio of tonka bean camphor and acid binding agent is 1:1～1:3,4-hydroxyl-3-{1,2; 3,4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } tonka bean camphor is 1:1～1:2 with mol ratio to trifluoromethyl benzyl bromine; Temperature of reaction is 25～45 ℃.
Concrete route is following:
The first step; 7.725g (0.05mol) phenyllacetyl chloride, 10.08g (0.10mol) methyl-phenoxide are dissolved in the 50mL methylene dichloride, add 13.35g (0.10mol) aluminum chloride, stirring 16h in-20 ℃; In the hydrochloric acid with reaction solution impouring 10% after the end; Phase-splitting, organic phase obtains bullion through saturated common salt washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtains white crystal 4-p-methoxy-phenyl phenylethylketone through recrystallizing methanol again.
Second step was dissolved in 2.26g (0.01mol) the first step product, 0.48g (0.02mol) magnesium powder, 1.67g (0.01mol) METHYL BROMOACETATE in the 15mL benzene, in 25 ℃ of dropping 0.01mol boron trifluoride acetonitriles, dropwised the back in stirring 3～4h under the vigorous stirring.Finish after-filtration, ETHYLE ACETATE washing filter residue, filtrating obtains 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate through 5% salt pickling, washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure.
The 3rd step was dissolved in 3.14g (0.01mol) second step product in the 15mL methylene dichloride, stirred to add 1.16g (0.01mol) triethyl silicane, 6.84g (0.06mol) trifluoroacetic acid, 0.01mol BFEE, backflow 8h down.After the end reaction solution is chilled to room temperature, adds 30% wet chemical, tell organic phase, wash again, anhydrous magnesium sulfate drying, concentrating under reduced pressure can obtain 4-phenyl-3-(4-p-methoxy-phenyl) ethyl n-butyrate.
The 4th step, get 0.4g (0.01mol) sodium hydroxide and be dissolved in the 15mL water, stir the above-mentioned aqueous sodium hydroxide solution for preparing of adding in 2.98g (0.01mol) the 3rd step product down, 6～8h refluxes.After the end reaction solution is chilled to room temperature, to wherein adding methylene dichloride, tells water, the hcl acidifying with 20% can obtain faint yellow solid, and filtration, washing obtain bullion.With ETHYLE ACETATE this bullion is carried out recrystallization, obtain white solid 4-phenyl-3-(4-p-methoxy-phenyl)-3-hydroxybutyric acid.
The 5th step, under 60 ℃ in 3.38g (0.01mol) PPA gradation add 2.7g (0.01mol) the 4th step product, 1h is stirred in the reinforced back that finishes.Be chilled to room temperature then, with the excessive PPA of 10% aqueous sodium carbonate flush away, filter, the filter cake washing promptly gets bullion, with methyl alcohol it is carried out recrystallization, obtains faint yellow solid 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline.
In the 6th step, gradation adds 0.378g (0.01mol) Peng Qinghuana in the ethanolic soln of 2.52g (0.01mol) the 5th step product, stirs 2h down in 25 ℃.Finish the back thin up, add 20% hcl acidifying again, methylene dichloride comes together and organic phase, carries out successively that 10% sodium bicarbonate aqueous solution is washed, washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 3-(4-p-methoxy-phenyl)-1-tetralol.
The 7th step was dissolved in 25mL1 with 12.6g (0.05mol) the 6th step product and 8.1g (0.05mol) 4 hydroxy coumarin, in the 2-ethylene dichloride, stirred gradation adding 4.305g (0.025mol) tosic acid down, the reinforced back backflow 24h that finishes.Finish the dilution of post-heating water, add methylene dichloride again and come together and organic phase, carry out hot water wash, anhydrous magnesium sulfate drying, concentrating under reduced pressure successively and obtain 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } tonka bean camphor.
The 8th step added 0.05mol Hydrogen bromide, 10mL acetic acid in 2.0g (0.05mol) the 7th step product, 6～8h refluxes.After the end reaction solution is chilled to room temperature,, uses dichloromethane extraction again to the sodium bicarbonate aqueous solution that wherein adds 5%; Organic phase is washed successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 4-hydroxyl-3-{1; 2,3,4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } tonka bean camphor.
In the 9th step, 3.84g (0.01mol) the 8th step product and 2.24g (0.02mol) potassium tert.-butoxide are dissolved in the 20mL acetonitrile, to wherein adding 2.39g (0.01mol) to the trifluoromethyl bromobenzyl; After stirring 16h under 25 ℃, removal of solvent under reduced pressure, thin up; Use dichloromethane extraction again, organic phase is washed successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 4-hydroxyl-3-[1,2; 3,4-tetrahydrochysene-3-{4-(4-trifluoromethyl benzyloxy) phenyl }-the 1-naphthalene] tonka bean camphor.
The characterization result of the first step product 4-p-methoxy-phenyl phenylethylketone is following:
m.p.?72～74℃
Ultimate analysis: C
15H
14O
2
% calculated value measured value
C 79.65 80.34
H 6.195 6.174
IR (KB
r): 2900～3000 cm
-1(C-H stretching vibration)
1678 cm
-1(C=O stretching vibration)
1506 cm
-1(aromatic ring frame vibration)
1263 cm
-1(C-C stretching vibration)
1029 cm
-1(C-O-C stretching vibration)
1H-NMR(CDCl
3，500MHz)δ,ppm：
3.879(s,3H),4.258(s,2H),6.941-6.959(m,2H),
7.265-7.358(m,5H),8.014-8.031(m,2H).
The characterization result of second step product 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate is following:
IR (KB
r): 3498 cm
-1(OH stretching vibration)
2900～3000 cm
-1(C-H stretching vibration)
1712 cm
-1(C=O stretching vibration)
1510 cm
-1(aromatic ring frame vibration)
1250 cm
-1(C-C stretching vibration)
1029 cm
-1(C-O-C stretching vibration)
The characterization result of the 3rd step product 4-phenyl-3-(4-p-methoxy-phenyl) ethyl n-butyrate is following:
IR (KB
r): 2900～3000 cm
-1(C-H stretching vibration)
1732 cm
-1(C=O stretching vibration)
1512 cm
-1(aromatic ring frame vibration)
1250 cm
-1(C-C stretching vibration)
1037 cm
-1(C-O-C stretching vibration)
The butyro-characterization result of the 4th step product 4-phenyl-3-(4-p-methoxy-phenyl) is following:
m.p.?120～122℃
Ultimate analysis: C
17H
18O
3
% calculated value measured value
C 75.56 75.46
H 6.667 6.689
IR (KB
r): 3412 cm
-1(OH stretching vibration)
2900～3000 cm
-1(C-H stretching vibration)
1710 cm
-1(C=O stretching vibration)
1512 cm
-1(aromatic ring frame vibration)
1246 cm
-1(C-C stretching vibration)
1032 cm
-1(C-O-C stretching vibration)
1H-NMR(CDCl
3，500MHz)δ,ppm：
2.591-2.640(m,1H),?2.665-2.710(m,1H),
2.890、2.905(d,2H),3.334-3.394(m,1H),
3.851(s,3H),6.811、6.828(d,2H),
7.047-7.083(m,4H),7.157-7.186(m,1H),?7.218-7.247(m,2H).
The characterization result of the 5th step product 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline is following:
m.p.?102～104℃
Ultimate analysis: C
17H
16O
2
% calculated value measured value
C 80.95 78.96
H 6.349 5.245
IR (KB
r): 2900～3000 cm
-1(C-H stretching vibration)
1682 cm
-1(C=O stretching vibration)
1508 cm
-1(aromatic ring frame vibration)
1250 cm
-1(C-C stretching vibration)
1034 cm
-1(C-O-C stretching vibration)
1H-NMR(CDCl
3，500MHz)δ,ppm：
2.797-2.856(m,1H),2.953-2.994(m,1H),
3.181-3.200(m,2H),3.408-3.459(m,1H),
3.836(s,3H),6.916、6.934(d,2H),
7.236-7.253(d,2H),7.282-7.309(m,1H),
7.357-7.388(m,1H),7.516-7.548(m,1H),
8.091-9.106(d,1H).
The characterization result of the 6th step product 3-(4-p-methoxy-phenyl)-1-tetralol is following:
m.p.?116～118℃
Ultimate analysis: C
17H
18O
2
% calculated value measured value
C 80.32 80.25
H 7.087 7.282
IR (KB
r): 3402 cm
-1(OH stretching vibration)
2900～3000 cm
-1(C-H stretching vibration)
1680cm
-1(C=O stretching vibration)
1518 cm
-1(aromatic ring frame vibration)
1250 cm
-1(C-C stretching vibration)
1036 cm
-1(C-O-C stretching vibration)
1H-NMR(CDCl
3，500MHz)δ,ppm：
1.857-1.976(m,2H),2.481-2.525(m,1H),
2.942-3.082(m,3H),3.838(s,3H),
5.005-5.025(m,1H),6.910、6.928(d,2H),
7.120-7.135(d,1H),7.225-7.292(m,4H),
7.646、7.662(d,1H).
The 7th step product 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } characterization result of tonka bean camphor is following:
Ultimate analysis: C
26H
22O
4
% calculated value measured value
C 78.39 80.07
H 5.527 6.038
IR (KB
r): 3428 cm
-1(OH stretching vibration)
2900～3000 cm
-1(C-H stretching vibration)
1678cm
-1(C=O stretching vibration)
1510 cm
-1(aromatic ring frame vibration)
1250 cm
-1(C-C stretching vibration)
1038 cm
-1(C-O-C stretching vibration)
1H-NMR(CDCl
3，500MHz)δ,ppm：
More?polar?isomer:
1.925(m,1H),2.487(m,1H),3.100(m,3H),3.815(s,3H),
4.883-4.894(m,1H),5.777?(s,1H),
6.877、6.891(d,2H),7.200-7.346(m,8H),
7.541-7.571(m,1H),7.558(m,1H).
Less?polar?isomer:
2.364-2.381(m,2H),3.005-3.098(m,2H),
3.237-3.269(m,1H),3.799(s,3H),
4.743-4.759(m,1H),6.233?(s,1H),
6.857、6.874(d,2H),7.176-7.376(m,8H),
7.522-7.556(m,1H),7.697、7.713(d,1H).
MS?m/z(%)?398(m-):396.98
The 8th step product 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } characterization result of tonka bean camphor is following:
IR (KB
r): 3432 cm
-1(OH stretching vibration)
2900～3000 cm
-1(C-H stretching vibration)
1712cm
-1(C=O stretching vibration)
1512 cm
-1(aromatic ring frame vibration)
1250 cm
-1(C-C stretching vibration)
1032 cm
-1(C-O-C stretching vibration)
The characterization result of the 9th step product 4-hydroxyl-3-[1,2,3,4-tetrahydrochysene-3-{4-(4-trifluoromethyl benzyloxy) phenyl }-1-naphthalene] tonka bean camphor is following:
Ultimate analysis: C
33H
25O
4F
3
% calculated value measured value
C 73.06 73.28
H 4.613 5.094
IR (KB
r): 3420 cm
-1(OH stretching vibration)
2900～3000 cm
-1(C-H stretching vibration)
1672cm
-1(C=O stretching vibration)
1512 cm
-1(aromatic ring frame vibration)
1250 cm
-1(C-C stretching vibration)
1028 cm
-1(C-O-C stretching vibration)
1H-NMR(CDCl
3，500MHz)δ,ppm：
1.290(s,1H),2.642(m,2H),2.698(m,1H),
2.912-3.167(m,2H),3.798(m,1H),5.114-5.227(m,2H),
6.890-8.019(m,16H).
MS?m/z(%)?398(m+):333.96,175.99,158.96,108.99.
Other material characterizes like embodiment 1.
Reactions step and embodiment 1 are identical, and difference is:
For the first step, methyl-phenoxide changes 5.04g (0.05mol) into, adds aluminum chloride down in 15 ℃.
For second step, metal reagent is selected 0.56g (0.01mol) iron powder for use, and solvent is selected THF for use, and METHYL BROMOACETATE changes 6.68g (0.04mol) into, drips 0.01mol boron trifluoride THF down in 35 ℃.
For the 3rd step, triethyl silicane changes 3.48g (0.03mol) into, and trifluoroacetic acid changes 1.14g (0.01mol) into, and boron trifluoride complex adopts 0.005mol boron trifluoride THF.
For the 4th step, sodium hydroxide concentration changes 3.20g (0.08mol) into, and recrystallization reagent is selected methyl alcohol for use.
For the 5th step, temperature of reaction is 90 ℃, and the PPA consumption is 16.90g (0.05mol), and 6h is stirred in the reinforced back that finishes.
For the 6th step, Peng Qinghuana changes 1.512g (0.04mol) into, and temperature of reaction is 40 ℃.
For the 7th step, 4 hydroxy coumarin changes 32.4g (0.20mol) into, and tosic acid changes 8.61g (0.05mol) into, and 8h is stirred in the reinforced back that finishes.
For the 8th step, Hydrogen bromide changes 0.08mol into.
For the 9th step, acid binding agent is selected sodium tert-butoxide 0.96g (0.01mol) for use, and the trifluoromethyl bromobenzyl is changed into 4.78g (0.02mol), and temperature of reaction is 45 ℃.
The compound confirmation method of this embodiment is identical with embodiment 1.
Embodiment 3
Reactions step and embodiment 1 are identical, and difference is:
For the first step, methyl-phenoxide changes 7.56g (0.075mol) into, adds 6.625g (0.05mol) aluminum chloride down in 0 ℃.
For second step, metal reagent is selected 2.56g (0.04mol) copper powder for use, and solvent is selected toluene for use, and METHYL BROMOACETATE changes 3.34g (0.02mol) into, drips the 0.02mol BFEE down in 55 ℃.
For the 3rd step, triethyl silicane changes 4.64g (0.04mol) into, and trifluoroacetic acid changes 3.42g (0.03mol) into, and boron trifluoride complex adopts the 0.02mol boron trifluoride acetonitrile.
For the 4th step, sodium hydroxide concentration changes 1.60g (0.04mol) into, and recrystallization reagent is selected acetonitrile for use.
For the 5th step, temperature of reaction is 120 ℃, and the PPA consumption is 10.14g (0.03mol), and 3h is stirred in the reinforced back that finishes.
For the 6th step, Peng Qinghuana changes 0.756g (0.02mol) into, and temperature of reaction is 55 ℃.
For the 7th step, 4 hydroxy coumarin changes 16.2g (0.10mol) into, and tosic acid changes 17.22g (0.10mol) into, and 4h is stirred in the reinforced back that finishes.
For the 8th step, Hydrogen bromide changes 0.04mol into.
For the 9th step, acid binding agent is selected sodium hydrogencarbonate 2.40g (0.03mol) for use, and the trifluoromethyl bromobenzyl is changed into 3.585g (0.015mol), and temperature of reaction is 35 ℃.
The compound confirmation method of this embodiment is identical with embodiment 1.
Embodiment 4
Reactions step and embodiment 1 are identical, and difference is:
For the first step, aluminum chloride changes 9.938g (0.075mol) into, and temperature of reaction is 5 ℃.
For second step, metal reagent is selected 1.68g (0.03mol) zinc powder for use, and solvent is selected ETHYLE ACETATE for use, and boron trifluoride complex is selected the boron trifluoride butyl ether for use.
For the 3rd step, triethyl silicane changes 2.32g (0.02mol) into, and trifluoroacetic acid changes 4.56g (0.04mol) into, and boron trifluoride complex adopts 0.015mol boron trifluoride methyl ether.
For the 4th step, sodium hydroxide concentration changes 2.00g (0.05mol) into, and recrystallization reagent is selected acetone for use.
For the 5th step, temperature of reaction is 100 ℃, and the PPA consumption is 13.52g (0.04mol), and 2h is stirred in the reinforced back that finishes.
For the 6th step, Peng Qinghuana changes 1.134g (0.03mol) into, and temperature of reaction is 45 ℃.
For the 7th step, 4 hydroxy coumarin changes 24.3g (0.15mol) into, and tosic acid changes 12.915g (0.075mol) into, and 12h is stirred in the reinforced back that finishes.
For the 8th step, Hydrogen bromide changes 0.05mol into.
For the 9th step, acid binding agent is selected triethylamine 2.02g (0.02mol) for use, and the trifluoromethyl bromobenzyl is changed into 4.78g (0.02mol), and temperature of reaction is 30 ℃.
The compound confirmation method of this embodiment is identical with embodiment 1.
Reactions step and embodiment 1 are identical, and difference is:
For the first step, methyl-phenoxide changes 7.56g (0.075mol) into, adds aluminum chloride down in-10 ℃.
For second step, metal reagent is selected 1.12g (0.02mol) iron powder for use, and METHYL BROMOACETATE changes 3.34g (0.02mol) into, drips 0.02mol boron trifluoride methyl ether down in 30 ℃.
For the 3rd step, triethyl silicane changes 3.48g (0.03mol) into, and trifluoroacetic acid changes 2.28g (0.02mol) into, and boron trifluoride complex adopts 0.01mol boron trifluoride butyl ether.
For the 4th step, sodium hydroxide concentration changes 2.40g (0.06mol) into, and recrystallization reagent is selected ethanol for use.
For the 5th step, temperature of reaction is 100 ℃, and the PPA consumption is 10.14g (0.03mol), and 4h is stirred in the reinforced back that finishes.
For the 6th step, Peng Qinghuana changes 0.756g (0.02mol) into, and temperature of reaction is 35 ℃.
For the 7th step, 4 hydroxy coumarin changes 16.2g (0.10mol) into, and tosic acid changes 8.61g (0.05mol) into, and 18h is stirred in the reinforced back that finishes.
For the 8th step, Hydrogen bromide changes 0.03mol into.
For the 9th step, acid binding agent is selected potassium tert.-butoxide 1.12g (0.01mol) for use, and temperature of reaction is 30 ℃.
The compound confirmation method of this embodiment is identical with embodiment 1.
Reactions step and embodiment 1 are identical, and difference is:
For the first step, temperature of reaction changes 10 ℃ into.
For second step, metal reagent is selected 0.56g (0.01mol) zinc powder for use, and solvent is selected toluene for use, and boron trifluoride complex is selected the boron trifluoride THF for use.
For the 3rd step, triethyl silicane changes 2.32g (0.02mol) into, and trifluoroacetic acid changes 5.70g (0.05mol) into, and boron trifluoride complex adopts the 0.02mol BFEE.
For the 4th step, sodium hydroxide concentration changes 0.80g (0.02mol) into, and recrystallization reagent is selected chloroform for use.
For the 5th step, temperature of reaction is 80 ℃, and the PPA consumption is 13.52g (0.04mol), and 2h is stirred in the reinforced back that finishes.
For the 6th step, Peng Qinghuana changes 0.945g (0.025mol) into, and temperature of reaction is 50 ℃.
For the 7th step, tosic acid changes 17.22g (0.10mol) into, and 14h is stirred in the reinforced back that finishes.
For the 8th step, Hydrogen bromide changes 0.02mol into.
For the 9th step, acid binding agent is selected sodium tert-butoxide 2.88g (0.03mol) for use, and temperature of reaction is 40 ℃.
The compound confirmation method of this embodiment is identical with embodiment 1.
Claims (10)
1. the preparation method of a fluorine mouse ketone is characterized in that may further comprise the steps:
The first step; Phenyllacetyl chloride, methyl-phenoxide are dissolved in the methylene dichloride by a certain percentage, under optimal temperature, add aluminum chloride, stir; After the end with in the reaction solution impouring hydrochloric acid; Phase-splitting, organic phase obtains bullion through saturated common salt washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtains white crystal 4-p-methoxy-phenyl phenylethylketone through recrystallizing methanol again;
Second step; Be dissolved in the first step product, metal reagent, METHYL BROMOACETATE in the organic solvent by a certain percentage; Drip a certain amount of boron trifluoride complex under vigorous stirring, the optimal temperature, dropwise the back and stir, finish after-filtration; ETHYLE ACETATE washing filter residue, filtrating obtains 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate through salt pickling, washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure;
The 3rd step; The second step product is dissolved in the methylene dichloride, adds triethyl silicane, trifluoroacetic acid, boron trifluoride complex by a certain percentage under stirring, reflux; After the end reaction solution is chilled to room temperature; Add wet chemical, tell organic phase, wash again, anhydrous magnesium sulfate drying, concentrating under reduced pressure can obtain 4-phenyl-3-(4-p-methoxy-phenyl) ethyl n-butyrate;
In the 4th step, it is soluble in water to get a certain amount of sodium hydroxide, stirs down in certain three step of flow control product, to add the above-mentioned aqueous sodium hydroxide solution for preparing, and refluxes; After the end reaction solution is chilled to room temperature, to wherein adding ETHYLE ACETATE, tells water, can obtain faint yellow solid with hcl acidifying, filtration, washing obtain bullion; This bullion is carried out recrystallization, obtain white solid 4-phenyl-3-(4-p-methoxy-phenyl) butyric acid;
The 5th step, under the optimal temperature in PPA gradation add a certain proportion of the 4th step product, stir the reinforced back that finishes; Be chilled to room temperature then, with the excessive PPA of aqueous sodium carbonate flush away, filter, the filter cake washing promptly gets bullion, with methyl alcohol it is carried out recrystallization, obtains faint yellow solid 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline;
In the 6th step, gradation adds a certain amount of Peng Qinghuana in ethanol or the methanol solution of the 5th step product, under optimal temperature, stirs; Finish the back thin up, add hcl acidifying again, methylene dichloride comes together and organic phase, washes successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 3-(4-p-methoxy-phenyl)-1-tetralol;
The 7th step was dissolved in 1 by a certain percentage with the 6th step product and 4 hydroxy coumarin, and in the 2-ethylene dichloride, gradation adds an amount of tosic acid under stirring, and refluxed in the reinforced back that finishes; Finish the dilution of post-heating water, add methylene dichloride again and come together and organic phase, carry out hot water wash, anhydrous magnesium sulfate drying, concentrating under reduced pressure successively and obtain 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } tonka bean camphor;
The 8th step added Hydrogen bromide, acetic acid in the 7th step product, reflux; After the end reaction solution is chilled to room temperature; To wherein adding aqueous sodium hydroxide solution alkalization, use methylene dichloride flush away unreacting substance again, tell water with hcl acidifying, use dichloromethane extraction again; Come together organic phase obtain 4-hydroxyl-3-{1 through washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure; 2,3,4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } tonka bean camphor;
In the 9th step, the 8th step product and certain proportion acid binding agent are dissolved in the acetonitrile, to wherein adding to the trifluoromethyl bromobenzyl; After stirring under the certain temperature, removal of solvent under reduced pressure, thin up; Use dichloromethane extraction again, organic phase is washed successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 4-hydroxyl-3-[1,2; 3,4-tetrahydrochysene-3-{4-(4-trifluoromethyl benzyloxy) phenyl }-the 1-naphthalene] tonka bean camphor.
2. the preparation method of fluorine mouse ketone according to claim 1 is characterized in that: in the said the first step, the mol ratio of phenyllacetyl chloride and methyl-phenoxide is 1:1～1:2, and the mol ratio of phenyllacetyl chloride and aluminum chloride is 1:1～1:2; Temperature of reaction is-20～15 ℃; Churning time is 16h, and hydrochloric acid is 10% hydrochloric acid.
3. the preparation method of fluorine mouse ketone according to claim 1; It is characterized in that: in said second step; Metal reagent is magnesium powder, zinc powder, iron powder or copper powder; The mol ratio of 4-p-methoxy-phenyl phenylethylketone and metal reagent is 1:1～1:4, and the mol ratio of 4-p-methoxy-phenyl phenylethylketone and METHYL BROMOACETATE is 1:1～1:4, and the mol ratio of 4-p-methoxy-phenyl phenylethylketone and boron trifluoride complex is 1:1～1:3; Organic solvent is toluene, benzene, THF or ETHYLE ACETATE; Temperature is 25～55 ℃; The boron trifluoride complex ligand can be ether, THF, acetonitrile, methyl ether or butyl ether; Churning time is 2.5～4h; Hydrochloric acid is 5% hydrochloric acid.
4. the preparation method of fluorine mouse ketone according to claim 1; It is characterized in that: in said the 3rd step; The mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate and triethyl silicane is 1:1～1:4; The mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate and trifluoroacetic acid is 1:1～1:6, and the mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl)-ethyl 3-hydroxybutanoate and boron trifluoride complex is 1:0.5～1:2; The boron trifluoride complex ligand can be ether, THF, acetonitrile, methyl ether or butyl ether; Return time is 8h; The wet chemical that adds is 30% wet chemical.
5. the preparation method of fluorine mouse ketone according to claim 1 is characterized in that: in said the 4th step, the mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl) ethyl n-butyrate and sodium hydroxide is 1:1～1:8; Recrystallization reagent can be ETHYLE ACETATE, acetone, chloroform, acetonitrile, methyl alcohol or ethanol; Return time is 6～8h; Hydrochloric acid is 20% hydrochloric acid.
6. the preparation method of fluorine mouse ketone according to claim 1 is characterized in that: in said the 5th step, the mol ratio of 4-phenyl-3-(4-p-methoxy-phenyl) butyric acid and PPA is 1:1～1:5; Temperature is 60～120 ℃; Reaction times is 1～6h, and aqueous sodium carbonate is 10% aqueous sodium carbonate.
7. the preparation method of fluorine mouse ketone according to claim 1 is characterized in that: in said the 6th step, the mol ratio of 3-(4-p-methoxy-phenyl)-1-Tetralone an intermediate of Sertraline and Peng Qinghuana is 1:1～1:4; Temperature of reaction is 25～55 ℃; Churning time is 2h; What add is 20% hydrochloric acid.
8. the preparation method of fluorine mouse ketone according to claim 1; It is characterized in that: in said the 7th step; The mol ratio of 3-(4-p-methoxy-phenyl)-1-tetralol and 4 hydroxy coumarin is 1:1～1:4, and the mol ratio of 3-(4-p-methoxy-phenyl)-1-tetralol and tosic acid is 1:0.5～1:2; Reaction times is 4～24h.
9. the preparation method of fluorine mouse ketone according to claim 1 is characterized in that: in said the 8th step, 4-hydroxyl-3-{1,2,3,4-tetrahydrochysene-3-(4-p-methoxy-phenyl)-1-naphthalene } tonka bean camphor and hydrobromic mol ratio be 1:1～1:8; Return time is 6～8h; What add is 10% aqueous sodium hydroxide solution, and what tell that water uses is 10% hydrochloric acid.
10. the preparation method of fluorine mouse ketone according to claim 1 is characterized in that: in said the 9th step, acid binding agent is potassium tert.-butoxide, sodium hydrogencarbonate or triethylamine; 4-hydroxyl-3-{1,2,3; 4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } mol ratio of tonka bean camphor and acid binding agent is 1:1～1:3,4-hydroxyl-3-{1,2; 3,4-tetrahydrochysene-3-(4-hydroxy phenyl)-1-naphthalene } tonka bean camphor is 1:1～1:2 with mol ratio to trifluoromethyl benzyl bromine; Temperature of reaction is 25～45 ℃; Churning time is 16h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4520007A (en) * | 1982-06-14 | 1985-05-28 | Shell Oil Company | Anti-coagulants of the 4-hydroxycoumarin type and rodenticidal compositions (baits) comprising such anti-coagulants |
| CN85107609A (en) * | 1984-09-26 | 1987-04-15 | 国际壳牌研究有限公司 | The preparation method of 4 hydroxy coumarin derivative |
| US4748185A (en) * | 1985-12-20 | 1988-05-31 | E. I. Du Pont De Nemours And Company | 4-hydroxycoumarin derivatives |
-
2011
- 2011-01-30 CN CN2011100328775A patent/CN102617537A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4520007A (en) * | 1982-06-14 | 1985-05-28 | Shell Oil Company | Anti-coagulants of the 4-hydroxycoumarin type and rodenticidal compositions (baits) comprising such anti-coagulants |
| CN85107609A (en) * | 1984-09-26 | 1987-04-15 | 国际壳牌研究有限公司 | The preparation method of 4 hydroxy coumarin derivative |
| US4748185A (en) * | 1985-12-20 | 1988-05-31 | E. I. Du Pont De Nemours And Company | 4-hydroxycoumarin derivatives |
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| Title |
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| OEE SOOK PARK，等: "Synthesis of 4-Hydroxycoumarin Derivatives-1: An Efficient Synthesis of Flocoumafen", 《ARCH. PHARM. RES.》 * |
| 周颖，等: "碘作为Lewis酸催化剂在合成中的应用进展", 《有机化学》 * |
| 张占辉，等: "分子碘催化的有机化学反应", 《化学进展》 * |
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