CN1011786B - Process for preparing 4-hydroxycoumarin derivatives - Google Patents
Process for preparing 4-hydroxycoumarin derivativesInfo
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- CN1011786B CN1011786B CN 85107609 CN85107609A CN1011786B CN 1011786 B CN1011786 B CN 1011786B CN 85107609 CN85107609 CN 85107609 CN 85107609 A CN85107609 A CN 85107609A CN 1011786 B CN1011786 B CN 1011786B
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Abstract
The present invention provides a method for preparing 4-hydroxycoumarin derivatives of a formula (I), and the 4-hydroxycoumarin derivatives have anticoagulant performance and can be used as raticide. In a formula I, R<1> and R<2> are respectively selected from hydrogen, halogen, alkyl which at most contains 6 carbon atoms and alkoxy which at most contains 6 carbon atoms, and the definition of R<3> is presented in the specification. The present invention comprises: under the condition that an organic solvent and catalyst exist, 4-hydroxyl coumarine and a compound of a formula (VI) [the definition of the R<1>, the R<2> and the R<3> in the formula (VI) are the same to previous definition, L is hydroxyl or a halogen atom] or corresponding 1, 2-dihydronaphthalene are condensed.
Description
The invention relates to the method for some 4 hydroxy coumarin derivative of preparation.
United States Patent (USP) 3,957,824(is corresponding to british patent specification 1,458,670) in a class 4 hydroxy coumarin derivative is disclosed, they have the anti-coagulant performance, can be used as rodenticide or are used for human medicine, its general formula is
R in the formula
1And R
2Identical or different, be hydrogen or halogen atom, chlorine or bromine is relatively good, or alkyl or alkoxy base, to contain the better of no more than six carbon atom; R
3Be a aromatic yl group with following formula:
M is 1 or 2 in the formula; Each R(works as m=2) identical or different, be halogen atom; Straight or branched alkyl or alkoxy base to contain the better of at least 2 carbon atoms, contain the better of 5-12 carbon atom; Cycloalkyl, cyclohexyl groups is better; Aralkyl, α-aromatic alkyl group is better; Phenyl or phenoxy group group, or the halogen substituted derivative of phenyl or phenoxy group group, the halogen derivative of para-orientation is relatively good.Halogen atom can be one or two, and chlorine or bromine is relatively good, and when m was 1, R was relatively good in contraposition.And when m is 2, have in two R groups one relatively good in contraposition, R
3In contain at least one, but no more than 3 halogen atoms are relatively good, preferably no more than 2 halogen atoms.
Above-mentioned formula I compound is like this preparation: having in the presence of dewatering agent such as the sulfuric acid, under without the condition of solvent or in organic solvent such as acetate, making the compound condensation of 4 hydroxy coumarin (II) and logical formula III; Perhaps under, make the compound condensation of 4 hydroxy coumarin (II) and logical formula IV without the solvent action solvent condition.
R
1, R
2And R
3Have implication given in the preamble, Hal is a halogen, and chlorine or bromine is relatively good.
The compound of structure formula IV can prepare like this: the compound with the universal architecture formula III is a raw material, in the situation solvent such, use such as the such reaction reagent of phosphorus tribromide, phosphorus trichloride or thionyl chloride it is handled such as methylene dichloride, chloroform or tetracol phenixin.
In above-mentioned preparation process, for the condensation reaction that formula II and formula III compound carry out in acetate, the minimum response temperature of employing is 110 ℃.When not having solvent to exist, the condensation reaction of formula II and (III) compound is normally carried out at 160 ℃～170 ℃.The reaction of formula II compound and (IV) compound carry out at 130 ℃～140 ℃ usually the 1190th～1195 page of (for these several range of reaction temperature in back, can referring to people such as Shadbolt at J.C.S.Perkin 1(1976) No.11 the above).
Two specific compounds of formula I are respectively wherein, R
1With R
2All be hydrogen, and R
3It is the compound (difenacoum) of 4-phenyl group; R
1And R
2All be hydrogen and R
3Be the 4-(4-bromophenyl) compound (brodifacoum) of phenyl group.
Disclose another kind of 4 hydroxy coumarin derivative in Britain's publication specification sheets 126,758 and the corresponding European publication specification sheets 629, they also have the anti-coagulant performance, particularly as rodenticide.By the wideest definition of these compounds, they have the structure of formula (V):
Z represents halogen atom in the formula, and the better n of chlorine atomic ratio is 0,1 or 2; And R
4Perhaps representative (1) comprises the group of phenylene, phenylene is directly or indirectly with 1,2,3,4-tetrahydro-naphthalene nucleus links to each other, have its rotary volume to be not more than the electrophilic atom or the group of the rotary volume of phenyl in fact in the contraposition of phenylene (with respect to the position that links to each other with this tetrahydro-naphthalene nucleus), this atom or group and said phenylene group constitute a polarizable structure; Perhaps representative (2) is selected from a group in the following groups:
Perhaps representative (3) comprises the group of phenylene, phenylene is directly with 1,2,3,4-tetrahydro-naphthalene nucleus links to each other, have in the contraposition of phenylene (position that is connected with this tetrahydro-naphthalene nucleus with respect to it) one directly or by oxygen and (or) furyl (furanyl) or the thiophenyl group of the coupled replacement of methylene radical, this furans or or the thiophenyl group electrophilic atom or group are arranged as substituting group in the position that forms polarizable structure with them, and the rotary volume of this atom or group is not more than the rotary volume of phenyl.
In the superincumbent formula (V), R
4Be defined as more specifically that to be selected from a following group relatively good:
X represents halogen atom or group CN, NO in the formula
2, SO
2, R
5, CF
3, OCF
3, COOR
6Or COR
5, R wherein
5Be C
1-6Alkyl group, n ' is 0,1 or 2, and Y is the fluorine or chlorine atom, its condition is that when X was halogen, n ' was 1 or 2;
In the formula definition of X, n ' and Y as mentioned above n " be 0 or 1, and D is Sauerstoffatom or group-O-(CH
2) m-,-(CH
2) m-,-O-,-O-(CH
2) m ,-O-,-(CH
2) m ,-O-(CH
2) p-,-(CH
2) m-or-CH=CH-, or the similar group of these group sulfur-bearings, wherein m is in 1～6 scope, p is in 1～6 scope, its condition is, when D is Sauerstoffatom and X when being halogen, n ' is 1 or 2, and when D be-during CH=CH-, X can be again a hydrogen atom.
（c）
The definition of X, n ' and Y such as above-mentioned in the formula;
In a group.X and n in the formula " definition such as above-mentioned, A is oxygen or sulphur atom; And D be Sauerstoffatom or-CH
2-group.
Top formula (V) compound is by (for example preparing with the directly similar method of aforesaid preparation, referring to United States Patent (USP) 3, in 957,824 and people such as Shadbolt at J.C.S.Perkin1, described in (1976) No.11 1190-～1195 pages).
We are surprised to find that now, can prepare aforesaid formula I and formula V compound with the productive rate that improves under the condition that is lower than the temperature of reaction that adopts till now.
According to the present invention, we provide a kind of method of the 4 hydroxy coumarin derivative of preparation following formula:
R in the formula
1And R
2Each is since hydrogen, halogen, contain the alkyl of six carbon atom and contain at most in the alkoxyl group of six carbon atom and select R at most
3Be selected from following groups:
（a）
X represents halogen atom or group C in the formula
1-12Alkyl, C
1-12Alkoxyl group, C
3-8Cycloalkyl, CN, SO
2R
5, CF
3, OCF
3, COOR
5Or COR
5, R wherein
5Be C
1-6Alkyl), n ' is 0,1 or 2, and Y is the fluorine or chlorine atom;
（b）
The definition of n ' and Y is the same in the formula, and the same or halogen of the definition of X, n " be 0 or 1, and D are Sauerstoffatom or group-O-(CH
2) m-,-(CH
2) m-O-,-O-(CH
2) m-O-,-(CH
2) m-O-(CH
2) p-,-(CH
2) m-or-CH=CH-, or the similar group of the sulfur-bearing of these groups, wherein m is in 1～6 scope, p is in 1～6 scope;
（c）
The definition of X, n ' and Y is with described in above (a) in the formula;
A group, X and n in the formula " definition with described in top (b), A is Sauerstoffatom or sulphur atom, and D ' be Sauerstoffatom or-CH
2-group, this method comprise, in the presence of organic solvent and catalyzer, makes the compound of 4 hydroxy coumarin and formula VI or corresponding 1, the condensation of 2-dialin,
R in the formula
1, R
2And R
3Definition with above-mentioned, and L is hydroxyl or halogen atom, it is characterized in that, solvent is selected from formic acid, formic acid and at least one C of boiling temperature in 60 ℃～105 ℃ scopes under atmospheric pressure
2-6The mixture of lipid acid with and boiling temperature be not less than 60 ℃ liquid halogenated hydrocarbon, and reaction is carried out in the reaction mixture refluxed temperature range at 60 ℃.
L in the formula VI is relatively good with OH, Br or Cl.
In the formula VI, R
1And R
2All be that hydrogen is relatively good.
When X was not hydrogen, it represented fluorine, chlorine or bromine atom or group CN, NO
2, CF
3Or OCF
3Better, represent chlorine or bromine atom or group CN or CF
3Then better.
R
3So that the better of following formula structure to be arranged:
And D is Sauerstoffatom, group-O-CH
2-,-CH
2-CH
2-CH
2-,-CH
2-CH
2Or-CH=CH-is relatively good.Be more preferably, n ' is 0, n, and " be 0 or 1, D is Sauerstoffatom or group-O-CH
2-, and X is group CF
3, H, CN or Br.
Using method of the present invention, to prepare following compounds be very favourable: " difenacoum ", " brodifacoum " or 3-(3-(4-(4-trifluoromethyl benzyloxy) phenyl)-1,2,3, and 4-tetrahydrochysene-1-naphthyl)-4 hydroxy coumarin.
Used organic solvent can be formic acid or its boiling temperature formic acid and at least one C in 60 ℃ to 105 ℃ scopes under atmospheric pressure
2-6The mixture of lipid acid.With the mixture of formic acid (100.5 ℃ of boiling temperatures) and glacial acetic acid (118 ℃ of boiling temperatures), its boiling temperature is in this scope, and it is better that particularly formic acid/acetate volume ratio is about 3: 1 mixture.
When adopting this solvent, appropriate catalyst can be mineral acid, as sulfuric acid, be more preferably phosphoric acid; The salt of acid is as sal enixum; Lewis acid is as iron(ic) chloride, zinc chloride or Repone K; Or silica gel.
Corresponding to the temperature of reaction of such solvent system 70 ℃ relatively good in the reflow temperature range, then better in the reflow temperature range at 80 ℃.
In method preferably of the present invention, solvent for use is a liquid halogenated hydrocarbon, and the halogenated alkane that is not less than 60 ° with its boiling temperature under the normal atmosphere is for well, and catalyst system therefor is a kind of sulfonic acid, is reflected at 60 ℃ and carries out in the reaction mixture refluxed temperature range.
Used halohydrocarbon is 1 liquid at ambient temperature.That very suitable is liquid chloroparaffin, for example C
2-4Two and three chloro alkane.
The example of this halogenated alkane comprises: 1,2-ethylene dichloride (83 ℃～84 ℃ of boiling points), 1,1,2-trichloroethane (113 ℃～114 ℃ of boiling points), 1 (74 ℃～75 ℃ of boiling points), 1, propylidene chloride 1 (87 ℃ of boiling points), 1,2-propylene dichloride (95 ℃～96 ℃ of boiling points) and 1,3-propylene dichloride (125 ℃ of boiling points) is conspicuous to other this class halohydrocarbon to the skilled person in the present technique field.Have been found that: 1,2-ethylene dichloride, vinyl trichloride and 1, the 3-propylene dichloride is most suitable.
The example of used sulfonic acid comprises methylsulfonic acid, trifluoromethanesulfonic acid and aryl sulfonic acid such as Phenylsulfonic acid and tosic acid.
In the method for the invention, the relative consumption to all ingredients does not have very strict requirement.But way is preferably, for every mole of formula VI compound, uses 1～4 mole 4 hydroxy coumarin better; Use 1～3 mole better.Under the situation of using sulfonic acid catalyst, then use 0.25～2 mole of sulfonic acid better to every mole of formula VI compound, use 0.5～1.5 mole sulfonic acid better.
Can further understand the present invention by the following example.
Embodiment 1
Under nitrogen protection; in Dean and Stark apparatus; with the 3-(4-(4-trifluoromethyl benzyloxy) phenyl)-1; 2; 3,4-tetrahydrochysene-1-naphthols (8 grams, 0.02 mole), 4 hydroxy coumarin (6.5 grams; 0.04 mole) and tosic acid (1.9 grams, 0.01 mole) 24 hours (methylene dichloride boiling point: 83～84 ℃) of backflow in methylene dichloride (80 milliliters).Then gained solution is cooled off, washing, evaporation obtains solid residue, is that eluent is purified with chromatography on silicagel column with the methylene dichloride, obtain 3-(3-(4-(4-trifluoromethyl benzyloxy) phenyl)-1,2,3,4-tetrahydrochysene-1-naphthyl)-4 hydroxy coumarin (9.9 grams, 90%), fusing point is 85 ℃～86 ℃.
Embodiment 2
With 1-chloro-3-(4-(4-trifluoromethyl benzyloxy) phenyl)-1,2,3,4-tetraline (2.08 grams, 0.005 mole) and 4 hydroxy coumarin (2.49 gram, 0.015 mole) add mixture (3: 1 volume/volume of the formic acid and the glacial acetic acid that contain phosphoric acid (100 milligrams); 8 milliliters) in.Mixture refluxes under nitrogen protection and stirred 3 hours.The gained mixture cools off and with the methylene dichloride dilution, obtains solution, washes this solution.The evaporation dichloromethane solution obtains solid residue, is that eluent is used chromatographic purification with the methylene dichloride on silicagel column, obtain 3-(3-(4-(4-phenylfluoroform benzyloxy) phenyl)-1,2,3,4-tetrahydrochysene-1-naphthyl)-and 4 hydroxy coumarin (1.6 gram 60%), fusing point: 85～86 ℃.
Embodiment 3～14
3-(3-(4-(4-trifluoromethyl benzyloxy) phenyl)-1,2,3,4-tetrahydrochysene-1-naphthyl)-4 hydroxy coumarin is the preparation of improving one's methods with method among the embodiment 1, in embodiment 8～14, and the amount of solvent more (130 milliliters).Provided these in the table I below and improved one's methods and the phase product yield, wherein S.M. represents raw material, and " hydoxy " is the naphthol derivative that uses among the embodiment 1, " chloro " is the 1-chloronaphthalene derivative that uses among the embodiment 2, PTSA is a tosic acid, and BSA is a Phenylsulfonic acid, and MSA is a methylsulfonic acid, DCE is 1,2-ethylene dichloride (83～84 ℃ of boiling points) TCE is vinyl trichloride (113～114 ℃ of a boiling point), and DCP is 1,3-propylene dichloride (125 ℃ of boiling points).
Embodiment 15
In Dean and Stark apparatus, with 3-(4 '-bromo biphenyl-4-yl)-1,2,3,4-tetrahydrochysene-1-naphthols (7.56 grams, 0.02 mole), 4 hydroxy coumarin (0.04 mole of 6.5 gram) and tosic acid (1.9 grams, 0.01, refluxed 24 hours in the 2-ethylene dichloride (130 milliliters) mole) 1.Cooling gained solution adds methylene dichloride (150 milliliters), this solution 5%(weight/volume) aqueous sodium carbonate (2 * 100 milliliters) and water (150 milliliters) wash drying (MgSO
4), evaporation obtains solid residue, is that eluent is used chromatographic purification with the methylene dichloride on silicagel column, obtain " brodifacoum ", i.e. 3-(3-(4 '-bromo biphenyl-4-yl)-1,2,3,4-tetrahydrochysene-1-naphthyl)-and 4 hydroxy coumarin (9.7 grams, 93%), 228～235 ℃ of fusing points.
Embodiment 16
Operate according to method described in the embodiment 15, just replace 1 with vinyl trichloride (20 milliliters), the 2-ethylene dichloride, the time of the mixture of answering that refluxes be 6 hours (be not 24 hours.Obtain " brodifacoum " (8.8 grams, 84%), 228～235 ℃ of fusing points.
Embodiment 17
Operate according to method described in the embodiment 15, just with 3-biphenyl-4-base-1,2,3,4-tetrahydrochysene-1-naphthols replaces bromo compound, products therefrom is 3-(3-biphenyl-4-base-1 for " difenacoum ", 2,3,4-tetrahydrochysene-1-naphthyl)-4 hydroxy coumarin, its fusing point is 215～219 ℃, and yield is 95%.
Embodiment 18
Improving one's methods of embodiment 16 is applied to the method for embodiment 17, obtains " difenacoum ", its fusing point is 215～219 ℃, and yield is 83%.
Embodiment 19
According to the operation of method described in the embodiment 17, just adopt 2-biphenyl-4-base-1, the 2-dihydronaphthalene replaces naphthols.Get " difenacoum ", its fusing point is 215～219 ℃, and yield is 76%.
Comparative Examples A (according to GB-A-2, the 126,578,10th page of the 44th row is to the 11st page of the 2nd row and the 7th page of the 55th～59 row)
With 3-(4-(4-difluoromethyl benzyloxy) phenyl)-1,2,3, the mixture of 4-tetrahydrochysene-1-naphthols (3.9 grams, 9.8 mmoles) and 4 hydroxy coumarin (1.8 grams, 11.1 mmoles) was 160～170 ℃ of heating 1 hour.After the gained mixture is cooled to envrionment temperature, on silicagel column, be the eluent chromatographic purification, obtain 3-(3-(4-(4-trifluoromethyl benzyloxy)-phenyl with the methylene dichloride) 1,2,3,4-tetrahydrochysene-1-naphthyl)-4 hydroxy coumarin (2.35 grams, 44%) fusing point: 85～86 ℃.
The table I
The sulfonic acid that every mole of S.M. of real S.M. reaction response uses (acid (mole)/S.M. (mole) ］ the solvent yield
Execute temperature-time 4 hydroxy coumarin/S.M.(mole))
The example (hour) mole number
3 hydroxy, 22 3 pTSA(1 that reflux) DCE 87
4 chloro, 24 3 pTSA(1 that reflux) DCE 74
5 hydroxy, 24 3 pTSA(0.5 that reflux) DCE 82
6 hydroxy, 24 3 pTSA(1.5 that reflux) DCE 82
7 hydroxy, 24 3 pTSA(0.5 that reflux) DCE 87
8 hydroxy, 26 1.05 pTSA(0.5 that reflux) DCE 88
9 hydroxy, 25 2 pTSA(0.5 that reflux) DCE 92.25
10 hydroxy, 25 1 pTSA(0.5 that reflux) DCE 90
11 hydroxy, 26 2 pTSA(0.5 that reflux) TCE 90
12 hydroxy, 26 2 pTSA(0.5 that reflux) DCP 90
13 hydroxy, 24 2 MSA(0.5 that reflux) DCE 92
14 hydroxy, 24 2 BSA(0.5 that reflux) DCE 92.5
Claims (16)
1, the method for the 4 hydroxy coumarin derivative of preparation formula I
R wherein
1And R
2Be hydrogen, R
3For
Wherein X is a hydrogen, bromine or CF
3, n is 0 or 1, D is-O-CH
2-, this method comprises: in the presence of organic solvent or catalyzer, with the compound of 4 hydroxy coumarin and formula VI or corresponding 1,2-dihydronaphthalene
(R in the formula
1, R
2And R
3Define the samely, L is hydroxyl or halogen atom) condensation, this method feature is: solvent is selected from formic acid, and formic acid is with under atmospheric pressure, at least one C that boiling point is 60 ℃-105 ℃
2-6The liquid halohydrocarbon that the mixture of lipid acid and boiling point are at least 60 ℃, this reaction are to carry out to the reflux temperature of reaction mixture at 60 ℃.
2, according to the process of claim 1 wherein that solvent is liquid halohydrocarbon, catalyzer is a sulfonic acid.
3, according to the process of claim 1 wherein that liquid halohydrocarbon is an alkyl chloride.
4, according to the method for claim 2, wherein liquid halohydrocarbon is an alkyl chloride.
5, according to the method for claim 3, wherein alkyl chloride is selected from two and trichlorine C
2-4Alkane.
6, according to the method for claim 4, wherein hydrochloric ether is selected from two and trichlorine C
2-4Alkane.
7, according to the method for claim 5, wherein alkyl chloride is selected from 1,2-ethylene dichloride, vinyl trichloride and 1,3-propylene dichloride.
8, according to the method for claim 6, wherein alkyl chloride is selected from 1,2-ethylene dichloride, vinyl trichloride and 1,3-propylene dichloride.
9, according to the process of claim 1 wherein that catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids.
10, according to the method for claim 2, wherein catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids.
11, according to the method for claim 3, wherein catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and right-toluene, sulfonic acid.
12, according to the method for claim 4, catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids.
13, according to the method for claim 5, wherein catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids.
14, according to the method for claim 6, wherein catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids.
15, according to the method for claim 7, wherein catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and tosic acid.
16, method according to Claim 8, wherein catalyzer is selected from methylsulfonic acid, Phenylsulfonic acid and tosic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85107609 CN1011786B (en) | 1984-09-26 | 1985-10-16 | Process for preparing 4-hydroxycoumarin derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848424317A GB8424317D0 (en) | 1984-09-26 | 1984-09-26 | 4-hydroxycourmarin derivatives |
| CN 85107609 CN1011786B (en) | 1984-09-26 | 1985-10-16 | Process for preparing 4-hydroxycoumarin derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85107609A CN85107609A (en) | 1987-04-15 |
| CN1011786B true CN1011786B (en) | 1991-02-27 |
Family
ID=25742113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85107609 Expired CN1011786B (en) | 1984-09-26 | 1985-10-16 | Process for preparing 4-hydroxycoumarin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1011786B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100521944C (en) * | 2000-01-18 | 2009-08-05 | 拜尔公司 | Combination of biological and chemical agents to combat rodents |
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|---|---|---|---|---|
| CN102617537A (en) * | 2011-01-30 | 2012-08-01 | 南京理工大学 | Preparation method of flocoumafen |
-
1985
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100521944C (en) * | 2000-01-18 | 2009-08-05 | 拜尔公司 | Combination of biological and chemical agents to combat rodents |
Also Published As
| Publication number | Publication date |
|---|---|
| CN85107609A (en) | 1987-04-15 |
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