WO1995015322A1 - Process for the preparation of substituted 4-hydroxycoumarins - Google Patents
Process for the preparation of substituted 4-hydroxycoumarins Download PDFInfo
- Publication number
- WO1995015322A1 WO1995015322A1 PCT/GB1994/002591 GB9402591W WO9515322A1 WO 1995015322 A1 WO1995015322 A1 WO 1995015322A1 GB 9402591 W GB9402591 W GB 9402591W WO 9515322 A1 WO9515322 A1 WO 9515322A1
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- WO
- WIPO (PCT)
- Prior art keywords
- acid
- catalyst
- solvent
- substituted
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
Definitions
- This invention concerns a process for preparing substituted 4-hydroxycoumarins.
- R is selected from hydrogen, phenyl, substituted phenyl, alkyl and substituted alkyl groups
- R is selected from hydrogen, phenyl, substituted phenyl, alkyl and substituted alkyl groups
- R is selected from hydrogen, phenyl, substituted phenyl, alkyl and substituted alkyl groups
- EP 177,080 has further modified the process for the manufacture of compounds of general formula (I) by reacting 4-hydroxycoumarin with compounds of general formula (II) in the presence of a catalyst and an organic solvent selected from formic acid, a mixture of formic acid and a least one C2-6 aliphatic acid having a boiling temperature at atmospheric pressure in the range of 60°C to 105°C and a liquid chlorinated alkane having a boiling temperature in the range 60°C to 125°C and effecting the reaction at a temperature in the range of 60°C to the reflux temperature of the reaction mixture.
- the catalyst is preferably a sulphonic acid, especially selected from methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid.
- a sulphonic acid especially selected from methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid.
- An object of this invention is to provide an improved process for preparing substituted 4- hydroxycoumarins of the general formula (I) defined above.
- the reaction may be conducted in liquid aromatic hydrocarbons, such as toluene, xylene or benzene with similar or even better yields than hitherto and with a considerably easier work-up technique.
- this invention provides a process for preparing compounds of general formula (I) above wherein R is selected from hydrogen, phenyl, substituted phenyl, alkyl and substituted alkyl groups by reacting 4- hydroxycoumarin and a substituted tetralol of the general formula
- R as defined above, in the presence of an organic solvent and a catalyst, characterised in that the solvent is an aromatic hydrocarbon.
- the aromatic hydrocarbon solvent is preferably selected from benzene, toluene and xylene.
- the reaction is preferably carried out at the boiling point of the solvent and preferably with the azeotropic removal of water.
- the catalyst for use in the process of the invention is preferably an acid, especially a sulphonic acid.
- Preferred sulphonic acid catalysts are p- toluenesulphonic acid, benzenesulphonic acid and methanesulphonic acid.
- Yet another alternative preferred catalyst for use in the invention is a carboxylic acid, especially a strong carboxylic acid, such as trichloroacetic acid.
- a further improvement which may result from the process of the invention is that better yields of product may be realisable using smaller quantities of the relatively expensive raw material 4-hydroxycoumarin and the catalyst, such as, p-toluenesulphonic acid.
- the catalyst such as, p-toluenesulphonic acid.
- the limiting factor in the choice of acid is that it may either be quantitatively removed from the reaction medium by filtration or may have sufficient solubility in the reaction medium that it is removable in the solvent stream on isolation of the product.
- Toluene (75cm 3 ) was removed by distillation and methanol (100cm 3 ) added. Boiling under reflux was continued for a further 2 hours during which time crystallisation occurred. The suspension was cooled to ⁇ 20°C and aged at this temperature overnight. The suspension was filtered and washed with methanol (2x20cm 3 ). Difenacoum (19.4g; 87.4%) of satisfactory quality was obtained.
- Brodifacoum was prepared in 94% yield based on 3-(4'-bromodiphenyl- 4-yl)-1,2,3,4-tetrahydro-l-naphthol.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Cephalosporin Compounds (AREA)
- Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
A process for preparing compounds of general formula (I) wherein R is selected from hydrogen, phenyl, substituted phenyl, alkyl and substituted alkyl groups comprises reacting 4-hydroxycoumarin and a substituted tetralol of general formula (II) wherein R is as defined above, in the presence of an aromatic hydrocarbon and a catalyst.
Description
DESCRIPTION Title: Process for the preparation of substituted 4- hydroxycoumarins.
This invention concerns a process for preparing substituted 4-hydroxycoumarins.
4-Hydroxycoumarins substituted in the 3-position having the following general formula (I)
X = OH, halogen; R as defined above GB 1,518,858 has further demonstrated the preparation of compounds of general formula (I) by the reaction of 4-hydroxycoumarin with compounds of general formula (III) in the presence of a suitable acidic catalyst.
R as defined above
EP 177,080 has further modified the process for the manufacture of compounds of general formula (I) by reacting 4-hydroxycoumarin with compounds of general formula (II) in the presence of a catalyst and an organic solvent selected from formic acid, a mixture of formic acid and a least one C2-6 aliphatic acid having a boiling temperature at atmospheric pressure in the range of 60°C to 105°C and a liquid chlorinated alkane having a boiling temperature in the range 60°C to 125°C and effecting the reaction at a temperature in the range of 60°C to the reflux temperature of the reaction mixture. The catalyst is preferably a sulphonic acid, especially selected from methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid. Whereas any of the above methods may be used on an industrial scale to manufacture compounds of general formula (I), they all have scope for improvement. Although the process of EP 017808 can be utilised conveniently on manufacturing scale, it still utilises 1, 2-dichloroethane, which is an environmentally harmful solvent.
An object of this invention is to provide an improved process for preparing substituted 4- hydroxycoumarins of the general formula (I) defined above.
We have surprisingly found that the reaction may be conducted in liquid aromatic hydrocarbons, such as toluene, xylene or benzene with similar or even better yields than hitherto and with a considerably easier work-up technique.
Accordingly this invention provides a process for preparing compounds of general formula (I) above wherein R is selected from hydrogen, phenyl, substituted phenyl, alkyl and substituted alkyl groups by reacting 4- hydroxycoumarin and a substituted tetralol of the general formula
wherein R as defined above, in the presence of an organic solvent and a catalyst, characterised in that the solvent is an aromatic hydrocarbon. The aromatic hydrocarbon solvent is preferably selected from benzene, toluene and xylene. The reaction is preferably carried out at the boiling point of the solvent and preferably with the azeotropic removal of water. The catalyst for use in the process of the
invention is preferably an acid, especially a sulphonic acid. Preferred sulphonic acid catalysts are p- toluenesulphonic acid, benzenesulphonic acid and methanesulphonic acid. Yet another alternative preferred catalyst for use in the invention is a carboxylic acid, especially a strong carboxylic acid, such as trichloroacetic acid.
At the end of the reaction period, excess solvent may be removed by distillation and replaced by, for example methanol. After stirring in the now mixed solvent of methanol and aromatic hydrocarbon, such as toluene, benzene or xylene, for a few hours, the product crystallises and may be isolated by techniques such as organic vacuum filtration and washing. The use of such solvent systems described herein may considerably and significantly lessen the environmental impact of any vapours which may escape via the scrubbing system to atmosphere. Furthermore, when the process of this invention is utilised, no aqueous effluents need be produced, thereby preventing accidental discharge of water contaminated with trace amounts of organic materials to the sewerage system. For these reasons alone the process of the present invention represents a significant improvement over prior art processes. A further improvement which may result from the process of the invention is that better yields of
product may be realisable using smaller quantities of the relatively expensive raw material 4-hydroxycoumarin and the catalyst, such as, p-toluenesulphonic acid. Thus, in the method cited in the literature, 2.0 mols of 4-hydroxycoumarin / mol tetralol have to be utilised for a good reaction whereas in the method of the present invention the ratio may be less than 2:1, typically of the order of 1.5:1. The amount of catalyst, such as p- toluenesulphonic acid, may be reduced from 1.05 mols/mol tetralol to as low as 0.16 mols/mol. Whereas this reduction in amount of catalyst is not significant in financial terms, the modification represents a significant advance in the ease of work-up of the product. The catalyst which is employed to bring about a good reaction is almost any strong acid. Previously, aromatic sulphonic acids have been successfully employed. These catalysts are adequate for the purpose but have the disadvantage of only having a small solubility in the solvent systems described herein. This may be the reason that much reduced quantities of, for example, p-toluenesulphonic acid are required in the present invention; the excess acid being insoluble in the reaction medium can take no part in the reaction. We have discovered that the more soluble trichloroacetic acid can act as the catalyst and give good reaction.
This may ease the work-up conditions as the catalyst is removed in the solvent on filtration of the final product. It is thus anticipated that any strong acid of pKa of <=0.9 may be utilised in the reaction. The limiting factor in the choice of acid (apart from pKa value being <=0.9) is that it may either be quantitatively removed from the reaction medium by filtration or may have sufficient solubility in the reaction medium that it is removable in the solvent stream on isolation of the product.
The invention will now be illustrated by means of the following examples.
Example 1 Preparation of 3-(3-biphenyl-4-yl-l,2,3,4- tetrahydro-l-naphthyl)-4-hydroxycoumarin. (Difenacoum)
A mixture of toluene (100cm3) and p- toluenesulphonic acid (2.0g; 11.16 mmol) was heated together under reflux in a reaction vessel equipped with a Dean and Stark apparatus. Any water present was removed via the Dean and Stark apparatus. After cooling to <30°C 4-hydroxycoumarin (12.0g; 74 mmol) and 3- (biphenyl-4-yl)-l,2,3,4-tetrahydro-l-naphthol (15.Og; 50 mmol) were added. The mixture was heated to reflux again and water removed via the Dean and Stark apparatus. Heating was continued for 20 hours when the reaction was deemed to be complete. Toluene (75cm3) was
removed by distillation and methanol (100cm3) added. Boiling under reflux was continued for a further 2 hours during which time crystallisation occurred. The suspension was cooled to <20°C and aged at this temperature overnight. The suspension was filtered and washed with methanol (2x20cm3). Difenacoum (19.4g; 87.4%) of satisfactory quality was obtained.
Example 2 Preparation of 3-[3-(4'-bromobiphenyl-4-yl)- 1,2,3,4-tetrahydro-l-naphthyl]-4-hyroxycoumarin. (Brodifacoum)
By the method described in Example l, Brodifacoum was prepared in 94% yield based on 3-(4'-bromodiphenyl- 4-yl)-1,2,3,4-tetrahydro-l-naphthol.
Claims
1. A process for preparing compounds of general formula (I)
ω wherein R is selected from hydrogen, phenyl, substituted phenyl, alkyl groups by reacting 4-hydroxycoumarin and a substituted tetralol of the general formula
wherein R is as defined above, in the presence of an organic solvent and a catalyst, characterised in that the solvent is an aromatic hydrocarbon.
2. A process as claimed in claim 1, characterised in that the solvent is selected from benzene, toluene and xylene.
3. A process as claimed in claim 1 and 2, characterised in that the reaction is carried out at the boiling point of the solvent.
4. A process as claimed in claim 1, 2 or 3, characterised in that the reaction is carried out with the azeotropic removal of water.
5. A process as claimed in any one of the preceding claims, characterised in that the catalyst is a sulphonic acid.
6. A process as claimed in claim 5, characterised in that the catalyst is selected from p-toluenesulphonic acid, benzenesulphonic acid and methanesulphonic acid.
7. A process as claimed in any one of claims 1 to 4, characterised in that the catalyst is a strong carboxylic acid.
8. A process as claimed in claim 6, characterised in that the catalyst is trichloroacetic acid.
9. A process as claimed in any one of the preceding claims, characterised in that the reaction is worked up by addition of a precipitant.
10. A process as claimed in claim 9, characterised in that the precipitant is methanol.
11. A process as claimed in any one of the preceding claims, wherein R is hydrogen.
12. A process as claimed in any one of the preceding claims, wherein R is — —<
13. A process as claimed in any one of the preceding claims, wherein R is — rf— /~βr 14. A process as one of the preceding claims , wherein R is 
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP95902843A EP0681577B1 (en) | 1993-11-30 | 1994-11-25 | Process for the preparation of substituted 4-hydroxycoumarins |
| ES95902843T ES2138182T3 (en) | 1993-11-30 | 1994-11-25 | PREPARATION PROCEDURE FOR SUBSTITUTED 4-HYDROXICUMARINES. |
| RU95115557A RU2128657C1 (en) | 1993-11-30 | 1994-11-25 | Method of preparing substituted 4-hydroxycumarines |
| BR9406075A BR9406075A (en) | 1993-11-30 | 1994-11-25 | Process for the preparation of a compound |
| FI953617A FI953617L (en) | 1993-11-30 | 1994-11-25 | Process for the preparation of substituted 4-hydroxycoumarins |
| DE69420702T DE69420702T2 (en) | 1993-11-30 | 1994-11-25 | METHOD FOR PRODUCING SUBSTITUTED 4-HYDROXY KUMARINE |
| JP7515466A JPH08509240A (en) | 1993-11-30 | 1994-11-25 | Method for producing substituted 4-hydroxycoumarins |
| DK95902843T DK0681577T3 (en) | 1993-11-30 | 1994-11-25 | Process for preparing substituted 4-hydroxycoumarins |
| KR1019950703102A KR100369750B1 (en) | 1993-11-30 | 1994-11-25 | Method for preparing substituted 4-hydroxycoumarin |
| AU11940/95A AU674809B2 (en) | 1993-11-30 | 1994-11-25 | Process for the preparation of substituted 4-hydroxycoumarins |
| CA002155127A CA2155127C (en) | 1993-11-30 | 1994-11-25 | Process for the preparation of substituted 4-hydroxycoumarins |
| NO952901A NO952901L (en) | 1993-11-30 | 1995-07-21 | Process for preparation of substituted 4-hydroxy coumarins |
| GR990403183T GR3032092T3 (en) | 1993-11-30 | 1999-12-08 | Process for the preparation of substituted 4-hydroxycoumarins. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9324517.3 | 1993-11-30 | ||
| GB939324517A GB9324517D0 (en) | 1993-11-30 | 1993-11-30 | Process for the preparation of substituted 4-hydroxycoumarins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995015322A1 true WO1995015322A1 (en) | 1995-06-08 |
Family
ID=10745872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1994/002591 Ceased WO1995015322A1 (en) | 1993-11-30 | 1994-11-25 | Process for the preparation of substituted 4-hydroxycoumarins |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0681577B1 (en) |
| JP (1) | JPH08509240A (en) |
| KR (1) | KR100369750B1 (en) |
| CN (1) | CN1050602C (en) |
| AT (1) | ATE184600T1 (en) |
| AU (1) | AU674809B2 (en) |
| BR (1) | BR9406075A (en) |
| CA (1) | CA2155127C (en) |
| DE (1) | DE69420702T2 (en) |
| DK (1) | DK0681577T3 (en) |
| ES (1) | ES2138182T3 (en) |
| FI (1) | FI953617L (en) |
| GB (1) | GB9324517D0 (en) |
| GR (1) | GR3032092T3 (en) |
| HU (1) | HU214208B (en) |
| IN (1) | IN178780B (en) |
| NO (1) | NO952901L (en) |
| RU (1) | RU2128657C1 (en) |
| SG (1) | SG52522A1 (en) |
| TW (1) | TW308592B (en) |
| WO (1) | WO1995015322A1 (en) |
| ZA (1) | ZA949470B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7253208B2 (en) * | 2004-04-08 | 2007-08-07 | Aryx Therapeutics | Materials and methods for treating coagulation disorders |
| PT1735296E (en) * | 2004-04-08 | 2010-02-09 | Aryx Therapeutics | Materials and methods for treating coagulation disorders |
| KR100833652B1 (en) * | 2006-12-28 | 2008-05-29 | 한국화학연구원 | Composition for the prevention or treatment of degenerative brain diseases, including pagoji seed extract that inhibits the activity of BAC-1 or an active substance isolated therefrom |
| CN102070427B (en) * | 2011-01-10 | 2013-06-05 | 南通功成精细化工有限公司 | Synthesis methods of flocumafen and flocumafen intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1458670A (en) * | 1973-05-23 | 1976-12-15 | Ward Blenkinsop & Co Ltd | Anti coagulant 3-tetrahydronaphthyl-4-hydroxy-coumarin deri vatives |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU697515A1 (en) * | 1978-03-17 | 1979-11-15 | Московский Ордена Ленина И Ордена Трудового Красного Знамени Химикотехнологический Институт Им. Д.И. Менделеева | Method of preparing 3-thio-derivatives of 4-hydroxycumarine |
| EP0098629B1 (en) * | 1982-06-14 | 1987-08-26 | Shell Internationale Researchmaatschappij B.V. | Anti-coagulants of the 4-hydroxycoumarin type, the preparation thereof, and rodenticidal compositions (baits) comprising such anti-coagulants |
| GB8424317D0 (en) * | 1984-09-26 | 1984-10-31 | Shell Int Research | 4-hydroxycourmarin derivatives |
| GB8531388D0 (en) * | 1985-12-20 | 1986-02-05 | Shell Int Research | 4-hydroxycoumarin derivatives |
| DE10161978A1 (en) * | 2001-12-17 | 2003-06-26 | Bayer Ag | Preparation of 2-haloacyl-3-amino-acrylic acid ester preparation, for use as intermediates for drugs and/or agrochemicals, from N-substituted 3-amino-acrylic acid ester and haloalkanoic acid anhydride |
-
1993
- 1993-11-30 GB GB939324517A patent/GB9324517D0/en active Pending
-
1994
- 1994-11-25 FI FI953617A patent/FI953617L/en unknown
- 1994-11-25 SG SG1996005478A patent/SG52522A1/en unknown
- 1994-11-25 HU HU9502259A patent/HU214208B/en not_active IP Right Cessation
- 1994-11-25 RU RU95115557A patent/RU2128657C1/en active
- 1994-11-25 AU AU11940/95A patent/AU674809B2/en not_active Ceased
- 1994-11-25 EP EP95902843A patent/EP0681577B1/en not_active Expired - Lifetime
- 1994-11-25 WO PCT/GB1994/002591 patent/WO1995015322A1/en not_active Ceased
- 1994-11-25 JP JP7515466A patent/JPH08509240A/en active Pending
- 1994-11-25 CN CN94191292A patent/CN1050602C/en not_active Expired - Fee Related
- 1994-11-25 CA CA002155127A patent/CA2155127C/en not_active Expired - Fee Related
- 1994-11-25 KR KR1019950703102A patent/KR100369750B1/en not_active Expired - Fee Related
- 1994-11-25 ES ES95902843T patent/ES2138182T3/en not_active Expired - Lifetime
- 1994-11-25 DE DE69420702T patent/DE69420702T2/en not_active Expired - Fee Related
- 1994-11-25 AT AT95902843T patent/ATE184600T1/en not_active IP Right Cessation
- 1994-11-25 DK DK95902843T patent/DK0681577T3/en active
- 1994-11-25 BR BR9406075A patent/BR9406075A/en not_active IP Right Cessation
- 1994-11-29 ZA ZA949470A patent/ZA949470B/en unknown
- 1994-11-30 IN IN1188MA1994 patent/IN178780B/en unknown
-
1995
- 1995-02-27 TW TW084101786A patent/TW308592B/zh active
- 1995-07-21 NO NO952901A patent/NO952901L/en not_active Application Discontinuation
-
1999
- 1999-12-08 GR GR990403183T patent/GR3032092T3/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1458670A (en) * | 1973-05-23 | 1976-12-15 | Ward Blenkinsop & Co Ltd | Anti coagulant 3-tetrahydronaphthyl-4-hydroxy-coumarin deri vatives |
Also Published As
| Publication number | Publication date |
|---|---|
| KR960700240A (en) | 1996-01-19 |
| TW308592B (en) | 1997-06-21 |
| JPH08509240A (en) | 1996-10-01 |
| HUT71986A (en) | 1996-03-28 |
| ATE184600T1 (en) | 1999-10-15 |
| DK0681577T3 (en) | 2000-01-31 |
| HU9502259D0 (en) | 1995-10-30 |
| FI953617A0 (en) | 1995-07-28 |
| FI953617A7 (en) | 1995-07-28 |
| IN178780B (en) | 1997-06-21 |
| GB9324517D0 (en) | 1994-01-19 |
| EP0681577B1 (en) | 1999-09-15 |
| NO952901D0 (en) | 1995-07-21 |
| EP0681577A1 (en) | 1995-11-15 |
| GR3032092T3 (en) | 2000-03-31 |
| ES2138182T3 (en) | 2000-01-01 |
| CN1050602C (en) | 2000-03-22 |
| AU674809B2 (en) | 1997-01-09 |
| KR100369750B1 (en) | 2005-08-17 |
| NO952901L (en) | 1995-09-21 |
| HU214208B (en) | 1998-01-28 |
| AU1194095A (en) | 1995-06-19 |
| DE69420702T2 (en) | 2000-05-31 |
| DE69420702D1 (en) | 1999-10-21 |
| CA2155127A1 (en) | 1995-06-08 |
| ZA949470B (en) | 1995-09-14 |
| CN1118597A (en) | 1996-03-13 |
| SG52522A1 (en) | 1998-09-28 |
| RU2128657C1 (en) | 1999-04-10 |
| FI953617L (en) | 1995-07-28 |
| BR9406075A (en) | 1996-01-16 |
| CA2155127C (en) | 2001-07-24 |
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