GB1586798A - Preparation of optionally substituted phenyl- and naphthyl-alkanoic acids - Google Patents
Preparation of optionally substituted phenyl- and naphthyl-alkanoic acids Download PDFInfo
- Publication number
- GB1586798A GB1586798A GB4878177A GB4878177A GB1586798A GB 1586798 A GB1586798 A GB 1586798A GB 4878177 A GB4878177 A GB 4878177A GB 4878177 A GB4878177 A GB 4878177A GB 1586798 A GB1586798 A GB 1586798A
- Authority
- GB
- United Kingdom
- Prior art keywords
- phenoxyphenyl
- mole
- mixture
- oxidation
- acetic acid
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/21—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen
- C07C51/255—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of compounds containing six-membered aromatic rings without ring-splitting
- C07C51/265—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of compounds containing six-membered aromatic rings without ring-splitting having alkyl side chains which are oxidised to carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/34—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with ozone; by hydrolysis of ozonides
Abstract
Phenylalkylcarboxylic acids of the formula (I) are prepared by oxidising alkene derivatives of the formula (II). The substituents R<1> to R<8> are defined in Claim 1. Examples of oxidising agents which can be used are potassium permanganate or chromium trioxide in acid medium or ozone-saturated oxygen. Ozonides formed as intermediates are decomposed with hydrogen peroxide. Phenylcarboxylic acids of the formula (I) can be used as pharmaceuticals by reason of their excellent anti-inflammatory properties. <IMAGE>
Description
(54) PREPARATION OF OPTIONALLY SUBSTITUTED
PHENYL- AND NAPHTHYL-ALKANOIC ACIDS
(71) We, CHINOIN GYOGYSZER ES
VEGYESZETI TERMEKEK GYARA RT., a body corporate organised under the laws of Hungary of 1--5 Toy., Budapest IV,
Hungary, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to a new process for the preparation of optionally substituted phenyl- and naphthyl-alkanoic acids.
These compounds include therapeutically useful anti-inflammatory agents.
The preparation of compounds of this class has been disclosed in U.S. Patent
Specification No. 3,600,437, German Patent
Specification No. 1,941,625, in Belgian
Patent Specifications Nos. 737,417 and 621,225, in British Patent Specifications
Nos. 971,700, 1,132,318 and 1,552,202, in
French Patent Specifications Nos. 1,549,728 and 1,545,270 and in Hungarian Patent
Specifications Nos. 166,290 and 168,046.
The common feature of all the processes mentioned above is that during the preparation of the phenylalkanoic acid or the phenylalkyl cyanide from which the acid may be formed by hydrolysis, the critical step is the formation of the bond between the carbon atom of the carboxylic acid group and the alkyl group. These synthesic methods either succeed with a bad yield or give the desired product by complex processing of intermediate products which are difficult to purify.
The disadvantages may be eleminated by a synthetic method which does not involve the bond problem of the carbon atom of the carboxylic acid. This problem is solved by the process disclosed in British Patent
Specification No. 1,522,202, according to which as starting materials acetylenes are used which are converted to esters in the presence of alcohol with thallium [II] nitrate with isomerisation and, if desired, the alkoxy-carbonyl group is converted to a carboxylic group by hydrolysis.
Our invention is directed to a process for the preparation of phenyl- and naphthylalkanoic acids of the general formula I
wherein
R' is hydrogen, C14 alkyl or C7~,0 aralkyl,
R2 is hydrogen or halogen,
R3 is C16 alkyl, C7~,0 aralkyl, phenyl,
phenoxy, or -NH-R4 wherein R4 is a
phenyl group optionally substituted
with one or two halogen atoms; or
R2 and R3 may together form a fused
benzene ring which may optionally be
substituted with C14 alkoxy group,
which comprises oxidizing an alkene
derivative of the general formula II
wherein
R', R2, R3, R4, R5, and R6 are as defined
above,
R7 and R3 are hydrogen, C14 alkyl, C56 cycloalkyl or phenyl, or
R7 and R8 together with the carbon atom
to which they are attached form a five
or six-membered ring.
The substituents in the present invention
mentioned below are always as defined
above.
The products are produced according to
the invention by oxidative splitting of the
carbon-carbon double bond. The process
may be performed on a large scale and the
yield is very good.
According to the invention olefins of the
general formula II are oxidized by chemical
oxidizing agents, preferably by chromic acid
or potassium permanganate or e.g.
converted to an ozonide and the ozonide is
decomposed by methods known per se.
According to another method of the
invention the oxidation may be carried out
with potassium permanganate in aqueous
acetic acid at a temperature of 0 to 50C,
preferably at about 3"C or in the presence
of sodium hydrogen carbonate in an organic
solvent, preferably in acetone at 0 to 500 C, preferably at 70C. The oxidation with
potassium permanganate may also be
performed in benzene if as crown complex
forming agent e.g. dicyclohexyl-l8-crown-6 is used. The oxidation may be carried out in
a homogeneous medium at 700C, preferably at 25"C, when oxidation is
completed within minutes.
A further preferred oxidation process is
the employment of an oxidizing agent
containing alkali metal periodate and alkali
metal permanganate, e.g. 97.50/0 of sodium
periodate and 2.5 /" potassium
permanganate. As a solvent preferably
tertiary butanol may be used. The oxidation
is completed in 6 hours in an excellent,
nearly quantitative yield.
According to another embodiment of the
present invention the alkene derivative of
the general formula II is oxidized with
chromium trioxide.
The oxidation is completed in acetic acid
at a temperature of 0 two 1000C, preferably at
about 70"C within 1 hour.
The alkene derivatives of the general
formula II may preferably be converted by
saturation of the double bond with ozone land by decomposing the ozonide obtained.
Through the solution of the olefin in e.g.
chloroform, methylene chloride, acetic
acid, or ethvl acetate oxygen saturated with
ozone is introduced at a temperature of
-500C to -800C, preferably at -780C. In
order to prevent polymerisation an acidic
hydrolysing medium containing hydrogen
peroxide is used. The acidic reaction
mixture is extracted with an organic solvent
and after removing the organic layer the carboxylic acids of the general formula I, wherein the substituents are as defined above, may be separated or, if desired metal salts or acid addition salts may be formed by reaction with bases such as alkali metal hydroxides, alkaline earth metal hydroxides or nitrogen-containing organic bases in aqueous medium or a solvent medium by known techniques of salt formation and isolated by crystallization or by evaporation of the solvent.
The alkene derivatives used as starting
materials may be conveniently prepared by
Wittig reaction or by dehydrating the
appropriate tertiary alcohols.
The invention is further illustrated by the following non-limiting Examples.
Examples
Example 1
188.23 g. (0.5 mole) of l,l-diphenyl-3-(3- phenoxyphenyl)-l-butene are dissolved in 200 ml. of methylenechloride. the mixture is cooled to -780C and ozonised oxygen is introduced into the mixture for 12 hours.
After the introduction is completed, the solvent is removed and the residue is dissolved in 100 ml. of acetic acid. The obtained solution is added dropwise to a mixture of 114 g. of 30% hydrogen peroxide, 5 ml. of sulfuric acid and 200 ml. of water under cooling. After the addition is complete, the solution is further heated to boiling for 2 hours, cooled and extracted with 3x500 ml. diethyl ether. The ethereal layers are washed with sodium hydroxide and the aqueous solution is acidified followed by extraction with 3x500 ml. of diethyl ether. The extract is evaporated after drying and the residue is distilled off.
The product obtained is 2-(3-phenoxyphenyl)-propionic acid.
Bp.: 190--192"C (0.4 mmHg).
nD5= 1.575 Example 2
Using the general method of Example 1, from 126.17 g. (0.5 mole) l,l-dimethyl-3-(3 phenoxyphenyl)-l-butene, 2-(3-phenoxyphenyl)-propionic acid is obtained.
Example 3
From 146.2 g. (0.5 mole) 2 - (3 phenoxyphenyl) - 1 - cyclohexylidene propane 2 - (3 - phenoxyphenyl) - propionic acid is obtained by the general method of
Example 1.
Example 4
150.69 g. (0.5 mole) of I - phenyl - 3 (3 - phenoxyphenyl) - I - butene is oxidised according to the general method of
Example 1, and thus 2 - (3 phenoxyphenyl) - propionic acid is obtained.
Example 5
46.98 g. (0.125 mole) of 1,1 - diphenyl 3 - phenoxyphenyl) - 1 - butene are dissolved in 500 ml. of acetic acid. 27 g.
CrO3 in 30 ml. of water is added dropwise to the solution at 700C. After heating for 1 hour the acetic acid is removed and the residue is treated with 500 ml. sulfuric acid.
The acidic solution is further worked up according to Example 1. 2 - (3 phenoxyphenyl) - propionic acid of boiling point: 19192"C (0.4 mmHg) is obtained.
Example 6
31.54 g. (0.125 mole) of 1,1 - dimethyl 3 - (3 - phenoxyphenyl)- 1 - butene is oxidised by the method of Example 5. 2 (3 - phenoxy - phenyl) - propionic acid is obtained.
Example 7
36.55 g. (0.125 mole) 2 - (3 phenoxyphenyl) - 1 cyclohexylidene propane is oxidised by the method of
Example 5 to 2 - (3 - phenoxy - phenyl) propionic acid.
Example 8
37.67 g. (0.125 mole) of I - phenyl - 3 (3 - phenoxyphenyl) - 1 - butene is oxidised by the method of Example 5 to yield 2 - (3 - phenoxyphenyl) - propionic acid.
Example 9
A mixture of 3.76 g. (0.01 mole) 1.1 diphenyl - 3 - (3 - phenoxy - phenyl) - 1 - butene, 100 g. of ice-cold water and 420 g.
acetic acid is stirred and 4.74 g. (0.03 mole) of potassium permanganate is added at such a rate that the temperature does not exceed 3"C. The mixture is filtered, alkalized, filtered and concentrated. After acidifying and working up the mixture according to
Example 1, 2 - (3 - phenoxyphenyl) propionic acid of boiling point of 19- 192"C (0.4 mmHg) is obtained.
Example 10
2.52 g. (0.01 mole) of 1,1 - dimethyl - 3 (3 - phenoxyphenyl)- 1 - butene is oxidised by the method of Example 9, and 2 - (3 - phenoxyphenyl)- 1 - butene is oxidised by the method of Example 9, and 2 - (3 - phenoxyphenyl) - propionic acid is obtained.
Example 11
2.92 g. (0.01 mole) 2 - (3 phenoxyphenyl)- 1 - cyclohexylidene propane is oxidised by the method of
Example 9 to 2 - (3 - phenoxyphenyl)propionic acid.
Example 12
Using the method of Example 9, 3.01 g.
(0.01 mole) 1 - phenyl - 3 - (3 phenoxyphenyl) - 1 - butene is used as starting material and thus 2 - (3 phenoxyphenyl) - propionic acid is obtained.
Example 13
47.30 g. 1,1 - diphenyl - 3 - (2 - fluoro 4 - biphenylyl) - I - butene is dissolved in 500 ml. of acetic acid and 27 g. CrO3 in 30 ml. of water is added dropwise at 700C. The solution is heated for 1 hour. The acetic acid is removed and the residue is acidified. The acidic solution is extracted with chloroform.
The chloroform solution is dried and evaporated. 2 - (2 - fluoro - 4 biphenylyl) - propionic acid is obtained, melting point: 1 l0--l 11 0C.
Example 14
To a mixture of 3.64 g. (0.01 mole) of 1,1 diphenyl - 3 - (6 - methoxy - 2 naphthyl) - 1 - butene. 100 g. of ice-cold water and 400 ml. of acetic acid, 4.74 g.
(0.03 mole) of potassium permanganate is added under stirring at 0 to 30C. The mixture is filtered, alkalized, filtered and concentrated. The solution is acidified, and extracted with chloroform. The chloroform solution is dried and evaporated. 2 - (6 methoxy - 2 - naphthyl) - propionic acid of melting point 153--1550C is obtained and the solid is recrystallized from a mixture of acetone and hexane.
Example 15
To a mixture of 3.4 g. (0.01 mole) 1,1 diphenyl - 3 - (4 - iso - butylphenyl) - I butene, 100 g. ice-cold water and 400 ml. of acetic acid 4.74 g. (0.03 mole) of potassium permanganate is added under stirring at 0 to 3etc. The mixture is worked up according to
Example 14 and thus a product of melting point 75--76"C 2 - (4 - isobutylphenyl) propionic is obtained, which may be recrystallised from petrolether.
Example 16
To a mixture of 4.72 g. 1,1 - diphenyl 3 - [2 - (2,6 - dichloroanilino) - phenyll - 1 - propene, 100 g. of ice-cold water and 400 ml. of acetic acid, 4.74 g. of potassium permanganate is added at 0 to 30C under stirring. The mixture is worked up according to Example 14 and thus 2 - [2,6 dichloroanilinophenyli acetic acid is obtained.
Mp.: 156--1580C.
WHAT WE CLAIM IS:
1. Process for the preparation of phenyland naphthyl-alkanoic acids of the general formula I
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (19)
1. Process for the preparation of phenyland naphthyl-alkanoic acids of the general formula I
wherein R1 is hydrogen, C14 alkyl, or C7 ,0 aralkyl,
R2 is hydrogen or halogen,
R3 is C1--6 alkyl, C7 ,0 aralkyl, phenyl,
phenoxy, or -NH-R4- wherein R4 is
a phenyl group optionally substituted
with one or two halogen atoms; or
R2 and R3 may together form a fused
benzene ring which may optionally be
substituted with a C14 alkoxy group,
which comprises oxidizing an alkene
derivative of the general formula Il
wherein
R', R2, R3, R4, R5 and R6 are as defined
above,
R7 and RB are hydrogen, C14 alkyl, C5~6 cycloalkyl or phenyl or
R7 and R8 together with the carbon atom
to which they are attached form a five
or six-membered ring.
2. A process as claimed in claim 1, which comprises conducting the oxidation with potassium permanganate.
3. A process as claimed in claim 2 which comprises conducting the oxidation at 0 to 5"C in the presence of aqueous acetic acid.
4. A process as claimed in claim 3 wherein the oxidation is conducted at about 3"C.
5. A process as claimed in claim 2 wherein the oxidation is conducted at 0 to 500C in the presence of sodium hydrogen carbonate and an organic solvent.
6. A process as claimed in claim 5 wherein said organic solvent is acetone.
7. A process as claimed in claim 2 wherein the oxidation is conducted in benzene in the presence of a crown complexing agent at 0 to 700C.
8. A process as claimed in claim I wherein the oxidation is conducted with a mixture of alkali metal periodate and alkali metal permanganate.
9. A process as claimed in claim 8 wherein the oxidation is conducted in tert-butanol with a mixture of sodium periodate and potassium permanganate.
10. A process as claimed in claim 1 which comprises conducting the oxidation with chromium trioxide.
II. A process as claimed in claim 10 which comprises conducting the oxidation at 0 to 1000C in the presence of aqueous acetic acid.
12 A process according to claim 11 wherein the oxidation is performed at about 70"C.
13. A process according to claim I which comprises conducting the oxidation with oxygen saturated with ozone.
14. A process as claimed in claim 13 wherein the oxidation is conducted at -50 to -80 C.
15. A process as claimed in claim 13 or 14 wherein a solution of said compound is oxidised in a solvent selected from chloroform, methylene chloride, acetic acid and ethyl acetate.
16. A process as claimed in any of claims 13-15 wherein the intermediate ozonide is decomposed in the presence of hydrogen peroxide.
17. A process as claimed in claim I, substantially as hereinbefore described.
18. A process as claimed in claim 1, substantially as hereinbefore described with reference to any one of the Examples.
19. Phenyl- and naphthyl-alkanoic acids of the general formula I whenever prepared by the process of any of the preceding claims.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUCI001695 HU180811B (en) | 1976-11-23 | 1976-11-23 | Process for preparing phenyl-alkyl-carboxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1586798A true GB1586798A (en) | 1981-03-25 |
Family
ID=10994629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB4878177A Expired GB1586798A (en) | 1976-11-23 | 1977-11-23 | Preparation of optionally substituted phenyl- and naphthyl-alkanoic acids |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5382751A (en) |
| CH (1) | CH627727A5 (en) |
| DK (1) | DK517977A (en) |
| ES (1) | ES464352A1 (en) |
| FI (1) | FI773552A (en) |
| GB (1) | GB1586798A (en) |
| HU (1) | HU180811B (en) |
| NL (1) | NL7712841A (en) |
| SE (1) | SE7713129L (en) |
| SU (1) | SU895282A3 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4885404A (en) * | 1985-07-12 | 1989-12-05 | The Upjohn Company | Flurbiprofen intermediate |
| WO1998005623A1 (en) * | 1996-08-02 | 1998-02-12 | Dompe' S.P.A. | A process for the preparation of 2-aryl-propionic and 2-aryl-acetic acids starting from aryl-olefins |
| US6770781B1 (en) * | 1998-10-30 | 2004-08-03 | Dompe′ S.p.A | Process for the preparation of alpha-arylalkanoic acids |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2950608A1 (en) * | 1978-12-29 | 1980-07-10 | Chinoin Gyogyszer Es Vegyeszet | METHOD FOR PRODUCING 2- (3-PHENOXY-PHENYL) -PROPIONIC ACID |
| JP6104831B2 (en) * | 2014-03-05 | 2017-03-29 | 東レ・ファインケミカル株式会社 | Method for producing benzoic acids |
-
1976
- 1976-11-23 HU HUCI001695 patent/HU180811B/en unknown
-
1977
- 1977-11-21 SE SE7713129A patent/SE7713129L/en not_active Application Discontinuation
- 1977-11-22 NL NL7712841A patent/NL7712841A/en not_active Application Discontinuation
- 1977-11-22 DK DK517977A patent/DK517977A/en not_active Application Discontinuation
- 1977-11-22 ES ES464352A patent/ES464352A1/en not_active Expired
- 1977-11-22 CH CH1426677A patent/CH627727A5/en not_active IP Right Cessation
- 1977-11-22 SU SU772545902A patent/SU895282A3/en active
- 1977-11-23 FI FI773552A patent/FI773552A/en not_active Application Discontinuation
- 1977-11-23 GB GB4878177A patent/GB1586798A/en not_active Expired
- 1977-11-24 JP JP14007977A patent/JPS5382751A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4885404A (en) * | 1985-07-12 | 1989-12-05 | The Upjohn Company | Flurbiprofen intermediate |
| WO1998005623A1 (en) * | 1996-08-02 | 1998-02-12 | Dompe' S.P.A. | A process for the preparation of 2-aryl-propionic and 2-aryl-acetic acids starting from aryl-olefins |
| US6770781B1 (en) * | 1998-10-30 | 2004-08-03 | Dompe′ S.p.A | Process for the preparation of alpha-arylalkanoic acids |
Also Published As
| Publication number | Publication date |
|---|---|
| SU895282A3 (en) | 1981-12-30 |
| FI773552A (en) | 1978-05-24 |
| ES464352A1 (en) | 1978-08-01 |
| NL7712841A (en) | 1978-05-25 |
| DK517977A (en) | 1978-05-24 |
| HU180811B (en) | 1983-04-29 |
| SE7713129L (en) | 1978-05-24 |
| JPS5382751A (en) | 1978-07-21 |
| CH627727A5 (en) | 1982-01-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| 746 | Register noted 'licences of right' (sect. 46/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |