HK1042289A1 - Method for producing derivatives of biphenyl-2-carboxylic acid - Google Patents
Method for producing derivatives of biphenyl-2-carboxylic acid Download PDFInfo
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- HK1042289A1 HK1042289A1 HK02103840A HK02103840A HK1042289A1 HK 1042289 A1 HK1042289 A1 HK 1042289A1 HK 02103840 A HK02103840 A HK 02103840A HK 02103840 A HK02103840 A HK 02103840A HK 1042289 A1 HK1042289 A1 HK 1042289A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract
The invention relates to a method for producing biphenyl-2-carboxylic acid derivatives of formula (I), wherein R<1> and R<2> can have the meanings given in the description and in the claims. The inventive method is suitable for use on an industrial scale.
Description
The invention relates to a method for producing biphenyl-2-carboxylic acid derivatives (I) which can be used on an industrial scale
Wherein R is1And R2Have the meaning as stated in the description and the claims.
Background
The biphenyl-2-carboxylic acids of formula (I) are very important intermediates in the production of useful active substances for medicaments, in particular for the production of medicaments which can be used as angiotensin-II-antagonists.
Processes for the preparation of biphenyl-2-carboxylic acids and derivatives thereof (I) are known from the prior art. One of the methods which is one of the main background of the present invention is described by Meyers et al (for example tetrahedron (1985) Vol.41, 837-860) for coupling aromatic Grignard compounds (II) with optionally substituted (2-methoxyphenyl) -2-oxazolines (III) according to scheme 1, wherein the corresponding (2-oxazolinyl) -2-biphenyl derivatives (IV) are obtained first.
Scheme I
ROXThe radical represents an optionally substituted oxazolin-2-yl radical. R1And R2The definition of radicals can be found in the description below andfound in the claims. Successfully converted to the corresponding carboxylic acid of formula (I) by saponification of the oxazoline (IV). Formally, saponification of formula (IV) can be carried out by two different reaction pathways. Scheme 2 is a reaction scheme illustrating a process for the preparation of biphenyl-2-carboxylic acids from unsubstituted oxazolinyl biphenyl-oxazolines (i.e., R)1And R2Hydrogen; rOXOxazolin-2-yl).
Scheme 2
In the first step, the saponification of the oxazoline to give the amino ester (Vb) is carried out according to reaction conditions known in the art (Meyers et al, J.org.chem. (1974) Vol.39, 2787-2793). The amino ester (Vb) is then saponified in a second reaction step to the carboxylic acid (I), for example by boiling it in 10-25% sodium hydroxide solution for several hours.
However, in large scale preparations, it is desirable to carry out the saponification in a one-pot process.
However, the large-scale acid saponification carried out in a one-pot process according to the known art (for example according to European patent 59983) leads to unsatisfactory results.
It is noted that the amino ester (Vb) partially precipitates after its formation, due to its low solubility in the solvents used according to the prior art (for example aqueous hydrochloric acid solution of EP 59983). (Vb) the precipitate is deposited on the stirrer and the walls of the reactor. Thus, the amino ester (Vb) continues to be removed from the reaction solution and, due to its low solubility, does not actually react further to form the desired compound (I). Further reduction results in the product (I) becoming embedded in the crystalline amino ester (Vb) and generally clumping.
Since the amino ester (Vb) is isolated on the one hand and subjected to a further reaction to form the end product insofar as the end product is worked up and purified, the disadvantages mentioned above add to the costs for the large-scale production of (I).
It was therefore an object and task of the present invention to provide a process for the preparation of derivatives/homogenates of biphenyl-2-carboxylic acids on a large scale and to overcome the disadvantages of the processes known from the prior art.
Detailed description of the invention
It has been found, surprisingly, that the disadvantages encountered in the prior art for the preparation of biphenyl-2-carboxylic acid derivatives can be avoided if the saponification of the oxazoline (IV) is carried out with hydrochloric acid in an inert organic solvent immiscible with water under elevated pressure and temperature.
The object of the present invention is a process for the large-scale preparation of biphenyl-2-carboxylic acid derivatives of the general formula (I)
Wherein
R1And R2Which may be the same or different, represents hydrogen, C which may optionally be substituted by halogen1-C6Alkyl radical, C1-C6-alkoxy, C1-C6-acyl group, C1-C6Alkoxycarbonyl, COOH, phenyl, benzyl, halogen, hydroxy, nitro or amino, or wherein
R1And R2Together with the adjacent carbon atom of the benzene ring form a saturated or unsaturated 5-or 6-membered carbocyclic group, which may optionally be substituted by C1-C4-alkyl, halogen, COOH, phenyl or hydroxy substitution;
it is characterized in that (2-oxazoline) -2-biphenyl derivatives with the general formula (IV) are saponified by hydrochloric acid in an inert organic solvent which is not mutually soluble with water under the conditions of heating and pressurizing,
wherein
R1And R2As defined above and ROXRepresents oxazolin-2-yl which may optionally be substituted by one or more halogen, hydroxy or C1-C4-alkoxy-substituted C1-C6Alkyl radical, C1-C6Alkoxy, optionally substituted by C1-C4Alkyl radical, C1-C4Phenyl, benzyl, pyridyl or C substituted by alkoxy, hydroxy, nitro or amino1-C6-alkoxycarbonyl mono-, di-, tri-or tetrasubstituted.
A preferred preparation process according to the invention is for the preparation of biphenyl-2-carboxylic acid derivatives of the general formula (I), wherein
R1And R2Which may be identical or different, is hydrogen, C which may optionally be substituted by fluorine, chlorine or bromine1-C4Alkyl radical, C1-C4-alkoxy, C1-C4-acyl group, C1-C4Alkoxycarbonyl, COOH, phenyl, benzyl, fluoro, chloro, bromo, hydroxy, nitro or amino, or wherein
R1And R2Forming, with the adjacent carbon atom of the benzene ring, an unsaturated 6-membered carbocyclic group, optionally substituted by C1-C4-alkyl, fluoro, chloro, bromo, COOH, phenyl or hydroxy substituted;
the method is characterized in that the (2-oxazolinyl) -2-biphenyl derivatives of the general formula (IV) are saponified with hydrochloric acid in an inert organic solvent which is immiscible with water under increased pressure and temperature.
Wherein
R1And R2As defined above and
ROXrepresents oxazolin-2-yl which may optionally be substituted by one or more of fluorine, chlorine, bromine, hydroxy or C1-C4-alkoxy-substituted C1-C4Alkyl radical, C1-C4-alkoxy, optionally substituted by C1-C4Alkyl radical, C1-C4Phenyl, benzyl or C substituted by alkoxy, hydroxy, nitro or amino1-C4-an alkoxycarbonyl group, mono-or di-substituted,
a particularly preferred process for preparing biphenyl-2-carboxylic acid derivatives of the formula (I) is
Wherein
R1And R2Which may be identical or different, is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, CF3Methoxy, ethoxy, COOH, phenyl, benzyl, fluoro, chloro, bromo, hydroxy, nitro or amino, or
Wherein R is1And R2Forming a fused benzene ring with the adjacent carbon atom of the benzene ring, which may be substituted with methyl, ethyl, n-propyl, isopropyl, tert-butyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxyl, as required, characterized in that (2-oxazolinyl) -2-biphenyl derivatives of the general formula (IV) are saponified with hydrochloric acid under increased pressure and temperature in an inert organic solvent containing water immiscible therewith,
wherein
R1And R2As defined above
ROXRepresents oxazolin-2-yl which is optionally mono-or disubstituted by one or more methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxymethyl, hydroxymethyl, methoxy or ethoxy groups, or phenyl which is optionally substituted by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy or hydroxy groups, or benzyl, methoxycarbonyl or ethoxycarbonyl groups.
The equally important process for preparing biphenyl-2-carboxylic acid derivatives of the general formula (I) according to the invention is, among others
R1And R2Which may be identical or different, represent hydrogen, methyl, CF3COOH, phenyl, fluoro or hydroxy, or wherein
R1And R2Form a fused benzene ring with the adjacent carbon atoms of the benzene ring,
characterized in that (2-oxazolinyl) -2-biphenyl derivatives of the general formula (IV) are saponified with hydrochloric acid in an inert organic solvent which is immiscible with water, under increased pressure and temperature, wherein
R1And R2As defined above and
ROXrepresents oxazolin-2-yl which may optionally be mono-or disubstituted by one or more methyl, ethyl, methoxy, ethoxy, phenyl or benzyl groups.
Of particular interest is a process for the preparation of biphenyl-2-carboxylic acid derivatives of the formula (I), wherein
R1And R2Which may be the same or different, represent hydrogen, methyl or CF3，
Characterized in that (2-oxazolinyl) -2-biphenyl derivatives of the general formula (IV) are saponified with hydrochloric acid in an inert organic solvent which is immiscible with water, under increased pressure and temperature, wherein
R1And R2As defined above and
ROXrepresents oxazolin-2-yl which is optionally mono-or disubstituted by methyl,
according to the invention, the procedure is particularly preferably carried out as follows. In a suitably sized reactor, 0.08 to 0.8, preferably 0.15 to 0.5, optimally about 0.2 liters of water and 3.0 to 6.0 moles, preferably 3.5 to 5.0 moles, optimally about 4.0 moles of hydrochloric acid are added per mole of oxazolin-2-yl-biphenyl (IV). Preferably, the hydrochloric acid is added as an aqueous solution, most preferably a 36.5% aqueous solution to produce a concentration of 20-30%, most preferably about 24% hydrochloric acid.
After inertization with a protective gas, preferably nitrogen, the reactor is evacuated (to about 50 mbar) and 0.05 to 0.2, preferably 0.08 to 0.15, optimally about 0.1 liter of inert organic solvent is added per mole of starting compound (IV). According to the invention, as inert organic solvents, aliphatic or aromatic hydrocarbons and aromatic chlorinated hydrocarbons having from 6 to 10 carbon atoms are possible. Preferably aliphatic or aromatic hydrocarbons having 7 to 8 carbon atoms. The solvents which can be used according to the invention are preferably toluene, xylene, chlorobenzene and methylcyclohexane. Methylcyclohexane is particularly preferred.
After the inert organic solvent is added, the reaction solution is heated to 160 ℃ at 120 ℃, preferably 150 ℃ at 130 ℃, and most preferably 145 ℃ at 140 ℃. The mixture is stirred at constant temperature for a further 3 to 10 hours, preferably 4 to 8 hours. The apparatus is sealed (using, for example, a shut-off valve which is closed and opened to the vapor) so that the heated reaction solution generates an internal pressure of 3 to 6 bar (excess pressure) in the apparatus, preferably 4 to 5 bar. The temperature can be varied according to the boiling point of the solvent used, thus establishing what is known as an internal pressure. This results in the invention having the further advantage that conventional devices, such as DIN enamel devices (pressure rating of 6 bar u) can be used.
The reactor was then cooled to a temperature indicated by the apparatus at maximum atmospheric pressure (20-50 ℃). Any insufficient pressure is adjusted as necessary with an inert gas. In working up, the reaction mixture is mixed with a suitable solvent or solvent mixture which enables the aqueous hydrochloric acid phase to be separated off without loss of product. Preference is given to using toluene, xylene or methylcyclohexane in combination with tetrahydrofuran. Particular preference is given to toluene and tetrahydrofuran being mixed in a ratio of about 1: 1. From 0.1 to 1 liter of the abovementioned organic solvent or solvent mixture is used per mole of starting compound (IV). It is preferred to use from 0.2 to 0.5 liter of the above-mentioned organic solvent or solvent mixture per mole of oxazoline (IV) added. Most preferably, about 0.3 to 0.35 liters of organic solvent or solvent mixture is used per mole of oxazoline (IV) added.
The lower aqueous phase is then separated off and the remaining upper phase is extracted with water several times, preferably 2 to 3 times, most preferably twice. According to the invention, the amount of washing water used in each extraction step is 0.05-0.5 l of water per mole of oxazoline (IV). Preferably, 0.1-0.2 l of water is used per mole of starting compound (IV) added in each extraction step.
The washed organic upper phase is then basified. The treatment according to the invention can be carried out with an aqueous alkali metal or alkaline earth metal hydroxide solution. Preference is given to using aqueous solutions of lithium, sodium or potassium hydroxide. A particularly preferred base according to the invention is aqueous sodium hydroxide. From 0.7 to 1 mol of base, preferably from 0.8 to 0.9 mol, are used per mole of starting compound (IV).
After phase separation, the lower phase was transferred to another reactor. The remaining upper phase is then basified in the manner described above. However, according to the present invention, the amount of alkali added in the first alkalization step is only about 10% by weight. After renewed separation of the lower phase, the combined aqueous extracts are distilled without any added solvent. About 0.05-0.5 liter of water, preferably 0.07-0.2 liter, optimally about 0.1 liter of water is distilled off per mole of starting compound (IV). After cooling to below 40 c, preferably 20-30 c, most preferably 25 c, 0.1-0.5 l, preferably about 0.2 l, of water is added per mole of starting compound added and the mixture is acidified with 1-5 moles, preferably 2-4 moles, most preferably about 3.5 moles of hydrochloric acid.
The precipitated product was centrifuged, washed with water and dried.
The following examples serve to illustrate some examples of the synthesis of biphenyl-2-carboxylic acid derivatives of general formula (I) according to the invention. It is of course merely an example to illustrate the method performed and not to limit the content of the invention.
Example 1
265 kg of 4' -monomethyl-2- (4, 4-dimethyloxazolin-2-yl) biphenyl, 205 l of water and 400 kg of 36.5% hydrochloric acid were placed in a 1200 l enamel stirrer. After inerting with nitrogen, the flask was evacuated to 50 mbar and a further 102.5 l of methylcyclohexane were added. After closing the vapor seal valve, the device was heated to about 140 ℃ within about 1 hour and then stirred at 140 ℃ and 145 ℃ for 4 to 8 hours. Thus generating an internal pressure of 4-5 atm. The apparatus is cooled to 20-30 ℃, adjusted to atmospheric pressure with nitrogen and 175 l of toluene and 150 l of THF are added. The lower aqueous phase was separated off and the remaining upper organic phase was extracted with 205 l of water and then 103 l of water. Another 512 l of water and 80 kg of 45% sodium hydroxide solution were added to the upper phase and, after settling, the lower phase was transferred to another 1200 l enamel mixing apparatus. The procedure was repeated with 103 l of water and 8.9 kg of 45% sodium hydroxide solution.
About 103 l of water are distilled off from the combined aqueous extracts, after cooling to 25 ℃ 205 l of water are added and 97 kg of 36.5% hydrochloric acid are added. The product was centrifuged, washed with water and dried.
Yield: 190 kg of 4' -methylbiphenyl-2-carboxylic acid (90%).
Example 2
251 kg of 2- (4, 4-dimethyloxazoline-2-yl) biphenyl, 205 l of water and 400 kg of 36.5% hydrochloric acid were placed in a 1200 l enamel stirrer. After inertization with nitrogen, a vacuum of about 50 mbar was applied and 102.5 l of methylcyclohexane were added. After closing the vapor seal valve, the device was heated to about 140 ℃ within 1 hour and stirred at 140 ℃ and 145 ℃ for an additional 4 to 8 hours. An internal pressure of 4-5 atmospheres is generated. The apparatus is cooled to 20-30 ℃ and a further 175 l of toluene and a further 150 l of THF are added, adjusted to atmospheric pressure with nitrogen. The lower aqueous phase is separated off and the remaining upper organic phase is extracted with 205 l of water and then with 103 l of water. Another 512 l of water and 80 kg of 45% sodium hydroxide solution were added to the upper phase and after settling, the lower phase was transferred to another 1200 l enamel stirring device. The procedure was repeated with 103 l of water and 8.9 kg of 45% sodium hydroxide solution. About 103 l of water are first distilled off from the combined aqueous extracts and, after cooling to 25 ℃, 205 l of water and 97 kg of 36.5% hydrochloric acid are added. The product was centrifuged, washed with water and dried.
Yield: 180 kg of biphenyl-2-carboxylic acid (91%)
Comparative example
265 kg of 4' -methyl-2- (4, 4-dimethyloxazolin-2-yl) biphenyl, 205 l of water and 400 kg of 36.5% hydrochloric acid were placed in a 1200 l enamel stirrer. After inerting with nitrogen, vacuum was applied to 50 mbar and the vapor seal closed, and the contents of the apparatus were heated to about 140 ℃ over about 1 hour and then stirred at 140 ℃ and 145 ℃ for an additional 4 to 8 hours. An internal pressure of 4-5 atmospheres is generated. The apparatus is cooled to 20-30 ℃, adjusted to atmospheric pressure with nitrogen and charged with 175 l of toluene and 150 l of THF. The lower aqueous phase was added to the waste water and the remaining upper organic phase was extracted with 205 l and then 103 l of water. Another 512 liters of water and 80 kg of 45% sodium hydroxide solution were added to the upper phase, and after settling, the lower phase was transferred to another 1200 liter enamel stirring apparatus. The procedure was repeated with 103 l of water and 8.9 kg of 45% sodium hydroxide solution. About 103 l of water are first distilled off from the combined aqueous extracts and, after cooling to 25 ℃, 205 l of water and 97 kg of 36.5% hydrochloric acid are added. The product was centrifuged, washed with water and dried.
Yield: 100 kg of 4' -methylbiphenyl-2-carboxylic acid (47%).
Claims (8)
1. Preparation method of biphenyl-2-carboxylic acid derivative with general formula (I)
Wherein
R1And R2May be the same or different and represents hydrogen, methyl, CF3，
Characterized in that (2-oxazolinyl) -2-biphenyl derivatives of the general formula (IV) are saponified with hydrochloric acid at a pressure of 3 to 6 bar and at 120 ℃ and 160 ℃ in an inert organic solvent immiscible with water, said inert organic solvent being an aliphatic or aromatic hydrocarbon or an aromatic chlorinated hydrocarbon having 6 to 10 carbon atoms;
in the formula
R1And R2As defined above and
ROXrepresents oxazolin-2-yl which may be mono-or disubstituted by methyl groups as desired.
2. A process as claimed in claim 1, wherein the saponification is carried out at a pressure of from 4 to 5 bar.
3. A process as claimed in claim 1 or 2, characterized in that 3.0 to 6.0 mol of hydrochloric acid are used per mole of starting compound of the formula (IV) in the saponification.
4. A process as claimed in any of claims 1 to 3, characterized in that 3.5 to 5.0 mol of hydrochloric acid are used per mole of starting compound of the formula (IV) in the saponification.
5. A process as claimed in any of claims 1 to 4, characterized in that aliphatic or aromatic hydrocarbons having 7 to 8 carbon atoms or chlorobenzene are used as organic solvent.
6. A process as claimed in any of claims 1 to 5, wherein toluene, xylene, chlorobenzene and methylcyclohexane are used as organic solvents.
7. A process according to any one of claims 1 to 6, characterized in that methylcyclohexane is used as organic solvent.
8. A process according to any one of claims 1 to 7, characterized in that the biphenyl-2-carboxylic acid derivative of the formula (I) prepared is 4' -methylbiphenyl-2-carboxylic acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19908504A DE19908504C2 (en) | 1999-02-26 | 1999-02-26 | Large-scale process for the preparation of derivatives of biphenyl-2-carboxylic acid by saponifying a (2-oxazolinyl) -2-biphenyl derivative with hydrochloric acid |
| DE19908504.8 | 1999-02-26 | ||
| PCT/EP2000/001162 WO2000051961A1 (en) | 1999-02-26 | 2000-02-12 | Method for producing derivatives of biphenyl-2-carboxylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1042289A1 true HK1042289A1 (en) | 2002-08-09 |
| HK1042289B HK1042289B (en) | 2005-12-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK02103840.4A HK1042289B (en) | 1999-02-26 | 2000-02-12 | Method for producing derivatives of biphenyl-2-carboxylic acid |
Country Status (34)
| Country | Link |
|---|---|
| EP (1) | EP1169289B1 (en) |
| JP (1) | JP4558946B2 (en) |
| KR (1) | KR100683432B1 (en) |
| CN (1) | CN1222500C (en) |
| AR (1) | AR022772A1 (en) |
| AT (1) | ATE253034T1 (en) |
| AU (1) | AU781070B2 (en) |
| BG (1) | BG105780A (en) |
| BR (1) | BR0008483B1 (en) |
| CA (1) | CA2364862C (en) |
| CO (1) | CO5160249A1 (en) |
| CZ (1) | CZ299385B6 (en) |
| DE (2) | DE19908504C2 (en) |
| DK (1) | DK1169289T3 (en) |
| EA (1) | EA003948B1 (en) |
| EE (1) | EE200100448A (en) |
| ES (1) | ES2208284T3 (en) |
| HK (1) | HK1042289B (en) |
| HR (1) | HRP20010616A2 (en) |
| HU (1) | HU227949B1 (en) |
| IL (2) | IL144619A0 (en) |
| NO (1) | NO20014045D0 (en) |
| NZ (1) | NZ514365A (en) |
| PE (1) | PE20001490A1 (en) |
| PL (1) | PL198060B1 (en) |
| PT (1) | PT1169289E (en) |
| SK (1) | SK12142001A3 (en) |
| TR (1) | TR200102476T2 (en) |
| TW (1) | TWI274051B (en) |
| UA (1) | UA58631C2 (en) |
| UY (1) | UY26035A1 (en) |
| WO (1) | WO2000051961A1 (en) |
| YU (1) | YU60401A (en) |
| ZA (1) | ZA200105925B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100355717C (en) * | 2005-12-09 | 2007-12-19 | 浙江工业大学 | Method for synthesizing diphenyl-2-carboxylic acid |
| RU2484117C2 (en) * | 2011-03-30 | 2013-06-10 | Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) | Using 4-biphenyl carboxylic acid derivatives as organic mechanoluminescent material and mechanoluminescent composition |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5223058A (en) * | 1975-08-15 | 1977-02-21 | Sankyo Co Ltd | Preparation of indanylpropionic acid derivatives |
| GB1592161A (en) * | 1976-08-13 | 1981-07-01 | Secr Defence | Biphenyl carboxylic esters and their use as liquid crystal materials |
| US4710513A (en) * | 1979-08-17 | 1987-12-01 | Merck & Co., Inc. | Substituted pyranone inhibitors of cholesterol synthesis |
| IL65219A (en) * | 1981-03-11 | 1986-03-31 | Wellcome Found | Pharmaceutical compositions containing diarylcarboxylic acids,some new such(substituted phenyl)benzoic and naphthoic acids,and their preparation |
| JPH051002A (en) * | 1991-02-15 | 1993-01-08 | Nikko Kyodo Co Ltd | Method for producing α-amino acid |
| JPH0761952A (en) * | 1993-06-17 | 1995-03-07 | Eisai Kagaku Kk | Production of halomethylbiphenylcarboxylic acid ester derivative |
| JP3420321B2 (en) * | 1994-02-03 | 2003-06-23 | 北陸製薬株式会社 | Method for producing 2,4,5-trihalogeno-3-methylbenzoic acid |
| CN1160309C (en) * | 1996-05-30 | 2004-08-04 | 赫彻斯特马里恩鲁斯公司 | Alkoxyamino-substituted fluorenones and their use as protein kinase C inhibitors |
| DE19632643C1 (en) * | 1996-08-13 | 1998-01-22 | Great Lakes Chem Konstanz Gmbh | Catalyzed coupling of aryl magnesium halides and bromoarylcarboxylic acid compounds to produce biphenylcarboxylic acids |
| AU2362399A (en) * | 1998-04-21 | 1999-10-28 | Rohm And Haas Company | Metal salt catalyzed process to oxazolines and subsequent formulation of chloroketones |
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- 2001-08-03 BG BG105780A patent/BG105780A/en unknown
- 2001-08-20 NO NO20014045A patent/NO20014045D0/en not_active Application Discontinuation
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| Date | Code | Title | Description |
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| PC | Patent ceased (i.e. patent has lapsed due to the failure to pay the renewal fee) |
Effective date: 20150212 |