WO2005026096A2 - Process for the production of alpha-alkoxy/hydroxy-beta-(p-hydroxyphenyl) propionic acid derivatives - Google Patents

Process for the production of alpha-alkoxy/hydroxy-beta-(p-hydroxyphenyl) propionic acid derivatives Download PDF

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WO2005026096A2
WO2005026096A2 PCT/EP2004/009621 EP2004009621W WO2005026096A2 WO 2005026096 A2 WO2005026096 A2 WO 2005026096A2 EP 2004009621 W EP2004009621 W EP 2004009621W WO 2005026096 A2 WO2005026096 A2 WO 2005026096A2
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alkyl
compounds
production
general formula
group containing
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PCT/EP2004/009621
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WO2005026096A3 (en
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Dieter Most
Pavol Jakubec
Kai Rossen
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Degussa Ag
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Priority to CA002539366A priority Critical patent/CA2539366A1/en
Priority to EP04764595A priority patent/EP1687252A2/en
Priority to JP2006526539A priority patent/JP2007505843A/en
Publication of WO2005026096A2 publication Critical patent/WO2005026096A2/en
Publication of WO2005026096A3 publication Critical patent/WO2005026096A3/en

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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
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • the present invention is directed at a process for the production of ⁇ -alkoxy/hydroxy- ⁇ - (p-hydroxyphenyl) propionic acid derivatives.
  • the invention concerns the production of compounds having the general formula (I)
  • WO0140159 suggests inter alia a multistage synthesis route in which the corresponding condensation product is generated from the corresponding methoxybenzaldehyde and ethoxyacetic acid ester under basic conditions and the product thus obtained is eliminated to the conjugated system. Hydrogenation is followed by conversion to the corresponding- acid, a classic resolution of racemates, elimination of the methyl protective group and finally another esterification. The total yield appears to be modest.
  • S. Ebdrup et al. propose a Wittig—Horner strategy starting from 4- (benzyloxy) benzaldehyde and ethyl-2- (diethylphosphinyl) -2-ethoxyacetate .
  • the object of the present invention was therefore to provide another production method for the compounds having the general formula (I) .
  • the method should be able to be used on an industrial scale very successfully from an economic and ecological perspective, i.e. it should be robust, start from as favourable starting materials as possible and involve few stages.
  • R 1 or R 2 are mutually independently H, (Cx-Cs) alkyl, (C 3 -Cs) cycloalkyl, (Ci-C 8 ) alkyl (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl ( (C ⁇ -C 8 ) alkyl) ⁇ 3 , (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 6 -C ⁇ 8 ) aryl, (C 7 -C 19 ) aralkyl radical, (C 6 -C ⁇ 8 ) aryl ( (C-C 8 ) alkyl) 1-3, the stated object is achieved quite surprisingly, but no less successfully for that and especially advantageously according to the invention, by reacting compounds having the general formula (II)
  • Y represents a nucleofugal leaving group, with compounds having the general formula (III)
  • Rl, R2 and X can assume the meaning stated above, under basic conditions.
  • groups X and Y the person skilled in the art has a free choice in principle, provided that they are compatible with the reaction. Hydrogen and electron- attracting groups are suitable for X. The introduction of electron-attracting groups further increases the acidity of (III), which makes it possible to use milder bases.
  • groups X the person skilled in the art can preferably choose examples that afterwards allow a hydrogen radical to be introduced at the ⁇ -carbon atom as easily as possible. This can be done by a substitution or reduction reaction or elegantly also by a decarboxylation and/or decarbonylation reaction. In the latter context the use of corresponding 1, 3-dicarboxyl or 1, 3-dicarbonyl derivatives is particularly worthy of mention.
  • X is a radical selected from the group containing CC1 3 , CN, COOR x , CORi, COCOORi.
  • the radical Y is a nucleofugal leaving group. This type of radical is familiar to the person skilled in the art (Organikum, VEB Deutscher Verlag, 1986, 16 th edition p. 170 ff) . Mechanistic analyses suggest that the reaction proceeds via p-quinone methide. It is of course also conceivable, however, that the reaction proceeds in the manner of SNi via substitution of the benzyl cation or in the manner of SN 2 via a direct substitution of the leaving group Y.
  • the mechanistic course of the reaction will be governed by the leaving group Y and the reaction conditions used.
  • radicals Y selected from the group containing OH, Cl, Br, OTs, OAc, 0C0CF 3 , OMs is conceivable.
  • radicals R 1 and R 2 the person skilled in the art does not need to observe any restrictive boundary conditions. As stated, they should be inert in respect of the reaction and be as inexpensive as possible. In this context H or (C ⁇ -C 8 ) alkyl are therefore preferred for both radicals. Emphasis should be given to the use of the methyl or ethyl radical for R 1 and/or R 2 .
  • the person skilled in the art also has a free choice of the solvent to be used. It should be as inexpensive as possible, again be inert under the reaction conditions and furthermore should allow the reaction to proceed in the best possible way.
  • Organic solvents having a aprotic dipolar character are preferred, such as e.g. NMP, DMPU, DMF, DMSO, sulfolane.
  • (C x -C 8 ) alkyl alcohols can also be used for the reaction, such as e.g. tert.-amyl alcohol, ethanol, propanol, tert . -butanol, isopropanol, n- or sec-butanol.
  • polar aprotic solvents such as THF, MTBE, DME or CH 3 CN or any mixtures of the cited solvents also seems conceivable.
  • the strength of the base to be used can be reduced more and more, so that (C ⁇ -C 8 ) alkyl alkoxides (preferably dissolved or suspended in (C ⁇ -C 8 ) alkyl alcohols) such as NaOMe, NaOEt, KOtBu etc., or stronger N bases such as Et 3 N, DBU, DBN, TMG, pentamethyl guanidine, diisopropyl ethylamine, phosphazenes (R. Schwesinger, H.Schlemper, Angew.Chem.99, 1212 (1987); R. Schwesinger, Nachr. Chem. Tech. Lab.
  • the reaction is preferably performed by introducing the base into the respective solvent and adding the compound (III) .
  • the substrate (II) is then added to the mixture and reacted at temperatures of -30°C to 120°C, preferably -20 °C to 100 °C, most particularly preferably -20°C to 80°C.
  • the chosen sequence of addition can also be the other way round, however.
  • the product is isolated by a method known to the person skilled in the art, e.g. after separating the salts by evaporating the filtrate in vacuo (-> ester) or after saponification, acidification preferably by crystallisation of the corresponding acid.
  • Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. -butyl, pentyl, hexyl, heptyl or octyl together with all bonding isomers can be regarded as (C ⁇ -C 8 ) alkyl.
  • (C 2 -C 8 ) alkenyl is understood to be a (C ⁇ -C 8 ) alkyl radical as set out above (with the exception of methyl) , that displays at least a double bond.
  • (C 2 -C 8 ) alkynyl is understood to be a (C ⁇ -C 8 ) alkyl radical as set out above (with the exception of methyl) , that displays at least a triple bond.
  • (C 3 -C 8 ) cycloalkyl is understood to be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals, etc. These can display radicals containing N or 0 atoms in the ring, such as e.g. 1-, 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2-, 3-tetrahydrofuryl, 2-, 3-, 4-morpholinyl .
  • a (C 6 -C ⁇ 8 ) aryl radical is understood to be an aromatic radical having 6 to 18 C atoms. These include in particular compounds such as phenyl, naphthyl, anthryl, phenanthryl and biphenyl radicals.
  • a (C 7 -C ⁇ 9 ) aralkyl radical is a (C 6 -C 8 ) aryl radical bonded to the molecule via a (C ⁇ -C 8 ) alkyl radical.
  • enantiomer- concentrated is understood to refer to the proportion of an enantiomer in the mixture with its optical antipode in a range between >50 % and ⁇ 100 %.
  • Example 1 Example 1:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention describes the production of compounds having the general formula (I) starting from compounds having the general formula (II) and (III) The products are intermediates for the production of bioactive substances.

Description

Process for the production of α-alkoxy/hydroxy-β- (p- hydroxyphenyl) propionic acid derivatives
The present invention is directed at a process for the production of α-alkoxy/hydroxy-β- (p-hydroxyphenyl) propionic acid derivatives. In particular the invention concerns the production of compounds having the general formula (I)
Figure imgf000002_0001
Compounds having formula (I) , in particular where X = H, are important intermediates for the production of biologically active compounds. For example, so-called peroxisome proliferator-activating receptor agonists (ragaglitazar) have a corresponding partial structure (J. Med. Chem. 2003, 46, 1306-17; Organic Process Research & Development 2003, 7, 82-88) .
A number of syntheses have become known for the production of the compounds under consideration. For example, WO0140159 suggests inter alia a multistage synthesis route in which the corresponding condensation product is generated from the corresponding methoxybenzaldehyde and ethoxyacetic acid ester under basic conditions and the product thus obtained is eliminated to the conjugated system. Hydrogenation is followed by conversion to the corresponding- acid, a classic resolution of racemates, elimination of the methyl protective group and finally another esterification. The total yield appears to be modest. S. Ebdrup et al. propose a Wittig—Horner strategy starting from 4- (benzyloxy) benzaldehyde and ethyl-2- (diethylphosphinyl) -2-ethoxyacetate .
In all cases production of the racemic compound requires a complex synthesis with many stages and expensive reagents before resolution into the enantiomers. As the costs and the environmental loading due to the resolution of the racemates, which occurs late on in the synthesis, require production of at least twice the amount of racemate, a simple and environmentally friendly synthesis of the compounds having formula (I) is important.
The object of the present invention was therefore to provide another production method for the compounds having the general formula (I) . The method should be able to be used on an industrial scale very successfully from an economic and ecological perspective, i.e. it should be robust, start from as favourable starting materials as possible and involve few stages.
This and other objects not mentioned in any more detail but obviously arising from the prior art are achieved by a process with the features of the present claim 1. Preferred embodiments of the process according to the invention are described in the subordinate claims depending on claim 1.
In a process for the production of compounds having the general formula (I)
Figure imgf000003_0001
wherein
X = H or a group having an electron-attracting effect, R1 or R2 are mutually independently H, (Cx-Cs) alkyl, (C3-Cs) cycloalkyl, (Ci-C8) alkyl (C3-C8) cycloalkyl, (C3-C8) cycloalkyl ( (Cι-C8) alkyl) ^3, (C2-C8) alkenyl, (C2-C8) alkynyl, (C6-Cι8) aryl, (C7-C19) aralkyl radical, (C6-Cι8) aryl ( (C-C8) alkyl) 1-3, the stated object is achieved quite surprisingly, but no less successfully for that and especially advantageously according to the invention, by reacting compounds having the general formula (II)
Figure imgf000004_0001
wherein
Y represents a nucleofugal leaving group, with compounds having the general formula (III)
Figure imgf000004_0002
wherein
Rl, R2 and X can assume the meaning stated above, under basic conditions.
Under the cited reaction conditions, compounds having formula (II) react so well with the nucleophile obtainable from (III) that the desired intermediates, such as e.g. α- alkoxy-β- (p-hydroxyphenyl) propionic acid can be obtained in up to a 90% yield. It is likely that the yield could be increased still further by additional process optimisation, According to the invention this process is started from compounds that are available commercially.
For access to compounds having formula (III) by synthesis, reference is made to the following literature: Monatshefte Chemie 1965, 1677-1689; J. Chem. Soc, Perkin Trans. 1: Org. Bioorg. Chem. 1976, 23, 2483-4; Synthesis 1975, 4, 269-70; J. Chem. Soc, . 1933, 1628; Chem. Ber. 1991, 8, 1853-1863; JACS 1988, 110, 209-213.
In selecting groups X and Y, the person skilled in the art has a free choice in principle, provided that they are compatible with the reaction. Hydrogen and electron- attracting groups are suitable for X. The introduction of electron-attracting groups further increases the acidity of (III), which makes it possible to use milder bases. As groups X the person skilled in the art can preferably choose examples that afterwards allow a hydrogen radical to be introduced at the α-carbon atom as easily as possible. This can be done by a substitution or reduction reaction or elegantly also by a decarboxylation and/or decarbonylation reaction. In the latter context the use of corresponding 1, 3-dicarboxyl or 1, 3-dicarbonyl derivatives is particularly worthy of mention. It is therefore particularly preferred if X is a radical selected from the group containing CC13, CN, COORx, CORi, COCOORi. The radical Y is a nucleofugal leaving group. This type of radical is familiar to the person skilled in the art (Organikum, VEB Deutscher Verlag, 1986, 16th edition p. 170 ff) . Mechanistic analyses suggest that the reaction proceeds via p-quinone methide. It is of course also conceivable, however, that the reaction proceeds in the manner of SNi via substitution of the benzyl cation or in the manner of SN2 via a direct substitution of the leaving group Y. The mechanistic course of the reaction will be governed by the leaving group Y and the reaction conditions used. The use of radicals Y selected from the group containing OH, Cl, Br, OTs, OAc, 0C0CF3, OMs is conceivable.
With regard to the radicals R1 and R2 the person skilled in the art does not need to observe any restrictive boundary conditions. As stated, they should be inert in respect of the reaction and be as inexpensive as possible. In this context H or (Cχ-C8) alkyl are therefore preferred for both radicals. Emphasis should be given to the use of the methyl or ethyl radical for R1 and/or R2.
The person skilled in the art also has a free choice of the solvent to be used. It should be as inexpensive as possible, again be inert under the reaction conditions and furthermore should allow the reaction to proceed in the best possible way. Organic solvents having a aprotic dipolar character are preferred, such as e.g. NMP, DMPU, DMF, DMSO, sulfolane. However, (Cx-C8) alkyl alcohols can also be used for the reaction, such as e.g. tert.-amyl alcohol, ethanol, propanol, tert . -butanol, isopropanol, n- or sec-butanol. The use of polar aprotic solvents such as THF, MTBE, DME or CH3CN or any mixtures of the cited solvents also seems conceivable. The use of the base is governed by the nature of the deprotonating substrate (III) to be used. For example, for compounds (III) where X = H stronger bases such as LDA, NaH, KH, LiHMDS, KHMDS or NaHMDS must be used. As the electron-attracting effect of the radical X increases, the strength of the base to be used can be reduced more and more, so that (Cι-C8) alkyl alkoxides (preferably dissolved or suspended in (Cι-C8) alkyl alcohols) such as NaOMe, NaOEt, KOtBu etc., or stronger N bases such as Et3N, DBU, DBN, TMG, pentamethyl guanidine, diisopropyl ethylamine, phosphazenes (R. Schwesinger, H.Schlemper, Angew.Chem.99, 1212 (1987); R. Schwesinger, Nachr. Chem. Tech. Lab. 38, 1214 (1990); H.Schlemper, University of Freiburg dissertation, 1990; R. Schwesinger, Chimia 39, 269 (1985); T.Pietzonka, D.Seebach, Chem. Ber. 124, 1837 (1990); H.- J.Gais, J.Vollhardt, .Krϋger, Angew. Chem.100, 1108 (1988); M. Fletschinger, B.Zipperer, H.Fritz, H.Prinzbach, Tetrahedron Lett. 28, 2517 (1987)) can be used for more CH- acid compounds (III) .
The reaction is preferably performed by introducing the base into the respective solvent and adding the compound (III) . The substrate (II) is then added to the mixture and reacted at temperatures of -30°C to 120°C, preferably -20 °C to 100 °C, most particularly preferably -20°C to 80°C. The chosen sequence of addition can also be the other way round, however. The product is isolated by a method known to the person skilled in the art, e.g. after separating the salts by evaporating the filtrate in vacuo (-> ester) or after saponification, acidification preferably by crystallisation of the corresponding acid.
Further processing can then take place by methods familiar to the person skilled in the art (see p. 1, line 13) .
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. -butyl, pentyl, hexyl, heptyl or octyl together with all bonding isomers can be regarded as (Cι-C8) alkyl. (C2-C8) alkenyl is understood to be a (Cι-C8) alkyl radical as set out above (with the exception of methyl) , that displays at least a double bond. (C2-C8) alkynyl is understood to be a (Cι-C8) alkyl radical as set out above (with the exception of methyl) , that displays at least a triple bond. (C3-C8) cycloalkyl is understood to be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals, etc. These can display radicals containing N or 0 atoms in the ring, such as e.g. 1-, 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2-, 3-tetrahydrofuryl, 2-, 3-, 4-morpholinyl .
A (C6-Cι8) aryl radical is understood to be an aromatic radical having 6 to 18 C atoms. These include in particular compounds such as phenyl, naphthyl, anthryl, phenanthryl and biphenyl radicals.
A (C7-Cι9) aralkyl radical is a (C6-C8) aryl radical bonded to the molecule via a (Cι-C8) alkyl radical. Within the meaning of the invention the term enantiomer- concentrated is understood to refer to the proportion of an enantiomer in the mixture with its optical antipode in a range between >50 % and <100 %.
The chiral structures shown refer to all possible diastereomers and enantiomers (R-, S-) as well as to mixtures thereof and the racemate.
The cited references are to be regarded as being included in the disclosure of this invention.
Examples : Example 1:
Figure imgf000009_0001
A
4-Hydroxybenzyl alcohol (1 g, 0.0081 mol, A) was suspended in acetonitrile (2 ml) , to which 2-methoxydimethyl malonate (0.0161 mol, 2.61 g, 2.2 ml, B) and DBU (0.0041 mol, 0.62 g, 0.61 ml, C) were added. The suspension was refluxed for 3 hours. The reaction mixture was cooled and the solvent evaporated. 20 ml water were added to the residue and the emulsion obtained was extracted with 3 x 20 ml ethyl acetate. The collected organic phases were dried over MgS04. After removal of the solvent by distillation a yellowish oil (1.92 g, 88 %) was obtained, which crystallised after being left to stand.
Example 2 :
Figure imgf000009_0002
2- (4-Hydroxybenzyl) -2-methoxydimethyl malonate (1 g, 0.0037 mol) was added to a solution of NaOH (0.0112 mol, 0.45 g) in water (4 ml) and the reaction mixture was stirred for 3 hours at room temperature. 13 ml of concentrated HC1 were then slowly added to the resulting solution and the emulsion was extracted with 3 x 10 ml ethyl acetate. The water phase was evaporated to dryness.
The resulting white solid was dissolved in dilute HC1 (5 ml water and 1 ml concentrated HCl) and refluxed for 16 hours, After cooling, the solution was extracted with 3 x 10 ml methyl isobutyl ketone. The combined organic phases were dried over MgS0 . After removal of the solvent by distillation an orange-coloured oil (0.5 g, 69 %) was obtained, which gradually crystallised after being left to stand.
Example 3 :
Figure imgf000010_0001
Potassium tert . -butylate (5.387 g, 0.0480 mol) was suspended in 2-methyl-2-butanol (30 ml) . Then methoxymethyl acetate (0.0480 mol, 5.000 g, 4.8 ml) and dimethyl oxalate (0.0480 mol, 5.668 g) were added. The suspension was stirred for 1 hour at room temperature under an N2 atmosphere. 4-Hydroxybenzyl alcohol (0.0408 mol, 5.065 g) was added in one portion and the reaction mixture refluxed for 30 minutes (oil bath 120 °C) . The thick suspension was cooled in an ice bath to 5 °C. 100 ml MTBE were added. The insoluble solid was filtered off and the filter cake washed with 30 ml MTBE. The filtrate was concentrated to dry it and the residue dried to constant weight in an oil pump vacuum. After evaporation and drying, α-methoxy-β- (p- hydroxyphenyl) methyl propionate was obtained as an orange- coloured oil (8.0 g, 79 %) . The methyl ester group was hydrolysed under the same conditions as in Example 2.

Claims

Claims :
1. Process for the production of compounds having the general formula (I)
Figure imgf000011_0001
wherein X is H or a group having an electron-attracting effect, R1 or R2 are mutually independently H, (Cι-C8) alkyl, (C3-C8) cycloalkyl, (Cι-C8) alkyl (C3-C8) cycloalkyl, (C3-C8) cycloalkyl ( (Cι-C8) alkyl) X-3, (C2-C8) alkenyl, (C2-C8) alkynyl, (C6-C18) aryl, (C7-Cι9) aralkyl radical, (C6-Cι8) aryl ( (Cι-C8) alkyl) ι_3, by reacting compounds having the general formula (II
Figure imgf000011_0002
wherein Y represents a nucleofugal leaving group, with compounds having the general formula (III)
Figure imgf000011_0003
wherein R1, R2 and X can assume the meaning stated above, under basic conditions.
2. Process according to claim 1, characterised in that R1 and/or R2 is H or (Cι-C8) alkyl, Y is a radical selected from the group containing OH, Cl, Br, OTs, OAc, OCOCF3, OMs, X is a radical selected from the group containing H, CC13, CN, COOR1, COR1, COCOOR1.
3. Process according to claim 1 and/or 2, characterised in that the reaction is performed in solvents selected from the group containing (Cι-C8) alkyl alcohols, NMP, DMPU, DMF, DMSO, sulfolane, THF, MTBE, CH3CN.
4. Process according to one or more of the preceding claims, characterised in that compounds selected from the group containing (Cι-C8) alkyl alkoxides, Et3N, DBU, DBN, TMG, pentamethyl guanidine, diisopropyl ethylamine, phosphazenes are used as base.
PCT/EP2004/009621 2003-09-18 2004-08-28 Process for the production of alpha-alkoxy/hydroxy-beta-(p-hydroxyphenyl) propionic acid derivatives WO2005026096A2 (en)

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CA002539366A CA2539366A1 (en) 2003-09-18 2004-08-28 Process for the production of alpha-alkoxy/hydroxy-beta-(p-hydroxyphenyl) propionic acid derivatives
EP04764595A EP1687252A2 (en) 2003-09-18 2004-08-28 Process for the production of alpha-alkoxy/hydroxy-beta-(p-hydroxyphenyl) propionic acid derivatives
JP2006526539A JP2007505843A (en) 2003-09-18 2004-08-28 Method for producing α-alkoxy / hydroxy-β- (p-hydroxyphenyl) propionic acid derivative

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3721704A (en) * 1967-02-17 1973-03-20 Geigy Chem Corp Esters of (dialkyl-4-hydroxy-phenyl)malonic acid and related compounds
US4081475A (en) * 1974-12-10 1978-03-28 Ciba-Geigy Corporation Trialkylsubstituted hydroxybenzyl malonates and stabilized compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3721704A (en) * 1967-02-17 1973-03-20 Geigy Chem Corp Esters of (dialkyl-4-hydroxy-phenyl)malonic acid and related compounds
US4081475A (en) * 1974-12-10 1978-03-28 Ciba-Geigy Corporation Trialkylsubstituted hydroxybenzyl malonates and stabilized compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ERICH GRAF VON ROEDERN ET AL: "Bis-substituted malonic acid hydroxamate derivatives as Inhibitors of human neutrophil collagenase (MMP8)" JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 16, 1998, pages 3041-3047, XP002319763 *
REINHARD SARGES ET AL: "Glucose transport-enhancing and hypoglycemic activity of 2-methyl-2-phenoxy-3-phenylpropanoic acids" JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, 1996, pages 4783-4803, XP002319864 *

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