US3818080A - 3-hydroxy-3-substituted glutaric acid derivatives - Google Patents
3-hydroxy-3-substituted glutaric acid derivatives Download PDFInfo
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- US3818080A US3818080A US00273417A US27341772A US3818080A US 3818080 A US3818080 A US 3818080A US 00273417 A US00273417 A US 00273417A US 27341772 A US27341772 A US 27341772A US 3818080 A US3818080 A US 3818080A
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- -1 3-hydroxy-3-substituted glutaric acid Chemical class 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- UWPRZEAGKZSQGU-UHFFFAOYSA-N 3-butyl-3-hydroxypentanedioic acid Chemical compound CCCCC(O)(CC(O)=O)CC(O)=O UWPRZEAGKZSQGU-UHFFFAOYSA-N 0.000 claims description 2
- NPQGZHYAXAOWQE-UHFFFAOYSA-N 3-decyl-3-hydroxypentanedioic acid Chemical compound CCCCCCCCCCC(O)(CC(O)=O)CC(O)=O NPQGZHYAXAOWQE-UHFFFAOYSA-N 0.000 claims description 2
- AOKDDUPYCZEHIM-UHFFFAOYSA-N 3-ethyl-3-hydroxypentanedioic acid Chemical compound OC(=O)CC(O)(CC)CC(O)=O AOKDDUPYCZEHIM-UHFFFAOYSA-N 0.000 claims description 2
- XIMVZSLUNQIRJQ-UHFFFAOYSA-N 3-hydroxy-3-pentadecylpentanedioic acid Chemical compound CCCCCCCCCCCCCCCC(O)(CC(O)=O)CC(O)=O XIMVZSLUNQIRJQ-UHFFFAOYSA-N 0.000 claims description 2
- OOHSMRXOWAGFBH-UHFFFAOYSA-N 3-hydroxy-3-propan-2-ylpentanedioic acid Chemical compound OC(=O)CC(O)(C(C)C)CC(O)=O OOHSMRXOWAGFBH-UHFFFAOYSA-N 0.000 claims description 2
- GGAWXSMRRDXBKS-UHFFFAOYSA-N 3-hydroxy-3-propylpentanedioic acid Chemical compound CCCC(O)(CC(O)=O)CC(O)=O GGAWXSMRRDXBKS-UHFFFAOYSA-N 0.000 claims description 2
- DRXNIKKXPCYTQV-UHFFFAOYSA-N 3-tert-butyl-3-hydroxypentanedioic acid Chemical compound OC(=O)CC(O)(C(C)(C)C)CC(O)=O DRXNIKKXPCYTQV-UHFFFAOYSA-N 0.000 claims description 2
- 230000000026 anti-ulcerogenic effect Effects 0.000 abstract description 5
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 abstract description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 60
- 239000000203 mixture Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 11
- 238000009835 boiling Methods 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 10
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 10
- 229910003446 platinum oxide Inorganic materials 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 9
- 238000002955 isolation Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- GEAWFZNTIFJMHR-UHFFFAOYSA-N hepta-1,6-diene Chemical class C=CCCCC=C GEAWFZNTIFJMHR-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- RXGUIWHIADMCFC-UHFFFAOYSA-N 2-Methylpropyl 2-methylpropionate Chemical compound CC(C)COC(=O)C(C)C RXGUIWHIADMCFC-UHFFFAOYSA-N 0.000 description 2
- NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- JJOYCHKVKWDMEA-UHFFFAOYSA-N ethyl cyclohexanecarboxylate Chemical compound CCOC(=O)C1CCCCC1 JJOYCHKVKWDMEA-UHFFFAOYSA-N 0.000 description 2
- XIRNKXNNONJFQO-UHFFFAOYSA-N ethyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC XIRNKXNNONJFQO-UHFFFAOYSA-N 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- JLIDRDJNLAWIKT-UHFFFAOYSA-N 1,2-dimethyl-3h-benzo[e]indole Chemical compound C1=CC=CC2=C(C(=C(C)N3)C)C3=CC=C21 JLIDRDJNLAWIKT-UHFFFAOYSA-N 0.000 description 1
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- QHNBKRVBKPWUKG-UHFFFAOYSA-N 2-Ethylglutaric acid Chemical compound CCC(C(O)=O)CCC(O)=O QHNBKRVBKPWUKG-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- VSMCWJLQFRGNJV-UHFFFAOYSA-N 4-benzylhepta-1,6-dien-4-ol Chemical compound C=CCC(O)(CC=C)CC1=CC=CC=C1 VSMCWJLQFRGNJV-UHFFFAOYSA-N 0.000 description 1
- UPDFVVLBKBYBOG-UHFFFAOYSA-N 4-propylhepta-1,6-dien-4-ol Chemical compound CCCC(O)(CC=C)CC=C UPDFVVLBKBYBOG-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- IAFQYUQIAOWKSB-UHFFFAOYSA-N Ethyl undecanoate Chemical compound CCCCCCCCCCC(=O)OCC IAFQYUQIAOWKSB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- DULCUDSUACXJJC-UHFFFAOYSA-N benzeneacetic acid ethyl ester Natural products CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- HHEIMYAXCOIQCJ-UHFFFAOYSA-N ethyl 2,2-dimethylpropanoate Chemical compound CCOC(=O)C(C)(C)C HHEIMYAXCOIQCJ-UHFFFAOYSA-N 0.000 description 1
- DBSADESEDBCPFO-UHFFFAOYSA-N ethyl 2-cyclopentylacetate Chemical compound CCOC(=O)CC1CCCC1 DBSADESEDBCPFO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940067592 ethyl palmitate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 150000002310 glutaric acid derivatives Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001254 nonsecretory effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
-
- 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
- C07C51/285—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with peroxy-compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/26—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings
- C07C55/28—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings monocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/29—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups containing rings
Definitions
- R is selected from the group consisting of an alkyl radical, containing more than 1 carbon atom and less than 18 carbon atoms, a cycloalkyl, cycloalkyl(alkyl) or benzyl radical.
- Typical alkyl radicals are ethyl, n-propyl, isopropyl, 3-butyl, t-butyl, n-decyl, pentadecyl, and the corresponding monovalent, saturated, acyclic-or branched-chain, hydrocarbon groupings of empirical formula C H where n is greater than I and less than 18.
- Cyclohexyl is a typical cycloalkyl radical of empirical formula C H and cyclopentylmethyl is an example of a cycloalkyl(alkyl) radical of empirical formula C,.H, These compounds are prepared by the method shown in Scheme A.
- Alkyl esters of carboxylic acids are reacted with 2- alkenyl magnesium bromides to form l,7-substituted 4- substituted-4-hydroxy-l,7-heptadienes, where R and R" are hydrogen or lower alkyl.
- the dienes are ozonized, then oxidized to provide 3-hydroxy-3-substituted glutaric acids.
- ethyl cyclohexanecarboxylate is converted to 4-cyclohexyl-4-hydroxy-l,6-heptadiene by reaction with allyl magnesium bromide, and ozonolysis followed by oxidation in acidic hydrogen peroxide provides 3-hydroxy-3cyclohexylglutaric acid.
- the compounds of the present invention have valuable pharmacological properties.
- a manifestation of this pharmacological utility is the anti-ulcerogenic activity demonstrated by standardized tests designed to detect that activity.
- 3-Hydroxy-3methylglutaric acid which is described in US. Pat. No. 3,070,512, does not exhibit anti-ulcerogenic acitvity.
- the cooled solution is added to a mixture consisting of 0.166 parts of platinum oxide and 50 parts by volume of water over a period of thirty minutes.
- the resulting mixture is heated at 100 for 2 hours, then allowed tocool to room temperature.
- 0.67 Parts of barium carbonate is added and the mixture is allowed to stir for 12 hours.
- This solution is treated with decolorizing charcoal and is filtered.
- the solvent is removed at reduced pressure and the product is obtained by trituration with chloroform.
- the product is 3-hydroxy-3-cyclohexylglutaric acid.
- Example 2 The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-n-decylglutaric acid.
- the formu 1 a of this compound is Using the procedure of Example 1, 40 parts of ethyl cyclopentylacetate in 150 parts by volume of tetrahydrofuran are added to 63.7 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4- cyclopentanemethyl-4-hydroxy- 1 ,6-heptadiene, boiling at 145 at 20 mm.
- the formula of the compound is CHz-COZH EXAMPLE 8
- 49 parts of ethyl phenylacetate in 150 parts by volume of tetrahydrofuran are added to 108 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4- benzyl-4-hydroxy-1,6-heptadiene, boiling at 153 at 20 3.8 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 60C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 30 parts by volume of acetic acid.
- This solution is concentrated to parts and a solution of 66 parts by volume of acetic acid, 60 parts by volume of water, 30 parts by volume of an aqueous 30% hydrogen peroxide solution, and 1.0 part by volume of sulfuric acid is added to the concentrate with stirring.
- This solution is heated for 2 hours at and is cooled to room temperature.
- the cooled solution is added to a mixture consisting of 0.200 parts of platinum oxide and 50 parts by volume of water.
- the resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature.
- 1.0 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-benzylglutaric acid.
- Example 2 The resulting mixture is heated at l for 2 hours, then allowed to cool to room temperature. 1.2 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. isolation and purification, as is described in Example 1, provides 3-hydroxy-3-n-propylglutaric acid.
- the formula of this compound is EXAMPLE Using the procedure of Example l, 40 parts of ethyl propionate in 150 parts by volume of tetrahydrofuran are added to 103 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-ethyl-4- hydroxy-l,6-heptadiene, boiling at 65 at 17 mm.
- 3L0 Parts of this l,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33 parts by volume of acetic acid, 32 parts by volume of water, 8.2 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of suifuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0. 16 parts of platinum oxide and 50 parts by volume of water.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
3-Hydroxy-3-substituted glutaric acid derivatives are prepared in two steps. An ester of a carboxylic acid is reacted with a 2alkenyl magnesium bromide and the resulting 4-substituted-4hydroxy-1,6-heptadiene is ozonized, then oxidized to form the 3hydroxy-3-substituted glutaric acid. These compounds have antiulcerogenic activity.
Description
United States Patent Baran et al.
[ June 18, 1974 3-HYDROXY-3-SUBSTITUTED GLUTARIC ACID DERIVATIVES Inventors: John Stanislaus Baran, Winnetka;
Donna Langford, Wilmette, both of I11.
Assignee: G. D. Searle & Co., Chicago, 111.
Filed: July 20, 1972 Appl. N0.: 273,417
US. Cl 260/535 P, 260/514 K, 260/521 R, 260/617 R, 260/618 R, 260/638 R, 424/305, 424/308, 424/313 Int. Cl. C07c 59/12 Field of Search 260/535 P References Cited UNITED STATES PATENTS 12/1962 Toulmin 260/53] R Primary EraminerLorraine A. Weinberger Assistant EraminerPaul J. Killos Attorney, Agent, or Firm-Elliot N. Schubert ABSTRACT 8 Claims, No Drawings 3-HYDROXY-3-SUBST1TUTED GLUTARIC ACID DERIVATIVES The present invention is concerned with 3-hydroxy- 3-substituted glutaric acid derivatives of the general formula, I,
wherein R is selected from the group consisting of an alkyl radical, containing more than 1 carbon atom and less than 18 carbon atoms, a cycloalkyl, cycloalkyl(alkyl) or benzyl radical. Typical alkyl radicals are ethyl, n-propyl, isopropyl, 3-butyl, t-butyl, n-decyl, pentadecyl, and the corresponding monovalent, saturated, acyclic-or branched-chain, hydrocarbon groupings of empirical formula C H where n is greater than I and less than 18. Cyclohexyl is a typical cycloalkyl radical of empirical formula C H and cyclopentylmethyl is an example of a cycloalkyl(alkyl) radical of empirical formula C,.H, These compounds are prepared by the method shown in Scheme A.
Alkyl esters of carboxylic acids are reacted with 2- alkenyl magnesium bromides to form l,7-substituted 4- substituted-4-hydroxy-l,7-heptadienes, where R and R" are hydrogen or lower alkyl. The dienes are ozonized, then oxidized to provide 3-hydroxy-3-substituted glutaric acids. Thus, ethyl cyclohexanecarboxylate is converted to 4-cyclohexyl-4-hydroxy-l,6-heptadiene by reaction with allyl magnesium bromide, and ozonolysis followed by oxidation in acidic hydrogen peroxide provides 3-hydroxy-3cyclohexylglutaric acid.
The compounds of the present invention have valuable pharmacological properties. A manifestation of this pharmacological utility is the anti-ulcerogenic activity demonstrated by standardized tests designed to detect that activity. 3-Hydroxy-3methylglutaric acid, which is described in US. Pat. No. 3,070,512, does not exhibit anti-ulcerogenic acitvity.
The anti-ulcerogenic utility of the instant compounds is evident from the results of a standardized test designed to detect the substances which inhibit the ulceration reported by Shay et al., Gastro-enterology, 5, 43
( 1945) to occur in rats subjected to fasting and pyloric ligation. in this test, male Charles River rats weighing 200-250 gm. are fasted 72 hr. prior to ligation. Immediately following ligation, the prescribed dose of compound, dissolved or suspended in 1.0 ml. of pH 2.0 hydrochloric acid, is intragastrically administered to each of a group of 6 animals. A like group of animals to which is identically and concurrently administered the acid alone serves as controls. Precisely 19 hours later, the stomachs of surviving animals are excised and examined under 5X magnification. The number of ulcers occurring in the non-secretory portion of each stomach is counted in 4 groups according to size 2 mm., 2-4 mm. 4-8 mm., and 8 mm.); and each rat receives a score, 1, which is a weighted average of the logarithms of the ulcer counts in the several size groups, determined by a formula found approximately optimal by discriminant function analysis to be Z=20.00 log (N +l )+0.22 log. (N +l )+46.76 log where N; N, are the observed ulcer counts of the increasing size groups. Since long-term studies in approximately 400 animals shows that the average 2 value for controls is 96.2, with a standard error per group of 6 equal to 18.97, a decrease in the average 2 score for a given test group, relative to concurrent controls, amounting to 37.5 or more is significant (P g 0.05) and a compound producing such a decrease is considered anti-ulcerogenic.
The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limiting either in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade (C.). Quantities of materials are expressed in parts by weight unless otherwise noted. Pressure is indicated in millimeters (mm.) of mercury.
EXAMPLE I To. 500 parts by volume of ether containing parts of allyl magnesium bromide is slowly added, with stirring, 40 parts of ethyl cyclohexanecarboxylate, dis solved in parts by volume of tetrahydrofuran. The reaction mixture is then cooled and a saturated ammonium chloride solution is slowly added while the solution is continuously stirred. 2 N Hydrochloric acid solution is added until all salts are dissolved. The ethereal layer is separated and the aqueous layer is extracted twice with benzene. The organic layers are combined and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by suction filtration and the organic solvent is removed by evaporation at reduced pressure. Fractional distillation provides 4-cyclohexyl- 4-hydroxy-1,6-heptadiene, boiling at 90 at 1.25 mm.
4.12 parts of 4-cyclohexyl-4-hydroxyl ,G-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through the solution for 25 minutes and the solution is flushed with oxygen. This solution is slowly added to 333 parts by volume of acetic acid. The resulting solution is concentrated to a volume of 40 parts. A solution consisting of 33.3 parts by volume of acetic acid, 30 parts by volume of water, 8.3 parts by volume of 30% hydrogen peroxide, and 0.66 parts of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is then cooled to room temperature. The cooled solution is added to a mixture consisting of 0.166 parts of platinum oxide and 50 parts by volume of water over a period of thirty minutes. The resulting mixture is heated at 100 for 2 hours, then allowed tocool to room temperature. 0.67 Parts of barium carbonate is added and the mixture is allowed to stir for 12 hours. This solution is treated with decolorizing charcoal and is filtered. The solvent is removed at reduced pressure and the product is obtained by trituration with chloroform. The product is 3-hydroxy-3-cyclohexylglutaric acid. The formula for this compound is EXAMPLE 2 Using the procedure of Example 1, 40 parts of ethyl palmitate in ISO parts by volume of tetrahydrofuran are added to 49 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-npentadecyl-4-hydroxy-1,6-heptadiene, boiling at l68-l70 at 0.4 mm.
6.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to -C. A stream of ozone is passed through this solution for minutes and the ozonized solution is added to 50 parts by volume of acetic acid. This solution is concentrated to parts and a solution of 66 parts by volume of acetic acid, 60 parts by volume of water, 16 parts by volume of an aqueous 30% hydrogen peroxidesolution and 1.32 parts by volume of an aqueous 30%.hydrogen peroxide solution and 1.32 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.333 parts of platinum oxide and parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 1.2 Parts of barium carbonate is added and this mixture is allowed to stir for l2 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-pentadecylglutaric acid, melting at 74-76. The formula of this compound is EXAMPLE 3 Using the procedure of Example 1, 40 parts of isobutyl isobutyrate in 150 parts by volume of tetrahydrofuran is added to 97 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4'isopropyl- 4-hydroxy-l,6-heptadiene, boiling at 4345 at 1.35
3.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 66 parts by volume of acetic acid, 33 parts by volume of water, 8.3 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0. 16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then ailowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-isopropylglutaric acid. The formula of this compound is EXAMPLE 4 Using the procedure of Example 1, 40 parts of ethyl pentanoate in 150 parts by volume of tetrahydrofuran is added to 108 parts of allyi magnesium bromide in 500 parts by volume of ether to provide 4-n-butyl-4- hydroxy-l ,6-heptadiene, boiling at -92 at 5.8 mm.
3.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to -20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 30 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 66 parts by volume of acetic acid, 32 parts by volume of water, 8.2 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at and is cooled to room temperature. The cooled solution is added to a mixture consisting of 8.16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. isolation and purification, as is described in Example 1, provide 3-hydroxy-3-n-butylglutaric acid. The formula of this compound is EXAMPLE 5 Using the procedure of Example 1, 40 parts of ethyl 2,2-dimethylpropionate in parts by volume of tetrahydrofuran are added to 103 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-tbutyl-4-hydroxy-l,fi-heptadiene, boiling at 82 at 0.7
31.0 Parts of this 1,6-heptadiene is dissolved in 50 this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33 parts by volume of acetic acid, 32 parts by volume of water, 8.2 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-t-butylglutaric acid. The formula of this compound is EXAMPLE 6 Using the procedure of Example 1, 40 parts of ethyl undecanate in 150 parts by volume of tetrahydrofuran is added to 68 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-decyl-4-hydroxy- 1,6-heptadiene, boiling at l08-l 12 at 0.3 mm.
4.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to C. A stream of ozone is passed through this solution for minutes and the ozonized solution is added to 33.2 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33.2 parts by volume of acetic acid, 30 parts by volume of water, 8.3 parts by volume of an aqueous 30% hydrogen peroxide solution and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0. 166 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-n-decylglutaric acid. The formu 1 a of this compound is Using the procedure of Example 1, 40 parts of ethyl cyclopentylacetate in 150 parts by volume of tetrahydrofuran are added to 63.7 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4- cyclopentanemethyl-4-hydroxy- 1 ,6-heptadiene, boiling at 145 at 20 mm.
4.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33 parts by volume of acetic acid, 30 parts by volume of water, 8.3 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is-heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-cyclopentylmethylglutaric acid, melting at 1 l2-l 14. The formula of the compound is CHz-COZH EXAMPLE 8 Using the procedure of Example 1, 49 parts of ethyl phenylacetate in 150 parts by volume of tetrahydrofuran are added to 108 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4- benzyl-4-hydroxy-1,6-heptadiene, boiling at 153 at 20 3.8 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 60C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 30 parts by volume of acetic acid. This solution is concentrated to parts and a solution of 66 parts by volume of acetic acid, 60 parts by volume of water, 30 parts by volume of an aqueous 30% hydrogen peroxide solution, and 1.0 part by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.200 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 1.0 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-benzylglutaric acid. The formula of this compound is EXAMPLE 9 Using the procedure of Example 1, 40 parts of ethyl butyrate in parts by volume of tetrahydrofuran is added to 98 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-n-propyl-4- hydroxy-1,6-heptadiene, boiling at 70 at 17 mm.
6.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to -20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 50 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 66 parts by volume of acetic acid, 60 parts by volume of water, 16 parts by volume of an aqueous 30% hydrogen peroxide solution, and L32 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.333 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at l for 2 hours, then allowed to cool to room temperature. 1.2 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. isolation and purification, as is described in Example 1, provides 3-hydroxy-3-n-propylglutaric acid. The formula of this compound is EXAMPLE Using the procedure of Example l, 40 parts of ethyl propionate in 150 parts by volume of tetrahydrofuran are added to 103 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-ethyl-4- hydroxy-l,6-heptadiene, boiling at 65 at 17 mm.
3L0 Parts of this l,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33 parts by volume of acetic acid, 32 parts by volume of water, 8.2 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of suifuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0. 16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. isolation and purification, as is described in Example 1. provides 3-hydroxy-3-ethylglutaric acid, melting at 97. The formula of this compound is What is claimed is: 1. Compounds of the structural formula ethylglutaric acid.
Claims (7)
- 2. As in claim 1, the compound which is 3-hydroxy-3-pentadecylglutaric acid.
- 3. As in claim 1, the compound which is 3-hydroxy-3-isopropylglutaric acid.
- 4. As in claim 1, the compound which is 3-hydroxy-3-butylglutaric acid.
- 5. As in claim 1, the compound which is 3-hydroxy-3-t-butylglutaric acid.
- 6. As in claim 1, the compound which is 3-hydroxy-3-n-decylglutaric acid.
- 7. As in claim 1, the compound which is 3-hydroxy-3-propylglutaric acid.
- 8. As in claim 1, the compound which is 3-hydroxy-3-ethylglutaric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US00273417A US3818080A (en) | 1972-07-20 | 1972-07-20 | 3-hydroxy-3-substituted glutaric acid derivatives |
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| Application Number | Priority Date | Filing Date | Title |
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| US00273417A US3818080A (en) | 1972-07-20 | 1972-07-20 | 3-hydroxy-3-substituted glutaric acid derivatives |
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| Publication Number | Publication Date |
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| US3818080A true US3818080A (en) | 1974-06-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| US00273417A Expired - Lifetime US3818080A (en) | 1972-07-20 | 1972-07-20 | 3-hydroxy-3-substituted glutaric acid derivatives |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4404144A (en) * | 1981-02-20 | 1983-09-13 | G. D. Searle & Co. | Unsaturated analogs of β-alkyl-β-hydroxy glutaric acid and esters thereof |
| EP0089674A1 (en) * | 1982-03-22 | 1983-09-28 | G.D. Searle & Co. | Pentanedioic acid derivatives |
| FR2528828A1 (en) * | 1982-06-17 | 1983-12-23 | Roussel Uclaf | PROCESS FOR THE PREPARATION OF 3-METHYL 3-HYDROXY GLUTARIC ACID AND INTERMEDIATE PRODUCT NECESSARY FOR THIS PREPARATION |
| US4554359A (en) * | 1984-01-09 | 1985-11-19 | G. D. Searle & Co. | 3-Substituted pentanedioic acids and derivatives thereof |
| FR2572397A1 (en) * | 1984-10-29 | 1986-05-02 | Guidotti & C Spa Labor | PROCESS FOR THE PREPARATION OF 3-HYDROXY-3-METHYL-GLUTARIC ACID |
| EP0194610A1 (en) | 1985-03-11 | 1986-09-17 | G.D. Searle & Co. | Substituted glutaric acid lactones in the treatment of hyperlipidemia |
| US4645858A (en) * | 1982-03-22 | 1987-02-24 | G. D. Searle & Co. | Pentanedioic acid derivatives |
| EP0329124A3 (en) * | 1988-02-18 | 1991-07-31 | G.D. Searle & Co. | Metabolites of pentanedioic acid derivatives |
| US5233063A (en) * | 1988-02-18 | 1993-08-03 | G. D. Searle & Co. | Metabolites of pentanedioic acid derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3070512A (en) * | 1960-04-18 | 1962-12-25 | Basic Res Corp | Process of splititing steroids |
-
1972
- 1972-07-20 US US00273417A patent/US3818080A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3070512A (en) * | 1960-04-18 | 1962-12-25 | Basic Res Corp | Process of splititing steroids |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4404144A (en) * | 1981-02-20 | 1983-09-13 | G. D. Searle & Co. | Unsaturated analogs of β-alkyl-β-hydroxy glutaric acid and esters thereof |
| US4645858A (en) * | 1982-03-22 | 1987-02-24 | G. D. Searle & Co. | Pentanedioic acid derivatives |
| EP0089674A1 (en) * | 1982-03-22 | 1983-09-28 | G.D. Searle & Co. | Pentanedioic acid derivatives |
| JPS58172341A (en) * | 1982-03-22 | 1983-10-11 | ジ−・デイ・サ−ル・アンド・コンパニ− | Pentane diacid derivative |
| FR2528828A1 (en) * | 1982-06-17 | 1983-12-23 | Roussel Uclaf | PROCESS FOR THE PREPARATION OF 3-METHYL 3-HYDROXY GLUTARIC ACID AND INTERMEDIATE PRODUCT NECESSARY FOR THIS PREPARATION |
| EP0097578A1 (en) * | 1982-06-17 | 1984-01-04 | Roussel-Uclaf | Process for the preparation of 3-methyl-3-hydroxyglutaric acid and an intermediate product for the preparation thereof |
| US4554359A (en) * | 1984-01-09 | 1985-11-19 | G. D. Searle & Co. | 3-Substituted pentanedioic acids and derivatives thereof |
| EP0156100A3 (en) * | 1984-01-09 | 1986-06-25 | G.D. Searle & Co. | 3-substituted hydroxypentanedioic acid hemiesters or anhydrides |
| FR2572397A1 (en) * | 1984-10-29 | 1986-05-02 | Guidotti & C Spa Labor | PROCESS FOR THE PREPARATION OF 3-HYDROXY-3-METHYL-GLUTARIC ACID |
| US4966993A (en) * | 1984-10-29 | 1990-10-30 | Laboratori Guidotti Spa | Process for preparation of 3-hydroxy-3-methyl-glutaric acid |
| EP0194610A1 (en) | 1985-03-11 | 1986-09-17 | G.D. Searle & Co. | Substituted glutaric acid lactones in the treatment of hyperlipidemia |
| EP0329124A3 (en) * | 1988-02-18 | 1991-07-31 | G.D. Searle & Co. | Metabolites of pentanedioic acid derivatives |
| US5233063A (en) * | 1988-02-18 | 1993-08-03 | G. D. Searle & Co. | Metabolites of pentanedioic acid derivatives |
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