GB2078726A - Carboxylic Acid Esters - Google Patents
Carboxylic Acid Esters Download PDFInfo
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- GB2078726A GB2078726A GB8114773A GB8114773A GB2078726A GB 2078726 A GB2078726 A GB 2078726A GB 8114773 A GB8114773 A GB 8114773A GB 8114773 A GB8114773 A GB 8114773A GB 2078726 A GB2078726 A GB 2078726A
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- carboxylic acid
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- 150000001733 carboxylic acid esters Chemical class 0.000 title claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 6
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 6
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000001240 enamine group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 6
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 239000004576 sand Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 abstract description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- KPWDGTGXUYRARH-UHFFFAOYSA-N 2,2,2-trichloroethanol Chemical compound OCC(Cl)(Cl)Cl KPWDGTGXUYRARH-UHFFFAOYSA-N 0.000 description 4
- UMLPONXXJIKBMA-UHFFFAOYSA-N 2-oxopyrrolidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCC1=O UMLPONXXJIKBMA-UHFFFAOYSA-N 0.000 description 4
- -1 carboxylic acid beta-lactams Chemical class 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- ORLCYMQZIPSODD-UHFFFAOYSA-N 1-chloro-2-[chloro(2,2,2-trichloroethoxy)phosphoryl]oxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(=O)OCC(Cl)(Cl)Cl ORLCYMQZIPSODD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229960003424 phenylacetic acid Drugs 0.000 description 2
- 239000003279 phenylacetic acid Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XTILJCALGBRMPR-UHFFFAOYSA-N 2-phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1.OC(=O)CC1=CC=CC=C1 XTILJCALGBRMPR-UHFFFAOYSA-N 0.000 description 1
- HOKIDJSKDBPKTQ-UHFFFAOYSA-N 3-(acetyloxymethyl)-7-[(5-amino-5-carboxypentanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(NC(=O)CCCC(N)C(O)=O)C12 HOKIDJSKDBPKTQ-UHFFFAOYSA-N 0.000 description 1
- IBBKJIHHXITFOF-UHFFFAOYSA-N 8-acetyl-7,7-dimethyl-2-oxo-6-thia-3,8-diazabicyclo[3.2.1]octane-3-carbonyl chloride Chemical compound ClC(=O)N1C(C2C(SC(C1)N2C(C)=O)(C)C)=O IBBKJIHHXITFOF-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/12—Preparation of carboxylic acid esters from asymmetrical anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/003—Esters of saturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
- C07C69/614—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety of phenylacetic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/08—Modification of a carboxyl radical directly attached in position 2, e.g. esterification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/28—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with modified 2-carboxyl group
- C07D499/32—Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/46—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with acyclic hydrocarbon radicals or such radicals substituted by carbocyclic or heterocyclic rings, attached to the carboxamido radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/60—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Carboxylic acid esters of the formula R-CO-O-R' are made by the selective alcoholysis with an alcohol of the formula HO-R' of a mixed anhydride of the formula: <IMAGE> wherein R is C1-6 alkyl, cycloalkyl up to C6, aryl, aralkyl with up to C5 in the alkyl moiety or a heterocyclic group, R' is any group capable of forming the alcohol HO-R' and X is C1-6 alkylene, bis[mono(C1-6)alkyl], a C1-5 group with an N, O or S heteroatom or <IMAGE> wherein Y is C1-5 or a C0-4 group with an N, O or S heteroatom and n is 0- 3.
Description
SPECIFICATION
Carboxylic Acid Esters
Description
This invention relates to the manufacture of carboxylic acid esters of the formula:
wherein R represents a C1C6 alkyl group, a cycloalkyl group having up to 6 carbon atoms, an aryl group, an aralkyl group having up to 5 carbon atoms in the alkyl moiety or a substituted or unsubstituted heterocyclic group, and R' represents a group capable of forming an alcohol of the formula H--OO-R', such as a C1-C6 alkyl group, a cycloalkyl group having up to 6 carbon atoms, an aryl group or an aralkyl group having up to 5 carbon atoms in the alkyl moiety, such aralkyl group being either an unsubstituted group, e.g. a benzyl, diphenylmethyl or trityl group, or a substituted group, e.g. with one or more substituents selected from halogen, alkoxy or nitro groups, or R' may represent an imido or enamine group.
The compounds of formula I are known and several of them are widely used in the pharmaceutical industry, because they include interalia penicillin esters and the corresponding sulphoxides, which are important intermediates in the synthesis of cephalosporine and other betalactamic antibiotics.
It is known that esters of very sensitive organic carboxylic acids, e.g. carboxylic acid beta-lactams, may be obtained by the reaction of alcohols with mixed anhydrides, which are in turn prepared from chlorocarbonic acid (DE-OS 1795413).
It is also known that esters of sensitive carboxylic acids are obtainable by starting from alcohols and carboxylic acids via the intermediate complex formed from N,N-disubstituted acid amides and carbonyl dichloride or, generally, by the action of halogenation agent, e.g. thionyl chloride (DE-OS 2233519) or an alkylchloroformate (DE-OS 2233520).
It has now been found, in accordance with the present invention, that carboxylic acid esters of formula I may be obtained by the selective alcoholysis of a mixed anhydride of the formula:
with an alcohol of the above-mentioned formula: H-O-R' (V) wherein R and R' has the above-defined meanings and X represents a C1-C6 alkylene group, a bis[mono(C,-C,)-alkyI] group, a C1C5 group comprising a heteroatom selected from N, 0 and S or a group of the formula
wherein Y represents a C1-C5 group or a C0-C4 group comprising a heteroatom selected from N, O and S and n is an integer from 0 to 3.
The reaction is preferably carried out at a temperature in the range from 5 to +50C, most suitably at OOC. Optionally, an inert organic solvent, such as methylene chloride, is employed.
The mixed anhydride of formula IV is obtained by the reaction of a carboxylic acid of the formula:
with an N-chlorocarbonyl-sec-amide of the formula:
wherein R and X have the above-defined meanings. This reaction is preferably carried out in an inert organic solvent immiscible with water, most suitably methylene chloride or tetrahydrofuran, and in the presence of an organic tertiary base, preferably pyridine or triethylamine. The reaction is advantageously carried out at a temperature in the range from 100 to +10 C, most preferably OOC.
The reaction time for the preparation of the mixed anhydride IV may typically range from 5 to 30 minutes, whereas the selective alcoholysis usually takes from 30 to 60 minutes, in either case under stirring.
In both reaction steps, the reactants may conveniently be employed in stoichiometric quantities, although, if desired, an excess of up to 10 mol % of the N-chlorocarbonyl-sec-amide, the alcohol or the tertiary base with respect to the carboxylic acid may be employed. The resulting carboxylic acid ester I is isolated from the reaction mixture and purified in a conventional manner, e.g. by the addition of water, separation of the organic layer, washing with water and subsequent drying and evaporation of the solvent.Alternatively, the solvent may be evaporated immediateiy after the reaction, whereupon the residue is dissolved in an organic solvent immiscible with water, e.g. methylene chloride or ethyl acetate, and mixed with water The organic layer is optionally washed with a NaHCO3 solution and repeatedly with water and finally worked up as indicated above.
The invention is illustrated but in no way limited by the following Examples.
Example 1 - Ethyl Ester of Phenylacetic Acid
Phenylacetic acid (6.8 g, 50 mmole) was dissolved in methylene chloride (50 ml), triethylamine (5 g, 50 mmole) was added and the solution was cooled to OOC. Subsequently, a solution of Nchlorocarbonyl-pyrrolidin-2-one (7.35 g, 50 mmole) in methylene chloride (30 ml) was introduced into the above solution and the reaction mixture was stirred for 30 minutes. Ethanol (2.3 g, 50 mmole) was slowly added and the reaction solution was stirred for 1 hour. After the addition of water (60 ml), the layers were separated and the organic layer was washed with water, dried and the solvent was evaporated.
Yield: 7.2 g (87.5%) of an oily product
IR spectrum (film): 1730 (vs) cm-' (C=O, ester)
H. NMR spectrum (CDCl3) 8: 1.24 (t, J=6 Hz, CH3), 3.58 (s, PhCH2CO), 4.21 (q, J=6 Hz, OCH2)
7.3 (s, C6H5)
Example 2 2,2,2-Trichlorethyl Ester of Phenylacetic Acid
A solution of N-chlorocarbonyl-pyrrolidin-2-one (7.35 g, 50 mmole) in methylene chloride (20 ml) was added dropwise with stirring, at a temperature of OOC, to a solution of phenylacetic acid (6.8 g, 50 mmole), pyridine (4 g, 50 mmole) and methylene chloride (50 ml). The reaction solution was stirred for 20 minutes, whereupon 2,2,2-trichloroethanol (7.47 g, 50 mmole) was added and stirring was continued for a further 30 minutes.The reaction product was isolated as indicated in Example 1.
Yield: 11.4 g (85%) of an oily product
IR spectrum (film): 1755 (vs) cm-l (C=0, ester)
Example 3 2,2,2-Trichloroethyl Ester of 6-phenoxyacetamido-penicillanic Acid
A solution of N-chlorocarbonyl-pyrrolidin-2-one (2.95 g, 20 mmole) in methylene chloride (15 ml) was added over a period of 10 to 1 5 minutes, with stirring at OOC, to a solution of 6phenoxyacetamido-penicillanic acid (7 g, 20 mmole), pyridine (1.6 g, 21 mmole) and methylene chloride (60 ml). The reaction mixture was stirred for 15 minutes, whereupon a solution of 2,2,2trichloroethanol (3.3 g, 22 mmole) in methylene chloride (15 ml) was added dropwise and the stirring was continued for a further 1 hour.Water (50 ml) was added, the mixture was stirred for 2 minutes and the organic layer was separated, washed with water (25 ml) and dried. Evaporation of the solvent yielded an oily residue.
Yield: 7.9 g (82.5%) of a product showing identical IR and rH NMR spectra to those cited in the literature [J.Org. Chem. 36(1971) 1259].
Example 4
Benzyl Ester of 6-phenoxyacetamidopenicillanic Acid
Pyridine (0.79 g, 10 mmole) was added to a solution of 3-chlorocarbonyl-8-acetyl-7,7-dimethyl 6-thia-3,8-diazabicyclo[3,2,1]octan-2-one (2.77 g, 10 mmole) in methylene chloride (50 ml), cooled to 0 C, and was immediately followed by the addition of 6-phenoxyacetamidopenicilianic acid (3.5 g, 10 mmole), whereupon the mixture was stirred for 15 minutes at OOC. A solution of benzylalcohol (0.972 g, 9 mmole) in methylene chloride (5 ml) was added dropwise over a period of 1 5 minutes to the reaction mixture and stirring was continued for 1 hour at 50C. Subsequently, the solvent was evaporated and the residue was dissolved in a mixutre of ether (50 ml) and water (50 ml), the organic layer was separated and the aqueous layer was repeatedly extracted with ether (20 ml). The combined ethereal extracts were washed with a saturated NaHCO3 solution and then water and dried.
Evaporation of the ether yielded an oily product.
Yield: 3.40 g (77%) of a product showing identical IR spectrum to that cited in the literature
[J.Org. Chem. 27 (1962)1381].
Example 5 2,2,2-Trichloroethyl Ester of 6-phenylacetamidopenicillanic Acid
The potassium salt of 6-phenylacetamidopenicillanic acid (7 g, 1 9 mmole), was added to a solution of pyridine (1.6 g, 21 mmole) in methylene chloride (70 ml), whereupon a solution of Nchlorocarbonyl-pyrrolidin-2-one (2.95 g 20 mmole) in methylene chloride (15 ml), was added dropwise with stirring at OOC. The reaction mixture was stirred for 10 minutes, whereupon a solution of 2,2,2trichloroethanol (3.3 g, 22 mmole) in methylene chloride (10 ml) was added and the stirring was continued for 1 hour. The product was isolated as indicated in Example 3. The residual product was crystallized by means of the addition of ether.
Yield: 6.71 9 (76.7%), m.p. 1580--1600C IR and 1H NMR spectra are identical to the data given in the literature [J. Org. Chem. 36(1971)
1259].
Example 6 p-Nitrobenzyl-6-phenylacetamidopenicill inate-1 -oxide
A solution of N-chlorocarbonyl-pyrrolidin-2-one (295 mg, 2 mmole) in methylene chloride (5 ml) was added at +50C, over a period of 10 minutes, to a solution of 6-phenylacetamidopenicillanic acid 1 -oxide (630 mg, 1.8 mmole), pyridine (160 mg, 2.02 mmole) and methylene chloride (10 ml). The mixture was stirred for 30 minutes, whereupon a solution of N-nitrobenzyl alcohol (337 mg, 2.2 mmole) in methylene chloride (10 ml) was added and the stirring was continued for 1.5 hours. Cold water (25 ml) was added, the mixture was stirred for 5 minutes, the layers were separated, the organic layer was washed with 5% w/w solution of NaHCO3 (10 ml) and subsequently with water (15 ml), dried and the solvent was evaporated.
Yield: 745 mg (85.3%) of the desired product.
The IR spectrum is identical to the data given in the literature (DE-OS 2064107).
Example 7 2,2,2-Trichloroethyl-6-phenoxyacetamidopenicillinate-1 -oxide
A solution of N-chlorocarbonyl-pyrrolidin-2-one (295 mg, 2 mmole) in tetrahydrofuran (5 ml) was added at a temperature of -100C, over a period of 1 5 minutes, to a solution of 6phenoxyacetamidopenicillanic acid 1 -oxide (660 mg, 1.8 mmole), pyridine (160 mg, 2.02 mmole) and tetrahydrofuran (10 ml) whereupon the reaction mixture was stirred for 15 minutes. Subsequently, 2,2,2-trichloroethanol (330 mg, 2.2 mmole) was added and the reaction mixture was stirred for a further 30 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride (20 ml) and water (20 ml), stirred for 5 minutes, the organic layer was separated and dried and the solvent was evaporated. Digestion of the residue in ether yielded the desired product with a m.p. 1 43--145 OC.
Yield: 721 mg (80%) of the product
IR and 1H NMR spectra are identical to the data given in the literature [J. Org. Chem. (1971) 1263].
Claims (6)
1. A process of manufacture of a carboxylic acid ester of the formula:
wherein R represents a C1-C6 alkyl group, a cycloalkyl group having up to 6 carbon atoms, an aryl group, an aralkyl group having up to 5 carbon atoms in the alkyl moiety or a substituted or unsubstituted heterocylic group and R' represents a group capable of forming an alcohol of the formula H--OO-R', which comprises reacting a carboxylic acid of the formula:
with an N-chlorocarbonyl-sec-amide of the formula:
and subjecting the resultant mixed anhydride of the formula:
to selective alcoholysis by means of an alcohol of the above-mentioned formula:: H-O-R' (V) wherein R and R' have the above-defined meanings and X represents a C1-c6 alkylene group, a bis[mono(C,-C,)-alkyI]-group, a C1-C5 group comprising a heteroatom selected from N, 0 and S or a group of the formula
wherein Y represents a C1-C5 group or a C044 group comprising a heteroatom selected from N, O and Sand n is an integer from 0 to 3.
2. A process according to claim 1, wherein R' represents a C1-C6 alkyl group, a cycloalkyl group having up to 6 carbon atoms, an aryl group, a substituted or unsubstituted aralkyl group having up to 5 carbon atoms in the alkyl moiety or an imido or enamine group.
3. A process according to claim 1 or 2, wherein the mixed anhydride (IV) is prepared in an inert organic solvent immiscible with water and in the presence of an organic tertiary base at a temperature of-lO0 to +10 C.
4. A process according to claim 1,2 or 3, wherein, the selective alcoholysis is carried out at a temperature of5 to +50C.
5. A process according to claim 1, substantially as described with reference to the foregoing
Examples.
6. A carboxylic acid ester of formula I, when manufactured by a process according to any preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU1409/80A YU41210B (en) | 1980-05-24 | 1980-05-24 | Process for preparing esters by alcoholysis of mixed onhydrides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2078726A true GB2078726A (en) | 1982-01-13 |
| GB2078726B GB2078726B (en) | 1983-12-07 |
Family
ID=25554058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8114773A Expired GB2078726B (en) | 1980-05-24 | 1981-05-14 | Carboxylic acid esters |
Country Status (5)
| Country | Link |
|---|---|
| AT (1) | AT375913B (en) |
| CH (1) | CH650494A5 (en) |
| DE (1) | DE3120453A1 (en) |
| GB (1) | GB2078726B (en) |
| YU (1) | YU41210B (en) |
-
1980
- 1980-05-24 YU YU1409/80A patent/YU41210B/en unknown
-
1981
- 1981-05-14 GB GB8114773A patent/GB2078726B/en not_active Expired
- 1981-05-22 DE DE19813120453 patent/DE3120453A1/en not_active Ceased
- 1981-05-22 AT AT0230781A patent/AT375913B/en not_active IP Right Cessation
- 1981-05-22 CH CH3365/81A patent/CH650494A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH650494A5 (en) | 1985-07-31 |
| GB2078726B (en) | 1983-12-07 |
| ATA230781A (en) | 1984-02-15 |
| AT375913B (en) | 1984-09-25 |
| YU41210B (en) | 1986-12-31 |
| DE3120453A1 (en) | 1982-02-25 |
| YU140980A (en) | 1983-01-21 |
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| PCNP | Patent ceased through non-payment of renewal fee |