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molecular formula C13H18O2 B1670340 (S)-(+)-Ibuprofen CAS No. 51146-56-6

(S)-(+)-Ibuprofen

Cat. No. B1670340
M. Wt: 206.28 g/mol
InChI Key: HEFNNWSXXWATRW-JTQLQIEISA-N
Attention: For research use only. Not for human or veterinary use.
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Patent
US05248815

Procedure details

Surprisingly, only a few methods for a stereospecific chemical synthesis for 2-aryl-alkanoic acids, especially 2-aryl-propionic acids, are known. Piccolo et al. (J. Org. Chem. 50, 3945-3946, 1985) describe a stereospecific synthesis by the alkylation of benzene or isobutylbenzene with (S)-methyl-2-(chlorosulfonyl)-oxy or 2-(mesyloxy) propionate in the presence of aluminum chloride yielding (S)-methyl-2-phenyl-propionate in good chemical yield (50-80%) and excellent optical yield of >97% as determined by rotation through inversion of configuration at the attacking carbon atoms. The reaction conditions are very similar as described in some patents (Jpn. Kokai Tokkyo Koho 5808045; Chem. Abstracts, 1983, 98; 143138 k; Jpn. Kokai Tokkyo Koho 7979246; Chem. Abstracts, 1980, 92, 6253 f) where racemic reagents have been used. Extensions of this type of reactions to other aromatic substrates, e.g. toluene, isobutylbenzene, tetraline, anisole, naphthalene, 2-methoxy-naphthalene are described in Jpn. Kokai Tokkyo Koho 7971932; Chem. Abstracts 1979, 91, 20125 b; Jpn. Kokai Tokkyo Koho 78128327; Chem. Abstracts 1978, 89, 23975 y; Jpn. Kokai Tokkyo Koho 81145241; Chem. Abstracts 1982, 96, 68650 z; Jpn. Kokai Tokkyo Koho 78149945; Chem. Abstracts 1979, 90, 168303 h; Jpn. Kokai Tokkyo Koho 7844537; Chem. Abstracts 1978, 89, 108693 h; Jpn. Kokai Tokkyo 77131551; Chem. Abstracts 1978, 88, 104920 h. In a recent paper Piccolo et al. (J. Org. Chem. 52. 10, 1987) describe a synthesis leading to R-(-) ibuprofen, whereas Tsuchihashi et al. (Eur. Pat. Appl. EP 67,698, (1982); Chem. Abstracts 98, 178945 y, (1983) report a stereospecific synthesis of the R-(-) ibuprofen-methylester with excellent yields of about 75.0% and high optical purity (>95%) in contrast to Piccolo et al. (J. Org. Chem. 32, 10, 1987) having an optical purity of 15% only for the R-(-) ibuprofen. However, the same authors have reported chemical yields of 68% of S (+) ibuprofen having an optical purity of 75-78%, only. Hayashi, et al. (J. Org. Chem. 48, 2195, 1983; in: Asymmetric Reactions and Processes In Chemistry; eds E. L. Eliel and S. Otsuka, ACS-Symposium Ser. 1985, 1982, 177) describe a stereospecific synthesis of S-(+) ibuprofen through asymmetric Grignard cross-coupling which are catalyzed by chiral phosphine-nickel and phosphine-palladium complexes. The enantiomeric excess of the coupling products with various alkenyl halides under the influence of the above-mentioned metal phosphine complexes, including amino acids, depends strongly on the ligand and ranges up to 94% with enantiomeric excesses in the 60-70% range. A very useful ligand has been found in chiral 2-aminoalkyl phosphines achieving reasonable chemical yields and high optical purity. Furthermore, optically active 2-aryl-alkonates have been synthesized via a Friedel-Crafts synthesis by Sato and Murai (Jpn. Kokai Tokkyo Koho JP 61,210,049 t 86,210,049, 1986) yielding 46% S-(+) ibuprofen. Giordano et al. (EP application 0 158 913, 1985) have reported a process for the preparation of optically active 2-aryl-alkanoic acids and intermediates thereof by halogenation on the aliphatic carbon atom to the ketal group and rearrangements of the haloketals yielding pharmacologically active 2-aryl-alkanoic acids. A stereochemical synthesis of 2-aryl-propionic acids is described by Robertson et al. (EP application 0 205 215 A2, 1986) using 2-(R1)-alkane as the carbon source for the fungi Cordyceps in particular for Cordiceps militaris, yielding enantiomeric S-(+) products of high optical purity.
[Compound]
Name
aromatic substrates
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One
Quantity
0 (± 1) mol
Type
solvent
Reaction Step Two
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Three
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Four
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Five
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Six
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Seven
[Compound]
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Eight
[Compound]
Name
R-(-) ibuprofen-methylester
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Nine
[Compound]
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Ten

Identifiers

REACTION_CXSMILES
[CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C1C2C(=CC=CC=2)CCC1.[C:21]1([O:27]C)[CH:26]=[CH:25]C=CC=1.C1C2C(=CC=CC=2)C=CC=1.C[O:40]C1C=CC2C(=CC=CC=2)C=1>C1(C)C=CC=CC=1>[OH:40][C:21]([CH:26]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH3:25])=[O:27]

Inputs

Step One
Name
aromatic substrates
Quantity
0 (± 1) mol
Type
reactant
Smiles
Step Two
Name
Quantity
0 (± 1) mol
Type
solvent
Smiles
C1(=CC=CC=C1)C
Step Three
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C(C(C)C)C1=CC=CC=C1
Step Four
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C1CCCC2=CC=CC=C12
Step Five
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C1(=CC=CC=C1)OC
Step Six
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C1=CC=CC2=CC=CC=C12
Step Seven
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
COC1=CC2=CC=CC=C2C=C1
Step Eight
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Smiles
Step Nine
Name
R-(-) ibuprofen-methylester
Quantity
0 (± 1) mol
Type
reactant
Smiles
Step Ten
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Smiles

Conditions

Other
Conditions are dynamic
1
Details
See reaction.notes.procedure_details.

Workups

CUSTOM
Type
CUSTOM
Details
yield (50-80%) and excellent optical yield of >97%
CUSTOM
Type
CUSTOM
Details
The reaction conditions
CUSTOM
Type
CUSTOM
Details
Abstracts 1979, 90, 168303 h
Duration
168303 h
CUSTOM
Type
CUSTOM
Details
Abstracts 1978, 89, 108693 h
Duration
108693 h
CUSTOM
Type
CUSTOM
Details
Abstracts 1978, 88, 104920 h
Duration
104920 h
CUSTOM
Type
CUSTOM
Details
with excellent yields of about 75.0% and high optical purity (>95%) in contrast to Piccolo et al. (J. Org. Chem. 32, 10, 1987)

Outcomes

Product
Name
Type
product
Smiles
OC(=O)C(C)C1=CC=C(CC(C)C)C=C1

Source

Source
Open Reaction Database (ORD)
Description
The Open Reaction Database (ORD) is an open-access schema and infrastructure for structuring and sharing organic reaction data, including a centralized data repository. The ORD schema supports conventional and emerging technologies, from benchtop reactions to automated high-throughput experiments and flow chemistry. Our vision is that a consistent data representation and infrastructure to support data sharing will enable downstream applications that will greatly improve the state of the art with respect to computer-aided synthesis planning, reaction prediction, and other predictive chemistry tasks.
Patent
US05248815

Procedure details

Surprisingly, only a few methods for a stereospecific chemical synthesis for 2-aryl-alkanoic acids, especially 2-aryl-propionic acids, are known. Piccolo et al. (J. Org. Chem. 50, 3945-3946, 1985) describe a stereospecific synthesis by the alkylation of benzene or isobutylbenzene with (S)-methyl-2-(chlorosulfonyl)-oxy or 2-(mesyloxy) propionate in the presence of aluminum chloride yielding (S)-methyl-2-phenyl-propionate in good chemical yield (50-80%) and excellent optical yield of >97% as determined by rotation through inversion of configuration at the attacking carbon atoms. The reaction conditions are very similar as described in some patents (Jpn. Kokai Tokkyo Koho 5808045; Chem. Abstracts, 1983, 98; 143138 k; Jpn. Kokai Tokkyo Koho 7979246; Chem. Abstracts, 1980, 92, 6253 f) where racemic reagents have been used. Extensions of this type of reactions to other aromatic substrates, e.g. toluene, isobutylbenzene, tetraline, anisole, naphthalene, 2-methoxy-naphthalene are described in Jpn. Kokai Tokkyo Koho 7971932; Chem. Abstracts 1979, 91, 20125 b; Jpn. Kokai Tokkyo Koho 78128327; Chem. Abstracts 1978, 89, 23975 y; Jpn. Kokai Tokkyo Koho 81145241; Chem. Abstracts 1982, 96, 68650 z; Jpn. Kokai Tokkyo Koho 78149945; Chem. Abstracts 1979, 90, 168303 h; Jpn. Kokai Tokkyo Koho 7844537; Chem. Abstracts 1978, 89, 108693 h; Jpn. Kokai Tokkyo 77131551; Chem. Abstracts 1978, 88, 104920 h. In a recent paper Piccolo et al. (J. Org. Chem. 52. 10, 1987) describe a synthesis leading to R-(-) ibuprofen, whereas Tsuchihashi et al. (Eur. Pat. Appl. EP 67,698, (1982); Chem. Abstracts 98, 178945 y, (1983) report a stereospecific synthesis of the R-(-) ibuprofen-methylester with excellent yields of about 75.0% and high optical purity (>95%) in contrast to Piccolo et al. (J. Org. Chem. 32, 10, 1987) having an optical purity of 15% only for the R-(-) ibuprofen. However, the same authors have reported chemical yields of 68% of S (+) ibuprofen having an optical purity of 75-78%, only. Hayashi, et al. (J. Org. Chem. 48, 2195, 1983; in: Asymmetric Reactions and Processes In Chemistry; eds E. L. Eliel and S. Otsuka, ACS-Symposium Ser. 1985, 1982, 177) describe a stereospecific synthesis of S-(+) ibuprofen through asymmetric Grignard cross-coupling which are catalyzed by chiral phosphine-nickel and phosphine-palladium complexes. The enantiomeric excess of the coupling products with various alkenyl halides under the influence of the above-mentioned metal phosphine complexes, including amino acids, depends strongly on the ligand and ranges up to 94% with enantiomeric excesses in the 60-70% range. A very useful ligand has been found in chiral 2-aminoalkyl phosphines achieving reasonable chemical yields and high optical purity. Furthermore, optically active 2-aryl-alkonates have been synthesized via a Friedel-Crafts synthesis by Sato and Murai (Jpn. Kokai Tokkyo Koho JP 61,210,049 t 86,210,049, 1986) yielding 46% S-(+) ibuprofen. Giordano et al. (EP application 0 158 913, 1985) have reported a process for the preparation of optically active 2-aryl-alkanoic acids and intermediates thereof by halogenation on the aliphatic carbon atom to the ketal group and rearrangements of the haloketals yielding pharmacologically active 2-aryl-alkanoic acids. A stereochemical synthesis of 2-aryl-propionic acids is described by Robertson et al. (EP application 0 205 215 A2, 1986) using 2-(R1)-alkane as the carbon source for the fungi Cordyceps in particular for Cordiceps militaris, yielding enantiomeric S-(+) products of high optical purity.
[Compound]
Name
aromatic substrates
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One
Quantity
0 (± 1) mol
Type
solvent
Reaction Step Two
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Three
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Four
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Five
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Six
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Seven
[Compound]
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Eight
[Compound]
Name
R-(-) ibuprofen-methylester
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Nine
[Compound]
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Ten

Identifiers

REACTION_CXSMILES
[CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C1C2C(=CC=CC=2)CCC1.[C:21]1([O:27]C)[CH:26]=[CH:25]C=CC=1.C1C2C(=CC=CC=2)C=CC=1.C[O:40]C1C=CC2C(=CC=CC=2)C=1>C1(C)C=CC=CC=1>[OH:40][C:21]([CH:26]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH3:25])=[O:27]

Inputs

Step One
Name
aromatic substrates
Quantity
0 (± 1) mol
Type
reactant
Smiles
Step Two
Name
Quantity
0 (± 1) mol
Type
solvent
Smiles
C1(=CC=CC=C1)C
Step Three
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C(C(C)C)C1=CC=CC=C1
Step Four
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C1CCCC2=CC=CC=C12
Step Five
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C1(=CC=CC=C1)OC
Step Six
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
C1=CC=CC2=CC=CC=C12
Step Seven
Name
Quantity
0 (± 1) mol
Type
reactant
Smiles
COC1=CC2=CC=CC=C2C=C1
Step Eight
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Smiles
Step Nine
Name
R-(-) ibuprofen-methylester
Quantity
0 (± 1) mol
Type
reactant
Smiles
Step Ten
Name
R-(-) ibuprofen
Quantity
0 (± 1) mol
Type
reactant
Smiles

Conditions

Other
Conditions are dynamic
1
Details
See reaction.notes.procedure_details.

Workups

CUSTOM
Type
CUSTOM
Details
yield (50-80%) and excellent optical yield of >97%
CUSTOM
Type
CUSTOM
Details
The reaction conditions
CUSTOM
Type
CUSTOM
Details
Abstracts 1979, 90, 168303 h
Duration
168303 h
CUSTOM
Type
CUSTOM
Details
Abstracts 1978, 89, 108693 h
Duration
108693 h
CUSTOM
Type
CUSTOM
Details
Abstracts 1978, 88, 104920 h
Duration
104920 h
CUSTOM
Type
CUSTOM
Details
with excellent yields of about 75.0% and high optical purity (>95%) in contrast to Piccolo et al. (J. Org. Chem. 32, 10, 1987)

Outcomes

Product
Name
Type
product
Smiles
OC(=O)C(C)C1=CC=C(CC(C)C)C=C1

Source

Source
Open Reaction Database (ORD)
Description
The Open Reaction Database (ORD) is an open-access schema and infrastructure for structuring and sharing organic reaction data, including a centralized data repository. The ORD schema supports conventional and emerging technologies, from benchtop reactions to automated high-throughput experiments and flow chemistry. Our vision is that a consistent data representation and infrastructure to support data sharing will enable downstream applications that will greatly improve the state of the art with respect to computer-aided synthesis planning, reaction prediction, and other predictive chemistry tasks.
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