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US 2003/0144275 A1Published application
Novel compounds and a novel process for their preparation
AssigneeAstraZeneca AB
InventorsKeith Fagnou, Mark Lautens
Life of this patent
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Abstract
The present invention is directed to a procedure for making an enantiomerically enriched compound containing a hydronaphthalene ring structure. The process involves reacting oxabenzonorbornadienes with nucleophiles using rhodium as a catalyst and in the presence of a phosphine ligand. The compounds synthesized may be used in pharmaceutical preparations for the treatment of a variety of diseases and conditions.
Claims68
A compound according to formula I:
- 87
- wherein R is selected from the group consisting of:
- (a) H;
- (b) a C1-C6 straight or branched alkyl;
- (c) a straight or branched C2-C6 alkenyl;
- (d) —(CH2)nR1, wherein R1 is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from:
- Cl;
- F;
- NO2;
- I;
- Br;
- a C1-C3 alkyl;
- and a C1-C3 alkoxy wherein n=0-3;
- (e) —C(O)R2, wherein R2 is selected from the group consisting of:
- H;
- —(CH2)nR1, wherein R1 is as described above and n=0-3;
- and —(CH2)nC(O)R3, wherein R3 is a C1-C6 straight or branched alkyl and n=0-3;
- (f) —C(O)(CH2)p—C(O)—O—R4, wherein R4 is a straight or branched C1-C6 alkyl and wherein p=0-3;
- (g) —Rd(CF3)j, wherein Rd is a C1-C3 straight or branched alkyl and j=1-3;
- (h) —(CH2)j-TMS, wherein TMS is trimethylsilyl, and j=1-3
- wherein X and Y are independently selected from the group consisting of H;
- NH2;
- F;
- Cl;
- Br;
- a C1-C3 alkyl;
- and a C1-C3 alkoxy;
- or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of:
- O;
- N;
- and S;
- and
- wherein Z is selected from O or NRa, wherein Ra is selected from:
- (i) phenyl;
- (j) (O)C—O—Rb, wherein Rb is a straight or branched C1-C6 alkyl;
- (k) —SO2—Rc, wherein Rc is selected from the group consisting of:
- i) C1-C6 straight or branched alkyl;
- ii) —(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from:
- Cl;
- F;
- NO2;
- CN;
- I;
- Br;
- a straight or branched C1-C3 alkyl;
- a C1-C3 alkoxy;
- and —C(O)Rf, wherein Rf is a C1-C3 alkyl;
- —(CH2)rCF3, wherein r=0-3;
- iii) —Rg(CF3)s, wherein Rg is a C1-C3 straight or branched alkyl and s=1-3;
- iv) —(CH2),-TMS, wherein TMS=trimethylsilyl and s=1-3;
- (l) —SO2—(CH2)q—Si(CH3)3 wherein q is 1-3.
48 more elements
A compound according to formula II:
- 88
- wherein R is selected from the group consisting of:
- (a) a C1-C6 straight or branched alkyl;
- (b) —(CH2)qR5, wherein q=0-3 and R5 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from:
- a straight or branched C1-C3 alkyl;
- a C1-C3 alkoxy;
- Br;
- I;
- Cl;
- CN;
- F;
- NO2;
- —(CH2)rCF3, wherein r=0-3;
- and —C(O)R6, wherein R6 is a C1-C3 alkyl;
- (c) —R7(CF3), wherein R7 is a C1-C3 straight or branched alkyl and s=1-3;
- (d) —(CH2)s-TMS, wherein TMS=trimethylsilyl and s=1-3;
- wherein X and Y are independently selected from the group consisting of H;
- NH2;
- F;
- Cl;
- Br;
- a C1-C3 alkyl;
- and a C1-C3 alkoxy;
- or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of:
- O;
- N;
- and S;
- and
- wherein Z is selected from O or NRa, wherein Ra is selected from:
- (e) phenyl;
- (f) (O)C—O—Rb, wherein Rb is a straight or branched C1-C6 alkyl;
- (g) —SO2—Rc, wherein Rc is selected from the group consisting of:
- i) C1-C6 straight or branched alkyl;
- ii) —(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from:
- Cl;
- F;
- NO2;
- CN;
- I;
- Br;
- a straight or branched C1-C3 alkyl;
- a C1-C3 alkoxy;
- and —C(O)Rf, wherein Rf is a C1-C3 alkyl;
- —(CH2)rCF3, wherein r=0-3;
- iii) —Rg(CF3)s, wherein Rg is a C1-C3 straight or branched alkyl and s=1-3;
- iv) —(CH2)s-TMS, wherein TMS=trimethylsilyl and s=1-3;
- (h) —SO2—(CH2)q—Si(CH3)3 wherein q is 1-3.
44 more elements
A compound according to formula IV:
- 90
- wherein:
- a) in which R8 is H or CH3;
- b) t=0-3
- c) R9 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from:
- a C1-C3 alkyl;
- a C1-C3 alkoxy;
- Cl;
- F;
- NO2;
- and CF3;
- or R9 together with N form a ring structure selected from:
- a phthalamide ring;
- a pyrrolidine ring;
- a piperidine ring;
- a tetrahydroquinoline ring;
- and an indole ring;
- said ring structure being optionally substituted at one or more positions with a group selected from:
- a C1-C3 alkyl;
- a C1-C3 alkoxy;
- Cl;
- F;
- NO2;
- and CF3;
- d) X and Y are independently selected from the group consisting of H;
- NH2;
- F;
- Cl;
- Br;
- a C1-C3 alkyl;
- and a C1-C3 alkoxy;
- or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of:
- O;
- N;
- and S;
- e) Z is selected from O or NRa, wherein Ra is selected from:
- (i) a straight or branched C1-C6 alkyl;
- (ii) phenyl;
- (iii) (O)C—O—Rb, wherein Rb is a straight or branched C1-C6 alkyl;
- (iv) —SO2—Rc, wherein Rc is an unsubstituted phenyl or a phenyl substituted with a C1-C3 alkyl or NO2;
- and
- (v) —SO2—(CH2)q—Si(CH3)3 wherein q is 1-3;
- and
- f) when Z is O, R10 is H;
- when Z is NRa, R10 is either H or CH3.
42 more elements
A compound selected from the group consisting of:
- (1S,2S)-2-methoxy-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(ethoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(isopropoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(1-propenyloxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(2-trimethylsilyl-ethoxy) 1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-benzyloxy-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-methoxybenzyloxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(2,2,2-trifluoro-ethoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-6,7-difluoro-2-methoxy-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-6-methoxy-5,6-dihydro-naphthol[2,3-d][1,3]dioxol-5-ol;
- (1S,2S)-6,7-dibromo-2-methoxy-5,8-dimethyl-1,2-dihydro-naphthalen-1-ol;
- (1R*,2R*)-acetic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
- (1R*,2 R*)-propionic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
- (1R,2R)-benzoic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
- (1R*,2R*)-formic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
- (1R*,2R*)-2-methyl acrylic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
- (1R*,2R*)-malonic acid ethyl ester (1-hydroxy-1,2-dihydro-naphthalen-2-yl) ester;
- (1R*,2R*)-malonic acid (1-tert-butylbimethylsiloxy-1,2-dihydro-naphthalen-2-yl) ethyl ester;
- (1S*,2S*)4-tert-butyldimethylsiloxy-1,4-dihydro-naphthalen-2-yl) acetic acid ethyl ester;
- (1R,2R)-2-(1-hydroxy-1,2-dihydro-naphthalen-2-yl)-isoindole-1,3-dione;
- (1S,2S)-N-(1-hydroxy-1,2-dihydro-naphthalen-2-yl)-benzene sulfonamide;
- (1R*,2R*)-2-pyrrolidin-1-yl-1,2-dihydro-naphthalen-1-ol;
- (1R*,2R*)-2-piperidin-1-yl-1,2-dihydro-naphthalen-1-ol;
- (1R,2R)-2-(3,4-dihydro-2H-quinolin-1-yl)-1,2-dihydro-naphthalen-1-ol;
- (1R,2R)-2-(methyl-phenyl-amino)-1,2-dihydro-naphthalen-1-ol;
- (1R*,2R*)-2-benzylamino-1,2-dihydro-naphthalen-1-ol;
- (1R*,2R*)-2-(4-methoxy-benzylamino)-1,2-dihydro-naphthalen-1-ol;
- (1R,2R)-2-indol-1-yl-1,2-dihydro-naphthalen-1-ol;
- (1S*,2R*)-2-(hydroxy-1,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester;
- (1S,2S)-2-phenoxy-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-nitrophenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-cyanophenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-acylphenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-trifluoromethylphenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-fluorophenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-chlorophenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-iodophenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1R,2R)-2-(4-bromo-phenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-methylphenoxy)-1,2-dihydro-naphthalen-1-ol;
- (1S,2S)-2-(4-methoxyphenoxy)-1,2-dihydro-naphthalen-1-ol;
- and
- (1S,2S)-2-(2-bromophenoxy)-1,2-dihydro-naphthalen-1-ol;
- 4-methyl-N-[(1R,2S)-2-(1-piperidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide;
- N-[(1R,2S)-2-(3,4-dihydro-1 (2H)-quinolinyl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
- N-[(1R,2S)-2-(3,4-dihydro-2(1H)-isoquinolinyl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
- N-[(1R,2S)-2-(1H-indol-1-yl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
- (1R,25)-2-methoxy-N-phenyl-1,2-dihydro-1-naphthalenamine;
- tert-butyl(1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenylcarbamate;
- N-[(1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide;
- N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-benzenesulfonamide;
- N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]-benzenesulfonamide;
- N-hydroxy-4-({methyl[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]amino}sulfonyl)-N-oxobenzenaminium;
- N-methyl-4-nitro-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]-benzenesulfonamide;
- (1R,2S)-N-methyl-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydro-1-naphthalenamine;
- N-[(1R,2S)-2-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
- N-[(1R,2S)-2-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
- 4-methyl-N-[(1R,25)-2-phenoxy-1,2,3,4-tetrahydro-1-naphthalenyl]benzenesulfonamide;
- (1R,25)-1-{[(4-methylphenyl)sulfonyl]aminol}-1,2,3,4-tetrahydro-2-naphthalenyl acetate;
- (1R,2S)-1-{[(4-methylphenyl)sulfonyl]amino}-1,2-dihydro-2-naphthalenyl benzoate;
- (1R,2S)-1-{[(4-methylphenyl)sulfonyl]amino}-1,2-dihydro-2-naphthalenyl pivalate;
- N-[(1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide;
- tert-butyl (1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenylcarbamate;
- and
- 4-nitro-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide.
62 more elements
A process for preparing (1S,2S)-N-(1-hydroxy-1,2-dihydro-naphthalen-2-yl)-benzene sulfonamide, comprising reacting oxabenzonorbornadiene with benzenesulfonamide, wherein said reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand.
A process for preparing (1S*,2R*)-2-(hydroxy-1,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester, comprising reacting oxabenzonorbornadiene with dimethyl malonate, wherein said reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand.
Dependencies are inferred from the claim text.