US20060079715A1 - Production of 2-amino-2-(4-alkylphenyl)ethyl]propane-1,3-diols - Google Patents
Production of 2-amino-2-(4-alkylphenyl)ethyl]propane-1,3-diols Download PDFInfo
- Publication number
- US20060079715A1 US20060079715A1 US11/288,549 US28854905A US2006079715A1 US 20060079715 A1 US20060079715 A1 US 20060079715A1 US 28854905 A US28854905 A US 28854905A US 2006079715 A1 US2006079715 A1 US 2006079715A1
- Authority
- US
- United States
- Prior art keywords
- compound
- formula
- ethyl
- octylphenyl
- propane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000004519 manufacturing process Methods 0.000 title abstract description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title abstract description 16
- PLDICAWLDKZBFW-UHFFFAOYSA-N 1-(2-bromoethyl)-4-octylbenzene Chemical compound CCCCCCCCC1=CC=C(CCBr)C=C1 PLDICAWLDKZBFW-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 abstract description 31
- 150000001875 compounds Chemical class 0.000 description 86
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 30
- 239000000203 mixture Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- RYOKCHIAMHPMLV-UHFFFAOYSA-N diethyl 2-acetamido-2-[2-(4-octylphenyl)ethyl]propanedioate Chemical compound CCCCCCCCC1=CC=C(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)C=C1 RYOKCHIAMHPMLV-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 16
- GNDIBYIKXCMJGO-UHFFFAOYSA-N [2-acetamido-2-(acetyloxymethyl)-4-(4-octylphenyl)butyl] acetate Chemical compound CCCCCCCCC1=CC=C(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)C=C1 GNDIBYIKXCMJGO-UHFFFAOYSA-N 0.000 description 15
- OEFKRBPTEVTSLY-UHFFFAOYSA-N 2-bromo-1-(4-octylphenyl)ethanone Chemical compound CCCCCCCCC1=CC=C(C(=O)CBr)C=C1 OEFKRBPTEVTSLY-UHFFFAOYSA-N 0.000 description 14
- FXWGCWKFKYSSLD-UHFFFAOYSA-N diethyl 2-acetamido-2-[2-(4-octylphenyl)-2-oxoethyl]propanedioate Chemical compound CCCCCCCCC1=CC=C(C(=O)CC(NC(C)=O)(C(=O)OCC)C(=O)OCC)C=C1 FXWGCWKFKYSSLD-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 150000003839 salts Chemical group 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- YURZVKRFVMTWMC-UHFFFAOYSA-N 1-(2-iodoethyl)-4-octylbenzene Chemical compound CCCCCCCCC1=CC=C(CCI)C=C1 YURZVKRFVMTWMC-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- XMWPVJOPHSHKHP-UHFFFAOYSA-N 3-amino-3-(hydroxymethyl)-1-(4-octylphenyl)butane-1,4-diol Chemical compound CCCCCCCCC1=CC=C(C(O)CC(N)(CO)CO)C=C1 XMWPVJOPHSHKHP-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- 0 *C1=CC=C(C(O)CC(N)(CO)CO)C=C1 Chemical compound *C1=CC=C(C(O)CC(N)(CO)CO)C=C1 0.000 description 9
- 229940126062 Compound A Drugs 0.000 description 9
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- NCIYVCYRCKQMJY-UHFFFAOYSA-N [2-acetamido-4-acetyloxy-2-(acetyloxymethyl)-4-(4-octylphenyl)butyl] acetate Chemical compound CCCCCCCCC1=CC=C(C(CC(COC(C)=O)(COC(C)=O)NC(C)=O)OC(C)=O)C=C1 NCIYVCYRCKQMJY-UHFFFAOYSA-N 0.000 description 7
- 150000007514 bases Chemical class 0.000 description 7
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- BUVAWTAMOZOVNN-UHFFFAOYSA-N 2-(4-octylphenyl)ethanol Chemical compound CCCCCCCCC1=CC=C(CCO)C=C1 BUVAWTAMOZOVNN-UHFFFAOYSA-N 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- CDKDZKXSXLNROY-UHFFFAOYSA-N octylbenzene Chemical compound CCCCCCCCC1=CC=CC=C1 CDKDZKXSXLNROY-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- SMEKUNROPXNPGN-UHFFFAOYSA-N 1-[4-(2-hydroxyethyl)phenyl]octan-1-one Chemical compound CCCCCCCC(=O)C1=CC=C(CCO)C=C1 SMEKUNROPXNPGN-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- -1 methanol Chemical compound 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- GARQDIVXKVBJFP-UHFFFAOYSA-N p-Octylacetophenone Chemical compound CCCCCCCCC1=CC=C(C(C)=O)C=C1 GARQDIVXKVBJFP-UHFFFAOYSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 2
- SWZTYAVBMYWFGS-UHFFFAOYSA-N fingolimod hydrochloride Chemical compound Cl.CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 SWZTYAVBMYWFGS-UHFFFAOYSA-N 0.000 description 2
- NIHITJCGPYUKLW-UHFFFAOYSA-N n-[1,4-dihydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl]acetamide Chemical compound CCCCCCCCC1=CC=C(C(O)CC(CO)(CO)NC(C)=O)C=C1 NIHITJCGPYUKLW-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WMMCAHOQTAECRL-UHFFFAOYSA-N 1-[4-(2-iodoethyl)phenyl]octan-1-one Chemical compound CCCCCCCC(=O)C1=CC=C(CCI)C=C1 WMMCAHOQTAECRL-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101100273284 Homo sapiens CASP4 gene Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- BLAKAEFIFWAFGH-UHFFFAOYSA-N acetyl acetate;pyridine Chemical compound C1=CC=NC=C1.CC(=O)OC(C)=O BLAKAEFIFWAFGH-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000005864 bromoacetylation reaction Methods 0.000 description 1
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- 230000002083 iodinating effect Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- JYQQWQJCEUMXQZ-UHFFFAOYSA-N methyl cyanate Chemical compound COC#N JYQQWQJCEUMXQZ-UHFFFAOYSA-N 0.000 description 1
- ZUZLIXGTXQBUDC-UHFFFAOYSA-N methyltrioctylammonium Chemical compound CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC ZUZLIXGTXQBUDC-UHFFFAOYSA-N 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/20—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms
- C07C17/202—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction
- C07C17/208—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction the other compound being MX
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
- C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Definitions
- the present invention relates to a process for the production of 2-amino-2-[2-(4-C 2-20 -alkyl-phenyl)ethyl]propane-1,3-diols, particularly 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol of formula hereinafter defined as Compound A.
- EP-A1-627,406 2-Amino-2-[2-(4-C 2-20 -alkyl-phenyl)ethyl]propane-1,3-diols are disclosed in EP-A1-627,406 the relevant disclosure of which is incorporated herein by reference.
- EP-A1-627,406 they have been found to be useful e.g. as immunosuppressants, e.g. in the prevention or treatment of acute allograft rejection or autoimmune diseases, or e.g. as described in WO 98/22100, in the prevention or treatment of xenograft rejection.
- Any alkyl group mentioned herein may be a straight or branched chain alkyl group.
- C 2-20 alkyl is octyl, particularly straight chain.
- protecting groups as R 3 are e.g. disclosed in “Protective Groups in Organic Synthesis”, T. W. Greene, J. Wiley & Sons New York (1981), 219-287, e.g. acyl such as formyl, acetyl, benzoyl; alkoxycarbonyl e.g. t.-butyloxycarbonyl; allyloxycarbonyl; trityl; etc.
- the reduction step g) may conveniently be performed using a reducing agent, e.g. NaBH 4 .
- a reducing agent e.g. NaBH 4 .
- the following treatment with an anhydride may be effected e.g. with acetic anhydride, preferably in the presence of a neutralizing agent, e.g. an aliphatic or organic amine, e.g. pyridine.
- Suitable basic compounds for use in step i) include an alkali metal hydroxide, e.g. NaOH, KOH or LiOH.
- Step i) may preferably be carried out in a polar solvent, e.g. an alcohol such as methanol, at reflux.
- Step j) may be effected in accordance with known hydrogenation methods, e.g. in the presence of a hydrogenation catalyst, e.g. Pd—C.
- a 2-amino-2-[2-(4-C 2-20 alkylphenyl)ethyl]propane-1,3-diol in free form or in salt form may be prepared by
- Steps h) and N) may be effected in accordance with methods known in the art, e.g. as disclosed above for steps j) and i), respectively, or in Examples 4 and 5 hereinafter.
- the reduction may comprise either a hydrogenation step, e.g. as disclosed above for step (j), followed by a reduction step, e.g. as disclosed above for step (g), or a reduction step as diclosed for step (g) comprising an intermediary hydrogenation step [e.g. as disclosed for step (j)] prior to the anhydride (R 4 CO) 2 O treatment.
- Step (N) may be carried out as indicated above.
- the invention provides a process for preparing 2-amino-2-[2-(4-C 2-20 alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
- Process steps (f) and (K) may be performed as disclosed above for (j) and (g), respectively.
- the reduction step (K) may be carried out in the presence of Ca (BH 4 ) 2 .
- the latter may be generated by reaction of NaBH 4 with CaCl 2 .
- Compound of formula (20′) may be prepared as disclosed in PCT/JP98/02998.
- the invention further provides a process for preparing a 2-amino-2-[2-(4-C 2-20 alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
- Process step (g′) is a reduction carried out in the same manner as in step (g). Suitable reducing agents may be e.g. as disclosed above for step (g). Steps (y) and (z) may be carried out as disclosed above for steps (j) and (N).
- a compound of formula (21′) as defined above may be reacted with a basic compound, e.g. an alkali metal hydroxide, to obtain a compound of formula (22) as defined above, which compound of formula (22) is then further treated as disclosed above for step (j).
- a basic compound e.g. an alkali metal hydroxide
- Suitable alkali metal hydroxide may be e.g. LiOH.
- Compound of formula (20) used as starting product in the preparation of a 2-amino-2-[2-(4-C 2-20 alkylphenyl)ethyl]propane-1,3-diol, is novel and also forms part of the present invention, as well as its preparation.
- Compound of formula (20) may be obtained by a process comprising
- Process step (a) may be performed in accordance with known bromoacetylation methods, e.g. in the presence of AlCl 3 .
- Process step (d) may conveniently be effected in the presence of sodium ethylate, in an anhydrous solvent such as anhydrous ethanol, and under an inert atmosphere, e.g. nitrogen, e.g. as disclosed in Example 13.
- Compound of formula (18) used in above step (d) may also be prepared by reacting a compound of formula (16) as defined above, with acetyl chloride to obtain a compound of formula (18′) wherein R is as defined above, which compound of formula (18′) is then brominated.
- the invention further provides a process for preparing a 2-amino-2-[2-(4-C 2-20 alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
- Process step (H) may preferably be effected in the presence of sodium ethylate, e.g. as disclosed for step (d) above.
- Process step (c) may conveniently be performed by reaction with an iodinating agent, e.g. an alkali metal iodide such as Nal or Kl.
- Process step (l) may be carried out under acidic conditions, e.g. trifluoroacetic acid.
- Suitable reducing agents include e.g. triethylsilane.
- Process step (C) may be performed as disclosed e.g. for (j).
- Process step (C′) may be carried out in accordance with methods known in the art, e.g. using a brominating agent, e.g. HBr, in the presence of a phase transfer-catalyst, e.g. an ammonium salt such as tricaprylmethylammonium halogenide, and further purification using e.g. aluminium oxide.
- a brominating agent e.g. HBr
- a phase transfer-catalyst e.g. an ammonium salt such as tricaprylmethylammonium halogenide
- Process step (b) may be carried out as disclosed for step (l) above.
- a compound of formula (2) as defined above preferably in the presence of a base, e.g. an alkali metal hydride such as NaH, or an alkali metal alkoxide, e.g. C 2 H 5 ONa or t.-C 4 H 9 OK.
- a base e.g. an alkali metal hydride such as NaH, or an alkali metal alkoxide, e.g. C 2 H 5 ONa or t.-C 4 H 9 OK.
- Process step e) may be carried out in accordance with known methods or e.g. as disclosed in Example 20.
- Compound A is preferably prepared
- the present invention also comprises each of the following steps disclosed above, respectively: step (b), step (c), step (C′), step (e), step (d), step (g′), step (g), step (x), step (f).
- salts include salts with inorganic acids, such as hydrochloride, hydrobromide, and sulfate, salts with organic acids, such as acetate, lactate, succinate or tartarate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts.
- Preferred salt is the hydrochloride salt.
- 2-amino-2-[2-(4-C 2-20 alkylphenyl)ethyl]-propane-1,3-diols, preferably Compound A may be converted into the hydrochloride salt form in accordance with known methods, e.g. by addition of HCl to the last reaction step such as in step (j), or prior to recrystallization such as in step (N).
- 2-Amino-2-[2-(4-C 2-20 alkylphenyl)ethyl]propane-1,3-diols and/or the intermediate compounds may be purified and/or separated by a conventional manner such as recrystallization, column chromatography, distillation, centrifugal separation, washing or drying.
- diethyl acetamido-2-(4-octylphenyl)-2-oxoethylmalonate (20) (2.00 g) in methanol (8 ml) is added sodium borohydride (858 mg) and the mixture is stood at room temperature for 1.5 hr.
- the suspension is diluted with ethyl acetate and washed successively with 1 N HCl, saturated aqueous NaHCO 3 solution and saturated brine.
- the ethyl acetate layer is dried over anhydrous MgSO 4 and concentrated.
- pyridine (4 ml)-acetic anhydride (8.8 ml) is stood at room temperature overnight.
- IR KBr 3400 (sh), 3250, 3050 (sh), 2910, 2850, 1580, 1520, 1470, 1060 cm ⁇ 1 .
- compound (20) may be hydrogenated in ethanol in the presence of 5% Pd/C and then treated with NaBH 4 and then with acetic anhydride-pyridine as disclosed above.
- diethyl acetamido-2-(4-octylphenyl)ethylmalonate (8) is prepared by hydrogenation of diethyl acetamido-2-(4-octan-1′-oylphenyl)-ethylmalonate in the presence of 5% Pd/carbon as disclosed above.
- Compound (8) has the same physico-chemical characteristics as indicated above.
- UV ⁇ max (MeOH) nm ( ⁇ ): 219.1(5017), 259.2(303.5), 264.5(392.4), 272.7(357.7).
- the reaction mixture is poured into ice water and the precipitated crystals are collected by filtration.
- the precipitate is recrystallized from hexane/ethyl acetate (2/1) to give the title compound (9) as colorless crystals.
- the resulting Compound (9) has the same physico-chemical characteristics as indicated in Example 4.
- the reduction of Compound (8) may be carried out using NaBH 4 and CaCl 2 , e.g. in aqueous ethanol.
- the resulting Compound (18) has the same physico-chemical characteristics as indicated in Example 11.
- 2-(4-octylphenyl)ethanol (5) (46.9 g) is added within 10 min to an aqueous solution containing 3.05 g Na 2 SO 3 , 252.9 g 48% HBr and 3.2 g tricaprylmethylammonium chloride.
- the reaction mixture is heated to 100° C. for 18 to 22 hours with stirring.
- the resulting 2-phase mixture is cooled to room temperature, diluted with toluene (150 ml) and the aqueous phase is then removed.
- the organic phase is washed twice with a volume of 100 ml of a 9% NaHCO 3 solution.
- the organic phase is treated with basic aluminium oxide, then filtered.
- the filter residue is washed with toluene (50 ml) and evaporated to yield compound (19) as a clear pale yellow oil.
- the resulting Compound (19) has the same physico-chemical characteristics as indicated in Example 14.
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Disclosed is a process for the production of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols.
Description
-
- 2-Amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols are disclosed in EP-A1-627,406 the relevant disclosure of which is incorporated herein by reference. On the basis of observed activity, e.g. as described in EP-A1-627,406, they have been found to be useful e.g. as immunosuppressants, e.g. in the prevention or treatment of acute allograft rejection or autoimmune diseases, or e.g. as described in WO 98/22100, in the prevention or treatment of xenograft rejection.
- In accordance with the present invention, new processes for an improved production route of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols, particularly Compound A, in free form or in salt form, have now been found. It is to be understood hereinafter that the process steps of the invention may lead to 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols in free form which may be converted into a salt form, or vice versa.
- Accordingly, there is provided a process for preparing a 2-amino-2-[2-(4-C2-20alkyl phenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
-
-
- j) hydrogenating the resulting compound (22)
- Any alkyl group mentioned herein may be a straight or branched chain alkyl group. Preferably C2-20alkyl is octyl, particularly straight chain.
- Examples of protecting groups as R3 are e.g. disclosed in “Protective Groups in Organic Synthesis”, T. W. Greene, J. Wiley & Sons New York (1981), 219-287, e.g. acyl such as formyl, acetyl, benzoyl; alkoxycarbonyl e.g. t.-butyloxycarbonyl; allyloxycarbonyl; trityl; etc.
- The reduction step g) may conveniently be performed using a reducing agent, e.g. NaBH4. The following treatment with an anhydride may be effected e.g. with acetic anhydride, preferably in the presence of a neutralizing agent, e.g. an aliphatic or organic amine, e.g. pyridine.
- Suitable basic compounds for use in step i) include an alkali metal hydroxide, e.g. NaOH, KOH or LiOH. Step i) may preferably be carried out in a polar solvent, e.g. an alcohol such as methanol, at reflux. Step j) may be effected in accordance with known hydrogenation methods, e.g. in the presence of a hydrogenation catalyst, e.g. Pd—C.
- As an alternative to above process, a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol in free form or in salt form may be prepared by
-
- N) treating the resulting compound of formula (9) with a basic compound.
- Steps h) and N) may be effected in accordance with methods known in the art, e.g. as disclosed above for steps j) and i), respectively, or in Examples 4 and 5 hereinafter.
- According to a further embodiment of the invention, there is provided a process for preparing 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
- x) reducing a compound of formula (20) as defined above, followed by a treatment with (R4CO)2O to obtain a compound of formula (9) as defined above; and
- N) treating the resulting compound of formula (9) with a basic compound.
- In process step x) the reduction may comprise either a hydrogenation step, e.g. as disclosed above for step (j), followed by a reduction step, e.g. as disclosed above for step (g), or a reduction step as diclosed for step (g) comprising an intermediary hydrogenation step [e.g. as disclosed for step (j)] prior to the anhydride (R4 CO)2O treatment. Step (N) may be carried out as indicated above.
- In a further or alternative embodiment, the invention provides a process for preparing 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
-
- K) reducing the resulting compound of formula (8) followed by a treatment with (R4CO)2O to obtain a compound of formula (9) as defined above; and
- N) treating the resulting compound of formula (9) with a basic compound.
- Process steps (f) and (K) may be performed as disclosed above for (j) and (g), respectively. Alternatively, the reduction step (K) may be carried out in the presence of Ca (BH4)2. The latter may be generated by reaction of NaBH4 with CaCl2.
- Compound of formula (20′) may be prepared as disclosed in PCT/JP98/02998.
- In a further or alternative embodiment, the invention further provides a process for preparing a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
-
-
- z) treating the resulting compound of formula (21″) with a basic compound.
- Process step (g′) is a reduction carried out in the same manner as in step (g). Suitable reducing agents may be e.g. as disclosed above for step (g). Steps (y) and (z) may be carried out as disclosed above for steps (j) and (N).
- As an alternative to above step (y),
- i′) a compound of formula (21′) as defined above may be reacted with a basic compound, e.g. an alkali metal hydroxide, to obtain a compound of formula (22) as defined above, which compound of formula (22) is then further treated as disclosed above for step (j).
- Suitable alkali metal hydroxide may be e.g. LiOH.
- Compound of formula (20), used as starting product in the preparation of a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, is novel and also forms part of the present invention, as well as its preparation. Compound of formula (20) may be obtained by a process comprising
-
-
- Process step (a) may be performed in accordance with known bromoacetylation methods, e.g. in the presence of AlCl3. Process step (d) may conveniently be effected in the presence of sodium ethylate, in an anhydrous solvent such as anhydrous ethanol, and under an inert atmosphere, e.g. nitrogen, e.g. as disclosed in Example 13. Compound of formula (18) used in above step (d) may also be prepared by reacting a compound of formula (16) as defined above, with acetyl chloride to obtain a compound of formula (18′)
wherein R is as defined above, which compound of formula (18′) is then brominated. - In a further or alternative embodiment, the invention further provides a process for preparing a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
-
- Process step (H) may preferably be effected in the presence of sodium ethylate, e.g. as disclosed for step (d) above.
- Compound of formula (7) used in process step (H) may be prepared by
-
-
- Process step (c) may conveniently be performed by reaction with an iodinating agent, e.g. an alkali metal iodide such as Nal or Kl. Process step (l) may be carried out under acidic conditions, e.g. trifluoroacetic acid. Suitable reducing agents include e.g. triethylsilane.
- Compound of formula (19), used as starting product in the preparation of 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, is novel and also forms part of the present invention as well as its preparation. Compound of formula (19) may be obtained by
-
- C′) brominating the resulting compound of formula (5).
- Process step (C) may be performed as disclosed e.g. for (j). Process step (C′) may be carried out in accordance with methods known in the art, e.g. using a brominating agent, e.g. HBr, in the presence of a phase transfer-catalyst, e.g. an ammonium salt such as tricaprylmethylammonium halogenide, and further purification using e.g. aluminium oxide.
- Compound of formula (19) may also be prepared by
- b) reducing a compound of formula (18) as defined above.
- Process step (b) may be carried out as disclosed for step (l) above.
- Compound of formula (19) is useful to prepare the intermediary compound of formula (8) used in process step (K)
- e) directly by reaction with a compound of formula (2) as defined above, preferably in the presence of a base, e.g. an alkali metal hydride such as NaH, or an alkali metal alkoxide, e.g. C2H5 ONa or t.-C4H9OK.
- Process step e) may be carried out in accordance with known methods or e.g. as disclosed in Example 20.
- According to the invention, Compound A is preferably prepared
- The present invention also comprises each of the following steps disclosed above, respectively: step (b), step (c), step (C′), step (e), step (d), step (g′), step (g), step (x), step (f).
- Examples of salts include salts with inorganic acids, such as hydrochloride, hydrobromide, and sulfate, salts with organic acids, such as acetate, lactate, succinate or tartarate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts. Preferred salt is the hydrochloride salt. 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]-propane-1,3-diols, preferably Compound A, may be converted into the hydrochloride salt form in accordance with known methods, e.g. by addition of HCl to the last reaction step such as in step (j), or prior to recrystallization such as in step (N).
- 2-Amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diols and/or the intermediate compounds may be purified and/or separated by a conventional manner such as recrystallization, column chromatography, distillation, centrifugal separation, washing or drying.
- The present Examples are illustrative of the invention.
- To a solution of diethyl acetamido-2-(4-octylphenyl)-2-oxoethylmalonate (20) (2.00 g) in methanol (8 ml) is added sodium borohydride (858 mg) and the mixture is stood at room temperature for 1.5 hr. The suspension is diluted with ethyl acetate and washed successively with 1 N HCl, saturated aqueous NaHCO3 solution and saturated brine. The ethyl acetate layer is dried over anhydrous MgSO4 and concentrated. To the residue is added pyridine (4 ml)-acetic anhydride (8.8 ml), and the mixture is stood at room temperature overnight. To the reaction mixture is added ice water and the mixture is extracted with ethyl acetate and washed successively with 1 N HCl, saturated aqueous NaHCO3 solution and saturated brine. The ethyl acetate layer is dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography using hexane-ethyl acetate as eluent to give the title compound (21) as a colorless oil.
- TLC Rf: 0.3 (hexane/ethyl acetate=½, silica gel 60F254 plate)
- IR (CCl4) 3390, 2930, 2860, 1750, 1690, 1510, 1370, 1230, 1040 cm−1.
- 1H-NMR (500 MHz, CDCl3) δ: 7.22 (2H, d, J=8.1 Hz, C6H2), 7.14 (2H, d, J=8.1 Hz, C6H2), 5.91 (1H, brs, NH), 5.84 (1H, dd, J=4.2 and 8.5 Hz, CH), 4.37 (1H, d, J=11.2 Hz, OCHa), 4.34 (1H, d, J=11.2 Hz, OCHb), 4.34 (2H, s, OCH2), 2.56 (2H, t, J=7.8 Hz, PhCH2), 2.54 (1H, dd, J=4.2 and 15.1 Hz, CHCHa), 2.36 (1H, dd, J=8.5 and 11.5 Hz, CHCHb), 2.10, 2.07 and 1.99 (each 3H, s, OAc), 1.90 (3H, s, NAc), 1.57 (2H, qui, J=7.8 Hz, CH2), 1.32−1.23 (10H, m, CH2×5), 0.87 (3H, t, J=7. 1 Hz, CH3)
- FAB-MS m/z: 432 (M−AcOH+H)+
- 2-Acetamido-4-acetoxy-2-acetoxymethyl-4-(4-octylphenyl)butyl acetate (21) (700 mg) is refluxed under heating for 5 hr in methanol (3.6 ml)/1 N NaOH (7.2 ml). The reaction mixture is diluted with water and subjected to XAD-II column using water and methanol as eluents. The methanol eluate is concentrated to give the title compound (22) as a pale-yellow solid. TLC Rf:0.5 (chloroform/methanol/acetic acid/water=70/20/6/4, silica gel 60F254 plate) IR (KBr) 3340, 2930, 2850, 1470, 1040 cm−1.
- 1H-NMR (500 MHz, DMSO-d6) δ: 7.20 (2H, d, J=8.1 Hz, C6H2), 7.10 (2H, d, J=8.1 Hz, C6H2), 6.66 (1H, brs, CHOH), 4.83 (1H, dd, J=3.0 and 10.0 Hz, CH), 4.72 and 4.61 (each 1H, brs, OH), 3.42 (2H, s, OCH2), 3.25 (1H, d, J=10.5 Hz, OCHa), 3.21 (1H, d, J=10.3 Hz, OCHb), 2.52 (2H, t, J=7.6 Hz, PhCH2), 1.71 (2H, brs, NH2), 1.55−1.51 (2H, m, CH2), 1.51 (1H, dd, J=3.2 and 14.4 Hz, CHCHa), 1.47 (1H, dd, J=10.1 and 14.4 Hz, CHCHb), 1.27−1.23 (10H, m, CH2×5), 0.85 (3H, t, J=7.1 Hz, CH3)
- FAB-MS m/z: 324 (M+H)+
- 5% Pd/carbon (13 mg) is suspended in ethanol (0.5 ml) and a solution of 2-amino-2-[2-hydroxy-2-(4-octylphenyl)ethyl]propane-1,3-diol (22) (107 mg) in ethanol (4 ml)-1 N HCl in ethanol (0.55 ml) is added. The mixture is stirred at room temperature for 10 days under 5 kg/cm2 hydrogen pressurization. The reaction mixture is filtered and the filtrate is concentrated to Compound A (hydrochloride) as colorless crystals.
- Decomposition: 260° C.
- TLC Rf: 0.55 (chloroform/methanol/acetic acid/water=70/20/6/4, silica gel 60F254 plate) IR (KBr) 3400 (sh), 3250, 3050 (sh), 2910, 2850, 1580, 1520, 1470, 1060 cm−1.
- UVλmax,(H2O) nm (ε): 210.7(4709), 264(392.4), 272(341.1)
- 1H-NMR (500 MHz, DMSO-d6) δ: 7.91 (3H, br s, NH3 +), 7.09 (2H, d, J=8.5 Hz, C6-H2), 7.07 (2H, d, J=8.5 Hz, C6-H2), 5.38 (2H, br s, OH×2), 3.51 (4H, s, CH2OH×2), 2.56 (2H, m, Ph—CH2), 2.49 (2H, m, Ph—CH2), 1.77 (2H, m, CH2), 1.51 (2H, m, CH2), 1.25 (10H, m, CH2×5), 0.83 (3H, t, J=7.5 Hz, CH3)
- EIMS m/z: 276 (M- CH2OH)+, 117, 105
- 5% Pd/carbon (20 mg) is suspended in ethyl acetate (0.5 ml) and a solution of 2-acetamido-4-acetoxy-2-acetoxymethyl-4-(4-octylphenyl)butyl acetate (21) (200 mg) in ethyl acetate (5 ml) and acetic acid (0.2 ml) are added. The mixture is stirred at room temperature for 6 days under 5 kg/cm2 hydrogen pressurization. The reaction mixture is filtered and the filtrate is washed successively with saturated aqueous NaHCO3 solution and saturated brine. The ethyl acetate layer is dried over anhydrous MgSO4 and concentrated to give the title compound (9) as colorless crystals. m.p. 111.8° C.
- TLC Rf:0.4 (hexane/ethyl acetate=½, silica gel 60F254 plate)
- IR (KBr) 3330, 2910, 2850, 1740, 1650, 1550, 1470, 1390, 1260, 1240, 1050 cm−1.
- UVλmax,(MeOH) nm (ε): 217.6(4772), 259.0(305.7), 264.5(394.6), 272.8(368.6)
- 1H-NMR (270 MHz, DMSO-d6) δ: 7.63 (1H, br s, NH), 7.07 (4H, s, C6-H4), 4.28 (2H, d, J=10.6 Hz, CHaOAc×2), 4.18 (2H, d, J=10.6 Hz, CHbOAc×2), ca. 2.5 (4H, m, Ph—CH2×2), 2.02 (6H, s, OCOCH3,×2), 1.94 (2H, m, CH2), 1.85 (3H, s, NCOCH3), 1.52 (2H, m, CH2), 1.24 (10H, m, CH2×5), 0.85 (3H, t, J=7.2 Hz, CH3)
- EIMS m/z: 433 (M)*, 373, 360, 300, 216, 157, 117, 105, 97
- 2-Acetamido-2-acetoxymethyl-4-(4-octylphenyl)butyl acetate (9) (7.37 kg) is refluxed under heating in methanol (51 L)-2N aqueous NaOH solution (34 L) for 6 hr. After cooling, the resulting precipitate is collected by filtration and washed thoroughly with water. The precipitate is dissolved in conc. HCl/ethanol (1:11) (20 L) and concentrated. The residue is recrystallized from ethyl acetate/ethanol to give Compound A (hydrochloride) as colorless crystals. The resulting Compound A has the same physico-chemical characteristics as indicated in Example 3.
- To a solution of diethyl acetamido-2-(4-octylphenyl)-2-oxoethylmalonate (20) (200 mg) in methanol (0.8 ml) is added sodium borohydride (85 mg) and the mixture is stood at room temperature for 2.5 hr. The reaction mixture is diluted with ethyl acetate and water, 1N HCl (2.24 ml) and acetic acid (0.26 ml) are added, followed by partitioning. The ethyl acetate layer is washed successively with saturated aqueous NaHCO3 solution and saturated brine. The ethyl acetate layer is dried over anhydrous MgSO4 and concentrated. The residue is stirred in ethanol (2 ml) in the presence of 5% Pd/Carbon (20 mg) and acetic acid (0.2 ml) for 8 days under 5 kg/cm2 hydrogen pressurization. The reaction mixture is filtered through a membrane filter and the filtrate is concentrated.
- The residue is dissolved in acetic anhydride (2.8 ml)-pyridine (1 ml), and the mixture is stood at room temperature overnight. The reaction mixture is poured into ice water and the precipitate is collected by filtration. The precipitate is recrystallized from hexane-ethyl acetate to give the title compound (9) as colorless crystals. The above-mentioned recrystallization filtrate is concentrated and purified by preparative TLC to give further the title compound (9) as colorless crystals. The resulting Compound (9) has the same physico-chemical characteristics as indicated in Example 4.
- Alternatively compound (20) may be hydrogenated in ethanol in the presence of 5% Pd/C and then treated with NaBH4 and then with acetic anhydride-pyridine as disclosed above.
- Diethyl acetamido-2-(4-octylphenyl)-2-oxoethylmalonate (20) (200 mg) is stirred at room temperature for 6 days in ethanol (2 ml) in the presence of 5% Pd/carbon (20 mg) under 5 kg/cm2 hydrogen pressurization. The reaction mixture is filtered and the filtrate is concentrated. The residue is dissolved in ethyl acetate and washed successively with saturated aqueous NaHCO3 solution and saturated brine. The ethyl acetate solution is dried over anhydrous MgSO4 and concentrated to give the title compound (8). m.p. 61° C.
- Alternatively diethyl acetamido-2-(4-octylphenyl)ethylmalonate (8) is prepared by hydrogenation of diethyl acetamido-2-(4-octan-1′-oylphenyl)-ethylmalonate in the presence of 5% Pd/carbon as disclosed above.
- Compound (8) has the same physico-chemical characteristics as indicated above. TLC Rf: 0.6 (hexane/ethyl acetate=1/1, silica gel 60F254 plate).
- IR (KBr) 3300, 2920, 2850, 1750, 1650, 1520, 1220, 1200 cm−1.
- UVλmax,(MeOH) nm (ε): 219.1(5017), 259.2(303.5), 264.5(392.4), 272.7(357.7).
- 1H-NMR (270 MHz, DMSO-d6) δ: 8.32 (1H, br s, NH), 7.08 (2H, d, J=7.9 Hz, C6-H2), 7.02 (2H, d, J=7.9 Hz, C6-H2), 4.13 (4H, q, J=7.3 Hz, OCH2CH3×2), 2.52 (4H, m, Ph—CH2×2), 2.37 (2H, m, CH2), 1.94 (3H, s, COCH3), 1.52 (2H, m, CH2), 1.24 (10H, m, CH2×5), 1.15 (6H, t, J=7.3 Hz OCH2CH3×2), 0.85 (3H, t, J=6.6 Hz, CH3)
- EIMS m/z: 388 (M-OCH2CH3)+, 318, 301, 244, 217, 171, 143.
- To a solution of diethyl acetamido-2-(4-octylphenyl)ethylmalonate (8) (1.37 kg) in methanol (5.5 L) is added sodium borohydride (720 g), and the mixture is stirred at room temperature for 2 hr. The suspension is diluted with ethyl acetate, and washed successively with 4N HCl, saturated aqueous NaHCO3 solution and saturated brine. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated. To the residue are added pyridine (3 L) and acetic anhydride (12 L), and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water and the precipitated crystals are collected by filtration. The precipitate is recrystallized from hexane/ethyl acetate (2/1) to give the title compound (9) as colorless crystals. The resulting Compound (9) has the same physico-chemical characteristics as indicated in Example 4.
- Alternatively, the reduction of Compound (8) may be carried out using NaBH4 and CaCl2, e.g. in aqueous ethanol.
- Diethyl 2-acetamido-2-[2-(4-octylphenyl)-2-oxoethyl]malonate (20) (4 g) is dissolved in methanol (150 ml) and sodium borohydride (tablet, 1.64 g) is added. The mixture is stirred for 1 hr under heating at 50° C. The solvent is evaporated and the residue is extracted with ethyl acetate. The extract is washed with brine and dried over sodium sulfate. The solvent is evaporated to give the title compound (21′) as colorless crystals. m. p.118-119° C.
- IR (KBr): 3228, 2927, 1640, 1566, 1071 cm−1.
- 1H-NMR (CDCl3): 0.86 (3H, t, J=6 Hz), 1.18-1.33 (10H, m), 1.48-1.64 (2H, m), 1.57 (2H, bs), 1.80 (1H, dd, J=8 Hz, J=10 Hz), 2.02 (3H, s), 2.34 (1H, d, J=10 Hz), 2.56 (2H, t, J=6 Hz), 3.39−3.47 (1H, m), 3.54-3.62 (1H, m), 3.68-3.80 (2H, m), 4.11 (1H, br. s), 4.85 (1H, d, J=7 Hz), 6.96 (1H, br. s), 7.14 (2H, d, J=8 Hz), 7.23 (2H, J=8 Hz)
- MS (EI) m/z: 365 (M+)
- 2-Acetamido-4-(4-octylphenyl)-2-hydroxymethylbutane-1,4-diol (21′) (0.73 g) is dissolved in methanol (10 ml). Thereto is added a solution of LiOH (0.86 g) in water (10 ml), and the mixture is refluxed under heating for 2 hr. The reaction mixture is cooled and extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. The solvent is distilled away and the mixture is purified by silica gel column chromatography to give the title compound (22) as a colorless and amorphous powder. The resulting Compound (22) has the same physico-chemical characteristics as indicated in Example 2.
- To a suspension of aluminum chloride (3.88 g) and bromoacetyl chloride (4.56 g) in dichloromethane (5 ml) is added dropwise over 1 hr a solution of octyl-benzene (16) (5.0 g) in dichloromethane (7 ml) under ice-cooling, and the mixture is stirred under ice-cooling for 1 hr. The reaction mixture is poured into ice water and extracted with ethyl acetate. The organic layer is washed successively with HCl, saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous MgSO4 and concentrated to give the title compound (18) as a colorless oil.
- TLC Rf: 0.4 (hexane/ethyl acetate=20:1, silica gel 60F254 plate)
- IR (CCl4) 2930, 2860, 1680, 1610, 1430, 1280, 1180, 1010 cm−1.
- 1H-HMR (500 MHz, CDCl3) δ: 7.90 (2H, d, J=8.5 Hz, C6H2), 7.29 (2H, d, J=8.5 Hz, C6H2), 4.44 (2H, s, BrCH2), 2.67 (2H, t, J=7.6 Hz, PhCH2), 1.63 (2H, qui, J=7.1 Hz, CH2), 1.32−1.26 (10H, m, CH2×5), 0.88 (3H, t, J=7.1 Hz, CH3)
- 13C-NMR (500 MHz, CDCl3) δ: 190.93, 149.95, 131.60, 129.05, 128.89, 36.06, 31.82, 31.01, 30.97, 29.38, 29.24, 29.19, 22.63, 14.08
- EIMS m/z: 312 and 310 (M)+, 217, 91
- 4′-Octylacetophenone (18′) [Step (a′)]
- Aluminum chloride (22.6 g) is suspended in dichloroethane (500 ml) and octylbenzene (16) (21.5 g) is added at room temperature. To the mixture is added acetyl chloride (8.87 g) under ice-cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water and extracted with ether. The organic layer is washed with brine and dried over sodium sulfate. The solvent is evaporated to give 4′-octylacetophenone (18′) as a colorless oil.
- 2-Bromo-4′-octylacetophenone (18) [Step (a″)]
- To a solution of 4′-octylacetophenone (18′) (23.9 g) in acetic acid (100 ml) is added hydrogen bromide-acetic acid solution (25%, 34 ml) under ice-cooling, which is followed by dropwise addition of bromine (5.3 ml). The mixture is heated to 30° C. and stirred for 3 hr. The solvent is distilled away and the mixture is purified by silica gel column chromatography to give 2-bromo-4′-octylacetophenone as colorless crystals.
- m. p. 33-34° C.
- The resulting Compound (18) has the same physico-chemical characteristics as indicated in Example 11.
- A solution of 2-bromo-4′-octylacetophenone (18) (5.0 g), diethyl acetamidomalonate (3.85 g) and sodium ethylate (1.20 g) in anhydrous ethanol (50 ml) is refluxed under heating under nitrogen atmosphere for 6 hr. The reaction mixture is diluted with hexane/ethyl acetate, washed with water, dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography using hexane/ethyl acetate as eluent to give the title compound (20) as a pale-yellow oil.
- TLC Rf: 0.5 (hexane/ethyl acetate=1/1, silica gel 60F264 plate)
- IR (CCl4): 3420, 2930, 2860, 1750, 1690, 1610, 1490, 1350, 1230, 1200 cm−1.
- 1H-NMR (500 MHz, CDCl3) δ: 7.87 (2H, d, J=8.3 Hz, C6H2), 7.25 (2H, d, J=8.3 Hz, C6H2), 7.11 (1H, s, NH), 4.26 and 4.40 (each 2H, q, J=7.1 Hz OCH2), 4.23 (2H, s, COCH2), 2.65 (2H, t, J=7.8 Hz, PhCH2), 1.96 (3H, s, Ac), 1.61 (2H, qui, J=7.3 Hz, CH2), 1.30−1.22 (10H, m, CH2×5), 1.23 (6H, t, J=7.1 Hz, CH3×2), 0.87 (3H, t, J=7.1 Hz, CH3)
- FAB-MS m/z: 448 (M+H)+
- To a solution of 2-bromo-4′-octylacetophenone (18) (1.0 g) in trifluoroacetic acid (2.5 ml) is added triethylsilane (1.12 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hr. The reaction mixture is poured into ice water and hexane and saturated aqueous NaHCO3 solution are added, which is followed by partitioning. The hexane layer is washed with saturated brine, dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography using hexane as eluent to give the title compound (19) as a colorless oil.
- TLC Rf:0.5 (hexane, silica gel 60F254 plate)
- IR (CCl4) 2930, 2860, 1510, 1470 cm−1.
- 1H-NMR (500 MHz, CDCl3) δ: 7.15 (2H, d, J=8.3 Hz, C6H2), 7.12 (2H, d, J=8.3 Hz, C6H2), 3.56 (2H, t, J=7.8 Hz, BrCH2), 3.14 (2H, t, J=7.8 Hz, PhCH2), 2.59 (2H, t, J=7.8 Hz, PhCH2), 1.61 (2H, qui, J=7.6 Hz, CH2), 1.35−1.27 (10H, m, CH2×5), 0.89 (3H, t, J=7.3 Hz, CH3)
- EIMS m/z: 298 and 296 (M)+, 217, 197 and 199, 117, 105, 91
- To a solution of 2-(4-octylphenyl)ethyl bromide (19) (99 mg) in 2-butanone (5 ml) is added Nal (126 mg) and the mixture is refluxed under heating for 3 hr. The reaction mixture is diluted with hexane and washed successively with saturated aqueous sodium sulfite solution and saturated brine. The hexane layer is dried over anhydrous Mg SO4 and concentrated to yield the title compound (7) as a colorless oil.
- TLC Rf:0.6 (hexane, silica gel 60F254 plate)
- IR (CCl4) 2930, 2860, 1510, 1470, 1170 cm−1.
- 1H-NMR (500 MHz, CDCl3) δ: 7.13 (2H, d, J=8.1 Hz, C6H2), 7.10 (2H, d, J=8.1 Hz, C6H2), 3.33 (2H, t, J=7.6 Hz, ICH2) 3.15 (2H, t, J=7.8 Hz, PhCH2), 2.57 (2H, t, J=7.8 Hz, PhCH2), 1.60 (2H, qui, J=7.8 Hz, CH2), 1.34−1.26 (10H, m, CH2×5), 0.88 (3H, t, J=6.6 Hz, CH3)
- EIMS m/z: 344 (M+), 245, 217, 119, 117, 91, 57, 43
- To a solution of diethyl acetamidomalonate (277 g) and sodium ethylate (86.6 g) in anhydrous ethanol (850 ml) is added a solution of 2-(4-octylphenyl)ethyl iodide (7) (146 g) in anhydrous tetrahydrofuran (533 ml), and the mixture is refluxed under heating for 6 hr. The reaction mixture is concentrated and partitioned between water and hexane, and the hexane layer is washed three times with water. The obtained hexane layer is dried over anhydrous magnesium sulfate and concentrated. The residue is recrystallized from hexane to give the title compound (8) as colorless crystals. The resulting Compound (8) has the same physico-chemical characteristics as indicated in Example 7.
- To a solution of 4′-(2-iodoethyl)octanophenone (200 g) in trifluoroacetic acid (319 ml) is added triethylsilane (195.7 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hr. The reaction mixture is concentrated, and the residue is distilled away under reduced pressure to give the title compound (7) as a pale-red oil. The resulting Compound (7) has the same physico-chemical characteristics as indicated in Example 15.
- 5% Pd/carbon (0.6 g) is added to a solution of 2-(4-octanoylphenyl)ethanol (10) (30 g) in abs. ethanol (150 ml). The mixture is stirred at room temperature for 2.5 hrs under 0.1 bar hydrogen. The reaction mixture is filtered and the filtrate is concentrated to afford compound (5) as a clear pale yellow oil.
- IR (NaCl): 3300, 2926, 2854, 1513, 1466, 1046 cm−1.
- 1H-NMR (200 MHz, CDCl3) δ: 7.12 (4H,s,C6H4); 3.87 (2H,t,J=7.7 Hz,CH2O); 2.85 (2H, t, J=7.7 Hz, Ph—CH2); 2.59 (2H, t, J=7.8 Hz, Ph—CH2); 1.61 (2H, q, J=7.8 Hz, CH2); 1.40−1.15 (10H, m, CH2×5); 0.89 (3H, t, 7.3 Hz, CH3)
- EIMS m/z: 234 (M+), 203, 135, 105
- 2-(4-octylphenyl)ethanol (5) (46.9 g) is added within 10 min to an aqueous solution containing 3.05 g Na2SO3, 252.9 g 48% HBr and 3.2 g tricaprylmethylammonium chloride. The reaction mixture is heated to 100° C. for 18 to 22 hours with stirring. The resulting 2-phase mixture is cooled to room temperature, diluted with toluene (150 ml) and the aqueous phase is then removed. The organic phase is washed twice with a volume of 100 ml of a 9% NaHCO3 solution. The organic phase is treated with basic aluminium oxide, then filtered. The filter residue is washed with toluene (50 ml) and evaporated to yield compound (19) as a clear pale yellow oil. The resulting Compound (19) has the same physico-chemical characteristics as indicated in Example 14.
- 60% NaH in oil (9.65 g) is added portionwise to a solution of diethyl acetamidomalonate (58.5 g) in dimethylformamide (240 ml) at such a rate to keep the temperature below 10° C. The resulting mixture is stirred for 90 min., the temperature being allowed to increase to room temperature. To this mixture is added dropwise within 15 min. a solution of 2-(4-octylphenyl)ethyl bromide (19) (40 g) in dimethylformamide (40 ml). The reaction mixture is heated to ca. 80° C. within ca. 25 min. and further stirred for ca. 3-5 hrs. After cooling to room temperature, water (280 ml) is added and the resulting mixture is further stirred until a beige precipitate is formed. The mixture is adjusted to pH 7 with 10% H2SO4. After cooling to ca. 2° C., the residue is filtered, washed with 200 ml water and then recrystallized in heptane to yield compound (8) as colorless crystals. The resulting compound (8) exhibits the same physico-chemical characteristics as indicated in Example 7.
Claims (2)
1-32. (canceled)
33. 2-(4-octylphenyl)ethyl bromide.
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AU2001285331B2 (en) | 2000-08-31 | 2006-04-06 | Merck & Co., Inc. | Phosphate derivatives as immunoregulatory agents |
BR0306811A (en) | 2002-01-11 | 2004-10-26 | Sankyo Co | Compound, pharmacologically acceptable ester thereof, pharmaceutical composition and methods for the prevention or treatment of autoimmune diseases, rheumatoid arthritis and rejection caused by the transplantation of various organs in a mammal |
BRPI0507944A (en) | 2004-02-24 | 2007-07-24 | Sankyo Co | pharmaceutical composition |
WO2006010630A1 (en) | 2004-07-30 | 2006-02-02 | Novartis Ag | Compound formulations of 2-amino-1, 3-propanediol compounds |
WO2007022718A1 (en) * | 2005-08-25 | 2007-03-01 | Chunde Liu | Alkyl aryl alkyl alcohols, their derivations and preparation process thereof |
US20090176744A1 (en) * | 2007-11-02 | 2009-07-09 | Concert Pharmaceuticals, Inc. | Deuterated fingolimod |
CN101959845A (en) * | 2008-03-19 | 2011-01-26 | 诺瓦提斯公司 | Process for preparing 2-amino-2-[2-(4-C3-C21-alkyl-phenyl) ethyl] propane-1, 3-diol compound |
CN105198760A (en) * | 2008-11-11 | 2015-12-30 | 诺华股份有限公司 | Salts of fingolimod |
ES2643161T3 (en) * | 2008-11-11 | 2017-11-21 | Novartis Ag | Hing crystalline forms of fingolimod |
JP5593164B2 (en) * | 2010-06-29 | 2014-09-17 | 株式会社クラレ | Method for producing primary alkyl halide |
EP2621889B1 (en) | 2010-10-01 | 2019-07-17 | Synthon BV | Process for making fingolimod hydrochloride crystals |
AU2011322115A1 (en) | 2010-10-28 | 2013-05-30 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of Fingolimod |
WO2012071524A1 (en) | 2010-11-24 | 2012-05-31 | Ratiopharm Gmbh | Arylsulfonate salts of fingolimod and processes for preparation thereof |
EP2658840B1 (en) | 2010-12-28 | 2019-07-03 | Synthon BV | Process for making fingolimod hydrochloride crystals |
US9216943B2 (en) | 2011-04-29 | 2015-12-22 | Dr. Reddy's Laboratories Ltd. | Preparation of fingolimod and its salts |
CN103539683A (en) * | 2012-07-17 | 2014-01-29 | 广东东阳光药业有限公司 | New crystal form of drug for treating sclerosis and preparation method thereof |
CN102796022B (en) * | 2012-08-27 | 2015-03-25 | 南京华威医药科技开发有限公司 | Method for preparing 2-amino-2-[2-(4-alkyl phenyl) ethyl]-1,3-propanediol hydrochloride |
AU2014206588A1 (en) | 2013-01-17 | 2015-07-23 | Shilpa Medicare Limited | Process for preparation of Fingolimod and its salts |
WO2014136047A2 (en) * | 2013-03-05 | 2014-09-12 | Biocon Limited | A process for the preparation of 2-amino-1,3-propane diol compounds and salts thereof |
ES2729404T3 (en) | 2013-11-25 | 2019-11-04 | Emcure Pharmaceuticals Ltd | Fingolimod hydrochloride process |
EP4173623A4 (en) | 2020-06-26 | 2024-07-24 | Osaka University | THERAPEUTIC AGENT FOR DRUG-INDUCED BRADYCARDIA AND BRADYARRHYTHMIA |
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US5604229A (en) * | 1992-10-21 | 1997-02-18 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
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JPS5912643B2 (en) | 1975-04-03 | 1984-03-24 | 和光純薬工業 (株) | Production method of phenethyl bromides |
JPS52108943A (en) | 1976-03-10 | 1977-09-12 | Teikoku Hormone Mfg Co Ltd | Alkyl phenyl ketone derivative |
JPS5951932B2 (en) | 1980-04-14 | 1984-12-17 | 東ソー株式会社 | Method for producing addition compounds of halobenzenes and olefins |
DD269856A1 (en) * | 1988-03-03 | 1989-07-12 | Univ Halle Wittenberg | LIQUID CRYSTALLINE AMPHIPHILE |
US5508272A (en) | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
IT1265101B1 (en) * | 1993-07-23 | 1996-10-30 | Erba Carlo Spa | DERIVATIVES OF 2-AMINO-4-PHENYL-4-BUTYRIC BONE ACID |
DE69524962D1 (en) | 1994-08-22 | 2002-02-14 | Welfide Corp | BENZENE DERIVATIVES AND THEIR MEDICAL USE |
GB9624038D0 (en) | 1996-11-19 | 1997-01-08 | Sandoz Ltd | Organic compounds |
WO1999001420A1 (en) | 1997-07-03 | 1999-01-14 | Taito Co., Ltd. | Process for the preparation of 2-aminomalonic acid derivatives and intermediates used in the process |
JP4079505B2 (en) | 1998-04-28 | 2008-04-23 | 田辺三菱製薬株式会社 | Novel process for the preparation of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol |
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1999
- 1999-11-09 WO PCT/EP1999/008577 patent/WO2000027798A1/en active IP Right Grant
- 1999-11-09 AT AT99971797T patent/ATE288414T1/en active
- 1999-11-09 DE DE69923579T patent/DE69923579T2/en not_active Expired - Lifetime
- 1999-11-09 EP EP04005240.9A patent/EP1457478B1/en not_active Expired - Lifetime
- 1999-11-09 PT PT99971797T patent/PT1129066E/en unknown
- 1999-11-09 ES ES04005240.9T patent/ES2644413T3/en not_active Expired - Lifetime
- 1999-11-09 JP JP2000580978A patent/JP4503184B2/en not_active Expired - Lifetime
- 1999-11-09 PT PT4005240T patent/PT1457478T/en unknown
- 1999-11-09 ES ES99971797T patent/ES2237970T3/en not_active Expired - Lifetime
- 1999-11-09 AU AU11614/00A patent/AU1161400A/en not_active Abandoned
- 1999-11-09 DK DK99971797T patent/DK1129066T3/en active
- 1999-11-09 EP EP99971797A patent/EP1129066B1/en not_active Expired - Lifetime
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2001
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Patent Citations (1)
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US5604229A (en) * | 1992-10-21 | 1997-02-18 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
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US20020072635A1 (en) | 2002-06-13 |
EP1457478A3 (en) | 2004-12-22 |
PT1457478T (en) | 2017-10-26 |
EP1129066A1 (en) | 2001-09-05 |
DK1129066T3 (en) | 2005-03-29 |
ATE288414T1 (en) | 2005-02-15 |
US20030229251A1 (en) | 2003-12-11 |
JP4503184B2 (en) | 2010-07-14 |
AU1161400A (en) | 2000-05-29 |
US7026522B2 (en) | 2006-04-11 |
JP2002529441A (en) | 2002-09-10 |
EP1129066B1 (en) | 2005-02-02 |
WO2000027798A1 (en) | 2000-05-18 |
PT1129066E (en) | 2005-05-31 |
DE69923579T2 (en) | 2006-01-12 |
EP1457478B1 (en) | 2017-07-19 |
ES2237970T3 (en) | 2005-08-01 |
DE69923579D1 (en) | 2005-03-10 |
ES2644413T3 (en) | 2017-11-28 |
US6605744B2 (en) | 2003-08-12 |
EP1457478A2 (en) | 2004-09-15 |
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