IE40256B1 - Derivatives of - methyldopa - Google Patents
Derivatives of - methyldopaInfo
- Publication number
- IE40256B1 IE40256B1 IE1934/74A IE193474A IE40256B1 IE 40256 B1 IE40256 B1 IE 40256B1 IE 1934/74 A IE1934/74 A IE 1934/74A IE 193474 A IE193474 A IE 193474A IE 40256 B1 IE40256 B1 IE 40256B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- solution
- hydrogen
- mixture
- acid
- Prior art date
Links
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims description 135
- -1 monocyclic carboxylic acid Chemical class 0.000 claims description 102
- 150000001875 compounds Chemical class 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 27
- 150000002148 esters Chemical class 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 10
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 7
- 239000012458 free base Substances 0.000 claims description 7
- 230000000903 blocking effect Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 230000037396 body weight Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 125000002015 acyclic group Chemical group 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 238000001640 fractional crystallisation Methods 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 230000001631 hypertensive effect Effects 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 235000012431 wafers Nutrition 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 229940125898 compound 5 Drugs 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 252
- 239000000243 solution Substances 0.000 description 212
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 207
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 156
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 147
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 109
- 238000002360 preparation method Methods 0.000 description 91
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 86
- 229940093499 ethyl acetate Drugs 0.000 description 84
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- 238000001914 filtration Methods 0.000 description 69
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 62
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- 239000003054 catalyst Substances 0.000 description 53
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 52
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 239000002904 solvent Substances 0.000 description 50
- 239000000047 product Substances 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- 239000000741 silica gel Substances 0.000 description 42
- 229910002027 silica gel Inorganic materials 0.000 description 42
- 229960001866 silicon dioxide Drugs 0.000 description 42
- 239000000706 filtrate Substances 0.000 description 37
- 239000007787 solid Substances 0.000 description 37
- 238000004809 thin layer chromatography Methods 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 25
- 229910000029 sodium carbonate Inorganic materials 0.000 description 25
- 239000000284 extract Substances 0.000 description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 229960000583 acetic acid Drugs 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 239000012453 solvate Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000000463 material Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 229910052708 sodium Inorganic materials 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 10
- 239000007789 gas Substances 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 159000000000 sodium salts Chemical class 0.000 description 8
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 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 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 6
- 235000004279 alanine Nutrition 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 150000003385 sodium Chemical class 0.000 description 6
- 150000003892 tartrate salts Chemical class 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229940091173 hydantoin Drugs 0.000 description 5
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229960002317 succinimide Drugs 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- QNAYBMKLOCPYGJ-UHFFFAOYSA-M alaninate Chemical compound CC(N)C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-M 0.000 description 4
- 239000003957 anion exchange resin Substances 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 3
- DEAFKLPWKKXYPV-UHFFFAOYSA-N 1-(1-chloropropyl)pyrrolidine-2,5-dione Chemical compound CCC(Cl)N1C(=O)CCC1=O DEAFKLPWKKXYPV-UHFFFAOYSA-N 0.000 description 3
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 241001077660 Molo Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 3
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000011149 active material Substances 0.000 description 3
- ZLSTXEBTAJKDKH-UHFFFAOYSA-N benzyl 4-amino-4-oxobutanoate Chemical compound NC(=O)CCC(=O)OCC1=CC=CC=C1 ZLSTXEBTAJKDKH-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 238000005341 cation exchange Methods 0.000 description 3
- 150000004683 dihydrates Chemical class 0.000 description 3
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- QFHPUEPQOHXZSF-UHFFFAOYSA-N 2-amino-2-methylpropanoic acid;hydrochloride Chemical compound Cl.CC(C)(N)C(O)=O QFHPUEPQOHXZSF-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- GDFAOVXKHJXLEI-VKHMYHEASA-N N-methyl-L-alanine Chemical compound C[NH2+][C@@H](C)C([O-])=O GDFAOVXKHJXLEI-VKHMYHEASA-N 0.000 description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 2
- XPDCGOWOCCQZSZ-UHFFFAOYSA-N S(=O)(Cl)Cl.O.C(C(=O)O)(=O)O Chemical compound S(=O)(Cl)Cl.O.C(C(=O)O)(=O)O XPDCGOWOCCQZSZ-UHFFFAOYSA-N 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- 101150052863 THY1 gene Proteins 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 150000003891 oxalate salts Chemical class 0.000 description 2
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Pyridine Compounds (AREA)
- Indole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
40256 The present invention is concerned with a-methyl-3,4-dihydroxyphenylalanine, the L-isomer of which is commonly referred to its L-o-methyIdopii or methyldopa. It is known thnt hypertension is preferably trented with L-a-methy1-3,4-dihydroxyphenyl-alanine since the n-l'orm of the compound is therapeutically inert and only the L-I'orm is therapeutically active. The removal of the l)-l"orm thereby lessens toxicity and increases effectiveness (see Patent Specification No..25653). The alkyl esters of L-or 1)1tt»methy 1 -3,4-dihydroxypheny 1 alanine are useful in the emergency treatment of hypertension by parental administration (see U.S. I'al.onl: :i,230, 143). It has now been found that certain other 1'sl.crs ami derivatives ol" 0J_. or K-a-methy1-3,4-dihydroxy-phenylalanine tin; active in the treatment ol" hypertension and l.hal. some such compounds have a much higher activity and thus require a lower dosage than the known compounds.
The present invention provides compounds of the formula: R3 (I) where n is O, 1, 'J, or 3; m is (),1, 2 or 3; each of and is a hydrogen atom or a ^ alkanoyl group; each of Rj and R2 is a hydrogen atom or a Cj_3 alkyl group; and is (A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear* carbon atoms and as nuclear hetero atom(s) one or two nitrogen atoms or one nitrogen and one sulfur atom, each ring in the sa i ti heterocyclic radical containing 5 or* <> member or* (it) a radical X-H. where X is -S-, or* -Nil- and H 4 4 contains up to 2 1 carbon atoms and is a hydrocarbon radical or* an acyl radical ol" an organic acyclic or monocyclic carboxylic acid containing not more than 1 hetero atom in the ring; and pharmaceutically acceptable acid-addition A..-U CH.. O R, I I I1 ell-— c—i:-o(-ch„) C(-CH_) — i: | C n | 2 m NH2 Rp 40256 Hill I * thereof.! In preferred embodiments <»t" the pri'scnl invent ion, n and m art: O oi' I, Aj and A., are II. It( and H., .'iff hydrogen or nieUiyl and H.j is l.lic liclcroL'yclic: ring.
() / -N V O which may he substituted by one more cj_3 alkyl groups, or R3 t is -X-R. where X is -()- or -Nil- and II. is tin acyl radical derived 4 4 I'i'diii an alkannic* acid conta i n i ng J l.o f> carbon atoms.
I'iirl. icii I arly pri'l'iM't-cd art; compounds in which R^ is II () n and in are (), It., is hydrogen anil Rj is hydrogen or methyl, compounds in which It.^ is t-butyIacetoxy, n and m are 0, R^ is hydrogen and R^ is hydrogen or methyl, and compounds in which H.j is acetamido, n is O, m is 1 and R^ and R^ are hydrogen; and I.lie hydrochloric* ac id-addi tit>n s;i I l.s o 1' such compounds.
The present, invent, ion further provides an ester oi' the- I. isomer of an amino acitl, substantially free of the U isomer, having llie formula t*H_ O R. 3 I! 11 '•II.; (■ — r — "(-' I'.,), (—<*'i ) it (II) »• i — * • ■ t. m .) m l i Nil., It., or a pharmarettl. i c*a I I y accept-ah 1 e ac i d—add i L ion salt thereol' where ni. It , and It are as defined above. With regard to the — I ■» I. isomer, it shoultl be noted that the asymmetric carbon atom is the one containing the amino and methyl group in t he acitl portion of the molecule. It: is this portion of the molecule that is referred to as being in the 1_. configuration. Note that the I_. configuration refers to the stereo configuration and not lo the optical rotation although in this case the L stereo conf ikhrat ion is the 1_ or laevo form of the optical isomer. However, it should also be noied that in some instances when II j and H., are d i rt'erenl groups I lie carbon atom lo which they are attar-hod is a I so an asymmetric carbon atom and can thus exist in either, the or 0 configuration. As is hereinafter pointed out, botli of the isomers of this portion of the compound are active.
As is further pointed out, these stereo isomers have been separated but their stereo configuration has not been determined so they are merely designated as the a and 3 isomer. In any event, Ixitii the a and B isomers are active regardl ess of their stereo con-f i gura I j on.
Tin- present invention still further provides a method of treating hypertension in a hypertensive non-human animal that comprises administering to the animal a therapeutically effective amount of a compound in accordance with the present invention.
In the treatment of hypertension, the compounds of the present invention are generally administered in amounts of from 0.005 to 300 mg./kg. of body weight of the animal, preferably from 0.05 to lOO mg./kg. and particularly 0.1 to 25 mg./kg.
In this regard, it should be noted that the dosage must be adjusted depend i ng upon the activity of the; compound, the response; desired in the reduction oi' blood pressure and also the weight of the animal. In the ranges given above, the more active compounds would tend to be given at the lower dosages and the less active compounds at the high dosages.
When the isomer of a compound of the present invention is given in the substantial absence of the I) isomer, the required dosage' of the f isomer is approximately one-half oi' that of the raeemaLc since the I) isomer is therapeutically inactive. However, th«: compounds of the present invention vary in activity to some degree arul thus the racemate of one of the less active compounds of the present invention may require several times the dosage of a more active compound. In general, the compounds will be 40236 amiiilsl.rred within the above dosages.
Tin? present invention also provides a pharmaceutical compos i I. ion comprising an inert pharmaceutical ly acceptable diluent ami a compound in accordance with Lhc present invention.
In a single dosage form ol" the composition of the present ! invention, the active compound is generally present in the ( composition in amounts of from 1 mg. to 2,000 mgs., preferably 5 mgs. to 1,000 mgs, and particularly 10 mgs. to 500 mgs, per unit dose. The single dosage form of the compound may be administered in a single slow-ucting dose or it may be administered in several small doses throughout the day,generally n l.o H individual dosages. The compositions are prfli-r.il> I y in orally admi n is I ral> I e form, as described Ix.-low.
A:: in Lhe im-l liod of I. rea I »;enl , reduced dosages of I lie L isomer substantially free of l.he I) isomer are requ i red as compared l.o tin.- racemate. However, the <1 i I'ferJUbe in activity of various compounds requires the use of different, dosages. In some; instances, l.he compounds are many times more act. ive than others and thus the racemate of one may require even less of a dosage than the L isomer of a second. In general, however, the dosages will be within the above ranges.
The present invention further provides a process for preparing a compound of the formula I above 4025G or an acid addition salt thereof that comprincs (a) the hydrolysis or reduction of an acid derivative of the formula R, CH, O I 3II RqO— Z-AJ ' CH, O /X I 11 A, -o—/y \—CTU—c—c V°-U T NH O N:' or H ch. /v I Aj-o — CN2-C-CO2 - a2-o -s-» o or an acid addition salt thoreof with a compcund of the formula f1 x, ( -CII2 ) n—c ( -CH, ) 2 m - 6 - 4025G wherein Y is -COOII, -COhalogcn or -carboxylic acid salt, n, m, A^, A2> R^, R2 and R^ aro as defined above,and is hydroxyl, alkali metal -O-, halogen or a subntitutcd -SO^-group; or 5 (c) the reduction of a compound of Fomula I in which R^ contains one or more reducible croups; or (d) the reaction of a compound of the formula where n, m, A^, A2, R^ and R2 aro as given • ° above and Z is -OH, -SII, halogen, r.ubstituted -SO^- group or -NII2 with an acylating agent ol' formula R^-H or R3~alkali metal where R^ is as defined above; or (e) the cyclization of a compound of the formula CI I, R.
I I A2~°—/ N,l2 R2 wherein n^ is 1, or 2 and A^, A2, R^, R2» n and m arr as defined above with an acylating agent 2o and, if desired, separating the stereoisomers by (1) fractional crystallization of one stereoisomer from solution or (2) forming diasteroeoisoraers with an optically active acid and crystallizing one of the of the diastereoisomers from the solution.
The present invention further provisos a process for preparing a compound of the fomula - 7 - CCH-(CH.) -C0_H 40256 P3fl i1 "°-rVCH2—= -fc-°(-cn2>n—=<-™2'»—1"3 m,2 R2 or an acid addition salt thereof where n, m, R^, R2 and Rj are as defined above that comprisos the hydrolysis or reduction of an acid derivative of ths formula R, ■-U ' f'J '■ . C C R O S?\—CH- c C —O(-CH-) C(-CII-) R- 3 I il 2 | 2 n | 2 m J R6°—W ™ R2 R7 or an acid addition salt thereof where each of R_, R, and R D O hydrogen or a blocking group, with at leant one being a blocking group. The hydrolynis or reduction is carried out under conventional conditions.
The present invention further provides a process for preparing a compound of the formula CH, O R, ✓v 1 " I no—/' Xr-cii_—c—c —o(-cti-) —ct-au) —r, t I £ n i < n J •JJ I no__U ') MII2 R2 or an acid addition salt thereof whera n, m, R^, R2 and Rj as defined above that comprises the esterification of an acid derivative of the formula CT13 I HO—^ V-CH2-C- I 1 H0-Jsv/ N,1n or an acid addition salt thereof with a compound of the formula f1 X_(-cn2>n—c —<-CH2)ra_R3 R2 402S6 where X, Y, n, in, llj, and are us defined above. The esLeril'icatlon is carricd out under conventional reaction conditions. i In a preferred embodiment of the present invention, the process is carried out with the amino acid portion of the molecule being in the I. stereo configuration.
The expressions " (-CH_) " and *(-(3 ,) " also 2 n 2 m include the branched chain alkylcne radicals such as CH, CH, C,H_ I 3 ,3 ,25 -CII- , -C- , and -CH- . Preferably n and m are 0 or 1.
CH3 The terminology "a monocyclic or bicyclic 5 to G members" means that the compounds contain one or two ring nitrogen atoms with an optional ring sulfur atom and from 3 to 12 ring carbon atoms. The compounds further contain one or two rings with 5 or 6 n*»«"v-orr in cach ring and the rings may be substituted by such groups as halogrtn, hydroxy1, amino or other such groups.
The terminology "R^ contains up to 21 carbon atoms 1 hetero atom" signifies that R^ contains a total of from 1 to 21 carbon atoms and is cither a hydrocarbon radical or an acyl radical of the formula ! R—C- where R is an acyclic or a monocyclic radical with not more than 1 hetero atom. As is hireinaft«T pointed out in the examples, the R group may be an alVy1 group, a heterocyclic radical or any other such radical. The nature of this R group does not appear to be critical and it may be widely varied. 4 0 2 S 6 The expression "pharmaceutical^ acceptable acid addition salt" is a well-known expression and includes those compounds which are made by tl»r reaction of the free barse with an inorganic or organic acid. It in-5 eludes the hydrochloride, the hydrobroraide,and Baits with sulfuric acid.
The phrase "the L isomer of an amino acid, substantially free of the D isomer" means that the D isomer is present in amounts not exceeding about 10%. However, 10 it is desirable that the amount of D isomer be close to 0%. In the examples which follow, when the L isomer is denignated, the compound is wc;l I over 99< in the L configuration.
The terminology "blocking group" signifies any 15 group that will protect the amino or hydroxyl groups during the reaction. Among the suitable blocling groups for the nitrogen atom are carbobenzyloxy, para-methoxy-carbobenzyloxy, trifluoroacetyl, and HC1. Suit-able blocking groups for the hydroxyl group are diphenyl 20 ketal for both hydroxyl groups and the acetyl and carbobenzyloxy for the individual hydroxyl groups as well as other such radicals. The substitutont in the "substituted -SO^- group" can be substantially any radical since these groups aro readily cleaved during the esterification re-25 action and the nature of the group is not at all critical.
The term "reducible groups" signifies any group which can be replaced by the hydrogen atom or can be partially or completely saturated by hydrogen. Such groups include -C11=CII-, -C=C-, -halogen, -NO^, and -CN. 30 The expression "acylating agent" designates an activated carboxylic acid derivative such as a carboxylic - lo - 40256 acid anhydride (including mixed anhydrides) cr a compound O » of the formula Rg-C-X^ where Rg is an organic radical and x2 is an easily removable group such a* halogen, p-nitrophenoxy or phenoxy. 5 When racemic mixtures are formed in accordance with the synthesis of the present invention, it is nome-times desirable to separate the mixtures into their L and D isomers. The isomers can l>e separated at any point in the synthesis and in most instances it in desirer to separate lo them prior to forming the final product. In other instances (an when R^ and R^ are different groups and tl e acid portion is in the I» configuration), a mixture'of diasterco-mers is formed as the final product and these may bo directly separated by crystallization or the formation of i 15 simple derivatives and crystallization. It is by far preferable, hov/ever, to start with th j desirei* isomer (i.e. the _T» irtomer) when the single isomer is desired. It is also possible to form a diastereoisoroer of the racemic mixtures formed in accordance with the nresenl. invention to 2o effect separation. In such inrtanccf, an optically active acid such ar. tartaric acid, 10-camphor sulfonic acid, malic acid, pyroylutamic acid or menthoxy acatic acid may be used, as desired. 'i'ho compounds of tl>o pros^nt invention can be used in the forr.i of compositions preferably administered in unit dosage form such as tablets, ->ills, capsules, powderr., granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions. For -11- 40256 preparing solid compositions such as tablets, the principal active ingredient is mixed with conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acidi, magnesium stearate, dicalcium phosphate, 5 gums and fractionally similar materials as pharmaceutical diluents or carriers. The tablets or pills cud be laminated or otherwise compounded to provide a dosage i'orm affording the advantage of prolonged or delayed action jr predetermined successive action of the 10 enclosed medication. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach IS and permits the inner component to pas3 intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, 20 shellac and cetyl alcohol, or cellulose acetate.
A particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating. The compounds are also useful when administered 25 in the form of suppositories or with a penetrant such as dimethyl sulfoxide.
The liquid forms in which the novel composition of the present invention may be incorporated for administration include suitably flavored emulsions with edible oils. - 12 - 40256 such as cottonseed oil, sesame oil, coconut oil and peunut oil as well as elixirs und similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, 5 cuch as, tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone ''mil XcliiLin. Sterile suspensions or solutions are required for parenteral use. Isotonic preparations containing suitable preservatives are also highly 10 desirable for injection use.
The term single dosage form as used in the specification refers to physically discrete units suitable as unitary dosage for warm-blooded animal subjects, each unit containing a predetermined quantity of active material 15 calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel single dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics 20 of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for therapeutic use in warm-blooded animals as disclosed in detail in this specification. Examples of suitable oral 25 single dosage forms in accord with this invention are (a) tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampoules vials, or segregated multiples of any of the foregoing, (b) and other forms as herein described. - 13 - 40256 The following examples are given to illustrate the invention and are not intended to limit it in any manner. All parts are given in parts by weight and temperatures on the Centigrade scale unless otherwise expressed. The"reduced pressure" 5 usimI in the examples is 15 Lo 25 mm. at 25 to 35°C. (unless otherwise indicated). When reduced pressure is used Lo remove a solvent, the resultunt product is often a solvate end thus the example refers to the formation of a "concentrated" product although all of the 10 solvent has been removed with the exception of that bound in the product. - 14 - 40256 EXAMPLE 1 A. Preparation of &-3 -{3,4 -<1 iphenylmethylenedio:ey-£hen^l)_^2^^T1Gth^lalaniJle_h^dJ^ocM;ori:de A mixture of 19.3 g. (0.0777 mole) of L-3-(3,4-5 dibydroxypheny1)-2-methylalanine hydrochloride [L-a-methyldopa hydrochloride] and 37 g. (0.156 mole) of dichlorodiphenylmcthane is immersed with slow stirring in a preheated oil bath at 190*C. Aftor reaction has started, as evidenced by vigorous gas evolution, the reaction mixture is stirred rapidly for six minutes at 190*c. removed from the hot oil bath and allowed, to cool to 25 -30*C. The crude product from 12 runs is combined, slurried with 3 1. of diethyl ether/filtered, washed with an additional 2 1. of diethyl ether and dried at 30*C. under 15 50 mm. pressure. Recrystallization is accomplished by dissolving Lho prodecL in othar.ol and adding ethyl acetate to precipitate the product. The procedure gives 255 g. (66.4%) of L-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalanine hydrochloride, rn.p. 267 - 268*C. dec. 20 Anal, calcd. for C2,H21N04HC1: C, 67.07; H, 5.39; N, 3.40 Found: C, 66.91; H, 5.29; N, 3.34 B. Preparation of L-N-carbobenzyloxy-3-(3,4-diphenyl-methylcnedioxy^henyl)-2-methylalaninc ~ A mixture of 175 g. (0.425 mole) of L-3-(3,4-25 diphenylmethylenedioxyphenyl)-2-methylalanine hydrochloride, 1750 ml. of acetone and 1750 ml. of water is stirred under nitrogen at a temperature below 10°C. while the pH is adjusted to 12.0 by the slow addition of a 10% sodium -15- 40256 hydroxide solution. Carbobenzyloxy chloride, 93 g. (0.545 mole) is added dropvise over 5-7 minutes to the reaction mixture at 20 - 30*C. accompanied by the simultaneous addition of a 10% sodium hydroxide solution to 5 maintain a pH of 12.0 - 12.2. After addition of the carbobenzyloxy chloride is complete, the reaction mixture is stirred at 25 - 30*C. for three hours. Host of the acetone is then removed under reduced pressure at 25 to 35*C. to precipitate the sodium salt of the desired N-carbobenzyloxy 10 derivative. The sodium salt is extracted into 1.5 1. of ethyl acetate, washed with 200 ml. of 5% sodium hydroxide solution and 200 ml. of a saturated sodium chloride solution and then dried over magnesium sulfate. After addition of 17.5 g. of decolorizing carbon and l'il t rat ion through a 15 magnesium sulfate pad, solvents are removed under reduced pressure at 25 to 35*C. The residue is slurried twice With 1 1. Of a mixture of iJ()% ethyl ether and 80* hexane (by volume) ami I i1tcred l.o give the sodium salt ol' the desired N-carbobenzyloxy derivative. This sodium salt is 20 dissolved in 1.5 1. of ethyl acetate, cooled to 10°C. and acidified to pH 2 with 6 N hydrochloric acid. The ethyl acetate extract is washed with 200 ml. of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure at 25 to 25 35*C. The N-carbobenzyloxy derivative is dried further at 25 - 30*C. and 0.2 - 0.3 cat. Hg to give 169 g. (78.0%) of L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalanine. - 16 - 40236 C. Preparation of succinimidomethyl L-N-carbobenzyloxy-3-(3.4-diphenylmethylenedioxyphenyl)-2-nethylalaninate A solution of 13.5 g. (0.0265 mole) of L-N-carbobenzyloxy-3 -(3,4-diphenylmethylenedioxyphenyl)-2-5 methylalanino, 2.7 g. (0.027 mole) of triethylamine and 5.19 g. (0.029 mole) of N-bromomethylsuccinimide in 35 ml. of dry dimethylformaaide is stirred at 25 - 30*C. for 16 hours. The reaction mixture is poured into 400 ml. of ice water and the product extracted into 200 ml. of a mixture of 50* 10 chloroform urul diethyl ether (by volume). The organic extract is washed with 50 ml. of a dilute (5%) sodium carbonate solution and 50 ml. of a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtration and concentration 15 under reduced pressure, the residue is recrystallized. Recrystallization is accomplished by dissolving the product in ethanol and adding hexane to precipitate the product. The process gives 12.1 g. (73.6%) of succinimidomethyl L-N-carbobenzyloxy-3-(3,4-diphenylraothylenedioxy)-20 phenyl)-2-methylalaninate, m.p. 143.0 - 145.0#C.
Anal, calcd. for C3gH32N2°8: C' 69,66; H» 5-207 N» 4.51 Found: C, 69.83; H, 5.14; N, 4.52 0. Preparation of succinipidomethyl L-3-(3,4-dihydroxy-phenyl)-2-mcthylalaninate hydrochloride hydrate 25 A suspension of 6.6 g. (0.0106 nole) of succin imidomethyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-methylaianinate in 180 ml. of absolute ethanol and 9 ml. of a 9.6 N ethanolic anhydrous hydrogen - 17 - 4 0 2 5 G chloride solution is hydrogenatcd with 3.3 g. of a 10* palladium-on-carbon catalyst at an initial pressure of 30 p.s.i. until hydrogen uptake is complete. After removal of catalyst by filtration, the filtrate is concentrated 5 under reduced pressure. The residue is extracted with 50 ml. of benzene and then 50 ml. of ethyl acetate. The insoluble solid is then shaken with 50 ml. of a mixture of 10* ethanol-"n*J ethyl acetate (by volume) and 10 ml of a saturated sodium carbonate solution. After filtration, the filtrate is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is redissolved in 25 ml. of absolute ethanol, treated with 5 ml. of a 9.6 N ethanolic-anhydrous hydrogen chloride solution and concentrated under reduced pressure to give 2.5 g. (62.7%) of succinimidomethyl I.-3-(3,4-i r> dihydroxyphenyl)-2-methylalaninate hydrochloride hydrate, homogeneous upon thin layer chromatography (fluorescent silica gel plate, 30% methanol-70% benzene (by volume) solvent] with an observed Rf = 0.5. 20 Anal, calcd. for Cj^H^N^g.HCl.H20: C, 47.81; H, 5.62; N, 7.44 Found: C, 48.09; H, 5.74; N, 7.42 EXAMPLE 2 A. Preparation of W-(l-chloroethyl)-succiniraide 25 N-vinylsuccinimide, 50.0 g. (0.40 mole) is dis solved in 1000 ml. carbon tetrachloride, 5.20 g. (0.020 mole) of stannic chloride is added and the mixture is - 18 - 40256 Stirred while being saturated with hydrogen chloride for 6 hours at 20 - 30°C. After 24 hours, the mixture is resaturated with hydrogen chloride for 1.5 hours. At the end of 48 hours, the solution is decanted and the gummy residue is 5 washed with ten 100 ml. portions of carbon tetrachloride. The combined extracts are slurried with 10 g. of diatcna-ceous earth and, filtered and the filtrate is concentrated under reduced pressure to approximately 400 ml. The N-(l-chloro-•thyl)-succinimide is filtered and dried at 20 - 30*C. 10 under reduced pressure to yield 38.4 g. (59%) of white solid melting at 83.5 - 84.5"C.
B. Preparation of a-succinisnidocthyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalanlnate A mixture of 30.66 g. (0.060 mole) L-N-carbo-i5 ben^yloxy-3- (3,4 -dipnenylmethylenedioxyphenyl) -2-methyl-alanine, 9.70 g. (0.060 mole) of N-(l-chloroethyl)-succinimide, 6.07 g. (0.060 mole) of triethylamine and 75 ml. of dry dimethylformamide is stirred at 95° for 19 hours. The reaction mixture is poured into 750 ml. of 2o water and the product extracted into three 500 ml. portions of ethyl acetate. The combined organic extracts are washed with three 300 ml. portions of 5% sodium hydroxide solution, then three times with 300 ml. of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After 25 filtering, the solution is treated with 5 g. of charcoal, filtered and the solvent is evaporated under reduced pressure to give 37.90 g. (99%) of a-succinimidoethyl L-N-carbobenzyloxy-3 -(3,4-diphenylmethylenedioxyphenyl)-2-methylalan'.nate as a mixture of diastereomeric isomers 30 (a and 0). - 19 - 40256 C. Preparation of a-succinimidoethyl £-3-(3,4-dihydroxy-phenyl) -2-raethylalaninate hydrochloride A suspension of 20.18 g. (0.032 mole} of a-succinimidoethyl ^-N-carbobenzyloxy-3-(3,4-diphenyl-5 methylenedioxyphenyl)-2-methylalaninate in 275 ml. of a mixture of 25* absolute ethanol and 75% ethyl acetate (by volume) is hydrogenated with 8.5 9. of 10% palladium-on-carbon catalyst at an initial prossure of 40 p.s.i. "i room temperature for 23 hours. The catalyst is filtered and the filtrate 10 evaporated under reduced pressure at 30 to 40*C. The residue is dissolved in 250 ml. of a mixture of 10% ethanol and 90£ ethyl acetate (by volume) and stirred with 20 ml. of saturated sodium carbonate solution and approximately 30 g. of anhydrous sodium carbonate for 10 minutes. After 15 filtration, the filtrate is dried over anhydrous magnesium sulfate, filtered and evaporated to dryn&3.> under reduced pressure. The residue is dissolved in 130 ml. of dry Chloroform .mil, the solution is cool ud iri ;in ice bath and saturated with hydrogen chloride for 15 minutes. The solid 20 is collected, washed by suspension in 100 ml. of anhydrous ether three times and then slurried in 300 ml. of ethyl acetate under N2 in a stoppered flask at room temperature overnight. The a-succinimidoethyl L-3-{3,4-dihydroxy-phenyl) -2-methylalaninate hydrochloride is collected, 25 stirred in 300 ml. of hexane for 2 hours and dried in a vacuum desiccator over CaCl2 to give 8.32 g. (62%) of hydrochloride as a mixture of a and 0 isomers, observed Rf "> 0.7 upon thin layer chromatography [fluorescent silica gel plate, usin« as solvent SO% methanol and 50£ benzene 30 (by volumejQ . - 20 - 40230 Anal, calcd. for C16H2()N206.HCl.l/2 CH3C02C2H5s C, 51.86; H, 6.05; N, 6.7 Found: c, 51.98; H, 5.87; N, 6.65 EXAMPLE 3 5 A. Separation of a-succinimidoethyl I*-N-carbobenzyloxy-3-(3 ,4-dihydroxyphenylmethylenedioxyphenyl)-2-methyl-alanlnate isomers The mixture of diasteromeric isomers of Example 2, 150.5 g., is dissolved in a boiling mixture of 1200 ml. 10 of benzene and 100 ml. of absolute methanol, and filtered, and the filtrate is concentrated to a volume of approximately 700 ml.. Absolute methanol, 100 ml., is added to the solution, which then is diluted to cloudiness with 1000 nil. of hexane, seeded and scratched to induce crystallization. The 15 mixture is coolcd at 5°C. for about 16 hours and the crude crystalline a-isomer is then collected, washed by suspension in 200 ml. of a 50:50 mixture (by volume) of benzene and hexane and dried at 70°C. The product weighs 68.1 g. and melts at 185.5 - 191*C. An analytical sample nelts at 20 199.5 - 201.5°C. after two additional recrystallizations.
Anal, calcd. for €37^34^2^8: 7^.02; H, 5.40; N, 4.41 Found: C, 70.22; H, 5.52; N, 4.29 The combined mother liquors and washings from the a-isomer are evaporated to dryness under reduced pressure 25 at 60°C. to give 79.3 g. of the 0-isomer as a very viscous oil. - 21 - 4 0 2 S 6 D. Preparation of a-succinimidoethyl £-3-(3,4-dihydroxy-phenyl)-2-methylalaninate hydrochloride dihydrate (P-isomer) _ A solution of 10.0 g. (0.016 mole) of a-succin-5 ixaidoethyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylene-dioxyyhenyl) -2-methylalaninate (0-isomer) in 140 ml. of a mixture of 25% absolute ethanol and 75* ethyl acetate (by volvune) Is hydrogenated with 4.2 g. of 10% palladium-on-carbon catalyst at an initial pressure of 40 p.s.i. and room 10 temperature for 20 hours until hydrogen uptake is complete. The catalyst is filtered under nitrogen, and the filtrate is acidified with 2.0 ml. of 9.4 N ethanolic hydrogen chloride and evaporated to dryness under reduced pressure at 30 to 40*C. The amorphous solid residue is dissolved in 50 ml. 15 warm 95% ethanol (5% water) and filtered, and the i'iltrnte is diluted to incipient cloudiness with anhydrous ether (68 ml.), seeded and scratched to induce crystallization. The product is collected and stirred in 300 ml. of anhydrous ether to remove any diphenylmethane. After one hour, 20 the solid is collected and dried at 70*C. overnight to give 3.7 g. of material melting at 123 - 126*C. (dec.). Recrystallization from 20 ml. of 95% ethanol affords 3.36 g. (51%) of a-succinimidoethyl L-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride dihydrate (0-isomer) as the 25 dihydrate melting at 129 - 131°C. (dec.) (dried at 70°C. overnight), homogeneous upon thin layer chromatography [fluorescent silica gel plate, using as solvent 50* methanol and 50"£ benzene (by volume)], Rf = 0.7. 4025G Anal, calcd. for C16H2()N206.HC1.2H20: C, 47.00; H, 6.16? N, 6.85 Found: C, 46.85, 47.09; H, 6.12, 6.16; N, 6.76, 6.61 5 CalJ40 - + 33.46*(C - 1.5 CH3OH) EXAMPLE 4 A. preparation of a-succinimidoethyl L-3-(3,4-dihydroxy-phenyl)-2-methylalaninate hydrochloride (a-isomer) A solution of 10.0 g. (0.016 mole) of a-succin-10 imidoethyl I,-N-carbobenzyloxy-3-(3,4 -diphenylmethylenedioxyphenyl) -2-methylalaninate (a-isomer) in 140 ml of a mixture of 25* absolute ethanol and 75* ethyl acetate (by volume) is hydrogenated with 4.2 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 40 p.s.i. at room 15 temperature for 27 '4 hours until hydrogen uptake is complete. - ml. of a 9.4 N ethanolic solution of anhydrous hydrogen chloride is added and catalyst is removed by filtration through a pad of diatomaceous earth. After concentrating under reduced pressure, the residue is extracted by 20 shaking with 200 ml. diethyl ether, twice with 200 ml. benzene and finally twice with 200 ml. of diethyl ether. The material remaining after these extractions is the desired a-succinimidoethyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrochloride (a-isomer) diethyl ether 25 solvate, Rf = 0.7 [thin layer chromatography fluorescent silica gel plate, using as solvent 50* methanol and 50* benzene (by volumej] contaminated with 12* diphenylmethane. [a]^4 =» -18.75 (C, 1.68, CH30H) . - 23 40256 EXAMPLE 5 A. Preparation of 2-trifluoroacetamidoethyl L-N-carbo-benzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-raethylalanlnate 5 A solution of 5.09 g. (0.010 mole) of L-N- carbobenzyloxy-3- (3,4-diphenylmethylenedioxyphenyl)-2- methylalanine, 1.01 g. (0.010 mole) of triethylamine and 1.76 g. (0.010 mole) of N-(2-chloroethyl)-2,2,2-trifluoro- acetamidc in 20 nl. dry dimethylformanide is stirred at 10 110*C. for 20 hours under nitrogen. The cooled reaction mixture is poured into 500 ml. of ice water and the product extracted into three 500 ml. portions of ethyl acetate.
The combined extracts are washed with 200 ml. of water, dried (MgSO^), filtered and concentrated to an oil under 15 reduced pressure. The residual oil is redissolved in 100 ml. ethyl acetate, extracted with two 50 ml. portions of a 5% sodium hydroxide solution, washed with 50 ml. of water and dried over magnesium sulfate. Filtering and concentrating under reduced pressure gives 4.92 g. of an 20 oil. Chromatography of this oil on 200 g. of silica gel and elution with a 5% solution of methanol in chloroform affords 4.11 g. (63.4%) of the 2-trifluoroacotaiaidoethyl L-N-carfcobcnzylo::y-3 -(3,4 -diphenylxethylenedio::yphenyl) - 2-methylalaninate 3s an oil, homogeneous upon thin layer 25 chromatography [fluorescent silica go1 plate developed with 5% methanol in 95* chloroform (by volume)] Rf = 0.8.
D. Preparation of 2-trifluoreiicrt^.r.ii(iocthyl L-3-(3,4-dihyaroxypher.y 1) -2-nv?thylalar>-inate hydrochloride A solution of 2.0 g. (0.0031 mole) of 2-trifluoro- 30 acetaxaic.oethyl L-;:-carbohcr.zyloxy-3 - (3,4 -diphenylmethylene- - 24 - 402SG dioxyphenyl)-2-methylalaninate in 125 nil. absolute ethanol and 1.0 g. of a 10% palladiura-on-carbon catalyst is hydrogenated at room temperature and an initial pressure of 36 p.s.i. •*«»■ f»iioiirH 4<> inliutl.fK until hydrogen uptake is 5 complete. Catalyst is removed by filtration under nitrogen through a diatomaceous earth filter pad and the filtrate is concentrated under reduced pressure at a temperature of 20 to 39*C. The residue is redissolved in 25 ml. absolute ethanol, converted to the hydrochloride by addition 10 of 2 ml. of 7.6 N ethanolic-anhydrous hydrogen chloride solution and then concentrated under reduced pressure. The residue is precipitated twice by dissolving in ethanol and adding sufficient ethyl ether to precipitate the product to give 600 mg. (66.6%) of 2-trifluoroacetamidoethyl L-3-15 (3,4-dihydroxyphenyli-2-methylalaninate hydrochloride as the ethanol solvate, homogeneous upon thin layer chromatography (fluorescent silica gel plate developed with 50% methanol and 50* chloroform (by volume)] ^ = 0.8.
Anal, calcd. for C^H^F^Og.HCl.C^OH: C, 44.40; 20 H, 5.59; N, 6.47 Found: C, 44.55; H, 5.29; N, 6.72 EXAMPLE 6 A. Preparation of 2-nicotinamidoethyl .L-N-carbobenzyloxy-3-{3,4-diphenylmethylenedioxyphenyl) -2-25 methylalaninate A solution of 5.84 g. (0.015 mole) of L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalanino, 1.52 g. (0.015 mole) of triethylamine and 402S6 2.77 g. (0.015 nolo) of M-(2-chloroethyl)-nicotinamide in 20 ml. dry dimethylfomamide is stirred under nitrogen at 95*C. for 20 hours. Tho cooled reaction mixture is poured into 200 ml. of ice water and the product exracted into 5 three 175 ml. portions of ethyl acetate. The combined extracts are washed with 100 ml. of saturated sodium bicarbonate solution, and, lOO ml of water, and dried (Mj{S04) After filtration, solvents are removed under reduced pressure to give 6.28 g. (85%) of 2-nicotinamidoethyl l-m-lo carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2- methylalaninate, homogeneous upon thin layer chromatography [fluorescent silica gel plate developed with 20% methanol in 80% benzene (by volume)J observed Rf = 0.45.
B. Preparation of 2-nicotinomidoothyl L.-3-(3,4-dihydroxy-15 phenyl) -2-ninthyialoninPtc flihyrlrcbro^iao A mixture of 1.0 g. (2.0 millimoles) of 2 — nicotinamido-ethyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-methylalaninate and 10 ml. of a 30 - 32% solution of anhydrous hydrogen bromide in acetic acid is 20 allowed to stand at 20 - 25°C. for 30 minutes until gas evolution is complete. The homogeneous solution is concentrated under reduced pressure at 20 - 25°C. and the residue is stirred with 50 ml. diethyl ether for 3 days. The nearly white solid is collected, washed with 50 ml. of 25 anhydrous ethyl ether and dried under high vaccum (0.1 to 0.3 mm. Hg.) at 20 - 25®C. to give GOO mg. (77%) of the 2-nicotinamidoethyl L-3-(3,4-d ihydroxyphenyl)-2-methyl-alaninate dihydrobromide, observed Rf = 0.5 upon thin layer chromatography [fluornscent silica qcl plate developed - L'fi - 4 0 2 5 6 with a solution consisting of equal parts (by volume) of n-butanol, acetic acid, 1% aqueous sodium bisulfite* benzene and acetone).
Anal, calcd. for CI8H2]N305.2HBr.2H20: C, 38.79; H, 4.88; 5 N, 7.54 Wound: C, 38.79; H, 4.56; N, 7.37 EXAMPLE 7 A. Preparation of g-chloroethylpivalate Zinc chloride, 400 mg., is fused at 0.2 - 0.5 ma 10 pressure and cooled to 25 - 30*C. under nitrogen. Pivaloyl chloride, 48 g. (0.40 mole) is added to the fused zinc chloride followed by acetaldehyde, 19.2 g. (0.44 mole). During addition of the acetaldehyde, which is done as rapid ly as possible, the reaction mixture is stirred and cooled 15 to prevent loss of acetaldehyde due to the exothermic nature of the reaction. After heating at reflux for 1 hour distillation gives 36 g. (55%) of a-chloroethylpivalate, b.p. 32 -34*C. at 4 mm.
B. Preparation of a-pivaloyloxyethyl -U-carbobenzyloxy-20 3-(3,4 -diphenyliaethylenedioxyphenyT) -2-methylalaninate To a stirred solution of 9.0 g. (0.018 mole) of L-N-carbobenzyloxy-3-(3,4-diphenyImethylenedioxyphenyl)- 2-methylalanine in 25 ml. dry dimethylforroamide is added 1.80 g. (0.018 mole) of triethylamine followed by 2.96 g. 25 (0.018 mole) of a-chloroethylpivalate. After stirring at 90 - 95*C. for 20 hours, the reaction mixture is poured into 350 ml. water and the product extracted three times with 100 ml. of ethyl ether. The ethereal extracts are - 27 - 40256 combined, washed with 50 ml. of a 5%. sodium hydroxide ■ solution, .inil r>() ml. ol' w;itf;r ;hk1 dried over anhydrous -« magnesium sulfate. After filtering, solvents are removed under reduced pressure to give 7.9 g. (68.9%) of crude. 5 a-pivaloyloxyethyl L-N-carbobenzyloxy-3-(3,4 -diphenylmethylenedioxyphenyl) -2-methylalaninate.
C. Preparation of a-pivaloyloxyethyl L-3-(3,4-dihydroxy-phenyl) -2—ncthylalaninate hydrochloride A solution of 7.8 g. of a-pivaloyloxyethyl L-li) N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalaninate in 140 ml. absolute ethanol and 11 ml. of an 8 N ethanolic-anhydrous hydrogen chloride solution is hydrogenated with 3.7 g. of a 10% palladium-on-carbon catalyst at 20 - 25*C. and an initial pressure of 35 p.s.i. 15 for 19 hours until hydrogen uptake ceases. After removing catalyst by filtration, ethanol is removed under reduced pressure. The residue is stirred overnight with 80 ml. benzene. The benzene is removed by decantation,and replaced with 80 ml. of hexano.the mixture is stirred and the hexane decanted 20 oil'. The residue is dissolved in 300 ml. ethyl acetate, stirred briefly with a mixture of 5 g. of solid sodium carbonate and 5 ml. saturated sodium carbonate solution and dried over anhydrous magnesium sulfate. After ititration,3 ml. of 9.6 N ethanolic-anhydrous hydrogen chloride is added and 25 the solution is ooncentriited under reduced pressure to dryness. Further drying at 65°C. and 0.2 mm. pressure gives 2.16 g. (47.2%) of the a-pivaloyloxyethyl ester hydrochloride.
Anal, calcd. for C17H 25NOg.HCl: C, 54.32; H, 6.97; N, 3.73 Found: C. 54.47; H, 7.36; N, 3.39 40256 EXAMPLE 8 A. Preparation of L-N-carbobenzyloxy-3-(3,4-dihydroxy-phcnyl)-2-methylalanino To a stirred solution of 3.0 9. (0.0126 mole) of 5 L_-J-(3,4-dihydroxyphenyl)-2-methylalanine sesquihydrate in 20ml. of 2 N sodium hydroxide solution maintained at 0*C. under a nitrogen atmosphere is added a solution of 3 ml. of carbobenzyloxy chloride in 10 nil. of diethyl ether.
After stirring at 0*C. for one hour, followed by one hour 10 at 25*C., the reaction mixture is extracted with 50 ml. of diethyl ether. The aqueous portion is acidified to pH 3 - 4 with a 6 N hydrochloric acid solution and the crude product is extracted into 100 ml. of ethyl acetate and washed three times with 25 ml. of water. After drying over IS anhydrous magnesium sulfate and filtering, the solvent is removed under reduccd pressure to give i.5 g. (J-i.5%j of L-N-carbobenzyloxy-3-(3,4-dihydroxyphenyl)-2-methylalanine as a viscous oil.
B. Preparation of pivaloyloxymethyl £.-3-(3,4-dihydroxy-20 phenyl)-2-nethylalaninate hydrochloride A mixture of 2.1 g. (6.1 mi I I imoles) ol" j^-N- carbobenzyloxy—3 -(3,4-dihydroxyphenyl)—2—methylalanine, 0.93 g. (6.2 in i I I imol c>s) ol" chl 01 oinethylpivalate , 0.63 g. (6.3 millimoles) of potassium bicarbonate and 0.15 g. potassium iodide in 25 60 ml. of acetone and 4 ml. of water is stirred at reflux under nitrogen for 18 hours. After concentration under reduced pressure, 50 ml. of water is added and the N-carbobenzyloxy derivative of the desired ester is extracted with three 50 ml. portions of diethyl ether. The ethereal - L'y - 40256 extract is washed with 50 ml. o£ water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue is dissolved in 100 ml. of absolute ethanol and 4 ml. of a 9.6 N ethanolic-anhydrous 5 hydrogen chloride solution and hydrogenated with 1 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 39 p.S.i. for 24 hours. After removal of catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue is dissolved in 5 ml. of water and 10 made basic to pH 8 with a saturated sodium carbonate solution and the insoluble product extracted into 25 ml. of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and filtered, 1 ml. of 9.6 N ethanolic-anhydrous hydrogen chloride solution is added and the solution is k concentrated under reduced pressure to give 0.50 g. (22.6%) of the hydrochloride of pivaloyloxymethyl L-3 — (3,4 — dihydroxyphenyl)-2-methylalaninate hydrochloride, Rf ™ 0.86 upon thin layer chromatography [fluorescent silica gel plate developed with a 5:2:3 (by volume) mixture 20 of n-butanol:acetic acid:water].
Anal, calcd. for C^gH^NOg.HCl: C, 53.11; H, 6.69; N, 3.87 Found: C, 53.76; H, 6.64; N, 3.69 EXAMPLE 9 A. Preparation of 1,2-ethylene bis L-N-carbobenzyloxy-3-25 (3,4-dihydroxyphenyl)-2-nethylalaninate A solution of 7.3 g. (0.023 mole) of L-N-carbo- benzyloxy-3-(3,4-dihydroxyphenyl)-2-methylalanine, 1.38 g. (0.01 mole) of 1,2-dibrorr.oethane and 2.1 g. (0.021 mole) - ;jo - 40256 of triethylaminc in 20 ml. dimethylfontiamide is heated ac 85 - 90*C. for 10 hours and then poured into 200 ml. water. The blocked bis ostcr is extracted with three 100 ml. portions of ethyl acetate and washed with 100 ml. of a 5 saturated sodium bicarbonate solution and 100 ml. of a saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure at 30 - 40*C., 5.3 g. (74%) of 1,2-ethylene bis I»-N-carbobenzy loxy-3 - (3,4-dihydroxyphenyl) -2-methyl -10 alaninate is obtained.
B. Preparation of 1,2-ethylene bis L-3-(3,4-dihydroxyphenyl) -2-methylalaninate dihydrochloride A solution of 5.0 g. (6.98 mi 1.1 imoles) of* 1,2-ethylene bi3 L-N-carbobenzyloxy-"*-(3,4-dihydroxyphenyl) -2-methyl-15 alaninate in 120 ml. of a mixture of 25* methanol and 75* ethyl acetate (by volume) is hydroyenated at an initial pressure of 35 p.s.i. with 2 g. of 10% palladium-on-carbon catalyst until hydrogen uptake is complete. After l'» I trat.ion to remove catalyst, solvents are removed under reduced 20 pressure. The residue is dissolved in a mixture of lo* ethanol and 90* ethyl acetate (by volume), and stirred with 5 ml. of a saturated sodium carbonate solution and 5 g. of solid sodium carbonatc. Anhydrous magnesium sulfate is added, the mixture is filtered and the filtrate acidified with 25 1 ml. of 9.6 N ethanolic-anhydrous hydrogen chloride solution. Solvents are removed under reduced pressure at a temperature of 20 to 30°C. to give 1,2-ethylene bis L-3-(3,4-dihydroxyphenyl)-2-methylalaninate dihydrochloride - 31 - 40256 as the ethyl acetate solvate.
Anal, calcd. for C22H28N2<>8.2HC1.2C4H802: C, 51.65; H, 6.65; N, 4.07 Founds C, 50.91; H, 6.69; N, 4.27 5 EXAMPLE 10 A. Preparation of 1,3-propylene bis ^-N-carbobenzyloxy-3-(3,4-dihydroxyphenyl)-2-methylalaninate A solution of 7.8 g. (0.023 raole) of L-N-carbobenzyloxy-3 -{3,4-dihydroxyphenyl)-2-methylalaninate, 2.1 g. 10 (0.020 mole) of triethylamine and 2.02 g. (0.010 mole) of 1,3-dibranopropane in 20 ml. dimethylformamide is heated under nitrogen for 15 hours at 95°C. and then poured into 200 ml. of water. The product is extracted with three 100 ml. portions of ethyl acetate and washed with 50 ml. of 15 a dilute soultuu bicarbonate solution (5%) , 50 ml. of water and finally 50 ml. of a saturated solution of sodium chloride. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, 5.4 g. (73.8%) of 1,3-propylene bis L-N-carbobenzyloxy-3-(3,4-dihydroxy-20 phenyl)-2-methylalaninate is obtained.
B. Preparation of 1,3-propylene bis L-3-(3,4-dihydroxyphenyl) -2-svethylalaninate dihycrochloride A solution of 5.4 g. (7.39 millimoles) of 1,3- propylene bis L-N-carbobenzyloxy-3-{3,4-dihydroxyphenyl)- ?5 2-methylalaninate in 100 ml. of a mixture of 25% ethanol and 75* ethyl acetate (by volume) is hydrogenated at an initial pressure of 35 p.s.i. with 2.5 g. of a 10% palladium-on-carbon catalyst - 32 - 40 256 at 25*C. until hydrogen uptake ceases. After removal of catalyst by filtration, solvents are removed under reduced pressure. The residue is dissolved in a mixture of lo£ methanol and ethyl acetate (by volume) arid, stirred with 5 ml. of a sat- 5 iirated sodium carbonate solution and 5 g. of solid sodium carbonate. Five grams of anhydrous magnesium sulfate is added, the mixture is filtered and the filtrate acidified with 1 ml. of 9.6 N ethanolic-anhydrous hydrogen chloride solution. The solution is concentrated under reduced 10 pressure to about 50 - 60 ml. said decanted from an insoluble gum. The gum is stirred with 25 ml. of ethyl acetate, filtered and dried to give 1.74 g. (33%) of 1,3-propylene bis L-3-( 3,4-dihydroxyphenyl)-2-methylalaninate dihydrochloridc as the ethyl acetate solvate, Rf = 0.56, 15 thin layer chrouatography (fluorescent silica gel plate developed with a solution containing equal parts (by volume) of n-butanol, acetone, acetic acid, water and benzene].
EXAMPLE 11 20 A. Preparation of 1-chloro-l-succinimidopropane Anhydrous hydrogen chloride is bubbled through a mixture of 10 g. (0.072 mole) of N-propenylsuccinimide and 1.04 g. of stannic chloride for 6 hours. The solution is allowed to stand at room temperature for 10 days, the 25 solution being saturated again with hydrogen chloride gas after 3 days and 4 days. Solvents arc removed under reduced pressure at 30 - 40°C. to give 1-chloro-l-succinimido-propane as a yellow oil. 402 5U B. Preparation of a-succinimidopropyl L.-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalaninate A solution of 10.2 g. (0.020 mole) of &-N-oarbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-3-5 methylalanine, 2.1 g. (0.021 mole) of triethylamine and 3.51 g. (0.020 mole) of 1-chloro-l-succinimidopropane in 20 ml. dimethylfozmamide is heated at 90*C. for 10 hours and then poured into 200 ml. water. The product is extracted with three' 100 ml. portions of ethyl ether and 10 washed with 50 ml. of 5% sodium hydroxide, 50 ml. of water and 50 ml. of a saturated solution of sodium chloride.
After drying over anhydrous magnesium sulfate and filtering, solvents are removed under reduced pressure to give 8.6 g. (68%) of a-succinimidopropyl L-N-carbobenzyloxy-3-(3,4-15 diphenylmethylenedioxyphenyl)-2-methylalaninate, nf - 0.2, thin layer chromatography (fluorescent silica gel plate developed with chloroform].
C. Preparation of a-succinimidopropyl L-3-(3,4-dihydroxy-phenyl)-2-methylalaninate hydrochloride 20 a solution of 8.6 g. (0.014 mole) of a-succin imidopropyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylene -dioxyphenyl) -2-methylalaninate in 120 ml. of a mixture oi' 25% ethanol ami 7r,y. ethyl .iLfcl.ite (by volume) is hydrogenated with 4 g. of a 10% palladium-on-carbon catalyst at an initial 25 pressure of 40 p.s.i. for 18 hours until hydrogen uptake Ceases. After removal of catalyst by filtration, solvents are removed under reduced pressure at 30 - 40°C. The residue is dissolved in a mixture of 10* ethanol and 90* ethyl acetate (by volume) and stirred with 5 ml. of saturated sodium - :t/» - 40256 cstbonste solution and excsss <>r solid sodium carbonate for 2 minutes. i<> grams of anhydrous magnesium sulfate is added, the mixture is filtered and the filtrate is acidified with 2 ml. of 9.6 N ethanolic-hydrogen chloride solution. 5 The solution is concentrated to dryness under reduced pressure, 100 ml. oi' ethyl acetate is added and the mixture concentrated again to dryness under reduced pressure.
Ethyl acetate, 100 ml., is added and after the mixture has been stirred at Ii5°C. for 1 hour, the product is removed by filtration -10 and dried under reduced pressure to give 3.0 g (51.0*) of a-succinimidopropyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrochloride as the ethanol solvate, Rf ■ 0.63, thin layer chromatography [fluorescent silica gel plate developed with a mixture ol' 30* methanol and 70* benzene (by volume. 15 Anal, calcd. for C17H22N206.HC1.C2H50H: C, 52.71; H, 6.75; N, 6.47 Found: C, 53.62; I), 6.51; N, 6.32 EXAMPLE 12 A. Preparation cf H-chloromethylglutarimide 20 Thionyl chloride, 8.35 g. (0.070 mole) is added slowly to a solution of 9.0 g. (0.063 mole) of N-hydroxy-raethylglutariitiide in 50 ml. benzene at 40°C. After addition is complete, the solution is stirred at reflux for 1.5 hours and then at rocn temperature for an a5 additional 1.5 hours. Benzene is removed under reduced pressure at 30 - 40°C. and the residue is distilled to give 5.4 g. (53%) of N-chloromethylglutarimide, b.p. 97 -100*C. at 0.1 mm. 40256 B. Preparation of glutarimidomethyl l4-IJ-carbobcnzylc::y-3-(3,4- C. Preparation of glutarimidomethyl I>-3-(3,4-dihydroxy-phenyl) -2-^othyialaninate hydrochloride 20 A solution of 12 g. (0.0189 mole) of glutar imidomethyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-nethylalaninate in 130 ml. of " mixture of 25* absolute ethanol ;iiiiI 75* ethyl acctaLp (l>y volume) is hydrogenated with 5 g. of a 10% palladium-on-carbon catalyst at 20 - 25°C. 25 and an initial pressure of 40 p.s.i. for 18 hours until hydrogen uptake ceases. After removing catalyst by filtration and concentrating to dryness under reduced pressure, the residue is dissolved in 200 ml. of a mixture of 10* absolute ethanol and 90* ethyl acetate (by volume) and stirred - 36 - 40256 with 5 ml. of a saturated sodium carbonate solution and excess ol' solid sodium carbonate for 2 minutes. 10 grams of anhydrous magnesium sulfate is added and after a few ' minutes is removed by filtration. Solvents are removed 5 under reduced pressure and, the residue is washed with 25 ml. of hexane and then 25 ml. of ethyl acetate.and dried under reduced pressure. The residue is retreated with sodium carbonate as before to remove the last traces of a-methyl-3,4-dihydroxyphenylalanine and converted to the hydro-10 chloride salt with 3 ml. of 9.6 W ethanolic anhydrous hydrogen chloride to give 3.0 g. (36%) of glutarimido-methyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrochloride as the ethyl acetate solvate, homogeneous upon thin layer chromatography [fluorescent silica gel plate 15 developed with a mixture Ol :»(>'£ methanol and 70% benzene (by volume)]^ Rf = 0.56.
Anal, calcd. for C, 51.99; H, 6.20; N, 6.38 Found: C, 52.15; H, 6.4 5; N, 6.53 20 EXAMPLE 13 A. Preparation of 2-[L-N-c.:rbchenzylo:cy-3-(3,4 -diphenyl-methyleneciio::yr-hcnyl) --methylnlanyloxymethyl] -1,2-benzisothiaiso.l-3 (2!l) -onr»-l, l-tlioxi.r^ A solution of 7.65 g. (0.015 nole) of L-N-carbo-25 benzyloxy-3-(3,4-diphenylmothylenodiojcyphonyl) -2-methyl-alanine, 1.5 g. (0.015 mole) triethylamino and 3.0 g. (0.015 mole) of N-chloroir.ethylsaccharin in 15 ml. dimethyl-formamidc is heated at 75 - 80°C. fcr 17 hours and then poured into 150 nl . of water-. • The product is extracted with 30 three 100 ml. portions of ethyl acetate, washed with - .17 - 40256 50 ml. of a saturated sodium bicarbonate solution( 50 ml. of water and SO nl. of a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, solvents are removed under reduced pressure to 5 give 9.3 g. (100%) of 2-[L-N-carbobenzyloxy-3-(3,4- diphenyImethylenedioxyphenyl)-2-aethylalanyloxymethyl]-1,2-b«nzisothiazol-3(2H)-one-1,1-dioxide, Rf =» 0.32, thin layer chromatography [fluorescent silica gel plate developed with chloroform]. 10 B. Preparation of 2-[J,-3-(3,4-dihydroxyphenyl)-2-methyl-alanyloxymethyl) *-l,2-benzi30thiaz0l-3 (2H) -one-1,1-dioxide hydrochloride A solution of 3.0 g. (0.0043 mole) of the 2-[L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-15 2 -methylalanyloxymethyi]-i,2-benzisothiazol-3(2H)-one-1,1-dioxide in 100 ml. absolute ethanol and 5 ml. of 8 N ethanolic anhydrous hydrogen chloride solution is hydrogenated with 1.5 g. of a 10% palladium-on-carbon catalyst at 20 - 25°C. and an initial pressure of 35 p.s.i. 20 for 20 hours until hydrogen uptake ceases. After removal of catalyst by filtration and conccnlration to dryness under reduced pressure, the residue is stirred with 50 ml. of ethyl acetate for 1 hour and tho ethyl acetate Is docanted off. The residue is dissolved in 200 ml. of a mixture of 20% ethanol 25 and HO% ethyl acetate (by volume) and stirred with 10 ml. of saturated sodium carbonate solution and excess of solid sodium carbonate. 10 grams of anhydrous magnesium sulfate is added and after a few minutes is removed by filtration and the filtrate is acidified with 1 ml. of 9.6 N ethanolic - 38 - 4 0 256 anhydrous hydrogen chloride solution. Solvents are removed under rcduced pressure to give 0.2 g. (10.0%) of 2-[L-3-(3,4-dihydroxyphenyl) -2-methylalanylo::ymethyl] -1,2-kenzisothiazol-3 (211) -one-1,1-dioxide hydrochloride as the 5 ethyl, acetate solvate, Rf = 0.74, thin layer chromatography [fluorescent silica gel plate developed with a solvent consisting of equal parts (by volume) of benzene, water, acetic acid, n-butanol and acetone.
Anal, calcd. for C18H18H2o7s.llCl. % WV C.49.08; 1° Ii, 4.55; N, 6.03 Found: C, 49.27; H, 4.76; N, 5.65 EXAMPLE 14 A. Preparation of l-nethyl-2-[L-H-carbobenzylo;£y-3-(3,4-dlhydro::yphanyl) -2-;ncthylalanylo:cyucthyl] -imidazole A solution of 7.8 g. (0.0226 mole) of L-N-carbobenzyloxy-3-(3.4-dihydroxyphenyl) -2-methylalanine, 4.2 g. (0.042 mole) tricthylamine and 3.34 g. (0.0256 mole) of 1-methyl-2-chloromothylimidazole in 20 ml. dimethyl form-amide is heated at 70 - 75°C. for 10 hours and then poured 20 into 200 ml. ol water. The product is e::trr.cted with three 100 ml. portions of ethyl acetate, washed with 50 ml. of a saturated soaiun bicarbonate solution and, 50 ml. of a saturated sodium chloride solution and concentrated under rcduced pressure to give 2.2 g. (22%) of 1-methyl-2-25 [L-N-carbobcn/.ylcxy-3-(3,4 -dihydroxyphenyl) -2-methyl-alanyloxymcthyl]-imidazole, homogeneous upon thin layer chromatography [fluorescent silica gel plate developed with a mixture of 15^' methanol and 85& chloroform (by volume) Rf = 0.66. - 39 - 40256 B. Preparation of L-lHnethyl-2-l2-(3,4-dihydroxybenzyl)-alanylo.xvmcthylT-iiniriazolc dihydrochlorida dihydrate A solution of 2.1 g. (4.78 millimoles) of 1-methyl- 2-(L-N-carbobenzyloxy-3-(3,4-dihydroxyphenyl)-2-methyl- 5 alar.yloxymethyl) -imidazole in 100 ml. absolute ethanol is hydrogenated with 1 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 35 p.s.i. for 4 hours. After removal of catalyst by filtration and concentration to 50 ml. under reduced pressure, 2 ail. of 9.6 N ethanolic-anhydrous 10 hydrogen chloride is added and the remainder of the solvents are removed under reduced pressure. The residue is stirred With 200 ml. of mixture ol" 20% ethanol and 80* ethyl acetate (by volume), lO ml. of saturated sodium carbonate solution and excess of solid sodium carbonate. Ten grams of anhydrous magnesium 15 sulfate is added and aft?r a few minutes is removed by filtration. The filtrate is acidified with 1 ml. of 9.6 N ethanolic-anhydrous hydrogen chloride solution. Solvents are removed under reduced pressure to give 0.2 g. (8.5%) of \ L—1 -methyl-2-[2-(3,4-dihydroxybenzy1)-alanyloxymethyl]-20 imidazole dihydrochloride dihydrate as the ethyl acetate solvate, Rf = 0.3 upon thin layer chromatography (fluorescent silica gel plate developed with a solution consisting of equal parts (by volume) of n-butanol, acetic acid, water, benzene and acetone. 25 Anal, calcd. for C18HlgN304.2HC1.2H20.^ C4H8°2= C, 44.55; H, 6.34; N, 9.17 Pound: C, 44.62; H, 6.84; N, 8.95 - -n> - 40256 EXAMPLE 15 A. Preparation of 1-methyl-3-chloromethylhydantoln Thionyl chloride, 30 ml., is added slowly over 20 minutes to a well stirred mixture of 25 9. (0.173 mole) 5 of 1-methyl-3-hydroxyinethylhy dan toin and 160 ml. benzene at reflux. After being stirred at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure, 70 ml. of benzene is added and the solution concentrated a9ain to dryness. After repeatin9 this 10 process once more with 70 ml. benzene, the residue is extracted with three 100 ml. portions of carbon tetrachloride. Removal of solvents under reduced pressure gives 15.7 g. (55.7%) of the l-methyl-3-chlorornethyl-hydantoin. 15 B. Preparation of l-methyl-3-lL-N-carbobenzyloxy-3-(3,4- diphenylmothylsnedioxyphenyl)-2-methylalanyloxymethyl]-hydantoin A solution of 10.2 g. (0.020 mole) of L-N-carbo-benzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methyl-20 alanine, 2.1 g. (0.021 mole) of triethylamine and 3.25 g. (0.020 mole) of 1-methyl-3-chloromethylhydantoin in 23 ml. dimethylformamide is heated at 70°C. for 18 hours and then poured into 230 ml. water. The product is extracted with three 100 ml. portions of ethyl acetate, washed with 50 ml. 25 of dilute sodium hydroxide solution (5%) , 50 ml. of water and 50 ml. of a saturated sodium chloride solution and dried over anhydrous maqnesium sulfate. After li 1 irat. ion solvents are removed under rcduced pressure to give 11.7 g. (92%) of 1-methy1-3-[L-N-carbobenzyloxy-3-(3,4 -diphonylmcthylene-30 dioxyphenyl)-2-:r.ct:hylaldnyloxyp>othyl 1 -liydantoin. - 41 - 40256 C. Preparation of L-l"7®ethyl-3-[2-(3,4-dihydroxybenzyl) -alanyloxymethyl]-hydantoin hydrochloride hydrate A solution'of 4.0 g. (6.3 millimoles) of l-methyl-3-[L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-5 2-methylalanyloxymethyl]-hydantoin in 140 ml. of absolute ethanoj. and 2 g. of a 10% palladium-on-carbon catalyst is hydrogenated at an initial pressure of 36 p.s.i. for 20 hours. After removal of catalyst by filtration and concentration to dryness under reduced pressure, the residue is 10 washed with 100 ml. ol" hexane. The hexane-insoluble material is dissolved in 150 Oil. of a mixture of 10< methanol and 90* ethyl acetate (by volume), stirred with 5 ml. of saturated sodium carbonate solution and excess oi' sodium carbonate, and dried over anhydrous magnesium sulfate. After filtration the 15 filtrate is acidified with 2 ml. of 9.6 N ethanolic- anhydrous hydrogen chloride ana conccntrated to dryness under reduced pressure. The residue is stirred with 80 ml. ethyl acetate for 3 hours, filtered and dried under reduced pressure to give 0.50 g. (18%) of L-l-methyl-3-20 12 — (3,4-dihydroxybenzyl)-alanyloxymethyl]-hydantoin hydrochloride hydrate as the ethyl acetate solvate.
Anal, calcd. for .HC1.H20. )£ C4"a° »: C, 46.84; H, 6.01; N, 9.64 Found: C, 46.28; H, 6.09; N, 9.06 25 EXAMPLE 16 A. Preparation of 2-pher.cxyethyl L-N-carbobenzyloxy-3-(3,4-diphcnylm3thylenedioxyphenyl)-2-m°thylalaninate A solution of 4.5 g. (O.OOS8 mole) of L-N-carbobenzyloxy-3- (3 ,4 -diphenylmethylenedioxyphenyl) -2-methyl-30 alanine, 0.90 g. (0.009 mole) of trifithylamine and 1.81 g. (0.009 mole) of 2-brorr.oethyl phenyl cl.lu.-r in 1 fj ml . ol' - 42 - 4025G dimethylformamidc is heated at 70 - 75*C. for 24 hours, then cooled and poured in ISO ml. of water. The product is extracted with three 100 ml. portions of ethyl ether, washed with 50^ral. of a 5% sodium hydroxide solution, 5 50 ol. of water and 50 ml. of a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After I'i 11.rsii. i on solvents are removed under reduced pressure to give 4.8 g. (86.5%) of 2-phenoxyethyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalaninate, 10 homogeneous upon thin layer chromatography [fluorescent silica gel plate developed with chloroform] Rf » 0.91.
B. Preparation of 2-phenoxyethyl L-3-(3,4-dihydroxybenzyl)-alaninate hydrochloride hemihydrate A solution of 4.7 g. (7.5 millimoles) of 2-phenoxy-15 ethyl L-N-carbobcnzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-methylalaninate in 120 ml. of absolute ethanol is hydrogenated with 1.7 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 20 p.s.i. for 20 hours.
After filtering off catalyst, solvents are removed under 20 reduced pressure and the residue is chromatographed on a column of 75 g. silica gel. Elution with 4 00 ml. of a mixture of 5% methanol 95% benzene (by volume) gives 1.42 g (58*) of ester base, m.p. 35 - 42°C. homogeneous upon thin layer chromatography (fluorescent silica gel plate developed with a mixture 25 of .'<<>'£ methanol and 7(}% benzene (by volume) HI" = 0.52. The base is converted to the hydrochloride salt by dissolving in 25 ml. of a mixture ol' 50* chloroform and 50* methanol (by volume) mixture and acidifying with 2 inl . of 9.6 N ethanolic anhydrous hydrogen chloride solution. Solvents are removed under - 43 - 40250 reduced pressure to give 2-phcnoxyethyl L-3-(3,4 -dihydroxybonzyl)-alaninate hydrochloride hemihydrate.
Anal, oalcd. for C18H21N05.HC1. *H20: C, 57.37; H, 6.15; N, 3.72 9 foundi C, 57.17; H, 6.16; N, 3.41 EXAMPLE 17 A. Preparation of 2-succininidocthyl L-N-carbobenzyloxy-3-(3.4 -diphenylrvathylcnodioxyDhenyl) -2-methylalaninate A solution of 4.5 g. (8.A millimoles of L-N-carbo-1® bon*yloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalanine* 0.90 g. (9 millimoles) of triethylamine and 1.85 g. (9.3 millimoles) of N-(2-bromcethyl)-succinimide in 15 ml. of dimethylfomamide is heated at 95aC. for 19 hours, then cooled and poured into 150 ml. of water-. The product is 15 extracted with three 100 ml. portions of ethyl ether, washud with 50 ml. of a 5% sodium hydroxide solution, 50 ml. of water and 50 ml. of a saturated sodiun chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvents are removed under reduced pressure to 20 give 4.8 g. (86%) of 2-succinimidoethyl L-N-carbobenzyloxy-3-(3,4-diphenylncthylenedioxyphenyl)-2-methylalaninate, homogeneous upon thin layer chrcmatography [fluorescent silica gel plato developed with chloroform] Rf * 0.27.
B. Preparation of 2-succinimidoethyl L-3-(3,4-dihydroxy-25 phenyl)-2-methylalaninate hydrochloride hemihydrate A suspension of 2.5 a. (3.94 millimoles) of 2- succinimidootnyl X<-N-carbobcnzylo::y-3-(3 ,4 -diphenyl- -44- 40286 m&thylenedioxyphenyl)-2-methylalaninate in 75- ml. methanol, 75 ml. ethanol and 3 ml. of a 7.6 N ethanolic-anhydrous hydrogen chloride solution is hydrogenated with 1.2 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 5 20 p.s.i. for 20 hours. After removal of catalyst by nitration, solvents are removed under reduced pressure and the residue is stirred with 25 ml. of benzene and then 25 nl. of ethyl acetate. The insoluble material is treated with 100 ml. of a mixture of 10% ethanol and 90% ethyl acetate (by volume} 10 f» ml. of a saturated sodium carbonate solution and 5 jj. of solid sodium carbonate. The organic extract is dried over anhydrous magnesium sulfate, then filtered and concentrated under rcduced pressure. One ml. of 9.6 N ethanolic-anhydrous hydrogen chloridc solution is added. Removal of 15 all solvents under reduced pressure gives 0.5 g. (33%) of the 2-succinimidocthyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninatc hydrochloride hemihydrate, homogeneous upon thin layer chromatography [fluorescent silica gel plate developed with a mixture ol" 30% methanol and 70S benzene (by volume)] 20 Rf = 0.4.
Anal, calcd. for C16H20N2O6.HCl. &!.,«>: C, 50.33; H, 5,54; N, 7.34 Found: C, 50.89; H, 5.65; N, 7.22 EXAMPLE 18 25 A. Preparation of 1,2-ethylene bis [L-N-carbobenzyloxy-3-(3,4 -diphcnylmethylcr.cc:io::y;jhcnyl) -2-ncthylalaninato] A solution of 10.18 g. (0.020 mole) of L-N-carbo- benzyloxy-3-{3,4-diphenyImethylenedioxyphenyl)-2-methyl - - -ir, - '40256 alanine, 2.12 g. (0.021 mole) of triethylamine and 0.99 g. (0.010 mole) of 1,2-dichloroethane in 35 ml. dimethyl-formamide is stirred under nitrogen at 105 - 110*C. for 28 hours and then poured into 400 ml. of ice water. The 5 product is extracted into 800 ml. of ethyl ether, washed with 100 ml. of a 5% sodium hydroxide solution and 100 ml. of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on 800 g. silica gel, 2.25 g. (21.5%) of 10 1,2-ethylene bis [L-N-carbobenzyloxy-3-(3,4-diphenyl-methylenedioxyphenyl)-2-methylalaninate eluted with chloroform.
B. Preparation of L,L-2-[2-(3,4-diphenylmethylenedioxy-benzyl)-alanyloxyT-ethyl 2-(3,4-dihydroxybenzyl)-15 alaninato bir.hydroocn oxalate A solution of 2.25 g. (2.2 mmole) of 1,2-ethylene bis [L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalaninate] in 100 ml. absolute ethanol is hydrogenated with 1.2 g. of 10% palladium-on-20 carbon catalyst at an initial pressure of 30 p.s.i. for 28 hours until hydrogen uptake is complete. After removal o»" catalyst by filtration, solvents are removed under reduced pressure. The residue is stirred with a mixture of 100 ml. of \(.)% ethanol and 90% ethyl acetate (by volume), 2 ml. of 25 saturated sodium carbonate solution and 3 g. of solid sodium carbonate for 15 minutes and then filtered. The filtrate is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed over silica gel and eluted with a mixture - 46 - 40256 ill' :»u"- iiii*I 11;11M> I nnil l«'ir/i-i»' (h.V volume) I o J^ive mjl. ol" product. Thi.3 product is converted to the oxalate salt with 500 rag. of oxalic acid in 10 ml. of ethanol by precipitation with sufficient ethyl ether. After one more 5 precipitation from 10 ml. of ethanol by adding sufficient ethyl'ether, 246 rag. (14%) ofL,L-2-[2-(3,4-diphenyl-methylenedioxybenzyl)-alanyloxy]-ethyl 2-(3,4-dihydroxy-benzyl)-alaninate bishydrogen oxalate is obtained.
Anal, calcd. for C35H3gN2°8*2C2H2°4: C' 59*08» H» 5-00; 10 N, 3.53 Found: C, 59.15; H, 5.18; N, 3.55 EXAJtPLE 19 A. Preparation of 2-phthaliinic'oethyl L-N-carbobenzyloxy-3-(3,4 - 105 - 110°C. overnight and then poured into 600 ml. «>(' ice water. The product is extracted into three 100 ml. portions of elhyl ether mid washed with 50 ml. of water Tin: el.herea I extract is dried over anhydrous magnesium sulfate, filtered and conccntrated under reduced pressure to give a 25 gummy solid. Chromatography over silica gel and elution with chloroform gives 10.88 g. (80%) of 2-phthalimidoethyl L-N-carbobenzyloxy-3-(3,4 -diphenylmethylenedioxyphenyl) -2- atcthylalaninato, Rf = 0.53, thin layer chromatography (fluorescent silica gel plate developed with chloroform]. - •) 7 - 40256 B. Preparation of 2-phthalimiJoethyl It-3-(3,4-dihydroxy-ohenyl)-2-methylalaninate hydrochloride A solution of 10.88 g. (0.0159 mole) of 2-phthal-imidoethyl L.-N-carbobenzyloxy-3-{3,4-diphenylmethylene-5 dioxyphenyl)-2-methylalaninate in 125 ml. ethyl acetate is hydrogenated with 6 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 31 p.s.i. for 5 hours until hydrogen uptake ceases. After removal of catalyst by filtration and removal of solvents under reduced pressure, 10 the residue is dissolved in 150 ml. absolute ethanol containing 4 ml. of 5.15 N ethanolic-anhydrous hydrogen chloride solution and hydrogenated with 4.3 g. of palladium-on-carbon catalyst at 27 - 38 p.s.i. for 5 days. Additional 4.3 g. amounts of 10% palladium-on-carbon catalyst are added 15 during this time. After removal of catalyst by filtration ana concentration under rcduccd pressure, the residue is washed with 100 ml. of petroleum ether and dissolved in ethanol. It is precipitated three times from ethanol by adding sufficient ethyl ether to precipitate the 20 product. The product is dried under reduced pressure to give 2.80 g. (41.8%) of 2-phthalimidoethyl L-3-(3,4-di-hydroxyphenyl)-2-methylalaninate hydrochloride, m.p. 138.0-140.0°C. dec., homogeneous upon thin layer chromatography (fluorescent silica gel plate developed with 50% methanol-25 50% benzene (by volume)] Rf = 0.61.
Anal, calcd. for C20H2QN2O6.HC1: C, 57.07; H, 5.03; N, 6.65; CI, 8.42 Found: C, 56.31; H, 5.62; N, 6.48; CI, 8.75 - 48 - EXAMPLE 20 A. Preparation of 2-acetoxyethyl L-N-carbobonzyloxy-3-(3»4-diphenvlmothylonoclioxypIi';nyl) -2-methylalaninate A solution of 10.0 g. (0.0196 mole) of L-N-S carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-methylalanine, 2.39 g. (0.0235 mole) triethylaaine and 2.40 g. (0.0196 mole) of 2-chloroethyl acetate in 30 ml. dimethylforraamidc is stirred under nitrogen at 110*C. for 20 hours and then poured into 500 ml.of ice water. The 10 product is extracted into four 200 ml. portions of ethyl ether which are combined and washed with 200 ml. of water, 200 ml. of a 5% sodium hydroxide solution and then 200 ml. of water. The product is dried over anhydrous magnesium sulfate and filtered, and solvents are removed under reduced 15 pressure. The residue is chromatographed on 700 g. silica gel. Elution with a mixture of 5% methanol and 95% chloroform (by volume) gives 5.60 g. (48%) of 2-acetoxyethyl l^-N-carbobenzyloxy-3-(3,4 -diphenylmethylenedioxyphenyl)-2-methylalaninate.
B. Preparation of 2-acetoxyethyl L-3-(3,4-dihydroxyphenyl)-20 2-methylalaninate A solution of 5.60 g. (0.0094 mole) of 2-acetoxyethyl L-N-carbobenzyloxy-3-(3,4-diphenyImethylenedioxyphenyl) -2-inethylalaninate in 100 ml. absolute ethanol is hydrogenated with 2.3 g. of a 10% palladium-on-carbon 25 catalyst at an initial pressure of 37 p.s.i. for 24 hours until hydrogen uptake is complete. After removal of catalyst by filtration and removal of solvents under reduced pressure, the residue is washed with 100 ml. of petroleum ether and dissolved in 124 ml. of a mixture of lO'V. ethanol and 90% ethyl acetate 30 < l>y vol iime). Sodium i ;»H>ona !.«.*, G. U g., and 4 ml. of a saturated - 49 - 40256 sodium carbonate solution are added and the mixture is stirred for 20 minutes, filtered, dried over anhydrous magnesium sulfate, filtered again and concentrated under reduced pressure. The residue is chromatographed on 5 silica gel and eluted with n mixture of 20< methanol and 80* benzene (by volume). Recrystallization is accomplished by dissolving it in ethyl acetate and adding sufficient cyclohexane to precipitate it to give 1.01 g. (36%) of 2-acetoxyethyl L-3 -(3,4-dihydroxyphenyl)-2-methylalaninate, m.p. 114 - 118*C. 10 dec.
Anal. Calcd. for C14H19N06: c» 56.55; H, 6.44; N, 4.71 Found: C, 56.64; H, 6.63; N, 4.33 EXAMPLE 21 A. Preparation of 2-benzamidoethyl -N-carbobenzyloxy-3-15 (3,4-diphenyImethylenedioxyphenyl)-2-im;tnylalaninate A solution of 10.0 g. (0.019G mole) of Lj-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalanine, 2.11 g. (0.021 mole) triethylamine and 3.64 g. (0.0196 mole) of N-(2-chloroethyl)-benzamide in 20 20 ml. dimethylformamide is stirred under nitrogen at 110°C. for 20 hours and then poured into 400 ml. of ice water. The precipitate is removed by filtration, washed with 100 ml. of water and dissolved in 200 ml. of ethyl ether. The ethereal solution is washed with 50 ml. of a 5% 25 sodium hydroxide solution and, so ml. of water, and dried over anhydrous magnesium sulfate. Drying agent is filtered off and the filtrate concentrated ur.der reduced pressure to give 11.21 g. (87%) of 2-benzamidocthyl L-N-carbobenzyloxy-3-(3,4-diphenyImethylenedioxyphenyl)-2-mothylalaninate, - 50 - 40256 Rf ■ 0.7, thin layer chromatography [fluorescent silica gel plate developed with a mixture or 5* methanol and 95* chloroform (by volume)].
B. ii'reparation of 2-benzamidoethyl L-3-(3,4-dihydroxy-5 phenyl) -2-nethylal"»ninate oxalate hemihydrate A solution of 11.21 g. (0.017 mole) of 2-benzamidoethyl L-N-carbobenzyloxy-3-(3,4 -diphenylmethylenedioxyphenyl) -2-methylalaninate in 100 ml. absolute ethanol is hydrogenated with 5.5 g. of 10% palladium-on-carbon 10 catalyst at an initial pressure of 30 p.s.i. for 7 hours.
» After removing catalyst by filtration and renvoving solvents under reduced pressure, the residue is stirred with 100 ml. petroleum ether overnight. The insoluble material is dissolved in 250 ml. or a mixLur-c ol" 1«* ethanol and 90* ethyl acetate 15 (by volume), shaken for 10 minutes with 12 ml. saturated sodium carbonate solution and 12 g. sodium carbonate and filtered. The filtrate is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
The residue is treated with 1.3 g. of oxalic acid dissolved 20 in 25 ml. of absolute ethanol, the oxalate salt being precipitated by addition of sufficient ethyl ether. Two more precipitations are carried out by dissolving the product in ethanol and adding sufficient ethyl ether to precipitate the product to give 1.60 g. (23%) of 2-benz-25 amidoethyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate oxalate hemihydrate, homogeneous upon thin layer chromatography [fluorescent silica gel plate developed with a mixture of SO* methanol :»iul 50'Jt chloroform (by volume)] Of' = 0.44. - r> I - 40256 Anal, calcd. for C19H22N205* *c2»i204.*h20: C, 58.24; H, 5.86; N, 6.79 Found: C, 58.39; H, 5.73; N, 6.37 EXAMPLE 22 5 A. Preparation of naphthaliaidomethyl If-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl)-2-methylalaninate A solution of 10.2 g. (0.020 mole) of L-N-carbo-benzyloxy-3 - {3,4 -diphenylmethylenedioxyphenyl) -2-methyl -alanine, 2.02 g. (0.020 mole) of triethylamine and 4.9 g. 10 (0.020 mole) of N-chloromethylnaphthalimide in 50 ml. dimethylformamide is stirred at 90°C. for 20 hours, then poured into 500 ml. ice water. The product is extracted into 200 ml. of ethyl acetate, washed with 50 ml. of a 5% sodium hydroxide solution, 50 ml. of water and 50 ml. 15 of saturated sodium chlcrido cclutior. and dried over anhydrous magnesium sulfate. After filtration, solvents are removed under reduced pressure to give 13.1 g. (91%) of naphthalimidomethyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-methylalaninate. 20 B. Preparation of naphthalimidomethyl L-3-(3,4-dihydroxy-phenyl)-2-mcthylalaninate hydrochloride A solution of 13 g. (0.0181 mole) of naphthalimidomethyl L-N-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-methylalaninate in 150 ml of a mixture of 25% absolute 25 ethanol and 75% ethyl acetate (by volume) is hydrogenated with 5 g. of a 10% palladium-on-carbon catalyst at 25°C. and an initial pressure of 40 p.s.i. for 24 hours until hydrogen - 52 - 40256 uptake is complete. After removing catalyst )y filtration and conccntrating the filtrate under rcduced pressure, the residue is dissolved in 200 ml. of a mixture' of 10* absolute ethanol jiiiil !>(>■£ ethyl acetate (by volume) and stirred with 5 ml. of 5 saturated sodium carbonate r.olution and 5 <(. of solid sodium carbonate for 10 minutes. The mixture is filtered a"d the filtrate is dried with anhydrous magnesium sulfate, filtered again and concentrated under reducec pressure.
The residue is washed with 100 ml. of hexane to remove 10 diphenylmethane, dissolved in 25 ml. of absolute ethanol i and acidified with 5 ml. of 8 N ethanolic-anhydrous hydrogen chloride solution. Addition of ethyl ether precipitates the hydrochloride salt of the naphtl alimido-methyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate. 15 EXA.VPLK 23 A. Preparation of racemic N-carbobenzyloxy-3-(3,4-dihydroxyphenyl)-?-methylalanine To a stirred solution of 8.0 g.(0.P378 mole) of racemic DL-3-(3,4-dihydroxyphenyl)-2-nethylalanine 20 in 60 ml. of 2 N sodium hydroxide solution urder nitrogen is added a solution of 9 ml. of cartobenzyloxy chloride in 2r> inl. diethyl ether. After being stirred at 0°C. for one hour, followed by one hour at 25°C., the reaction mixture is extracted with 50 ml. of diethyl ether. The 25 aqueous portion is acidified to pH 3 with 6 N hydrochloric acid and the crude product is extracted into 100 ml. of ethyl acetate and washed thrc times v/ith 35 r.l. of water. - r>:» - 40256 After dryinq over anhydrous maqnenium sulfate and filtering, solvent is removed under retlucod pressure to givo 4.5 q. (34%) of the racemic N-corbobenzyloxy-3-(3,4-dihydroxyphenyl) -2-methylalanine as a viscous oil. 5 B. Preparation of racemic pivaloyloxymethyl ?-(3,4-dlhydroxyphenyl)-2-methylalaninate hydrochloride A solution of 4.2 g. (0.012 mole) of racemic N-carbobenzyloxy-3-(3,4-dihydroxyphenyl) -2-ciethylalanine, 1.3 g. (0.013 mole) of triethylamine and 1.26 g. 10 (0.013 mole) of chloromethylpivalate in 20 ml. dimethyl-formamide is stirred at 90°C. for 20 hours and then poured into 200 ml. or water. The product is extracted into 100 mi. of ethyl acetate and washed with 25 ml. of a saturated sodium bicarbonate solution and 25 ml. of water. After 15 drying over anhydrous ra?onesitw. sulfate ?nd filtering, the filtrate is concentrated under reduced pressure to give the N-carbobenzyloxy derivative of the desired ester. This material is dissolved in 100 ml. of absolute ethanol containing 10 ml. of a 9.6 N ethanolic-anhydrous hydrogen 20 chloride solution and hydrogenated with 3 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 35 p.s.i. for 24 hours. After removing catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue is dissolved in 25 ml. of water, 25 made basic with a saturated sodium carbonate solution to pll 8 and the insoluble product is extracted with loo ml. of ethyl acetate. After drying over anhydrous magnesium sulfate and filtering, 5 ml. of 9.6 N ethanolic anhydrous hydrogen chloride solution is added and the solution con-30 centrated under reduced pressure to give 1.5 g. (22.6%) of - 54 - 40256 the hydrochloride of the raccmic pivaloyloxymothyl 3-(3,4-dihydroxyphenyl)-2-mcthylalaninato, homogeneous upon thin layer chromatography [fluorc;:scont silica gel plate developed with a (by volume) mixture of ii-butanol- 5 acetic acid a"d water] Rf = 0.86.
EXAMPLE 24 Preparation of 2-acetamidoethyl ^-3-(3,4-dihydroxyphenyl)-2-methylalcninate hydrochloride A slurry of 38.3 g. (0.30 mole) of L_-3-(3,4-10 dihydroxyphenyl)-2-methylalanine hydrochloride ethanol solvate (ol>l i in:l° .hi «• I hano 1 i «• solul ion of the hydrochloride und^r reduccd pressure) and 14 6.4 g. (1.42 mole) of U-acetylethanolaminc, under nitrogen, is warmed to 194 - 103°C. Thionyl chloride, 84.8 g. ^■5 (0.713 mole) is added over 15 minutes with stirring. The reaction mixture foams vigorously during the addition.
After addition is complete, the reaction mixture is stirred at 104 - 108°C. for 18 hours. Additional thionyl chloride, 42.4 g. (0.357 mole) is added over seven 20 minutes. The reaction mixture is stirred 104 - 108°C. for another hours, then cooled to 30°C. and concentrated under reduced pressure to yield a viscous oil.
This oil is slurried with 100 ml. of chloroform and the chloroform is removed under- reduced pressure* This is 25 repeated three more times and then the oil is washed with 100 ml. of benzene which is decanted. The residue is dissolved in 700 ml. of isopropanol and added to 6 1. of ethyl ether. The precipitate which forms is washed with 500 ml. of ethyl ether'and shaken with 6 1. of a mixture of 10% ethanol and 9<)*A ethyl acet.ite (by volume), 150 ml. of saturated sodium carbonate solution arid IOO . of sodium carboriatc. The _ 55 - 40 256 organic extract is dried over anhydrous magnesium sulfate, filtered and conccntrated under reduced pressure to give the free base of the acetainidocthyl ester. This base is treated with 15 g. of fumaric acid in 300 uil. of iso-5 propanol and the fumarate salt precipitated by adding sufficient ethyl ether. The fumarats salt is precipitated once more from isopropanol by adding sufficient ethyl ether and then converted back to the free base as before by shaking with 200 ml. ol' a mixture of lo£ ethanol and 90£ ethyl 10 acetate (by volume), 20 ml. of a saturated sodium carbonate solution and 20 g. solid sodium carbonate. The free base is converted to the hydrochloride salt by dissolving in 100 ml. of absolute ethanol and, adding lO ml. 9.6 N HC1, and is precipitated by addition to 1 1. of ethyl ether. After three 15 precipitations from ethanol and ethyl ether are carried out as above, 15.1 g. (15%) of the hydrochloride salt of the 2-acetamidoethyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrochloride is obtained, Rf = 0.57, thin layer chromatography I fluorescent silica ool plate developed 20 with a mi xl lire «»l" mcthano I and SO'Jf. benzene (by volume)J .
Anal, calcd. for C14II2()N205.HC1: C, 50.52; II, 6.36; N, 8.41 Found: C, 50.49; H, 6.69, N, 8.49 ' EXAMPLE 25 Preparation of 3-acetamidopropyl L-3-(3,4-dihydroxyphenyl)-25 2-methylalaninate hydroaan oxalate hydrate Thionyl chloride, 275 ml., is added to 250 g. of L.-3-(3,4 -dihydroxyphenyl) -2-methylalaninate sesquihydrate at 25*C. and the mixture is heated on the steam bath.
After being heated lor- two hours, the thick reaction mixture is - 56 - 40256 dilutci with 7.'. ml. d inetliy I. t\>«:ni.i!'iiiir dissolved in 25 ml. of benzene ami stirred on tin steam bath until gas evolution ceases. 100 ml ; of benzene in added and the crude sulfurous acid enter is romovd by filtration, washed with 5 100 ml. of benzene, 100 ml. of chloroform and 100 ml. of ether and dried under rcduced pressure to give 280 g. of the sulfurous acid ester intermediate, ir..p. 199*C. dec.
A mixture of 13.7 g. of the crude sulfurous acid ester intermediate, 24.9a y. (0.212 mole) of N-acetyl-10 propanolamine and 2 g. of onhyoroun dimethylformanidc is stirred on the steam bath for 20 hours and cooled. The reaction rii:cture is washed with six 200 ml. portions of ethyl ether, and, I'our 200-ml. portions of methylene chloride and dried under reduced pressure. The semi-solid material 15 remaining in utirrod with 200 ml. of a mixture of 20% ethanol and 80S ethyl acetate (by volume), 20 ml. saturated sodium carbonate solution and 20 o. solid sodium carbonate. The organic extract in dried over anhydrous magnesium sulfate and filtered, and the filtrate i:; added I <> a solution of . 2 j$. oxalic, acid 20 in 50 ml. etlianol. Rcr.iov.il of solvents under rcduced pressure is then accomplished and the product is precipitated by dissolving it in :>0 ml. of ethanol and adding 500 ml. of ethyl ether. The product is acain precipitated by dissolving in ~jQ ml. of ethanol and adding 500 ml. of 25 ethyl acetate to give 3-aceta:uidopropyl L-3-(3,4-dihydroxy-pheny) -2-nathyi.ilanir.ato hylroocn oxalate hydrate, Rf = 0.45, thin layer chior.iato irrj hy [fluorescent silica gel plate developed with a mixture of 25% methanol and 75% chloroform (by volume)] . - 57 - 40250 Anal, calcd. for clsH22tJ205.C2H2C>4 .H20: C, 48.80; H, 6.26; N, 6.69 Found: c, 48.73; H, 6.85; H, 6.68 EXAMPLE 26 5 Preparation of 2-methylthioethyl £-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrogen oxalate Thionyl chloride, 275 ml., is added to 250 g. of L-3-{3,4-dihydroxyphenyl)-2-methylalaninate sesquihydrate at 25*C. and the mixture is heated on the steam bath. 10 After beln.U heated For two hours, the thick reaction mixture is diluted with 7.5 ml. dimethylformamide in 25 ml. of benzene and stirred on the steam bath until gas evolution ceases. 100 ml. of benzene is added and the crude sulfurous acid ester is removed by filtration, washed with 15 ICO ml. of banronc, 100 ml. of chloroform and 100 ml. of ether and dried under reduced pressure to give 280 g. of the sulfurous acid ester intermediate, m.p. 199*C. dec.
A mixture of 30 g. of the crude sulfurous acid oster, 34.6 g. (0.375 mole) of 2-hydroxyethy 1 methyl sulfide 20 and 6 g. of anhydrous dimethylformamide is stirred on the steam bath for 23 hours one* cooled. The reaction mixture is washed with four 100 ml. portions of ethyl ether and throe 100 ml. portions of methylene chloride. The remaining material is stirred with 250 ml. of a mixture of 20% ethanol 25 and 80*4 ethyl acetate (by volume), 30 ml.saturated sodium carbonatc solution and 60 g. solid sodium carbonate, and then filtered. The insoluble material is washed with three 250 ml. portions of a mixture of 20£ ethanol and 80< ethyl acetate (by volume), combined with the i'irst ethanol-ethylacetate - Ob - 40256 ■ >xt r.ii't ami dried over anliyu;: in.i>|!V"£ chloroform (by volume)} Rf = 0.83, m.p. 15 35-90°C. dec.
Anal, calcd. for C"131!19N04S .C21I204: C, 47.99; II, 5.64; N, 3.73 Found: C, 48.OT; H, 6.10; N, 4.07 LXAflPLH 21 20 A. Preparation of D,L-3-(3,4-diphenylmethylcnedioxv-phen^j)-2-methylalanine hydrochloride A mixture of 38.6 g. (0.155 mole) cf racemic-3-(3,4-dihydroxyphenyl)-2-methylalanine hydrochloride and 74 g. (0.312 mole) of dichlorodiphenylmcthane is immersed 25 with slow stirring in a preheated oil bath at 190*C. After reaction has started, the reaction mi prof'tic*- *t ethanol and adding ethyl acetate to precipitate '>,1,-3-(3,4-diphenyl-5 mcthylenedioxyphenyl)-2-methylalanine hydrocl loride.
B. Preparation of D,L-H-carbobenzyloxy-3-(3,4-diphenylmethylenedioxyphenyl) -2-methylalanine A mixture of 175 g. (0.425 r.*ole) of racemic-3-(3,4-diphenyImethylenedioxyphenyl)-2-:aethylalnnine hydro-10 chloride, 1750 ml. of acetone and 17r>0 ml. of water is stirred under nitrogen at a temperature below 10°C. while the pi I is adjusted to 12.0 by the sloi addition of a 10% sodium hydroxide solution. Carboberzyloxy chloride, 93 g. (0. r>4r» mo.lo) ;s added dropwise over 5-7 minutes to the l'i reaction mixture at 20 - 30°C. accompanied by the simultaneous addition of a 10% sodium hydror'tfr ~r?ution to maintain a pll of 12.0 - 12.2. After addition of the carbobenzy loxy chloride is complete, the reaction rixture is stirred at 25 - 30°C. for three hours. Most of the acetone 20 is then removed under reduced pressure at 25 to 35°C. to precipitate the sodium salt of the desired N- rarbobenzyloxy derivative. The sodium salt ir. extracted inti 1.5 1. of ethyl acetate, washed with 200 ml. of 5% sodium hydroxide solution and 200 ml. of a saturated sndium chloride solu-25 tion and dried over marries i urn sulfate. Alter addition of 17.5 g. of decolorizing carbon and filtration through a magnesium sulfate pad, solvent:: are removed under rcduced pressure at 25 to 3r>"C. The residue is slurried two times wi t)i 1 1. of a mixture of c?0'£ ethyl ether arid 80"^ hexane (by volume) - r»o - 40256 solution and filtered to give the sodium salt of the desired N-carbobenzyloxy derivative. Thin sodium salt in dissolved in 1.5 1. of ethyl acetate, cooled to 10*C. and acidified to pfl 2 with 6 N hydrochloric acid. The ethyl 5 acetate extract is washed with 200 ml. of a saturated sodium chloride solution, dried over liagneriur: sulfate, filtered and concentrated under reduced presrure at 25 to 35*C. The N-carbobenzyloxy derivative is dried further at 25 - 30*C. and 0.2 - 0.3 mm. Ilg to give D.L-N-carbo-10 benzyloxy-3-(3,4-diphenyImethylenedioxyphenyl)-2-methyl-alanine.
C. Preparation of D,I»-succinimi dome thy 1 N-carbobenzyloxy-3-(3,4-diphenyImethylenedioxyphenyl)-2-methylalaninate A solution of 13.r> g. (0.0265 nolo) of D,L-N-15 carbobenzyloxy-3-(3,4-diphenyImethylenedioxyphenyl)-2-methylalanine, 2.7 g. (0.027 mole) of triethylamine and 5.19 g. (0.029 mole) of H-bromomethylsuccinimide in 35 ml. of dry dimethylformamide is stirred at 25 - 30°C. for 16 hours. The reaction mixture in poured into 400 ml. of ice 20 water and the product extracted into 200 ml. of a mixture of 50< chloroform anil diethyl «:Lh<:r (by volume). The organic extract is washed with 50 ml. of a dilute (5%) sodium carbonate solution and 50 ml. of a saturated sodium chloride solution and then dried over anhydrcus magnesium 25 sulfate to remove water. Alter filtration and concentration under reduced pressure, the residue i* recrystallized. Recrystallization is accomplished by dissolving the product in ethanol and adding hexane to precipitate D,L-succinimidomethyl N-cajfbobenzy loxy-3-(3,4-diphenylmethylene-30 dioxyphenyl)-2-methylalaninate.
- SI - 40256 t D. Preparation of D.Ii-succinlnidomethvl 3-(3,4-dihydroxy-phenyl)-2- mothylalanlnate A suspension of 6.6 g. (0.010G mole) of racemic succinimidomethyl N-carbohenzyloxy-3-(3,4-dipI*cnylmethy lene-5 dioxyphcnyl)-2-methylalaninate in 180 ml. of absoluto ethanol and 9 ml. of a 9.6 N ethanolic anhydrous hydrogen I chloride solution is hydrogenated with 3.3 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 30 p.s.i. until hydrogen uptake is complete. After removal 10 of catalynt !»y filtration, the filtrate is concentrated under reduced pressure. The residue in extracted with 50 ml. of benzene and then 50 ml. of ethyl acetate. The insoluble solid is then shaken with 50 ml. of a mixture of 10< ethanol and 90< ethyl acetate (by volume) and lO ml. of 15 a saturated sodium carbonate solution. After filtration, the filtrate is dried over anhydrous raagnesiuii sulfate, filtered and concentrated under reduced pressure to give D,I>-succininidomethyl 3- (3,4-dihydro:typheny 1) -2-methylalaninate as the base. 20 T. Preparation of succinimidomethyl T,-3-(3,'-dihydroxyphenyl) -2-methylalaninate hydrochloride tydrate via recrystallizotion of diastereomeric salte A solution of 0.47 g. (3.1 millimoles) ol" (-)-tartaric acid in 10 ml. of a mixture ol" 50t absolute ethanol and 50< ethyl 25 acetate (by volume) is added under nitrogen at 20 - 2S°C. to a solution of 1.0 g. (3.1 millimoles) of D,L-succinimido-methyl 3-(3,4-dihydroxyphenyl)-2-methylnlnninate in 10 ml. of absolute ethanol. After the solution has been warmed to 40 -60*C., ethyl acetate is added to incipient cloudiness. The 30 solution is then cooled slowly to 25°C. and finally stored at 5-10°C. for 12 hours. The insoluble crude tartrate salt is removed - 62 - 40256 by filtration and dried at 20 - 25*C. and 0.2 - 0.5 mm. pressure. This recrystallization procedure ir repeated until the melting point and optical rotation of the tartrate salt are essentially constant. 5 The mother liquor from the initial crystalliza tion is concentrated at 15 - 20 mm. and 40 - 50°C. The residue is shaken with 25 ml. of a mixture ol' 1(K ethanol and 90% «-1 »iy i acetatc (by volume) and IO ml. ol' a saturated sodium carbonate solution. After filtration, the filtrate 10 in dried over anhydrous magner.ium sulfate, filtered and conccntrated at 15 - 20 mm. and 40°C. to a gup. The residue is dissolved in 5 ml. of absolute ethanol and added under nitrogen to a solution of 0.3 g. of (+) tartaric acid in 10 ml. ol' a mixlurc ol' .■>()'£ absolute ethanol and 50% ethyl acetate 15 (I»y volume). Tin* solution is warmed Lo 40 - 60°C. and ethyl acetate is added to incipient cloudiness. The solution is cooled slowly to 25°C. and then stored at 5 - 10°C. for 14 hours. The insoluble crude tartrate salt is removed by filtration. Repetition of this recrystallizr.tion procedure 20 gives the other optical antipodo of succinimjeomethyl 3-(3,4-dihydroxyphcnyl)-2-methylalaninate as the tartrate salt.
The optically active tartrate salts are converted to the optically active hydrochloride salts by the follow-25 ing method. The tartrate salt of suc:inimido L-3-(3,4- dihydroxyphenyl)-2-nethylalaninate ir; shaken with 50 ml. of a mixture ol* IO'£ ethanol and 9()X ethyl acetate (by volume) and 10 ml. of a saturated sodium carbonate solution. After filtration, the filtrate is dried over unhyurous magnesium 30 sulfate, filtered and concentrated u'idcr reduced pressure. — 63 — 40256 The residue is rcdissolved in 25 ml. of absolute ethanol, .treated with 5 ml. of a 9.6 N ethanolic-anhydrous hydrogen chloride solution and conccntrated under reduced pressure to give succinimidomethyl L.-3-(3,4-dihydroxyphenyl)-2-5 methylalaninate hydrochloride hydrate, homogeneous upon thin layer chromatography (fluorescent silica gel plate, using 30* methanol ant! 70< benzene (by volume) as solvent} with an observed Rf = 0.5.
EXAMPLE 28 10 Resolution of racemic pivaloyloxymethyl 3-(3,4-dihydroxy-phenyl)-2-methylalaninate by direct recrystallization Racemic pivaloyloxymethyl 3-(3,4-dihydroxyphenyl)-2-methylalaninato hydrochloride is prepared as in Example 23. 3(> a. of racemic pivaloyloxymethyl 3-(3,4- 15 dihydroxyphenyl)-2-methylalaninate hydrochloride is slurried at 35°C. in 100 ml. of 1.0 N hydrochloric acid.
The 11 r it I i sso I ved solids are filtered off. The saturated solution then seeded at 35°C. with pivaloyloxyuethyl D-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride hydrate. 20 The mixture is cooled to 20°C. in 30 minutes and allowed to stand at 20°C. for 0.5 hour. The separated naterial is isolated by filtration, washed twice with 5 nl. cold water and dried at 0.1 - 0.5 mm. and 20 - 25°C. fox 20 hours to give pivaloyloxymethyl D^3-(3,4-dihydroxyphenyl)-2-methyl- 25 alaninate hydrochloride hydrate.
The mother liquor from the oreceding step is heated to 35°C. and is seeded at 35°C. with pivaloyloxymethyl I*-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride. The mixture is then cooled to 20°C. over 30 - 64 - 40256 minuter, and allowed to stand at 20*C. for 0.5 hour. The precipitated material is isolated by filtration, washed twice with S ml. cold water and dried at 0.1 - 0.5 mm. and 20 - 25*C. for 20 hours to give pivaloyloxymethyl .L-3-(3,4-5 dihydroxyphenyl)-2-methylalaninate hydrochloride hydrate.
EXAMPLE 29 A. Preparation of a-succinimidoethyl L-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride dihydrate (B-isomer) by fractional crystallization 10 io jr. of a-succinimidoethyl l.-3-(:i,4- dihydroxyphenyl)-2-methylalaninate hydrochloride (a- and R-inomer mixture) of Example ?. is dissolved in 50 ml. warm Oil othanol (5% v/ater). The solution is diluted to incipient cloudiness wi th anhydrous ether, seeded and scratched to indue lr> crystallization. After cooling tlio solut ion at 5 - 10°c. for 12 hours, I hi* precipitated soiid is collected, and dried at 7()°('. Additional similar recrystallizations from a mixture ol' 95% ethanol and 5% aqueous ethyl ether (by volume) give material melting at 123 - 1?6*C. (doc.). A final recryr.tallization fron 91% 20 ethanol affords l-succinimidoethyl L-3-(3,4-tihydroxyphenyl)-2-methylalaninate hydrochloride dihydrate (R-isomer) as the dihydrate melting at 120 - 131°C. (dec.) (dried at 70*C. overnight), honogeneous upon thin layir chromatography Ifluorescent silica gel plate, usin# 50% methfinol and 50% benzene 25 (by volume) as solvent], Hi" = 0.7.
B. Preparation of a-succinimidoethyl L-3-(3,4-dihydroxy-phonyl)-2-methylalaninate hydrochloride hydrate (ft-isomer) * The mother liquor from the first crystallization 30 of the B-isomer of a-succinimidoethyl L-3-(3,4-dihydroxy- - 65 - 40256 phenyl) -2-methylalaninate hydrochloride hydrate which is rich in the corresponding a-isomer, in concentrated at 15 -20 ran. and 40 - 4*>*C. The residue in dissolved in 20 ml. of warm 95% ethanol (5% water), diluted to incipient cloudi-5 ness with ethyl acetate, and seeded and scratched to precipitate the enriched a-isomer of a-succinimidoethyl L-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride hydrate.
Additional precipitations from 91% ethanol (5% water) and ethyl acetate give the a-isomor as the ethyl acetate K, solvate, Rf = 0.7 (thin layer chromatography, fluorescent silica gel plate, using 50% methanol and 50% benzene (by volume) as solvent].
EXAMPLE 30 Preparation of pivaloyloxymethyl L-3-(3,4-dihydroxyphenyl)-15 2-methylalaninate hydrochloride A solution of 0.95 g. (4.0 millimoles) of L-3-(3,4-dihydroxyphenyl)-2-methylalanine ses^uihydratr and 0.61 g. (4.06 millimoles) ol" pivaloyloxymethyl chloride in 5 ml. dimcthylsulfcxide in stirred ,->t 20 - 25#C. for 23 hours. 20 The solution is diluted with 10 ml. distillec water and passed through a column containing 5 g. of weakly basic anion exchange resin on the base cycle. After elution with water, the.- I'ractions giving a positive ferric chloride test are combined and added to a column of j5 3 g. of weakly acidic cation exchange re-in on the acid cycle. Unreacted L-3-(3,4-dihydroxy*>henyl)-2-methyl- * alanine is eluted with distilled water until a negative ferric chloride tent is obtained, the est-<»r ir then eluted with 1 N acetic acid. The ester fraction, 50 ml. (pll 3.2), - 6f» - 40256 in acidified to pll 2.0 with 1 N hydrochloric acid and lyophilizcd at 0.1 - 0.3 run. for 20 hours to give pivaloyloxymethyl ■ L.-3- (3,4-dihydrcryp'irryH -2-mothyl-alaninatc hydrochloride as the acetic ncir' «r»lvate. 5 Anal, calcd. for Cjgll^NOg.IICl. H c2h4°2: c» 52.11; II, 6.69; N, 3.58 Pound: C, 52.11; II, 6.49; », 3.73 EXAMPLE 31 Preparation of a-succinimiuoethyl L-3-(3,4-dihydroxyphenyl)-10 2-mcthylalaninate hydrochloride ~ A solution of 0.°5 g. (4.0 millimoles) of L-3-(3,4-dihydroxyphenyl)-2-methylalanine sesquihydratr and 0.65 g. (4.0 mmolc) of H-(a-chloroethyl)-succinimide in 5 ml. dimethylsulfoxidc is stirred at 20 - 25°C. fcr 23 hours. 15 The solution i.«? diluted with 10 ml. distilled water and passed through a column containing 5 j. of weakly basic anion exchange resin on the basic cycl«. r elution with water, the fractions Kivinj; a positive ferric chloridc test aro combined and added to a column 20 of 3 g. of a weakly acidic cation exchange rerin on the acid cycle. Unreacted L-3-(3,4-dibyilroxyphenyl)-2-methylalanine is eluted with distilled water until a negative ferric chloride test is obtained and the ester is then eluted with 1 N acetic acid. The ester fraction, 55 ml. 25 (pH 3.2), is treated with 1 M hydrochloric acid to pH 2.0 and lyophilizcd at 0.1 - 0.3 mm. for 20 hour? to give •i -nuccininidocthyl L-3 - (3,4-di hydroxy phenyl) - 2-mothy1-nlaninatn hydrochloride acetic acid solvate. 40256 Anal, calcd. for ci6,,2oN2°6*,,Cl* ^C2M4°2: C' 50'96«* H, 5.73; N, 7.13 Found: C, 50.48; II, 6.13; II, 6.77 BXAf'PLK 32 5 Preparation of 3-acctamidopropyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrogen oxalate hydrate Thionyl chloride, 275 ml., is added to 250 g. of L-3- (3,4-dihydroxyphenyl) -2-methylalan* rat« «*>squihydrate at 25*C. and the mixture is heated on the steam bath. 10 After boilit; heated for two hour's, the thick reaction mixture is diluted with 7.5 ml. dimethylformamicVs dissolved in 25 ml. of benzene and stirred on the steam bath until gas evolution ceases. 100 ml . of benzene is added ant", the crude sulfurous acid ester is removed by filtretior, washed with lr> 100 ml. of benzene, 100 ml. of chloroform anc 100 ml. of ether and dried under reduced pressura to give 280 g. of the sulfurous acid ester intermediate, m.p. 199°C. dec.
A mixture of 13.7 g. of the crude sulfurous acid ester intermediate, 24.98 g. (0.212 mole) of M-acetyl-20 propanolamine and 2 g. of anhydrous dimethylformamide is stirred on the steam hath for 20 hours and cooled. The reaction mixture is washed with six 200 ml. portions of ethyl other and four 200-ml. portions ol' methylene chloride, and dried under reduced pressure. The semi-rolid material 25 remaining is stirred with 200 ml. ol' a rnixlurc: ol i.thanol atul H<>% ' by 1 .ic<' I.a I. a (l»y vo I time) , 20 ml . sa I: uratod sodium carbonnte solution and 20 g. solid sodium carhonato. The organic extract is dried over anhydrous magnesium sulfate and filtered, and the filtrate is added to a solution of 3.2 g. oxalic acid - 68 - 40256 t in 50 ml. ethanol. Removal of solvents under reduced pressure is then accomplished and the product is precipitated by dissolving it in 50 ml. of ethanol and adding 500 ml. o£ ethyl ether. The product is again precipitated 5 by dissolving it in 50 ml. of ethanol and adding 500 ml. of ethyl acetate to give 3-acetamidopropyl L-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrogen oxalate hydrate, Rf - 0.45, thin layer chromatography [fluorescent silica gel plate developed with a mixture of 25% methanol and 75% chloroform 10 (by volume)).
Anal, calcd. for C^5H22N205.C2H204.II20: C, 48.80; II, 6.26; N, 6.60 Found: C, 48.73; II, 6.85; II, 6.68 EXAMPLE 33 10 Preparation of 2-acetamidoethyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrochloride A slurry of 88.3 g. (0.30 mole) of L-3-(3,4- dihydroxyphenyl)-2-methylalanine hydrochloride ethanol solvate (by concentration of an ethanolic solution of the 20 hydrochloride under reduced pressure) and 146.4 g. (1.42 mole) of M-acetylethanolamine, under nitrogen, is wanned to 104 - 108#C. Thionyl chloride, CI.8 g. (0.713 mole) in added over 15 minuten with stirring. The reaction mixture foams vigorously during the addition. 21 After addition is complete, the reaction mixture is stirred at 104 - 108°C. for in hours. Additional thionyl chloride, 42.4 g. (0.357 mole) is added over Eoven minuter,. The reaction mixture in allowed to stir at 10' -108°c. for another hours, then cooled to 30°C. and - 6!> - <10256 conccntrated under reduced pressure to yiolM a viscous oil.
This oil is slurried with 100 ml. of chloroform and the chloroform removed under reduced pressure. This is repcaced three more times and then tho oil is washed with 5 100 ml. of benzene which in decanted. The rcnidue is dissolved in 700 ml. of isopropanol and added to 6 1. of ethyl other. The precipitate Lh.it forms is washed with 500 ml. of ethyl ether and shaken with 6 l.of a mixture of 10% ethanol and 90% ethyl acetate (by volume), 150 ml. of saturated sodium 10 carbonate solution and 100 g. of sodium carbonate. The organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reducad pressure to give the free base of the acetamidoethyl eiter. This base is treated with 15 g. of fumaric acid in 300 ml. of iso-15 propanol and tho fumaratc salt precipitated by adding sufficient ethyl ether. The fumarate salt is precipitated once more from isopropanol by adding sufficiett ethyl ether and then converted back to the free Lose as before by shaking with 200 ml. ol' a mixture of 10% ethanol arid 90% ethyl 20 acetate (by volume), 20 ml. of a saturated sodium carbonate solution and 20 g. solid sodium carbonate. The free base is converted to the hydrochloride salt by dissolving it in loo ml. of absolute ethanol, adding 10 ml. 9.6 N HC1 and precipi-taiinjtby addition to 1 1. of ethyl ether. After three 25 precipitations from ethanol;,ncl ethyl ether as carried out above, 2-acetamidoethy1 L-3-(3,4-dihydroxyphenyl)-2-methyl-alaninate hydrochloride is obtained, Rf = 0.57, thin layer chromatography (fluorescent silica gel plate developed with •« mixture of 50% methanol and 50% benzene (by volume)] . - 7(> - 40256 Am.'I. culcl. Ii.ii- f,i4»20»-,OI. .lirl : C, $0.r>:»; H, ft.36; !J, F..41 Found: C, 50.49; H, 6.CO; N, 8.4' EXAfrpl.i: 34 A. Preparation of L-3- (3,4-diacotoxy»honvl) -?-methyl-5 alanine hydrochloride To a mixture o£ 320 ml. glacial acetic acid and 24 ml. acetyl chloridc is added in one portion 69.4 g. (0.?*>l mole) of L-3-(3,4-dihydroxyphenyl) -2-i'ethylalanine sesquihydrate. The temperature of tho reaction mixture 10 rises to approximately 50°C. and a clear solition results.
At thiv. lemperatur>-, an addi tiona] 01 >nl. r>f acetyl chloride iinldi'ii over 10 minuter.. The rorultiny clnar, |>«iJ• > yellov solution .in a] lowed to stand at 20 - 25°C. for 11 hours. Arihydrou:-. ethyl ether, 400 ml., if? a-lded over lr> 15 Riinut"-.. When addition is almost complete, a white Ft.-lid begins »< precipitate. Tho ni.x'iuro ir. stirred at '.*•? - ?r>*r. for 30 minutes, anil at 5 - 10°C. l'or 1 hour and is then cooled at -10°C. for 2 hours. The solid is removed by filtration, si-r.pcnded in 150 ml. of a mixture of 30% acetic acid and 2<> 7<>'& ethyl ether (by volume), filtered and washed with 500 ml. ethyl .'fther. After drying at 70°C. for 2 hoirs, 83.7 g. (8B'A) of L-3-(?• ,4-diacetoxyphenyl) -2-nethylalanine hydrochloride, m.p. lOf, .0 - 197.0°C., is obtained. h. Preparation of L-3-(3,4-diacetoxyMhonyl)-2-raethylalanyl 2r> chloride hydrochloride A mixture of 6.fin g. (0.020 mole) of L-3-(3,4- 'lineotoxyphenyl) -2-methylalanine hydr^chloride and 40 ml. of thionyl chloride is stirred at 60°C. for 2 'lours until solution i:; complete. Excess of thionyl chloride is removed - 71 - 40256 at 15 - 20 nun. and 40 - 50°i*. Methyl ^no chloride# 50 ml., is added and Mir mixture is r«n*onoentrated at. 11 - 20 mm. and 40 - lo"!*. This i s repealed »»iu*o more with another r>0 ml. of methylene chloride. After drying at 0.2 - 0.1 mm. r> at 40*C. for 30 minutes, 1.-3-{3,4-di«icetOxyphenyl) -2-methylalanyl chloride in obtained.
C. Preparation of .succinimidomethyl T.-3-(3,4-dihydroxy-phenyl) -2-methylalaninate hydrochloride hydrate A solution of 3.10 g. (10millimoles of ji-3-(3,4- 10 diacetoxypheny1)-2-methyla 1 any1 chloride hydiochloride in 20 i.il. chloroform ir: added to a solution cf 3.07 y. (in mi I I i moles) c» I* N-hydroxyii:e I. hy I succ i n i m i do in 20 ml. chloroform at. 25°C. f-Cter stirring at reflux for 20 hours, most ;vf tho eh 1 oroform jr. removed at 15 - 10 nun. and 30 - 40°C. 11 The res idue ir. diluted with 10 ml. of IN hydrochloric acid ami extracted with two 20 mJ. portions of ethyl ether. The aiiiirour. extract is stirred under nitrogen at 20 - 25°C. for '■> hours. After lyophi 1 ization at P.l - 0.3 mm. for 20 hrurr-, t.'io .residue i r. treated with 50 ml. of a mixture of 10% 20 utliarol- and 9()% ethyl acetate (by volume), 5 ml. ol" a saturated sodium car'-onate solution and 1 e. of scliti sodium i-arhonate. After filtration, the filtrate is dried ovei anhydrous magnesium sulfate, filtered arc' concentrated at 11 20 itun. an-: 30 - 40°''. Tho residue ir redissolved 2r« in 21 inl. of absolute ethanol, treate-.l with. . ml. of a ."• ethanolic inhvdrous hydrogen chlciidc solution an, -1 -d i hydroxyphenyl )-2-methyla Ian.' nate hvdro-cliloride hydrat-*, Ih-iuiiien^our. upon thin layer chromatography 40256 [fluorescent silica-gel plate, usinjt 30% methanol and 70% benzene (by volume) solvent] with an observed Rf = 0.5. rcx/vrnM.i: 3 s A. Preparation of the N-carboxyanhydride of. 1.-3-(3,4-5 dihydroxyphenyl) -2-methylalanine 7 Phosgene gas is bubbled through a mixture of 9.0 g. (0.038 mole) of L-3-(3,4-dihydroxyphenyl)-2-methylalanine sesquihydrate in 500 ml. tetrahydrofuran for 25 minutes until the solution ir. saturated. Duiiny the 10 addition, the temperature of the reaction mi>ture rises to 45°C. The solution in stirred with nitrocen gas bubbling through for an additional 50 minutes. Insolu) lo material is removed by filtering through a diatomaceous earth pad and tho filtrate is conccntrated to ai oil at 15 - 20 mm. 15 pressure and 30 - 35#C. The residue Ls dissolved in 75 ml. ethyl acetate and hexane in added to the cloudpoint. After cooling for several days at 0 - 5°C., the precipitated solid is removed by filtration and dried at 0.1 - 0.3 mm. pressure at 25°c. to give the N-car?n>xyanhydrido of L-3-20 (3,4-dihydroxyphenyl)-2-methylalanine.
B. Preparation of succinimidomethyl L-3-(3,4-dihydroxy-phenyl)-2-methylalaninate hydrochloride hydrate A solution of 2.37 g. (10 millimoles) of the N-carboxy- anhydride of L-3-(3,4-dihydroxyphenyl)-2-nethylalanine and 25 1.20 y. (10 millimoles) ol" N-liydroxymethy 1 siicc initnide is heated at reflux until all of the N-carboxyar»hydritie has reacted.
After concentrating at 15 - 20 mm. pressure and 30 - 40°C., the residue is extracted with 50 ml. of benzene and then - 73 - 402SG !>») mi . of el.hyl aeel.ate. The insoluble solid is then shaken wi III .*><) ml. cl' ;i mixture ol' H)% ethanol and 90% elhyl acetatc (by volume) anil 10 ml. of a saturated sodium carbonato solution. After* filtration, the 1'iltrate is dried 5 over anhydrous magnesium sulfate, i'iltered and concentrated under reduced pressure. The residue is redissolved in 25 ml. of absolute ethanol, treated with 5 ml. of a 9.6 N ethanolic anhydrous hydrogen chloride solution and concentrated under reduced pressure to give succininidomethyl L.-3-(3,4-H) dihydroxyphenyl)-2-methylalaninate hydrochloride hydrate, homogeneous upon thin-layer chromatography J fluorescent silica gel plate, using :H)% methanol and 7()% benzene (by volume) as solvent' with an observed Ml' = O.5.
KXAMtM.E 36 15 A. Preparation of |;-3-( 3 ,4-di pheny 1 methyl enedioxyphenyl ) -2-mt: thy la I an i tic hydrochloride A mixture of 19.3 g. (0.0777 mole) oi" L-3-(3,4-dihydroxypheny1)-2-methylalanine hydrochloride and 37 g. (0.156 mole) oi' dichlorodiphenylinethane is immersed with 2() slow stirring in a preheated oil bath at 190°C. After reaction has started, as evidenced by vigorous gas evolution, the reaction mixture is stirred rapidly for 6 minutes at 19(>°i:., removed from the hot oil bath and allowed to coo1 to 25 - 30°C. The crude product from 12 runs is combined, slurried with 3 I. of diethyl ether-, filtered, w.ishi'il with an adi I i I i ona I 2 I. of diethyl ether and dried al .'li/V. under !»<> mm. pressure. Ilecryslal ligation is accompIished by dissolving tin- product in ethanol and adding elhyl acetate to precipitate the product. The - 74 - 40296 procedure gives 255 g. (6fi.4%) of L-3-(3,4-dipheny1-methylenedioxyphcnyl)-2-methylalanine hydrochloride, m.p. 267 - 268*C. dec.
B. Preparation of a-succinimidocthyl J,-3-(3,4-diphcnyl-5 methylenedioxyphenyl)-2-methylalaninatc A solution of 1.4 g. (4.0 mnolc) of L - 3 - (3,4 -diphenylmethylenedioxyphenyl)-2-methylalanine and 0.65 g. (4.0 millimoles) of N-(o -ehJ oroethyl )-succinimide in 5ml. dimethylsulfoxidc is stirred at 20 - 25"C. for 23 hours. 10 Water, 150 ml., is added followed hy a saturated sodium carbonate solution until a pH of 8 is obtained. The product is extracted into 500 ml. of ethyl ether which is then washed with four 25 ml. portions of water, dried.over anhydrous magnesium sulfate and filtered. Concentration at 15 15 - 20 nun. and 35 - 40°C. gives cruda a-succinimidoethyl L-3-(3,4-diphcnyImethylenedioxyphenyl)-2-methylalaninate of sufficient purity for use in the next step.
C. Preparation of a-succinimidoethyl L-3-(3,4-dihydroxy-phenyl)-2-mcthylalaninatc hydrochloride 20 A sunpnnsion of 1.0 g. (2.0 mil I ii»oles)or 0-:.urc i n- imidoethyl L-3- (3,4-diphcny 1 mothylen^tlioxyphrnyl) -2- mcthylalaninato in 25 ml. of a mixture- of absolute otlmnol and ~/H'£ i-lliyl ;ici'l:iil c (l»y volume) is hydroyenati.-d with l.O jj . of 10% palladium-on-carbon catalyst at an initial pressure 25 of 40 p.s.i. and room temperature for 23 hourr-. The catalyrt is filtered and tho filtrate evaporzted under reduced pressure at 30 to 40°c. The renidue is dissolved in 50 ml. of a mixture of 1(K ethanol and 90% ethyl acetate (by volumtj - 7r, - 40256 and stirred with 5 ml. ol' saturated sodium carbonate solution and approximately 5 g. of anhydrous sodium carbonato for 10 minutes. After filtration, the filtrate is dried over anhydrous magnesium svlfate, filtered 5 and evaporated to dryness under reducad pressure. The residue is dissolved in 20 ml. of dry chloroform and, the resulting solution is cooled in an icc bath and saturated with hydrogen chloridc gas for 15 minutes. The solid is collectcd, washed by suspension in 25 ml. of anhydrous lo ether three times and then slurried in 25 nl. of ethyl acetate under in a stoppered flas'; at rooir. temperature overnight. The insoluble solid is ronoveu by filtration, stirred with 30 ml. hexane for 2 hours and dried in a vacuum desiccator over CaCl^ to give a-succinimidoethyl L-3-: r> (3,4-dihydroxyphnnyl) -2-mothylalaninate hydrochloride as a mixture of a- and H-isomers, observed Rf = 0.7 upon thin layer chromatography [fluorescent silica gel plate using 50% methanol and 50% benzene (by volume) as solvent}.
EXAMPLE 37 20 A. Preparation of L-3-(3,4-diacetoxyphenyl)-2-methyl-alanine hydrochloride To a mixture of 320 ml. glacial acetic acid and 24 ml. acetyl chloride is added in one portion> 69.4 g. (0.291 mole) of L-3-(3,4-dihydroxyphenyl)-2-ncthylalanine 25 sesquihydrate. The temperature of tho reaction mixture rises to approximately 50°C. and a cloar solution results.
At this temperature, an additional 85 ml. of acetyl chloride is added over 10 minutes. The resulting clear, pale yellow solution is allowed to stand at 20 - 25°C. fcr 14 hours. - 76 - 40256 Anhydrous, ethyl other, 400 ml., ir. added ovor 15 minuter..
When addition is*, almost eompl «•!•.<», a white ;:oH«l beginr. to preejpi tatc. The mixture i:: :;t Lrml at 20 - 2ri°r. for 30 minutes ami at. 5 - l<>°<:. tor 1 hour and is then cooled at 5 -10°C. for 2 hours. The solid is removed by filtration, suspended in J.50 ml. ol' a mixture oi' 30% acetic acid and 70% ethyl ether (by volume), filtered and washed with.500 ml. ethyl ether. After drying at 70°C. for 2 hours, 83.7 g. (88%) of JL-3-(3,4-diacetoxyphenyl)-2-methylalanine hydrochloride, m.p. 10 lir.,0 - 197.0#C., is obtained.
D. Preparation of a-succinimidoethyl L-3-(3,4-diacetoxy-phcnyl)-2-methylalaninate hydrochloride A solution of 1 .*><> g. (5 millimoles) oi" K-3-(3,4-diacetoxyphenyl) -2-r.iethylalanine hydrochloride, 0.51 g. 15 (5 mmole) of triethylamii.o and 0.81 g. (5 millimoles) H- (ti-chloroethyl) -succinimide in 5 ml. of dii»ethyl sulfoxide in stirred at 20 - 25°C. for 20 - 24 hours. Dimethyl sulfoxide is removed by stirring with 20 ml. ethyl ether for several minutes and then decanting off tie ethyl ether, i) Thir; extraction process is carried out three times. The residue is dissolved in 10 ml. of absolute etl-anol and the product precipitated by the addition of excess of ethyl ether. This precipitation process is repeated two more times to give pure ei-succinimidoethyl L-3-(3,4-diacetoxy-2S phenyl)-2-methylalaninate hydrochloride.
EXAMPLE 38 Preparation of EXAMPLE 39 A. Preparation of N-(1-chloroethyl)-maloimide Stannic chloride, 5.20 g. (0.020 mole) is added 25 to a solution of 49.2 g. (0.40 mole) of N-vinylnaleimide in 1 1. of carbon tetrachloride and the mixture is stirred while being saturated with hydrogen chloride for 6 hours at 20 - 30#C. After 24 hours, the mixture is resaturated with hydrogen chloride for 1.5 hours. At tho end of 48 30 hours, the solution is decanted and the gummy residue is - 7H - 40250 washed with ten 100 ml. portions of carbon tetrachloride.
\ Tho combined extracts aro slurried with 10 of diatoma-tvous earth and I"i I l.crt.'d, mul I lie lilliut.c is c-onccntrul ed under reduced pressure to approximately 400 ml. Tho N-(l-chloro-5 ethyl) -maleiraide is filtered and drio:l at 20 - 30*C.
U. Preparation of a-maleimidoethyl L-3-(3,4-dihydroxy-phenyl)-2-methylalaninate hydrochloride A solution of 0.0^ g. (4.0 millimoles of L-3-(3,4-dihydroxyphenyl)-2-methylalanine sesquihydrate and 0.64 g. 10 (4.0 millimoles) of N-( o-c-h I oroethyl )-mal e iniide in 5 ml. dimethyl-sulfoxide is stirred at 20 - 25°C. for 23 hours. The solution is diluted with 10 ml. distilled water and passed through a column containing 5 g. of weakly basic anion exchange resin on the basic cycle. After elution with water, 15 the fractions "iving a positive ferric chloride test are combined and added to a coluiw of 3 «. of a weakly acidic cation exchange resin on tho acid cycle. Unreacted L-3-(3,4-dihydroxyphenyl)-2-methylalanine is eluted with distilled water until a negative ferric chloride tent is 20 obtained anil tho ester is then eluted with 1 N acetic acid. The ester fraction, 55 ml. (pll 3.?), is treated wit*> 1 N hydrochloric acid to pit 2.0 and lyophilizod at 0.1 -0.3 mm. for 20, houjrs to give a-maleimidoethyl L-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrcVilor.'do. 2r> C. Preparation of u-succinimidoothyl L-3- (3,4-dihydroxy-pjionylJ_-2-methylal_an_inate hydroc!iloride A solution of 1.0 g. (j.,7 millimoles) of a-maleimidoethyl l.-3-{3,4-dihydroxvphenyl)-2-methylalaninate hydrochloride in 25 ml. absolute ethanol ir. hydrocenated with - 79 - 40256 1.0 g. of 10% palladium-on-carbon catalyst at atmospheric pressure and 25°C. until one equivalent of hydrogen has been taken up. The catalyst is filtered off and the filtrate evaporated under rcduced pressure at 30 to 40*C. The residue is dissolved in 50 ml. of a mixture of 10% ethanol and 90% <>(hyl acetate (by volume) and stirred with 5 ml. of saturated sodium carbonatc solution and approximately 5 g. of anhydrous sodium carbonate for 10 minutes. After filtration, the filtrate in dried ovor anhydiour. magnesium sulfate, filtered and evaporated to dryness under rcduced pressure. The residue is dissolved in 20 ml. of dry chlorofom and, the solution is cooled in an ice bath and saturated with hydrogen chloride for 15 minutes. The solid is collected, washed by suspension in 25 ml. of anhydrous ether three times and then slurried in 25 ml. of ethyl acetate under N., in a stoppered flank at 20 - 25°C. overnight. The insoluble solid ir. removed by filtration, stirred with 30 ml. hexane for 2 hours and dr?ed in a vacuum desiccator over CaCl^ to give a-«-uccinimidoethyl !_•- 3- (3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride as a mixture of i- and ^-isomers, observed P.f = 0.7 upon thin layer chromatography (fluorescent rilica gel plate, usinjj 50% methanol and 50% benzene (by volume) as solvent].
EXAMPI.K 40 A. Preparation of a-chlorocthyl 3-chloro-2,2 -dimothyl-propionate Zinc chloride, 400 mg. ir. fused at 0.2 - 0.5 mm. pressure and cooled to 25 - 30°C. under nitrogen. 3-Chloro-2,2-dimethylpropionylchloride, 62 g. (0.40 mole) is added 40250 to the fused zinc chloridc followed by acetaldehyde, 19.2 g. (0.44 mole) . During addition of the acetaldel-yde, which is done as rapidly an' possible, the reactior. nixture is stirred and cooled to prevent loss of acetaldehyde due to 5 the exothermic nature of the reaction. After heating at reflux for 1 hour, distillation gives a-chloroethyl 3-chloro-2,2-dimcthylpropionate. n. Preparation of a-(3-chloro-2,2-dimethylpxopionyloxy)-ethyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate 10 hydrochloride A solution of 0.95 g. (4.0 milLimoles) of L-3-(3,4- dihydroxyphcnyl)-2-methylalanine sesqaihydratc and 0.81 g. (4.06 millimoles) of o-chloroethyl 3-chloro-2,2 -dimethyl- I propionate in 5 ml. dimethylsulfoxide is stirred at 20 -lr> 2S#C. for 23 hours. Tho solution is diluted vith 10 ml. distilled water and passed through a colui.ji containing 5 g. of weakly basic anion exchange resin on the base cycle.
After elution with water, the I'racLions giving a positive ferric chloride test are combined and added to 20 a column of 3 y. of weakly acidic cation exel ango resin on the acid cycle. Unreacted L-3-(3,4-dihydroxyphenyl)-2-raetliylalnnine is eluted with distilled water until a negative ferric chloride test is obtained, the ester is then eluted with 1 N acetic acid. Tho ester fraction, 25 50 ml. (nil 3.2), in acidified to pll 2.0 with 1 N hydrochloric acid and lyophilizcd at 0.1 - 0.3 mm. for 20 hours to give i-(3-chloro-2,2-dimethylpropionyloxy)-ethyl L-3-{3,4-dihydroxyphe.nyl)-2-methylalaninate hydrochloride as the acetic acid solvate. - fcl - 40256 C. Preparation of a-pivaloyloxyethyl L-3-(3,4-dihydroxy-phenyl)-2-methylalaninate hydrochloride A solution of 1.5 g. (3.66 ranolc) cf a-(3-chloro-2,2-dimethylpropionyloxy)-ethyl L^3-(3,4-dihydroxyphenyl)-5 2-methylalaninate hydrochloride in 20 ml. absolute ethanol is hyurogenated with 1.0 g. of a 10% palladium-on-carbon catalyst at 20 - 25*C. at atmospheric pressure until one equivalent of hydrogen has been taken up. After removal of catalyst by filtration, ethanol is removed at IS - 20 mm. 10 and 30 - 35*C. The residue is dissolved in 40 ml. ethyl acctatc, stirred briefly with a mixture of 2 «». of solid sodium carbonate and 2 ml. saturated nn N ethanolic-anhydrous hydrogen 15 chloridc in added and the solution concentrated under rcduced pressure to dryness. Further drying at 65*C. and 0.2 mm. pressure gives tho a-pivaloyloxyethyl ester hydrochloride.
EXAMPLE 41 20 A. Preparation of benzyl succinamate A mixture of 23.4 g. (0.20 nole) of succinamic acid, 25.4 g. (0.20 mole) of benzyl chloride, 20.2 g. (0.20 mole) triethylamine and 250 ml. dimethylformamide is stirred at 95#C. for 20 hours. Tho reactirn mixture is 25 diluted with 500 ml. water and the product extracted into two 200 ml. portions of ethyl other. The comlined I extracts arc washed with two 50 ml. portions of saturated sodium bicarbonate solution anil, then two 5o ml. portions of water,and dried over anhydrous magnesium sulfate. After - 82 - 402S6 ln'iiij; nil.f'fcd, tho solution is concentrated at 15-20 mm. and 40*C. to give benzyl succinamate.
I B. Preparation of benzyl N-hydroxymethyl3uccinamate To a stirred solution of 20.7 g. (0.10 mole) of 5 benzyl succinamate in 150 ml. Qthyl acetate at 25"C. is added 3.0 g. of paraformaldehyde and 1 ml. of a 20% (by weight) solution of ethanolic potassium hydroxide. After the solution has been stirred at 25°C I'or 20 hours, hexane is added to the cloudpoint and tho mixturo is cooled at 5#C. for 24 hours. " Solvents arc decanted off and the renidue is washed with 25 ml. hexano to give benzyl N-hydroxymethylsuccinamate.
C. Preparation of benzyl H-chloromothylsuccinornate A solution of 24.2 g. (0.10 mole) of benzyl N-hydroxymothylsuccinamate and 28.9 g. (0.11 molo) of tri-15 phonylphosphine in 500 ml. carbon tetrachloride is stirred at reflux for 12 hours. After filtering and v?ashing the precipitate with benzene, tho organic solventr are removed at 15 - 20 ran. and 30 - 40°C. to give benzyl N-chloro-methylsuccinamato of sufficient purity for usr in the next 20 ntop.
D. Preparation of bonzylsuccinamidonnthyl L-N-carbo-benzyloxy-3-(3,4-diphonylnethylenodioxyphrnyl)-2-mr; thy 1 alanine A solution of 10.2 g. (0.020 molo) of L-N-carbo- 25 benzyloxy-3- (3,4-diphenylmethylonedioi:ypheny 1) -2-methyl- alanino, 2.02 g. (0.020 molo) of triethylamirr and 5.12 g. (0.020 mole) of benzyl N-chloromothylsuccinanato in 20 ml. - 8:J - 40 256 dimethylformamide is stirred at 70#C. for 5 hours, then at 20 - 30°C. for 5 hours and finally pourcii iuto 200 ml. of water. The product is extracted with three 100 nl. portions of ethyl acetate, washed with 50 ml. of a 5% sodium 5 hydroxide solution, 50 ml. of water and 50 ml. of saturated sodium chloride solution and dried over anhydrous magncr.ium sulfate. After filtering, solvents are removed at 15 -20 mm. and 30 - 40#C. to give bcnzylsuccinanidomethyl 1.-N-carl>ol»enzyloxy-3- (3,4-dinhenyImethylenedioxyphenyl) -2-10 methylalanine. r. Preparation of succinamidomethyl L-3-(3,4- ral. of a saturated sociiur; carbonate solution and excess of solid sodium carbonate for 2 minutes. 25 io of anhydrous magnesium sulfate is r-»c'de<". and after a few minutes is removed by filtration. f>c-l vonts are removed under reduced pressure and, the residue is washed with 25 ml. of l'o>:aiio and then Hr> ml . of ot.hyl acetate and dried - 84 - V — 40256 under rcduccd pressure. The residue is retreated with sodium carbonatc as before to remove the last traces of a-methy1-3,4-dihydroxyphenylalanine and converted to the hydrochloride salt with 3 ml. of 9.6 N ethanolic-anhydrous 5 hydrogen chloridc to give succinamidoaethyl L-3-(3,4-dihydroxyphenyl) -2-methylalaninate hydrochloride.
F. Preparation of succinimidomethyl I»-3-(3,4-dihydroxy-phenyl)-2-methylalaninate hydrochloric** hvdrate A mixture of 3.95 g. (10 millimoles) of succinamido-10 methyl L-3-(3,4-dihydroxyphenyl)-2-mnthylalarinate hydrochloride and 100 ml. acetyl chloridc is stirred at 25"C. for 6 hours. 'Ih«: mixture; is ronccn I ra t.e< I ;i(. I fi - 2() mm. ; 111 < I . ;ind the residue is dissolved in 25 ml. of I N hydroch J ori c acid. The resulting solution is stirred under nitrogen at 20 - 25°C. 15 for 5 hour's. Ai't^r lyophi lization at O.l -0.3 mm. for 20 hours, the residua is treated with 50 ml. of a mixture of 10% ethanol and 9()i ethyl acetate (by volumc)> 5 ml. of a saturated sodium carbonatc solution and 5 g. of solid sodium carbonate. After filtration, the filtrate is dried over 20 anhydrous magnesium sulfate, filtered and concentrated at 15 - 20 mm. and 30 - 40°C. The residue is recissolved in 25 ml. of absolute ethanol, treated with 5 ml. of a 9.6 N ethanolic-anhydrous hydrogen chlorido solutior and concentrated under reduced pressure to givo succinimidomethyl 25 L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrochloride hydrate, homogeneous upon thin layer chronatc •jraphy [fluorescent silica gel plate, using methanol and 7ot ben/ene (by Volume) as solvent^ with an observed Hf _ 0.5. - 85 - 40256 E.'-JlUPLH 42 A. Preparation of 2-hydroxyothyl L-3-(3,4-dihydroxyphenyl) -2-mothylalaninato hydrochloride ______ A solution of 0.05 g. (4.0 millimoles) of L-3-(3,4-5 dihydroxyphenyl)-2-mcthylalaninc sesquihydratr and O.^l g. (4.06 millimoles) of 2-bromoethanol in 5 ml. dimethyl sulfoxide is stirred at 60°C. for 5 hours and th«»p a? loved to cool to 20 - 25°C. over 23 hours. The solution is diluted with 10 ml. distiller1, water and pasr.ed through a column contain-10 ing 5 g. of weakly basic anion exchanye resm on the base cycle. After olution with water, the fractions giving a positive ferric chlorido tost arc cci bincd and added to a column of 3 g. ol" weakly acidic- cation exchange rn:?in cn tl»»» acid cycle. linreacted L-3 - ( 3, -1 -«! ihydruxy-15 phony 1)-2-mntliy]nJaninc is eluted witi djr.tillcd water until a negative fcrric chloride tost is obtained, and the ostcr is then eluted with 1 N acetic acid. The ester fraction, 50 ml. (pH 3.2), is acidified to pH 2.0 with 1 N hydrochloric acid and lyophilizcd at 0.1 - 0.3 mm. for 20 ?0 hours to give 2-hydroxyethyl L-3- (3,4-dii.yt'roxvphnnyl) -2-methylalaninate hydrochloride.
Preparation of 2-acotoxyethyl .L-3 - (3, 4-dil-ydroxy-phenyl) -2-rnethylalanipate A mixture of 1.0 g. (3.4 millimoles) of 2-hydroxy-25 ethyl 1^-3-(3,4-dihydroxyphenyl)-2-methylalaninato hydrochloride and 50 ml. acetyl chloride is ntirrcd at 25°C. for ft hourr;. After the mixture has been concentrated at 15-20 mm. and :»5°C. , the residue is dissolved in 25 ml. of 1 N hydrochloric acid .iml stirred under nitroyen at 20 - 25°C. for 5 - 86 - 40280 hourn. After lyophiligation at 0.1 - 0.3 mm. for 20 hours, • • » . • *. i ; ' * , ♦ ♦ • tho residue in treated with SO ml. of a mixl.urr- ol' /()# ethanol and 90"t ethyl ticelate (by volume), !i ml. of a saturated / sodium carbonate solution and 5 g. of solid rodiujft carbonate.
S After filtering, the filtrate is dried over anh^Arous magnesium sulfate, filtered and concentrated at- 15 - 20 mm. and 30 - 40°C.
The residue is chromatographed on silica gel and eluted with a mixture ol" iJOTt methanol and 80< benzene (by volume). 10 nncrystalligation is accomplished by dissolving the ester in warm ethyl acetate and adding sufficient cyclchexane to precipitate the desired 2-acetoxyethyl L-3-(3,4-dihydroxyphenyl) -2-mc-thylalaninate, m.p. 114 - 118#C. dec.
EXAMPLE 4 3 15 Preparation of 2-acetoxyethyl ^-3-(3,4-dihydroxyphenyl)-2-methylalaninate A mixture of 1.0 g. (3.4 millimoles) of ii-hydroxy-ethyl L-3-(3,4-dihydroxyphenyl)-2-methylalaninate hydrochloride and 50 ml. ir.ethaner.ulfonylchloridc ic stirred at 20 25#C. for 6 hours. Concentration at 15 - 20 nm. and 35°C. followed by drying at 0.1 - 0.5 mm. and 40#C. gives the crude mothancsulfonyl derivative. To this is added 10 ml. of dimethylsulfoxide and 6.6 g. (10 millimoles) of lithium acetate and the mixture is stirred at 60°c. for 6 hours. Following 25 the addition of excess ol" ethanolic anhydrous hydrogen chloride solution, dimethylsulfoxide is removed by stirring three times with 50 ml. ethyl other and decanting off the ethyl ether. Tho residue is dissolved in .15 ml. of IN hydrochloric acid and is stirred under nitrogen at 20 - 25*C. for - 87 - 402SU 1 hour. After lyophilization at 0.1 - 0.3 mm. for 20 hours, the residue is treated with 50 ml. of a mixture of 10% ethanol and 901 ethyl acetate (by volume) 5 ml. of a saturated sodium carbonate solution and 5 g. of solid sodium 5 carho:»ate. After filtration, the filtrate is dried over anhydrous magnesium sulfate, filtered and corcentratod at 15 - 20 mm. and 30 - 40°C.
The residue is chromatographed on rilica gel and eluted with a mixture of 20% methanol and 80% benzene (by volume) Re-10 crystallization of the ester is accomplished by dissolving it in ethyl acetate and adding sufficient cyclohexane to precipitate the desired 2-acetoxyethyl JL-3-(3,4-dihydroxyphenyl) -2-methylalaninato, m.p. 114 - HO"'*. dec. nxAf*PT.r 44 HARD GELATIN CAPSULES cm. succinimidomethyl L.-3- (3,4-dihydroxyphenyl) -2-methylalaninato hydrochloride hydrate 200 Cornstarch l'SO 20 Magnesium stearate, powder 50 Talc 50 Tho finoly powdered jnyrodi'intn are mixed thoroughly and then encapsulated in 1000 two-)>ioco hard gelatin capsules oach containing 200 mgs. of succinimido-."5 methyl L-3- (3,4-dihydroxyphenyl) -2-mothylalaninate hydrochloride hydrato. - 88 - 40#bu i i / VAhUT:: 1000 tablets cach containing 100 men. of a-succinimidoethyl £-3-(3,4-dihydroxyphenyl)-2-methyl-5 alaninate hydrochloride dihydrate (B-isomer) are prepared from tho following ingredients: / Gra. u-succiniinidocthyl L.-3-(3,4-dihydroxy phenyl) -2-methylalani.iate hydrochloride dih/dratc 10 (H-inomer) 100 Lactosrc 50 Starch 50 Calcium stearate 10 Talc 10 15 The finely powdered ingredients aro mixed thoroughly and then tablotod by a slugging procedure.
EXAMPLE 46 HARD GELATIN CAPSULES Five thousand two-nmco hard gelatin capnulns, 20 eacli containing 4nn mu. of a-pivaloylaxyethyl I,-3-(3,4-dihydroxyphonyl)-2-methylalaninate hyJrochloride arc prepared from the following .ingredients: Gm • 'i-»>ivaloylo:;yethyl .L.-3- (3,4-dikydroxyi>h When the compounds oi' the present invention are tested orally, distinct. aril. i -hyp<; rtens i v«> activity is noted. The compounds also show aril, i-liypcrt.cris i vc activity when tested i iit.rapci-i tonca 1 ly . In somo instances the compounds show substantially more activity than l.-a-mc; t hy 1 dopu . - i>») -
Claims (1)
1. 40256 ri.AIMS:- I. A compound ol' t.lie formula: V"3 ? P1 / CH„ C C 0(-CH )— C(-CH )— R (I) • -- 2 | 2 n | / d ID J Ao-O-JU^ U NIC„ R J ■XX / where n is O, I, 2 or 3; m is O, 1, 2 or 3; each of A and ~ ~ 1 5 A., is a hydrogen atom or a Cj_galkanoyl group; each of R^ and R,, is a hydrogen atom or a C. , alkyl group; and R_ is (A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and as nuclear hetero al.om(s) one or two nitrogen atoms or one nitrogen and one lo sulfur atom, each ring in the said heterocyclic radical containing 5 or 6 members, or (B) a radical X-R4 where X i:; -S- or -Nil- and contains up to 21 carbon atoms and ia hydrocarbon radical v>r an acy I radical ol' an organic acyclic or monocyclic carboxylic acid containing not more I r> l.han I hetero atom in the ring; and pharmaceutically acceptable acid-addition salts thereof. Tin- free base form of a compound as claimed in (Maim I. • A plia rmaccut i ca I 1 y acceptable ac i d-acld i t i on s;»l t ol" a compound as (Maimed in claim I. 20 4. A compound as claimed in Claim 1 in which n and m are o, U and H., are hydrogen and H is I? -o 4 !>. The hydroch I c,r i c acid-addition salt ol' a compound as I a i mi'iI i ri Claim 4 . - 91 - * * 40256 b. A compound as claimed in 1*1 aim 1 in which n and m aro I), H| Is methyl, H., is hydrogen and is 0 7. Tho hydrochloric acid-addition salt of a compound as claimed in Claim 6. 8. A compound as claimed in Claim 1 in which n and m are O, Rj and n2 are hydrogen, X is -0- and R^ is f —c—C(-(:H3)3 9. The hydrochloric acid-addition salt of a compound as K) claimed in Claim 8. If). A compound as claimed in Claim 1 in which n and m aro O, U is methyl, R^ is hydrogen, X is-O- and R^ is 0 1!—t: (-Cll.t) I I. The hydrochloric ac i d-a«lcl i 1 ion sail ol' a compound as I claimed in Claim If). 112. A compound as claimed in Claim 1 in which n is 0, Rj and are hydrogen, m is 1, X is -Nil- and R^ is -CO-CIl 1 . The hydrochloric acid-addition salt of a compound as claimed in (Maim 12. 14. An ester ol' the L isomer ol' an amino acid, substantially I'ree of the D isomer-, having the formula: - 9L> - f":* \[ fi 40230 nh, in which m, n, R1, R2 and R3 are as defined in Claim 1. 15. The free base form of an ester as claimed in Claim 14. 5 16. A pharmaceutically acceptable acid-addition salt of an ester as claimed in Claim 15. 17. An ester as claimed in Claim 14 in which n and m are O, II and H.j arc hydrogen ami H.^ is c I ;i i mcil in Claim 17. 19. An ester as claimed in Claim 14 in which n and m are O, R is methyl, R2 is hydrogen and R3 is 0 II -n o 15 2D. A hydrochloric acid-addition salt of a compound as claimed in Claim 19. 21 . An ester as claimed in Claim 14 in which n and m are (), R arid H., arc hydrogen, X is -()- and H^ is -CO-C ( -Cll.j ) .j 2o 22. The hydrochloric acid-addition salt of an ester as claimed - 93 - • »/ * • 40256 i ri C I a i m J 1 . 23. An ester as claimed in Claim 14 in which n and m aro (j, Hj is methyl, H., is hydrogen, X is -0- and R^ is -co-c(-cii3)3 r» 24. The hydrochloric acid-addition salt of an ester as claimed in Claim 23. 2f>. An ester as claimed in Claim 14 in which n is O, R^ and H., are hydrogen m is 1, X is -NH- and R. is J — 4 -co-ci1.j ID The hydrochloric ac i d-add i t i on sail, ol' an ester as c I aimed in Claim 1:5. 27. A method ol' treating hypertension in a hypertensive non-hiiniari animal which compr ises administering to the animal a thcropeutica11 y effective amount of" a compound as claimed 15 in any one of Claims 1-26. ;!M. A method a:; claimed i i. Claim 27 in which the compound i:. admi ni sl.e red in amounts ol' from about 0.005 to about :»()() mg./kg. of body weight of the animal. 29. A method as claimed in Claim 27 in which the compound 2C) is administered in amounts of from about 0.05 to about 100 mg./kg. oT body weight of the animal. .')(). A method as claimed in Claim 27 in which the compound is administered in amounts of from about C.l to about 25 mg./kg. of body weight of the animal. 25 31. A pharmaceutical composition comprising an inert - '14 - 40250 pharmaceutically acceptable diluent and a compound us claimed in any oni; of Claims 1-26. A pharmaceutical compos i I i on as claimed in Claim 31 containing from 1 mg. to 2,000 mg. of the said compound 5 pur unit dose. 33. A pharmaceutical composition as claimed in Claim 32 containing from 5 mg. to 1,000 mg. of the said compound per unit dose. 34. A pharmaceutical composition as claimed in Claim 33 1() containing from 10 mg. to 500 mg. of the said compound per unit dose. 35. A composition as cl •'tinted in any one of Claims 31-34 in orally administ rable form. 36. A composition as claimed in Claim 35 in the form of 15 tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonl'uls, dropperfuls ,«n^oules vials, or segregated mu I I. Lpl es of any of the foregoing, or orally administ rable solutions or suspensions. 37. A composition as claimed in any one of Claims 31-34 in parenterally administrable form. 38. A composition as claimed in .my one of Claims 31-34 in the form of a suppository. 39. A composition as claimed in Claim 35 in the form - 95 - » '* V* 4 0 2 S 6 >>l ill! < • 111 IW'U'-l'Oat I'll lablcl. . 4M. A method ol" preparing a compound as claimed in Clnim I comprising the hydrolysis or reduction of an acid derivative of the formula: v XX f«3? f. ci,_^_c-o(-c"2)—6 NH «o (-ch2>S- or an acid-additon salt thereof in which n, m, R , R_ and R_ arc as defined in Claim 1 and each of R_ , R, and R_ is 3 O 7 hydrogen or a blocking group, with at lease one being a blocking group. 10 41. A method of preparing a compound as claimed in Claim 1 that comprises the esterification of an acid derivative of the formula: CH or Nil., CH3 I -C CO, I Nil.. CH3 0 A]-0_>!^\— CHj-> A;-oij) *l i 2 \/ c « s-» o 15 or an acid-addition salt thoreof with a compound of the , n. I o nmi la: X,-(-CH -)— C— (-CM ) -R_ 1 2 n i d m 3 20 in which Y is -COOH, -COhalogen or -carboxylic acid salt, n> ™. Aj , A#), Rj , R2 and R^ are as defined in Claim 1 and Xj is hydroxyl, alkali metal -0-, halogen or a substituted — SO gi'oup. 96 * *' V 4 0 2 5 G •I/. A nit ■ I IkmI t>l' | 11 - i ■ -i . •«iiii|>i>ini«l a:. in t'liilm I thai i'(4n|ti>i set; Vftliu-1 I ott *» I" a clmipotuul as claimant itt I'litim t in wltich II contains one or more reducible groups. 43. A method ol* preparing a compound us claimed in Claim 1 that comprises the reaction ol' a compound of the formula: f"3 T1 V "flT™2- | —'COSt-CH2>n-®<-CH2)«- in which n, m, Ajf Ag, R^ and Rg are as defined in Claim 1 above and 7. is -OH, -SH, halogen, a substituted -SO,- group or -Nil., with an acylating agent or a compound of formula ««• or H.j-alkali metal where; R.^ is as defined above. 44. A method of preparing a compound as claimed in Claim I that comprises the cyclization of a compound of the formu I a: ch.. r, 0 ^ I l « a,-u_^\ cm — c co., ( -ch- ) —— c ( -ch.,) nhcch_(ch0) —c0oh i I jj _ <; n | dm d i nh2 r2 1S in which n^ is 1, or 2 ; A , Ag, R^, Rg, n and m are as dcl*ini;d in Claim I with an acylating agent. ID 4f>. A method as claimed in any one of Claims 40-44 including the further step of separating the steroisomers by (1) fractional crystallization of one stereoisomer from solution or- ( L') forming d i as tereo i somcrs with an optically active at-itl ;in«t crystallizing oru; of tin; diastereomers from the so I ii I i on • - y7 - 40256 46. A method as claind in any one of Cluims 40-44 in which the startingmaterial is in the L configuration. 47. A method as claimed in Claim 41 in which A^ and Ag are hydrogen. 48. A method of preparing a compound as claimed in Claim 1 substantially as hereinbefore described in any one of Examples 1 -43. 49. A compound us claimed in Claim 1, when prepared by a method as claimed in any one of Claims 40-48. 5(). A pharmaceutical composition as claimed in any one of Claims 31-39, in which the active ingredient is a compound as claimed in Claim 49. 51. A composition as claimed in Claim 31, substantially as hereinbefore described in Example 44, 45 or 46. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS. - 98 -
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US40060973A | 1973-09-25 | 1973-09-25 | |
US05/482,102 US3983138A (en) | 1973-09-25 | 1974-06-25 | Amino acid esters |
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IE40256L IE40256L (en) | 1975-03-25 |
IE40256B1 true IE40256B1 (en) | 1979-04-25 |
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Family Applications (1)
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IE1934/74A IE40256B1 (en) | 1973-09-25 | 1974-09-18 | Derivatives of - methyldopa |
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JP (1) | JPS58208256A (en) |
AR (1) | AR210248A1 (en) |
BG (1) | BG25790A3 (en) |
CS (1) | CS200172B2 (en) |
DD (1) | DD116454A5 (en) |
DK (1) | DK478574A (en) |
EG (1) | EG11695A (en) |
ES (1) | ES430320A1 (en) |
FI (1) | FI61687C (en) |
HU (1) | HU171136B (en) |
IE (1) | IE40256B1 (en) |
IL (1) | IL45669A (en) |
NO (1) | NO145690C (en) |
PH (1) | PH11794A (en) |
RO (1) | RO69156A (en) |
SE (1) | SE421789B (en) |
SU (2) | SU608471A3 (en) |
YU (2) | YU37117B (en) |
ZM (1) | ZM14074A1 (en) |
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JPH01107949A (en) * | 1987-10-22 | 1989-04-25 | Kawasaki Steel Corp | Method for reusing non-repaired tundish |
PT1751087E (en) * | 2004-06-04 | 2012-09-10 | Xenoport Inc | Levodopa derivatives, and compositions and uses thereof |
US7709527B2 (en) * | 2006-12-21 | 2010-05-04 | Xenoport, Inc. | Levodopa dimethyl-substituted diester prodrugs compositions, and methods of use |
-
1974
- 1974-09-03 DD DD181243A patent/DD116454A5/xx unknown
- 1974-09-11 DK DK478574A patent/DK478574A/da not_active Application Discontinuation
- 1974-09-12 SE SE7411508A patent/SE421789B/en not_active IP Right Cessation
- 1974-09-12 NO NO743274A patent/NO145690C/en unknown
- 1974-09-13 FI FI2680/74A patent/FI61687C/en active
- 1974-09-16 ZM ZM140/74A patent/ZM14074A1/en unknown
- 1974-09-16 IL IL45669A patent/IL45669A/en unknown
- 1974-09-17 PH PH16292A patent/PH11794A/en unknown
- 1974-09-17 YU YU2514/74A patent/YU37117B/en unknown
- 1974-09-17 CS CS746376A patent/CS200172B2/en unknown
- 1974-09-18 IE IE1934/74A patent/IE40256B1/en unknown
- 1974-09-18 HU HU74ME00001776A patent/HU171136B/en unknown
- 1974-09-23 BG BG7400027759A patent/BG25790A3/en unknown
- 1974-09-23 RO RO7480046A patent/RO69156A/en unknown
- 1974-09-23 AR AR255680A patent/AR210248A1/en active
- 1974-09-23 ES ES430320A patent/ES430320A1/en not_active Expired
- 1974-09-24 SU SU742063140A patent/SU608471A3/en active
- 1974-09-24 EG EG416/74A patent/EG11695A/en active
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1976
- 1976-01-27 SU SU762316005A patent/SU620204A3/en active
-
1981
- 1981-02-27 YU YU0503/81A patent/YU37313B/en unknown
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1983
- 1983-04-07 JP JP58060117A patent/JPS58208256A/en active Granted
Also Published As
Publication number | Publication date |
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SU608471A3 (en) | 1978-05-25 |
IE40256L (en) | 1975-03-25 |
SU620204A3 (en) | 1978-08-15 |
IL45669A (en) | 1977-08-31 |
SE7411508L (en) | 1975-03-26 |
YU251474A (en) | 1982-06-18 |
JPS632545B2 (en) | 1988-01-19 |
NO145690C (en) | 1982-05-12 |
DD116454A5 (en) | 1975-11-20 |
SE421789B (en) | 1982-02-01 |
EG11695A (en) | 1977-10-31 |
BG25790A3 (en) | 1978-12-12 |
NO145690B (en) | 1982-02-01 |
FI61687C (en) | 1982-09-10 |
CS200172B2 (en) | 1980-08-29 |
IL45669A0 (en) | 1974-11-29 |
YU37117B (en) | 1984-08-31 |
FI268074A (en) | 1975-03-26 |
NO743274L (en) | 1975-04-21 |
YU50381A (en) | 1983-04-27 |
ES430320A1 (en) | 1977-02-16 |
RO69156A (en) | 1981-11-24 |
ZM14074A1 (en) | 1976-11-22 |
YU37313B (en) | 1984-08-31 |
PH11794A (en) | 1978-07-05 |
AR210248A1 (en) | 1977-07-15 |
DK478574A (en) | 1975-05-20 |
JPS58208256A (en) | 1983-12-03 |
FI61687B (en) | 1982-05-31 |
HU171136B (en) | 1977-11-28 |
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