MXPA98001205A - Compounds of amino acids salts and processes for the production of mis - Google Patents
Compounds of amino acids salts and processes for the production of misInfo
- Publication number
- MXPA98001205A MXPA98001205A MXPA/A/1998/001205A MX9801205A MXPA98001205A MX PA98001205 A MXPA98001205 A MX PA98001205A MX 9801205 A MX9801205 A MX 9801205A MX PA98001205 A MXPA98001205 A MX PA98001205A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- acid salt
- free
- salt
- ranitidine
- Prior art date
Links
- 239000011780 sodium chloride Substances 0.000 title claims abstract description 183
- -1 amino acids salts Chemical class 0.000 title claims abstract description 173
- 150000001875 compounds Chemical class 0.000 title claims description 106
- 238000000034 method Methods 0.000 title description 35
- 238000004519 manufacturing process Methods 0.000 title description 16
- 239000002253 acid Substances 0.000 claims abstract description 126
- 150000003839 salts Chemical class 0.000 claims abstract description 90
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- VMXUWOKSQNHOCA-UKTHLTGXSA-N ranitidine Chemical group [O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-UKTHLTGXSA-N 0.000 claims description 91
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 73
- 229960001520 Ranitidine Hydrochloride Drugs 0.000 claims description 65
- 229960000620 Ranitidine Drugs 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 56
- 239000002904 solvent Substances 0.000 claims description 56
- 150000001412 amines Chemical class 0.000 claims description 43
- 150000003254 radicals Chemical class 0.000 claims description 37
- 241000894007 species Species 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000012535 impurity Substances 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 11
- 239000000010 aprotic solvent Substances 0.000 claims description 10
- 239000012458 free base Substances 0.000 claims description 10
- 239000003586 protic polar solvent Substances 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- SBQLYHNEIUGQKH-UHFFFAOYSA-N Omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 8
- 230000000875 corresponding Effects 0.000 claims description 8
- 229960000381 omeprazole Drugs 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 230000003115 biocidal Effects 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2,5-dimethylpyridine Chemical compound CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-Chloropyridine Chemical class ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 150000008043 acidic salts Chemical class 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- PKRHOIOVOBITKL-UHFFFAOYSA-N 2,3-dimethylpyridine;hydrochloride Chemical compound Cl.CC1=CC=CN=C1C PKRHOIOVOBITKL-UHFFFAOYSA-N 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- 230000001376 precipitating Effects 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 235000011149 sulphuric acid Nutrition 0.000 claims 1
- 238000006276 transfer reaction Methods 0.000 abstract description 28
- 238000002360 preparation method Methods 0.000 abstract description 24
- 150000001413 amino acids Chemical class 0.000 abstract description 13
- VMXUWOKSQNHOCA-LCYFTJDESA-N Ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 38
- 239000000047 product Substances 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 20
- 238000006386 neutralization reaction Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 230000002378 acidificating Effects 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000005755 formation reaction Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 8
- QKZAKNGMLXUWOU-UHFFFAOYSA-N 2,5-dimethylpyridine;hydrochloride Chemical compound Cl.CC1=CC=C(C)N=C1 QKZAKNGMLXUWOU-UHFFFAOYSA-N 0.000 description 7
- HVFLCNVBZFFHBT-ZKDACBOMSA-N Cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 7
- 229960002100 cefepime Drugs 0.000 description 7
- 238000011109 contamination Methods 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000005712 crystallization Effects 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 230000001131 transforming Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 239000012296 anti-solvent Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010899 nucleation Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 3
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 3
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 3
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 3
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 3
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 3
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000004059 degradation Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229940079866 intestinal antibiotics Drugs 0.000 description 3
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
- 229960000707 Tobramycin Drugs 0.000 description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-N Tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- JXDFEQONERDKSS-UHFFFAOYSA-N betazole Chemical class NCCC=1C=CNN=1 JXDFEQONERDKSS-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005063 solubilization Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N 2-((2,6-Dichlorophenyl)imino)imidazolidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- DFFCDIMSXJYMTB-AATRIKPKSA-N 2-[(E)-2-(6-carbamimidoyl-1H-benzimidazol-2-yl)ethenyl]-3H-benzimidazole-5-carboximidamide Chemical group C1=C(C(N)=N)C=C2NC(/C=C/C3=NC4=CC=C(C=C4N3)C(=N)N)=NC2=C1 DFFCDIMSXJYMTB-AATRIKPKSA-N 0.000 description 1
- LPIDQLZQEGPBCO-UHFFFAOYSA-N 2-chloropyridine;hydrochloride Chemical compound Cl.ClC1=CC=CC=N1 LPIDQLZQEGPBCO-UHFFFAOYSA-N 0.000 description 1
- CLEOLMCNUMTXHU-UHFFFAOYSA-N 2-chloropyridine;sulfuric acid Chemical compound OS(O)(=O)=O.ClC1=CC=CC=N1 CLEOLMCNUMTXHU-UHFFFAOYSA-N 0.000 description 1
- OIALIKXMLIAOSN-UHFFFAOYSA-N 2-propylpyridine Chemical compound CCCC1=CC=CC=N1 OIALIKXMLIAOSN-UHFFFAOYSA-N 0.000 description 1
- UMTFFEVYCNPRJB-UHFFFAOYSA-N 7-piperidin-1-yl-5,10-dihydro-3H-imidazo[2,1-b]quinazolin-2-one;hydrate;dihydrochloride Chemical class O.Cl.Cl.C=1C=C2NC3=NC(=O)CN3CC2=CC=1N1CCCCC1 UMTFFEVYCNPRJB-UHFFFAOYSA-N 0.000 description 1
- MKKYBZZTJQGVCD-XTCKQBCOSA-N ARBEKACIN Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)CC[C@H]1N MKKYBZZTJQGVCD-XTCKQBCOSA-N 0.000 description 1
- 229950001961 BETAMICIN Drugs 0.000 description 1
- RHRAMPXHWHSKQB-GGEUKFTFSA-N BETAMICIN Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)O)[C@@H](N)C[C@H]1N RHRAMPXHWHSKQB-GGEUKFTFSA-N 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N Bricaril Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- JOATXPAWOHTVSZ-UHFFFAOYSA-N Celiprolol Chemical compound CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 JOATXPAWOHTVSZ-UHFFFAOYSA-N 0.000 description 1
- 229960002320 Celiprolol Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N Diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 229960002394 Lisinopril Drugs 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- 229940041033 Macrolides Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N Melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- VNUWSJDTXCKTQL-UHFFFAOYSA-N N,N'-bis[3-(benzylamino)propyl]heptane-1,7-diamine;tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.C=1C=CC=CC=1CNCCCNCCCCCCCNCCCNCC1=CC=CC=C1 VNUWSJDTXCKTQL-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- PGBHMTALBVVCIT-VCIWKGPPSA-N Neomycin Chemical class N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 1
- 229960000808 Netilmicin Drugs 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N Pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N Terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 Terazosin Drugs 0.000 description 1
- 229960000195 Terbutaline Drugs 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960005397 arbekacin Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 229960002114 betazole Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000005591 charge neutralization Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000004027 organic amino compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 125000002743 phosphorus functional group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- ZNCXUFVDFVBRDO-UHFFFAOYSA-L pyridine;sulfate Chemical compound [O-]S([O-])(=O)=O.C1=CC=NC=C1 ZNCXUFVDFVBRDO-UHFFFAOYSA-L 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000005476 size effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Abstract
A stoichiometric reaction of transfer of the radical acid to the preparation of a salt of an amino compound is revealed. The transfer reaction of the radical acid provides salts of amino acids of high purity and has a crystalline structure of uniform size and shape.
Description
COMPOUNDS OF AMINO ACID SALTS AND PROCESSES FOR THE PRODUCTION OF THE SAME
FIELD OF THE INVENTION. This invention relates to salts of amino acids and a process for the production and isolation of these. The present process is a transfer reaction of the stoichiometric acid radical (Yoo Reaction) that provides salts of specific organic amino acids with high purity.
BACKGROUND OF THE INVENTION. Acid salts of organic free amines are of particular importance for the pharmaceutical, cosmetic and agrochemical industries since the salt form of the organic free amine compounds allows easy storage and handling, particularly of liquids, and chemical stability is improved and physical, pH and solubility of organic free amines in water and other solvents. The formation of acid salts of organic amines is typically the final step in the process of
REF: 26838 manufacture these pharmaceutical raw materials for use in tablets, capsules, pills, granules, powders, pills, injectable solutions and the like. This is, therefore, critical to eliminate the possibilities of contamination by impurities of additional reactions during the production process and degradation and structural transformation of the final product due to the excess of reaction components. It is also critical to control crystal size and uniformity of amino acid salts during the production process since the size and shape of the crystal greatly affect the stability, hygroscopicity and solubility of the product. Typically, the processes by which the organic amino acid salts are produced include a neutralization reaction of a strong acid, such as, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid or acetic acid with the organic free amine or the reaction of an organic acid in solvent with the organic free amine followed by the addition of an antisolvent to induce the crystallization of the organic amino acid salt compound. Alternatively, the solvent can be removed to leave the organic amino acid salt compound as a residue. Another process by which salts of organic amino acids are produced include the use of solvent in which the free organic amine and the acid salt of the organic amine have significantly different solubilities. The neutralization reaction is carried out in the presence of a strong acid in the solvent. Each of these processes has serious defects that affect the properties of the organic amino acid salt product. For example, because the exothermic neutralization reaction is a direct reaction between an acid and a base, it is difficult to control the speed of the reaction. Consequently, the size and shape of the crystal can not be easily controlled.
In addition, some organic amines are unstable in the acidic conditions required by the exothermic neutralization reaction. It is, therefore, impossible to produce acid salts of these amine compounds by an exothermic neutralization reaction in the presence of a strong acid.
Additionally, the use of excess acid in the exothermic neutralization reaction can cause contamination of the amino acid salt by several additional reactions and / or degradation or structural transformation of the final amine salt compound due to the presence of residual acid. Similarly, in the case of amines having two or more pKa values, the use of excess acid in the neutralization reaction may result in the formation of more than one species of the amine salt, for example a mixture of amine salts mono-acid and di-acid, for example. It is extremely difficult and expensive to produce the equivalent acid salt for each pKa of an organic free amine molecule having two or more pKa values and obtain the hydrate of the acid salt corresponding to each pKa of the organic amino acid salt. Generally, if an organic free amine has more than one pKa, the formation of the amine salt by an exothermic neutralization reaction results in a complete conversion of the free amine or results in a mixture of mono-, di- or , tri-, etc; or the hydrates of the amino acid salts, depending on the amount of acid used. In the exothermic neutralization reaction the nucleation occurs immediately upon the reaction of a free amine base with a strong acid in a solvent, such as ether or ethanol. Consequently, the salt forms rapidly, allowing little or no selectivity in the formation of acid mono-, di-, tri- forms of the salt. It is almost impossible to obtain a kind of pure amino acid salt that is free from contamination by acid salts having different amounts of acid per organic amine by conventional production methods. This has made it problematic, particularly in the pharmaceutical industry, since the amount of acid and corresponding hydrates present in an organic amino acid salt having more than one pKa has a significant effect on the solubility, stability, pH and hygroscopicity of the amine salt. Many compounds of crystalline organic amine salts can exist in more than one polymorphic form, and each polymorph exhibits different thermodynamic properties depending on its crystalline structure. For example, ranitidine, which is a H2-antagonist, exists as forms I and II, although the production reaction for ranitidine can be influenced to provide one predominant form or the other. In any case, conventional methods for producing ranitidine and other salts of organic amino acids are severely restricted by the solubility of the organic free amine and its acid salt. Restrictions in the selection of the solvent have several obstacles in the production of a particular polymorph of salts of organic amino acids. This is, therefore, a need for a process for preparing organic amine salts in pure and highly crystalline form in order to meet pharmaceutical requirements and specifications. Preferably, the process must be operable on an industrial scale. In particular, the process must proceed in a controllable manner so that the molar amount of acid per mole of free amine can be adjusted to provide the desired number of acid molecules of an amino acid salt and the corresponding hydrate thereof. In addition, the product of the organic amino acid salt should be in a form that is readily applicable to the final preparation of the compounds for pharmaceutical, cosmetic, agrochemical, etc. use.
BRIEF DESCRIPTION OF THE INVENTION In one aspect of the present invention a novel process for the preparation of an organic amino acid salt compound is provided. It has been found according to the present invention that the rate of the transfer reaction of the acid radical and consequently, the size and shape of the crystals of the resulting amino acid salts and the formation of particular species of amino acid salts, by example, mono-, di-, tri-, etc., acid salts of a free amine having more than one pKa can be affected by the selection of an amino acid donor compound having a pKa to a lesser desirable degree of at least pKa of the donor compound and organic free amine. It has also been found according to the present invention that the polymorphic form of the resulting organic amino acid salt can be controlled precisely and easily by properly adjusting the polarity of the solvent system used to perform the acid radical transfer reaction. Thus, according to the present invention there is provided a method for preparing an acid salt of an amino compound comprising placing a donor compound having at least one amino acid salt radical in solution with a free amine compound, said donor compound has a lower pKa lower than the greater pKa of the free amine compound, to provide a transfer of an acidic radical of the donor compound to the free amine compound giving the product thereof an acidic salt of the free amine compound. In a preferred embodiment of the invention, the polarity of the protic and aprotic solvent is adjusted by means of this selectivity to produce a desired polymorph of the crystalline compound. In another aspect of the invention, there is provided a product of an acid salt of an amino compound having at least pKa values, wherein said acid salt product is a single species that is substantially free of other species of said acid salt. In a preferred embodiment of the invention, the product of the acid salt of an amino compound is ranitidine hydrochloride. In yet another aspect of the invention, there is provided a method for preparing ranitidine hydrochloride Form I that is substantially free of ranitidine hydrochloride Form II comprising the treatment of free ranitidine base with a donor compound capable of transferring HCl to the ranitidine base. free in a solvent solution having a convenient polarity to precipitate ranitidine hydrochloride Form I. In a preferred embodiment of the invention, ranitidine hydrochloride Form I is a monoacid salt which is substantially free of diacyl salt of ranitidine hydrochloride ( n> l). In another aspect of the invention, there is provided a process for removing impurities from a mixture of an amino acid salt compound comprising more than one species of the amino acid salt compound, said process comprising placing said mixture in a solution with an amino acid salt. free amino compound having a pKa value between two pKa values of the mixture of the amino acid salt compound, to provide a selective transfer of the acid salt radical of the amino acid salt compounds comprising said mixture to the amine free from this to remove impurities from the mixture, produce as the product of this a single species of the compound of an amino acid salt.
BRIEF DESCRIPTION OF THE DRAWINGS.
Figure 1 is a standard of the x-ray powder fraction of n HCl ranitidine (n = l) (Form I) prepared by the method of the present invention. Figure 2 is an FT-IR spectrum of n HCl ranitidine (n = l) (Form I) prepared by the method of the present invention. Figure 3 is an H-NMR spectrum of n HCl ranitidine (n = 1) in D20 prepared by the method of the present invention.
Figure 4 is a published C-NMR spectrum of n HCl ranitidine (n = 1) (Analytical Profiles of Drug Substances, "Ranitidine", Hohnjec, et al., Vol.15, 1986, p.533-559.) Figure 5 is a C-NMR spectrum of ranitidine n HCl (n> 1) in CD3OD prepared by a conventional exothermic neutralization reaction using hydrogen chloride. Figure 6 is an H-NMR spectrum of n HCl ranitidine (n> 1) in D20 prepared by a conventional exothermic neutralization reaction using hydrogen chloride. Figure 7 is an H-NMR spectrum of n HCl ranitidine (n = l) prepared by the method of USP 4,128,658.
DETAILED DESCRIPTION OF THE INVENTION.
The present invention provides a process for the industrial production of an acid salt of an amino compound having one or more pKa values. The present process is a reaction of transferring the acid radical of a donor amino acid salt or a donor polymeric amino acid salt to free amines as the receptors of the acid radical, which produces an acid salt of a free amino compound. The present process overcomes the different difficulties and disadvantages inherent in the typical processes used to produce acid salts of amino compounds. In addition, the present process is provided for the selective formation of a particular species or mixture of acid salt species of amino compounds. As used herein the term "species" means a particular form of a compound of an amino acid salt, such as, for example, a mono-acid salt, a di-acid salt, etc., or a particular poly-oric structure or hydrate of a compound of a crystalline amino acid salt.
In the present process, the reaction of an organic free amine (receptor) with a compound of an amino acid (donor) salt in a specified system of organic solvent at room temperature or elevated temperature can be manipulated to provide the transfer of an acidic radical from the donor compound to a free amine receptor compound in an equimolar manner. That is, there is an equimolar amount of acid radicals per pKa of the receptor compound transferred from the donor amino acid salt or the donor polymeric amino acid salt of the free amine (receptor) based on the difference in pKa between the donor amine and the amine receiver The selection of the donor compound suitable for use in the present process may depend on the pKa of the receptor compound, the desired species of the product of an amino acid salt and / or the solubility of a donor compound in the reaction solvent. In general, the donor compound can be selected so as to have a pKa to a lesser desirable degree of at least one pKa of the receptor compound (free amino compound) to ensure the transfer of an acidic radical to the receptor compound. The difference between the pKa values of the donor and receptor amino compounds can affect the rate of the acid transfer reaction, which changes the shape and size effects of the crystals of the amino acid salt in this way. By increasing the difference between the pKa of the donor and the receptor amines, the reaction rate increases. Thus, the rate of the acid transfer reaction can be selectively targeted by selecting a compound of a donor amino acid salt having a desired pKa relative to the pKa of the receptor-free amino compound. The donor compound used in the present acid radical transfer reaction is an organic complex of an amino compound with an acid radical represented by the formula (I):
R "
R'-N ": H-X 0 R
where R, R 'and R "are each independently H, an alkyl group having from 1-20 carbon atoms, preferably from one to ten carbon atoms and more preferably, from one to six carbon atoms or an aryl group having one to nine carbon atoms, and preferably, one to six carbon atoms or R, R 'and R ", together with N can form a heterocyclic amine. The R, R 'and R "can be independently substituted with for example, an alkyl group or an aryl group, each having from one to six carbon atoms, a nitrogen, oxygen, silica, sulfur, or phosphorus groups, an halogen, an amino group or combinations of these. (R, R 'and R ") N in the formula (I) is an amino compound, such as, for example, alkylamine, aromatic amine, cyclic saturated or unsaturated amine. HX is an acid radical, such as, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and any other mineral acid, such as, for example, acetic acid, fumaric acid or maleic acid. The reaction of the complex organic amine acid salt with a free amino compound to transfer an acidic radical to the free amino groups can be carried out in the presence of a suitable solvent, therefore, the complex amino acid salt does not dissociate easily in the solvent. In general, in order to select an appropriate donor compound the pKa of the donor compound must be less than at least the greater pKa of the receptor-free amino compound. The pKa of the donor and receptor compounds are based on the basic nitrogens there. A donor compound suitable for the preparation of a monoacid salt of an amino compound having two pKa values due to the presence of at least two basic nitrogens must include, for example, these amino compounds have a pKa greater than the lowest pKa of the receptor compound but smaller than pKa greater than the receptor compound, for example, a pKa value between the two pKa values of the receptor compound. Similarly, the preparation of the di-acid salt of an amino compound has two values because the basic nitrogens require a donor compound having a pKa lower than the pKa of the receptor compound. The preparation of a monoacid salt of a compound having three pKa values requires a donor compound having a pKa value between the highest pKa value and the second highest pKa value of the receptor compound. The di-acid salt of an amino compound having three pKa values is prepared using a donor amino compound having a pKa value between the lower pKa value and the second higher pKa value of the free receptor amine. In preparing the tri-acid salt of an amino compound having three pKa values, the donor compound must have a pKa value below the pKa minor value of the receptor compound. As can be seen from the examples above, a monoacid salt or a selective multi-acid salt of an amino compound can be selectively prepared by using a donor compound having an appropriate pKa relative to the pKa (s) of the receptor compound. The Lange's Handbook of Chemistry, 14th de., J. A. Dean de. McGraw-Hill, New York, New York, 1992, Table 8.8 which is incorporated herein in its entirety in reference, discloses the value (s) of pKa of a number of organic amino compounds that can be used in the practice of the present reaction of acid radical transfer. Preferred donor compounds used in the practice of the present invention to prepare ranitidine HCl, for example, include HCl pyridine, HCl dimethyl pyridine, HCl chloropyridine and quinoline, and more preferably, HCl 2, 5-dimethylpyridine. Therefore, in the preparation of the mono-acid salt of ranitidine hydrochloride by the method of the present invention, any amino acid salt having a pKa between 2.3 and 8.2 and which is soluble in the selected solvent can be used. In addition to its pKa value, the donor compound can be selected based on its solubility in the solvent or solvents used in the reaction. The donor compound must be soluble in the selected solvent in order for the transfer of the acid radical from the donor amine to the receptor amine to occur.
Thus, unlike conventional methods that are used to prepare amino acid salt compounds, the present method for preparing an acid salt of an amino compound does not depend on the neutralization between an acid and a base to effect the formation of the compound of the amino acid. amino acid salt. Instead, the important factors in the present method are the difference of the amine basicity between the donor compound and the receptor compound and the solubility of the reaction compounds in the reaction solvent system, which effects the transfer of the acid radical. Although the investigation of the mechanisms of the acid radical transfer reaction is current and the Applicant does not wish to be bound to a particular theory or theories, it is believed that the reaction of the donor amino acid compound of the formula (I) with the receptor compound of free amine can be represented by the following general reaction scheme H0 (R, R ', R ") N CL + (R' RV)?
(in solution) e (R, R ', R ") N CL + (R', R" R H
R '"
I where N - R "" is a free amino compound, R, R 'and R'
RV
are defined above and R '", R" ", Rv are similarly defined The reaction of the donor amino acid compound of the formula (I) with the free amino receptor compound is believed to involve a transient soluble formation between the basic nitrogen (s) of the free amine and the less basic amine of the donor compound, which results in the transfer of the acidic radical from the less basic donor to the free amino compound.The solvent used in the present process can be selected on the basis of its polarity, solubility and solubilities in that of the free amino receptor compound and the production of the amino acid salt of the reaction, the receptor compound must be soluble in the solvent.
In any case, the solvent must not be a good solvent for the amino acid salt produced in the reaction, where the amino acid salt produced must precipitate in the solvent all the time. While the amino acid salt produced is formed, the solubility of these compounds of the amino acid salt in the solvent decreases. As discussed above, it is necessary that the donor amino acid salt be soluble in the selected solvent in order for solubilization to occur. For example, it can be easily recognized by one skilled in the art that many compounds with free amines are readily soluble in hydroxyl solvent. The selection of the donor compound for an acid transfer reaction in a hydroxyl solvent, in any way, may be more limited. A suitable donor compound for use with the hydroxyl solvent is 2,5-dimethyl pyridine HCl, for example. Thus, the selection of the solvent should depend in part on the solubilities and the solubilization of the reactants and the product of the reaction. The solvent can also be selected on the basis of the polarity of the solvent and the desired crystalline form of the acid salt produced. It is known that several acid salt compounds can have two or more polymorphic structures. For example, ranitidine hydrochloride exists in Form I or Form II. The polarity of the solvent affects the polymorphic form of the crystalline product, depending on which polymorphic form of the product is desired, either a protic or aprotic solvent of low polarity or a protic or aprotic solvent of high polarity can be selected. Low polarity protic and aprotic solvents include, for example, mixtures of tetrahydrofuran and ethyl acetate (1: 1, v). High polarity solvents include, for example, hydroxyl solvent, such as, ethanol and isopropanol, which are used in the production of ranitidine HCl, for example. In the present acid radical transfer reaction nucleation can be done to occur very slowly. If desired, a very long precipitation period may be employed in the production of the amino acid salt produced. For example, the period of precipitation can range from days to weeks. Because nucleation can be done to occur slowly, nucleation in a mixed solvent system can generally be delayed until the solvent mixture is homogeneous. Thus, it is possible to directly affect the polymorphic state of the amino acid salt produced by the reaction without the use of a strong acid or an anti-solvent. Consequently, the product of the present acid radical transfer reaction exhibits an increase in polymorphic purity in comparison to the amino acid salt compounds formed by an exothermic neutralization reaction, for example.
The present stoichiometric acid radical transfer reaction is directed to terminate the precipitation of the acid salt produced over time. The temperature at which the reaction is carried out can be varied to increase or decrease the speed of the reaction. Generally the reaction is carried out at a temperature in the range from near room temperature to about 40 ° C. Preferably, the reaction is carried out at room temperature. In any case, because the transfer reaction of the acid radical of this invention is carried out in the absence of free acid or antisolvent, the temperature of the reaction may rise without any detrimental effect on the integrity of the product. The temperature of the reaction can be raised in order to affect the rate of the transfer reaction of the acid radical and size and shape of the crystalline product without causing any structural transformation of the amino acid salt produced by the acid hydrolysis or without causing tautomerism of the product. Thus, if desired, the present process can be carried out at elevated temperature above and around the boiling point of the solvent system.
The crystallization of the product amino acid salt can be aided by stirring the reaction mixture during the reaction or, if desired, inducing crystallization with an appropriate product amino acid salt. The desired species of an amino acid salt compound can be produced by selecting a donor compound from the amino acid salt having a low pKa relative to the pKa (s) of the receptor free amine and / or by adjusting the molar amount of the reactants . This is in order to produce a monoacid salt of an amino compound having two or more pKa values due to the acid nitrogens, the molar amount of the donor amino acid salt used in the reaction is approximately equimolar to the amount of free amine receptor. in the reaction. Similarly, di-acid amine salts can be produced by the present process by adjusting the molar amounts of the donor amino acid salt to the free amine receptor about 2: 1. The present acid radical transfer reaction can be used in the preparation of a wide variety of amino acid salt products. The present process can be used to prepare acid salts of amino compounds such as, for example, ranitidine, to increase the polymorphic and / or purity of the hydrochloric salt thereof; omeprazole, to produce a monohydrochloride salt thereof in the absence of a free strong acid; lisinopril, to produce the selected number of acid radicals per amino acid salt thereof; diltiazem, to increase the stability and purity of it; elanapril, to selectively adjust the pH and increase the stability of it; pirenzepine, to increase the polymorphic purity of this; melphalan, to increase its solubility; celiprolol, clonidine, mexilena, metoclopranide, terbutaline, terazosin, thiamin, to increase the purity of each of said compounds; antibiotics that have one or more basic nitrogens, such as β-lactams, quinolones, cyclopentanoids, macrolides, peptide antibiotics, glycopeptides, carbohydrate antibiotics, and the like; cefepime; and the amino class glycosides of antibiotics, for example, betamicin, gentamicin, tobramycin, netlimicin and the like. The present process is particularly useful in the production of acid salts of β-lactam antibiotics since the β-lactam antibiotics are unstable under acidic conditions and, therefore, can not be easily made by conventional methods using an exothermic neutralization reaction and a strong acid. The hygroscopicity, pH, solubility, structure and polymorphic stability of the amino acid salt produced by the process of the present invention can be effected selectively by adjusting the amount of the acid transferred by free amino receptor compound. The amount of the acid transferred from the compound donor of the amino acid salt to the amine receptor molecule can be effected by the selection of the donor molecule having a pKa having a desired lower degree of the pKa of the donor compound. The size and crystalline form of the amino acid salt compound produced by the present transfer reaction of the amino acid can be effected by the polarity of the solvent system used in the reaction. The amino acid salt of a particular compound can be consistently obtained in pure form as a simple species that is substantially of any other structural form of the amino acid salt compound used in the present process. By "substantially " of other forms of the compound means that other forms, for example, acidic or polymorphic salt having different numbers of acids in the amine present in a sample of a compound to an amount sufficient to produce a peak or peaks that can be detected by H-NMR spectroscopy or to an amount sufficient to provide a standard detectable by dust diffraction in X-Rays. The present 2
The process also provides compounds of the amino acid salt of size, shape and selective polymorphic configuration. For example, the present acid radical transfer reaction provides ranitidine HCl Form I which is substantially free of Form II. In addition, because the present process does not require the use of a strong acid or the direct reaction of an acid and a base, the amino acid salt produced by the present reaction does not undergo structural transformations that can induce the change in color or physical properties or chemical compounds. Accordingly, the amino acid salt compounds produced by the present acid radical transfer reaction have significantly improved shelf life compared to similar compounds produced by an exothermic neutralization reaction. Additionally, the transfer reaction of the acid radical of the present invention provides amino acid salt compounds of significantly improved purity due, in part, to the removal of the acid known to induce additional reactions resulting in impurities, and the ability to effect selectively the speed of the acid transferred. The process of the present invention provides ranitidine hydrochloride having a significantly improved purity compared to ranitidine hydrochloride prepared by known methods. When the ranitidine hydrochloride is prepared by an exothermic neutralization reaction as described in US Patent 4, 128, 658 it undergoes a structural transformation due to the presence of excess acid or strong acid (HCl). The structural transformation of the amine can induce color change, alteration of the physical and chemical properties of the compound and the formation of dangerous impurities, all can have an effect on the shelf life and / or therapeutic effectiveness of the compound. In addition, the preparation of hydrochloride. of ranitidine by the process of US Pat. No. 4,128,658 provides ranitidine hydrochloride Form I which is contaminated by Form II, which is formed at the same time that the acid salt begins to crystallize. Crystallization begins as soon as free ranitidine base is added to the alcohol-HCl solution, even before the addition of the antisolvent. Additionally, the use of excess hydrochloric acid in the neutralization reaction results in the production of n HCl (n> 1) ranitidine, which consists of one mole of free ranitidine base and more than one mole hydrochloric acid. The n HCl (n > l) ranitidine is extremely hygroscopic and acidic and has very low solubility in organic solvent. Thus, the n HCl (n> 1) ranitidine can not exist in crystalline form in the atmosphere or as a mixture of ranitidine hydrochloride Form I or Form II because of its hygroscopicity. Because of its low solubility of the n H1 (> 1) ranitidine hydrochloride in organic solvent it is extremely difficult to remove this contaminant from the desired product. For example, when nHCl (n = 1) ranitidine is contaminated with a very small amount of nHCl (n> 1) ranitidine, the mixture becomes acidic because the contaminant nHCl (n> 1) ranitidine rapidly absorbs moisture from the atmosphere. When nHCl (n = l) ranitidine is contaminated with nHCl (n> l) ranitidine the contaminant accelerates the degradation and / or color change of ranitidine hydrochloride in the atmosphere. Figure 6 provides an H-NMR spectrum of nHCl (n> 1) of ranitidine prepared by a conventional neutralization reaction using a strong acid. The H-NMR spectrum of a monoacid salt a form of nHCl (n = l) of ranitidine prepared by the present method is shown in Figure 3. As can be seen, the existence of ranitidine nHCl (n> 1) can be detected easily by H-NMR spectroscopy by the presence of two peaks between peaks at about 3.9 and about 3.5 PPM and two peaks between about 3.4 and about 2.9 PPM. The H-NMR spectrum of the monohydric form of nHCl (n = l) of ranitidine does not have these four peaks. All the characteristic features of the nHCl (n = l) of ranitidine produced by the present method are as discussed in the Analytical Profile of Drug Substance, vol. 15, 1986, incorporated herein by reference. The ranitidine hydrochloride produced by the present stoichiometric acid radical transfer reaction is substantially free of contamination by nHCl (n >l) ranitidine and ranitidine HCl Form II. Consequently, the ranitidine hydrochloride of the present invention is less hygroscopic, more stable to atmosphere and light and the crystals are of uniform size and shape. The present acid radical transfer reaction can also be used to purify a species of a desired amino acid salt from a mixture of more than one species of the amino acid salt. Removing the impurities from a mixture of an amino acid salt containing more than one species of the amino acid salt is carried out by placing the mixture in a solution with a free amino compound having a pKa value between two pKa values of the mixture of the compound of the amino acid salt, which results in the selective transfer of the acid radical from the impurities to the free amine. This reaction produces, like the product, a simple species of the amino acid salt compound. In a preferred embodiment of the invention, the process is used to purify a simple ranitidine hydrochloride species from a mixture of ranitidine hydrochloride containing more than one species thereof.
In order that the invention can be fully understood the following examples are given as a way of illustration only and are intended not to limit the method.
EXAMPLE 1 Preparation of ranitidine hydrochloride Form I.
Free ranitidine base (50g, 0.16 mol) was dissolved in 500 ml of a mixture of industrial methyl alcohol (250 ml, 74 ° o.p.) and ethyl acetate (250 ml). 24.13g (0.168 mol) of 2,5-dimethylpyridine hydrochloride was added to the reaction mixture with stirring and under atmospheric moisture protection. The ranitidine hydrochloride was allowed to crystallize with stirring. The crystals were filtered, washed with the mixture of industrial methyl alcohol (25 ml) and ethyl acetate (25 ml) and dried at 50 ° C under reduced pressure to give 50 g of ranitidine hydrochloride of Form I, which it is free from contamination of the ranitidine n-hydrochloride of Form II (n> 1) and other impurities. Analytical profiles of ranitidine hydrochloride product of this reaction was obtained by X-ray powder diffraction (Figure 1), FT-IR analysis (Figure
2), and H-Nuclear Magnetic Resonance (H-NMR) (Figure
3) . For comparative purposes, the H-NMR spectrum of ranitidine hydrochloride obtained by the method of USP 4,128,658 was obtained in the same manner as above and is shown in figure 7. It is believed that the two peaks between about 3.4 and close to 2.9 PPM in the H-NMR spectrum are due to the uncontrolled reaction where more than one mole of hydrochloric acid reacted by free amine.
EXAMPLE 2 Preparation of ranitidine hydrochloride Form I
Ranitidine free base (6.28 g (0.02 mol), pKa 2.3, 8.2) was charged in 120 ml of a mixture of a solvent system of low polarity 60 ml of anhydrous tetrahydrofuran and 60 ml of anhydrous ethyl acetate. 3.02g (0.021 mol) of 2,5-dimethyl pyridine hydrochloride (pKa 6.43) was added to the reaction mixture with stirring and under atmospheric moisture protection. The ranitidine hydrochloride was allowed to crystallize with stirring. The crystals were filtered, washed with 40 ml of a mixture of tetrahydrofuran (20 ml) and ethyl acetate (20 ml) and dried at 50 ° C under reduced pressure to give 6.3 g of ranitidine hydrochloride of pure Form I which was free of ranitidine hydrochloride of Form II and n HCl (n> 1) of ranitidine and other impurities.
EXAMPLE 3 Preparation of ranitidine hydrochloride Form I
Ranitidine free base (6.28g (0.02 mol)) was charged in 120 ml of a mixture of a solvent system of low polarity 60 ml of anhydrous tetrahydrofuran and
60 ml of anhydrous ethyl ether. 3.02g (0.021 mol) of 2,5-dimethyl pyridine hydrochloride was added to the reaction mixture with stirring and under protection from atmospheric humidity. The ranitidine hydrochloride was allowed to crystallize with stirring. The crystals were filtered, washed with 40 ml of a mixture of tetrahydrofuran (20 ml) and ethyl ether (20 ml) and dried at 50 ° C under reduced pressure to give 6.3 g of ranitidine hydrochloride of pure Form I which was free of ranitidine hydrochloride of Form II and n HCl (n> 1) of ranitidine and other impurities.
EXAMPLE 4 Preparation of ranitidine hydrochloride Form I
Ranitidine free base (31.4g (0.1 mol)) was charged in 200 ml of a mixture of a low polarity solvent system 160 ml of anhydrous tetrahydrofuran and 160 ml of ethyl alcohol. 15.8g (0.11 mol) of 2,5-dimethyl pyridine hydrochloride was added to the reaction with stirring and under protection from atmospheric humidity. The ranitidine hydrochloride was allowed to crystallize at room temperature with stirring. The crystals were filtered and washed with 40 ml of a mixture of tetrahydrofuran (20 ml) and ethyl ether (20 ml) and dried at 50 ° C under reduced pressure to give 30 g of ranitidine hydrochloride of pure Form I which was free of Form II and n HCl (n> 1) of ranitidine and other impurities.
EXAMPLE 5 Preparation of ranitidine hydrochloride Form I
Ranitidine free base (6.28g (0.02 mol)) was charged in 100 ml of anhydrous tetrahydrofuran. 3.02g (0.021 mol) of 2,5-dimethyl pyridine hydrochloride was added to the reaction mixture with stirring and under protection from atmospheric humidity. The ranitidine hydrochloride was allowed to crystallize at room temperature with stirring. The crystals were filtered and washed with 30 ml of tetrahydrofuran and dried at 50 ° C under reduced pressure to give 6.0 g of ranitidine hydrochloride of pure Form I which was free of Form II and n HCl (n> 1) of ranitidine. and other impurities.
EXAMPLE 6 Preparation of ranitidine hydrochloride Form I.
Free ranitidine base (50g, 0.16 mol) was dissolved in 500 ml of a mixture of industrial methyl alcohol (250 ml, 74 ° o.p.) and ethyl acetate (250 ml). 24.13g (0.168 mol) of 2,5-dimethylpyridine hydrochloride was added to the reaction mixture with stirring and under atmospheric moisture protection. The ranitidine hydrochloride was allowed to crystallize with stirring. The crystals were filtered, washed with the mixture of industrial methyl alcohol (25 ml) and ethyl acetate (25 ml) and dried at 50 ° C under reduced pressure to give 50 g of ranitidine hydrochloride of Form I, which it is free from contamination of Form II, nHCl (n> 1) of ranitidine and other impurities.
EXAMPLE 7 Preparation of ranitidine hydrochloride of Form Y.
Free ranitidine base (106 g (1.29 mol)) was charged in 130 ml of ethanol and diluted with 240 ml of toluene under a constant flow of nitrogen. 40.5 g (0.35 ml) of pyridine HCl was added at room temperature. The reaction mixture was stirred until a suspension resulted, while being diluted with 50 ml of a 1: 1.5 mixture of ethanol / toluene. After stirring for one hour, 200 ml of isopropanol were added. The mixture was stirred for another hour and filtered. The filtrate was washed with 3 X 100 ml of isopropanol and dried under vacuum at 50 ° C to give 95 g (90%) of crude product. The IR analysis confirms that it is pure Form I ranitidine hydrochloride.
EXAMPLE 8 Preparation of ranitidine hydrochloride Form II in the absence of water.
Ranitidine free base (31.4g (0.1 mol)) was dissolved in 300 ml of 2-propanol at 40-50 ° C. 12.7 g (0.11 mol) of 2,5-dimethyl pyridine hydrochloride was added to the reaction mixture with stirring. The ranitidine hydrochloride was allowed to crystallize at room temperature with stirring. The crystals were filtered and dried at 50 ° C under reduced pressure to give 32 g of ranitidine hydrochloride of pure Form II which was free of Form I, n HCl (n> 1) of ranitidine and other impurities.
EXAMPLE 9 Preparation of ranitidine hydrochloride Form II
Pyridine hydrochloride (2.6 g) were added to a solution of ranitidine (6 g) in 2-methylpropan-2-ol.
The mixture was stirred at 40 ° C to allow the product to crystallize and the stirred result was cooled to 20 ° C. The product was filtered, washed with 2-methylpropan-2-ol and dried at 50 ° C under reduced pressure to give (5.96 g) of ranitidine hydrochloride of Form II which had a melting point of about 141-142 ° C. .
EXAMPLE 10 Preparation of Ranitidine Hydrochloride Form II
The process of Example 8 was repeated except that butan-2-ol was used in place of 2-methylpropan-2-ol and the mixture was stirred at 55 ° C. The resulting ranitidine hydrochloride was Form II and had a melting point near 141-142 ° C
EXAMPLE 11 Preparation of ranitidine hydrochloride Form II.
Ranitidine (6 g) was dissolved in industrial methyl alcohol 74 ° o.p. (42 ml) at room temperature (about 20 °). 2.6 g (0.168 mol) of pyridine hydrochloride was added to the solution. The temperature of the solution above 27 ° C and the mixture was seeded to induce crystallization. The crystallized product gave a thick stirring at about 25-27 ° C. After 0.5 hours the stirred was cooled to 10-12 ° C for 0.5 hours. The product was filtered, washed with industrial methyl alcohol (5 ml) and dried at 50 ° C under reduced pressure to give 5.4 g of ranitidine hydrochloride of Form II having a melting point of about 139-140 ° C. .
EXAMPLE 12 Purification of ranitidine hydrochloride Form I from a mixture containing more than one species of ranitidine hydrochloride.
Ranitidine free base (50 g (0.1 mol)) was dissolved in industrial methyl alcohol (74 ° o.p. (200 ml)) containing 0.16-0.192 equivalents of hydrochloric acid. The 2-propyl pyridine (5 g) were dissolved in a reaction mixture. Ethyl acetate (200 ml) was slowly added to the solution. The crystallized ranitidine hydrochloride was filtered, washed with a mixture of industrial methyl alcohol 74 ° o.p. (50 ml) and ethyl acetate (50 ml) and dried at 50 ° C. The product (50 g) was obtained as a crude colored solid having a melting point near 133-134 ° C.
EXAMPLE 13 Purification of ranitidine hydrochloride Form II in the absence of water of a ranitidine hydrochloride mixture containing more than one species of ranitidine hydrochloride.
An equivalent (about 5.3 ml) of concentrated hydrochloric acid was added to a solution of ranitidine (20 g) in a mixture of propan-2-ol (300 ml) at 45 ° C. The mixture was heated to 50 ° C and then 0.4 g of pyridine was added to the reaction mixture. The resulting solution was stirred at 50 ° C to allow the product to crystallize. The stirred was cooled to 10-12 ° C and the product was filtered, washed with propan-2-ol (2 X 27) and dried at 50 ° C under reduced pressure to give 22 g of ranitidine hydrochloride of Form II which has a melting point of 139-141 ° C.
EXAMPLE 14 Purification of ranitidine hydrochloride Form II from a mixture containing more than one species of ranitidine hydrochloride.
The ranitidine hydrochloride of Form II (35 g) prepared by the method of USP 4,128,658 was heated in a mixture of propan-2-ol (520 ml) and pyridine (0.2 g) and the resulting solution was stirred at 50 °. C. The product was allowed to crystallize at 50 ° C. The agitation was cooled to 10-12 ° C and the product was filtered, washed with propan-2-ol (2x30 ml) and dried at 50 ° C under reduced pressure to give ranitidine hydrochloride of form II (34 g) which has a melting point of 139-141 ° C
EXAMPLE 15 Purification of ranitidine hydrochloride Form II from a mixture containing more than one species of ranitidine hydrochloride.
The ranitidine hydrochloride of Form II (50 g) prepared by the process of USP 4,128,658 and 0.3 g of pyridine was dissolved in industrial methyl alcohol
74 ° o.p. (200ml) at 70 ° C. The solution was allowed to cool and the product will crystallize away from 40 ° C. The resulting stirring was cooled to 0 ° C and the product was filtered, washed with industrial methyl alcohol (20 ml) and dried at 50 ° C under reduced pressure to give 47.7 g of ranitidine hydrochloride of form II having a point of fusion of 140-142 ° C
EXAMPLE 16 Purification of Ranitidine hydrochloride of form II from a mixture containing more than one species of ranitidine hydrochloride.
Concentrated hydrochloric acid (HCl) (1.4 ml) was added to a solution of ranitidine (6 g) in 2-methylpropan-2-ol. The mixture was stirred at 40 ° C to allow the product to crystallize and the resulting stirring was cooled to 20 ° C. In addition the concentrated HCl
(about 0.2 ml) was added to the mixture and stirred for one hour at 20 ° C. 0.04 g of pyridine was added to the reaction mixture. The product was filtered, washed with 2-methylpropan-2-ol and dried at 50 C under reduced pressure to give 5.96 g of ranitidine hydrochloride of form II having a melting point of 141-142 °.
EXAMPLE 17 Purification of Ranitidine hydrochloride from the form
II of a mixture containing more than one species of ranitidine hydrochloride.
The process of Example 12 was repeated except that butan-2-ol was used in place of 2-methyl-2-propan-2-ol and the mixture was stirred at 55 ° C to give 6.1 g of ranitidine hydrochloride in the same way II which has a melting point of 140-141 ° C.
EXAMPLE 18 Purification of ranitidine hydrochloride Form II from a mixture containing more than one species of ranitidine hydrochloride.
Ranitidine free base (6 g) was dissolved in industrial methyl alcohol 74 ° o.p. (42 ml) at room temperature (about 20 °). An equivalent
(about 1.6 ml) of concentrated HCl was added to the solution. The temperature above 27 ° C and 0.3 g of pyridine was added to the reaction mixture. The solution was seeded to induce crystallization. The crystallized product had a thick agitation at 25-27 ° C. After 0.5 hours the stirred was cooled to 10-12 ° C for 0.5 hours. The product was filtered, washed with industrial methyl alcohol (5 ml) and dried at 50 ° C under reduced pressure to give 5.4 g of ranitidine hydrochloride of Form II having a melting point of about 139-140 ° C. .
EXAMPLE 19 Preparation of mono-acid salt of omeprazole (5-Methoxy- [[(a-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -H-benzomidazole)
The pure mono-acid salt of omeprazole free from contamination of the di-acid salt of omeprazole and other impurities is prepared by the stoichiometric acid transfer reaction using one mole of acid salt 2,5-dimethyl pyridine (pKa = 6.3) with a mole of omeprazole free base (pKa 4.0 and 8.7) in a highly polar solvent, such as acetonitrile or a hydroxylic solvent, or in a low polarity solvent, such as tetrahydrofuran. The crystals of omeprazole mono-acid are allowed to form at room temperature with stirring. The crystals are filtered and washed with a sufficient quantity of the solvent and dried at a temperature under reduced pressure to give a pure mono-omeprazole.
EXAMPLE 20 Preparation of acid salts of cefepime (7- [2- (2-aminothiazol-4-yl) -20 (z) -methoxyaminoacetimido] -3- [(1-methyl-1-pyrrolidino) methyl] -3- cefem-4-carboxylate) Production of a mono-acid salt of zwitterion cefepime The monochloride salt (C19H24N6OsS2.HCl .XH20) is prepared by a transfer reaction of a stoichiometric amino acid using one mole of pyridine hydrochloride with one mole of zwitterion of cefepime in either a low polarity solvent system (water with acetone or 5% aqueous methanol) or a solvent system of high polarity (methylene chloride).
The dihydrochloride salt (C19H24N605S2.2HC1.XH20) is prepared by a stoichiometric amino acid transfer reaction using two moles of 2-chloropyridine hydrochloride with one mole of zwitterion of cefepime in either a low polarity solvent system (water with acetone or 5% aqueous methanol) or a solvent system of high polarity (methylene chloride (80%) with methanol (20%)).
Half a mole of the sulfuric acid salt [(C19H24Ng05S2) 2.H2S04] is prepared by a stoichiometric acid transfer reaction using one mole of pyridine sulfate [(C5H5N) 2.H2S04] with two moles of zwitterion of cefepime in either a low polarity solvent (water with acetone or 5% aqueous methanol) or a high polarity solvent (methylene chloride (80%) with methanol (20%)). The mono-sulfuric acid salt [C19H24N605S2.H2S04] is prepared by a stoichiometric acid transfer reaction using one mole of 2-chloropyridine sulfate [(C5H5NC1) 2.H2S04] with one mole of zwitterion of cefepime in any one solvent of low polarity (water with acetone or 5% methanol 2
aqueous) or a solvent of high polarity (methylene chloride (80%) with methanol (20%)). Crystallization, filtration, washing and drying of the crystals is carried out as described in example 7.
EXAMPLE 21 Preparation of the acid salts of the aminoglycoside class of antibiotic compounds
Sulfuric acid salts equivalent to each pKa value of each aminoglycoside antibiotic compound listed below were prepared by a stoichiometric acid transfer reaction. Each of the aminoglycoside compounds contains five basic nitrogens. Arbekacin n H2S04 Betamycin n H2S04 Gentamicin n H2S04 Netilmicin n H2S04 Paromomicin n H2S04 Tobramycin n H2S04 A donor compound of the organic amine sulfuric acid salt reacts with the aminoglycoside antibiotic to a desired molar amount of each reagent as described in example 8. The high polarity solvent used for the reactions is ethanol; The low polarity solvent is chloroform. The value, n, in the salt of the resulting aminoglycoside antibiotic is 1, 1.5, 2 or 2.5.
EXAMPLE 22 Preparation of amino acid salts of various compounds
The size the state and the desired crystalline form of the following organic amine salts compounds are prepared by the stoichiometric acid transfer reaction in different polar solvent systems as described in example 7, using an appropriate donor and receptor compounds and a adequate solvent. salts of DN-9693: 7- (1-piperdinyl) -1, 2, 3, 5-tetrahydroimidazo [2, 1-b] kinasolin-2-one. 2HC1 or 1HC1 salts of BYM43351: 1- (cyclohexylmethyl) -4- [4- (2,3-dihydro-2-oxa-lH-imidazo [4, 5-b] quinolin-7-yloxy) -1-oxobutyl] piperazine. 2HC1 or 1HC1 MDL 27,695: 1, 19-diphenyl-2,6,6, 14, 18-tetra-azanonadecane salts. 4HC1 or 2HC1 ukrain salts: 5, 5 ', 5"trihydroxide - [phosphinothiolidine-tris (imino-2, l-ethanediyl-tris [5-methyl-ludidoninium]]. 6HC1 or 3HC1 salts of JM3100: 1,1'- [1,4-phenylene-bis (methylene) bis [1,4,8,10-tetra-azacyclotetra decane]]. 8HBr or 2HBr salts of BBE: trans-1,2-bis (5-amidino-2-benzimidazolyl) ethylene 4HC1 or 2HC1 salts of SK &F 1056895: N, N-Dimethyl-8,8-dipropyl-2-azaspiro [4, 5] decane-2-propanomine (in a hydroxylic solvent) salts of ametazole: 2- ( pyrazol-3-yl) ethylamine 2HC1 or HCL Framycetin salts 4H2S04 or 2H2S04
salts of liblomicin 3HCL, 2HC1 or HCL
Claims (46)
1. A method for preparing an acid salt of an amino compound, characterized in that it comprises placing a donor compound having at least one radical of an amino acid salt in solution with a free amino compound, said donor compound having a pKa below at least pKa In order to provide a transfer of a radical of the acidic salt of the donor compound to the free amino compound, the product of these is an amino acid salt of a free amino compound.
2. The method of claim 1, characterized in that the acid radical is transferred from the donor compound to the free amino compound in a stoichiometric reaction.
3. The method of claim 1, characterized in that it further comprises crystallizing the amino acid salt of the free amine.
4. The method of claim 3, characterized in that it also comprises the subsequent steps of isolating, washing and drying the product.
5. The method of claim 1, characterized in that the amino acid salt of the free amine consists essentially of a simple species of a compound of an amino acid salt.
6. The method of claim 1, characterized in that an approximately equimolar amount of each of the free amine compounds and the donor compound are placed in a solution to produce a monoacid salt of the free amino compound,
7. The method of claim 6, characterized in that the monoacid salt is ranitidine hydrochloride.
8. The method of claim 7, characterized in that the donor compound is dimethylpyridine hydrochloride.
9. The method of claim 6, characterized in that the monoacid salt of ranitidine hydrochloride is substantially free of ranitidine acid salt having more than one acid radical per amino compound radical.
10. The method of claim 9, characterized in that the monohydric salt of ranitidine hydrochloride has Form I which is substantially free of ranitidine Form II.
11. The method of claim 7, characterized in that the donor compound and the free amino compound are placed in solution in protic or aprotic solvent having low polarity.
12. The method of claim 1, characterized in that the donor compound has the general formula, R'-N®: H-X0 I R characterized in that R, R 'and R "are each independently H, an aryl group having from one to nine carbon atoms or an alkyl group having from one to twenty carbon atoms, or R, R' and R" together with N form a substituted or unsubstituted heterocyclic amine, R '-N is an amino compound and XH is R " an acid radical.
13. The method of claim 12, characterized in that the acid radical is selected from the group consisting of HCl, H2SO4, HBr and H3P04.
14. The method of claim 13, characterized in that the donor compound is selected from the group consisting of acid pyridine salt, acid salt of dimethylpyridine, chloropyridine, acid salt of quinoline, and derivatives thereof.
15. The method of claim 1, characterized in that the amino acid salt of the free amino compound is an antibiotic of the acid salt of aminoglycoside.
16. The method of claim 1, characterized in that the donor compound and the free amino compound are placed in solution in a protic or aprotic solvent having a low polarity.
17. The method of claim 16, characterized in that the solvent comprises a mixture of organic solvents.
18. The method of claim 1, characterized in that the donor compound and the free amino compound are placed in solution in a protic or aprotic solvent having a high polarity.
19. The method of claim 18, characterized in that the solvent comprises a mixture of organic solvents.
20. The method of claim 19, characterized in that the polarity of the solvent mixture is adjusted to provide a desired polymorph of the product.
21. The method of claim 1, characterized in that the free amino compound and the donor compound react at room temperature.
22. The method of claim 1, the product is a monoacid salt of omeprazole, which is substantially free of the di-acid salt of omeprazole.
23. The method of claim 1, characterized in that the free amino compound has two pKa values and the donor compound has a pKa value between the two pKa values of the free amino compound.
24. The method of claim 23, characterized in that the product is a monoacid salt of the free amino compound or a corresponding hydrate thereof.
25. The method of claim 1, characterized in that the free amino compound has two pKa values and the donor compound has a pKa value that is less than the smaller pKa value of the free amino compound.
26. The method of claim 25, characterized in that the product is a di-acid salt of the free amino compound or a corresponding hydrate thereof.
27. The method according to claim 1, characterized in that the free amino compound has three pKa values and the donor compound has a pKa value that is less than the lowest pKa value of the free amino compound.
28. The method of claim 27, characterized in that the product is a tri-acid salt of the free amino compound or a corresponding hydrate thereof.
29. The method according to claim 1, characterized in that the free amino compound has three pKa values and the donor compound has a pKa value between the highest pKa value and the second highest pKa value of the free amino compound.
30. The method of claim 29, characterized in that the product is a monoacid salt of the free amino compound or a corresponding hydrate thereof.
31. The method according to claim 1, characterized in that the free amino compound has three pKa values and the donor compound has a pKa value between the second highest pKa value and the lowest pKa value of the free amino compound.
32. The method of claim 31, characterized in that the product is a monoacid salt of the free amino compound or a corresponding hydrate thereof.
33. A method for preparing ranitidine hydrochloride of Form I which is substantially free of ranitidine hydrochloride of Form II, characterized in that it comprises treating ranitidine free base with donor compound capable of transferring HCl to ranitidine free base in a solution of a solvent having a convenient polarity for precipitating the ranitidine hydrochloride of Form I.
34. The method of claim 33, characterized in that the donor compound has a pKa in the down range near 8 and up close to 3.
35. The method of claim 33, characterized in that the donor compound has a pKa of about 6.0 to about 6.6.
36. The method of claim 33, characterized in that the solvent is a protic or aprotic solvent having low polarity.
37. The method of claim 33, characterized in that the solvent comprises a mixture of anhydrous tetrahydrofuran and anhydrous ethyl ether in a ratio of 1: 1 (v / v).
38. The method of claim 33, characterized in that the donor compound is selected from the group consisting of pyridine HCl, dimethylpyridine HCl, chloropyridine HCl, quinoline HCl and derivatives thereof.
39. The method of claim 33, characterized in that the donor compound is 2, 5-dimethylpyridine HCl.
40. The method of claim 39, characterized in that the ranitidine n hydrochloride is a monoacid salt which is substantially free of ranitidine hydrochloride (n> 1).
41. The method of claim 33, characterized in that ranitidine hydrochloride is a monoacid salt where n greater than 1 and a monoacid salt of ranitidine hydrochloride is substantially free.
42. A method for removing impurities from a mixture of a compound of an amino acid salt comprises more than one species of said amino acid salt compound, characterized in that it comprises placing said mixture in solution with a free amino compound having a pKa value between two pKa values of the mixture of the amino acid salt compound, to provide a selective transfer of the acid salt radical of the compounds of the amino acid salt comprising said mixture to the free amine thereby eliminating impurities, giving as a product of this a single species of compounds of the amino acid salt. free by means of that to eliminate impurities, giving as a product of this a single species of compounds of the amino acid salt.
43. The method of claim 42, characterized in that the mixture comprises more than one species of ranitidine hydrochloride.
44. The method of claim 43, characterized in that the free amino compound is pyridine.
45. The method of claim 43, characterized in that the mixture and the donor compound are placed in solution in a protic or aprotic solvent having low polarity.
46. The method of claim 43, characterized in that the mixture and the donor compound are placed in solution in a protic or aprotic solvent having high polarity.
Applications Claiming Priority (3)
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US08/515,790 US5686588A (en) | 1995-08-16 | 1995-08-16 | Amine acid salt compounds and process for the production thereof |
US08515790 | 1995-08-16 | ||
PCT/US1996/013246 WO1997007112A1 (en) | 1995-08-16 | 1996-08-16 | Amine acid salt compounds and process for the production thereof |
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MXPA98001205A true MXPA98001205A (en) | 1998-04-01 |
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US (1) | US5686588A (en) |
EP (1) | EP0859768B1 (en) |
JP (1) | JPH11508601A (en) |
KR (1) | KR100259205B1 (en) |
CN (1) | CN100338050C (en) |
AT (1) | ATE230737T1 (en) |
AU (1) | AU713507B2 (en) |
BR (1) | BR9610288A (en) |
CA (1) | CA2227264C (en) |
DE (1) | DE69625699T2 (en) |
IL (1) | IL123212A0 (en) |
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US5973005A (en) * | 1998-02-26 | 1999-10-26 | Bio-Bontanica, Inc. | Aqueous creatine solution and process of producing a stable, bioavailable aqueous creatine solution |
US7772220B2 (en) * | 2004-10-15 | 2010-08-10 | Seo Hong Yoo | Methods and compositions for reducing toxicity of a pharmaceutical compound |
US7303768B2 (en) * | 1998-07-24 | 2007-12-04 | Seo Hong Yoo | Preparation of aqueous clear solution dosage forms with bile acids |
EP1113785B1 (en) | 1998-07-24 | 2005-04-13 | Seo Hong Yoo | Clear aqueous solutions of bile acids |
US20050158408A1 (en) * | 1998-07-24 | 2005-07-21 | Yoo Seo H. | Dried forms of aqueous solubilized bile acid dosage formulation: preparation and uses thereof |
US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
US6316020B1 (en) | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
US6780880B1 (en) * | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
EP1255566A2 (en) * | 2000-02-04 | 2002-11-13 | Seo Hong Yoo | Preparation of aqueous clear solution dosage forms with bile acids |
US7145125B2 (en) | 2003-06-23 | 2006-12-05 | Advanced Optical Technologies, Llc | Integrating chamber cone light using LED sources |
ES2339790T3 (en) * | 2004-08-30 | 2010-05-25 | Seo Hong Yoo | NEUOPROTECTOR EFFECT OF UDCA SOLUBILIZED IN FOCAL ISCHEMICAL MODEL. |
ATE506955T1 (en) * | 2004-10-15 | 2011-05-15 | Seo Hong Yoo | COMPOSITIONS FOR REDUCING THE TOXICITY OF CISPLATIN, CARBOPLATIN AND OXALIPLATIN |
CA2585471A1 (en) * | 2004-11-01 | 2006-05-11 | Seo Hong Yoo | Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis |
US20060160783A1 (en) * | 2004-12-30 | 2006-07-20 | Transform Pharmaceuticals, Inc. | Novel omeprazole forms and related methods |
WO2006109324A2 (en) * | 2005-04-13 | 2006-10-19 | Lupin Limited | Processes for preparation of amorphous cefepime acid addition salts |
ITMI20051684A1 (en) * | 2005-09-13 | 2007-03-14 | Harvest Lodge Ltd | PROCEDURE FOR THE PRODUCTION OF AMINO ACID DICHLORIDRATE |
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US4107424A (en) * | 1972-10-06 | 1978-08-15 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | 1-N-[(S)-α-hydroxy-ω-aminoacyl] derivatives of 3',4'-dideoxykanamycin B and 3'-deoxykanamycin B antibiotics |
GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
SE7804231L (en) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
GB2067991B (en) * | 1980-01-08 | 1983-10-19 | Glaxo Group Ltd | Process for the preparation of a furan derivative |
CA1171096A (en) * | 1980-01-08 | 1984-07-17 | Glaxo Group Limited | Process for the preparation of a furan derivative |
IL63968A (en) * | 1980-10-01 | 1985-10-31 | Glaxo Group Ltd | Form 2 ranitidine hydrochloride,its preparation and pharmaceutical compositions containing it |
AR226777A1 (en) * | 1981-02-20 | 1982-08-13 | Glaxo Group Ltd | A PROCEDURE FOR THE PREPARATION OF RANITIDINE |
US4406899A (en) * | 1982-03-04 | 1983-09-27 | Bristol-Myers Company | Cephalosporins |
GB8415254D0 (en) * | 1984-06-15 | 1984-07-18 | Glaxo Group Ltd | Amine derivatives |
GB8907700D0 (en) * | 1989-04-05 | 1989-05-17 | Fine Organics Ltd | Preparation of substituted ethenes |
GB9009240D0 (en) * | 1990-04-25 | 1990-06-20 | Glaxo Group Ltd | Chemical compounds |
US5338871A (en) * | 1991-12-20 | 1994-08-16 | Torcan Chemical Ltd. | Preparation of form 1 ranitidine hydrochloride |
-
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- 1995-08-16 US US08/515,790 patent/US5686588A/en not_active Expired - Lifetime
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1996
- 1996-08-16 AU AU67255/96A patent/AU713507B2/en not_active Ceased
- 1996-08-16 BR BR9610288A patent/BR9610288A/en unknown
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- 1996-08-16 EP EP96927432A patent/EP0859768B1/en not_active Expired - Lifetime
- 1996-08-16 CN CNB961973366A patent/CN100338050C/en not_active Expired - Fee Related
- 1996-08-16 AT AT96927432T patent/ATE230737T1/en not_active IP Right Cessation
- 1996-08-16 WO PCT/US1996/013246 patent/WO1997007112A1/en active IP Right Grant
- 1996-08-16 JP JP9509483A patent/JPH11508601A/en active Pending
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- 1996-08-16 CA CA002227264A patent/CA2227264C/en not_active Expired - Fee Related
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