CA2243650C - Process for preparing purine derivatives - Google Patents

Process for preparing purine derivatives Download PDF

Info

Publication number: CA2243650C
Authority: CA; Canada
Prior art keywords: formula; compound; amino; group; hydroxy
Prior art date: 1996-01-26
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

CA002243650A

Other languages

English (en)

French (fr)

Other versions

CA2243650A1 (en

Inventor

Humberto B. Arzeno

Steven D. Axt

Colin C. Beard

Charles A. Dvorak

Paul R. Fatheree

Lawrence E. Fisher

Yeun-Kwei Han

Eric R. Humphreys

Jan P. Lund

Sam Linh Nguyen

Douglas Leslie Wren

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

F Hoffmann La Roche AG

Original Assignee

F Hoffmann La Roche AG

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1996-01-26

Filing date

1997-01-21

Publication date

2006-08-15

1997-01-21 Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG

1997-07-31 Publication of CA2243650A1 publication Critical patent/CA2243650A1/en

2006-08-15 Application granted granted Critical

2006-08-15 Publication of CA2243650C publication Critical patent/CA2243650C/en

2017-01-21 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

238000004519 manufacturing process Methods 0.000 title claims abstract description 16
229940083251 peripheral vasodilators purine derivative Drugs 0.000 title description 2
125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 title 1
150000003839 salts Chemical class 0.000 claims abstract description 74
238000000034 method Methods 0.000 claims abstract description 51
230000008569 process Effects 0.000 claims abstract description 34
150000001875 compounds Chemical class 0.000 claims description 133
UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 105
-1 2-substituted glycerol Chemical class 0.000 claims description 97
238000006243 chemical reaction Methods 0.000 claims description 64
239000002253 acid Substances 0.000 claims description 44
125000004423 acyloxy group Chemical group 0.000 claims description 30
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
125000006239 protecting group Chemical group 0.000 claims description 26
239000001257 hydrogen Substances 0.000 claims description 21
229910052739 hydrogen Inorganic materials 0.000 claims description 21
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
125000002102 aryl alkyloxo group Chemical group 0.000 claims description 17
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
150000002314 glycerols Chemical class 0.000 claims description 14
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 11
238000009833 condensation Methods 0.000 claims description 11
230000005494 condensation Effects 0.000 claims description 11
238000006460 hydrolysis reaction Methods 0.000 claims description 11
125000004432 carbon atom Chemical group C* 0.000 claims description 10
230000007062 hydrolysis Effects 0.000 claims description 10
238000007327 hydrogenolysis reaction Methods 0.000 claims description 8
125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 8
125000005905 mesyloxy group Chemical group 0.000 claims description 7
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 7
239000011968 lewis acid catalyst Substances 0.000 claims description 6
VTLHBYSIWPFXJM-UHFFFAOYSA-N [3-phenylmethoxy-2-(propanoyloxymethoxy)propyl] propanoate Chemical group CCC(=O)OCOC(COC(=O)CC)COCC1=CC=CC=C1 VTLHBYSIWPFXJM-UHFFFAOYSA-N 0.000 claims description 5
125000003545 alkoxy group Chemical group 0.000 claims description 5
WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 5
150000002431 hydrogen Chemical class 0.000 claims description 4
QHHLLMASUBEZEZ-UHFFFAOYSA-N 1,3-bis(phenylmethoxy)propan-2-yloxymethyl acetate Chemical compound C=1C=CC=CC=1COCC(OCOC(=O)C)COCC1=CC=CC=C1 QHHLLMASUBEZEZ-UHFFFAOYSA-N 0.000 claims description 3
125000003580 L-valyl group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 claims description 3
SGMJPROPRZAPNK-UHFFFAOYSA-N [2-(acetyloxymethoxy)-3-phenylmethoxypropyl] acetate Chemical compound CC(=O)OCOC(COC(C)=O)COCC1=CC=CC=C1 SGMJPROPRZAPNK-UHFFFAOYSA-N 0.000 claims description 3
125000001475 halogen functional group Chemical group 0.000 claims 8
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims 3
IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 abstract description 94
239000000047 product Substances 0.000 abstract description 49
239000000543 intermediate Substances 0.000 abstract description 42
150000002148 esters Chemical class 0.000 abstract description 19
239000012535 impurity Substances 0.000 abstract description 15
239000007858 starting material Substances 0.000 abstract description 12
238000000746 purification Methods 0.000 abstract description 8
239000007795 chemical reaction product Substances 0.000 abstract description 5
238000010521 absorption reaction Methods 0.000 abstract description 3
239000003443 antiviral agent Substances 0.000 abstract description 2
229960002963 ganciclovir Drugs 0.000 description 104
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
239000000203 mixture Substances 0.000 description 68
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
238000002360 preparation method Methods 0.000 description 37
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 32
229940024606 amino acid Drugs 0.000 description 28
235000001014 amino acid Nutrition 0.000 description 28
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 27
239000000243 solution Substances 0.000 description 27
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
238000001914 filtration Methods 0.000 description 22
229960004295 valine Drugs 0.000 description 22
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 21
MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 20
125000005843 halogen group Chemical group 0.000 description 20
239000002904 solvent Substances 0.000 description 19
150000001413 amino acids Chemical class 0.000 description 18
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
229960004150 aciclovir Drugs 0.000 description 17
239000003054 catalyst Substances 0.000 description 17
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Natural products C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 17
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
125000000217 alkyl group Chemical group 0.000 description 15
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
229940002612 prodrug Drugs 0.000 description 14
239000000651 prodrug Substances 0.000 description 14
239000003153 chemical reaction reagent Substances 0.000 description 13
239000011541 reaction mixture Substances 0.000 description 13
238000010992 reflux Methods 0.000 description 13
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 11
125000002252 acyl group Chemical group 0.000 description 11
125000003277 amino group Chemical group 0.000 description 10
239000002585 base Substances 0.000 description 10
239000003795 chemical substances by application Substances 0.000 description 10
230000032050 esterification Effects 0.000 description 10
238000005886 esterification reaction Methods 0.000 description 10
150000008554 L-valines Chemical class 0.000 description 9
230000015572 biosynthetic process Effects 0.000 description 9
238000004128 high performance liquid chromatography Methods 0.000 description 9
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 9
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
229910052799 carbon Inorganic materials 0.000 description 8
238000002955 isolation Methods 0.000 description 8
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 8
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 8
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
239000012458 free base Substances 0.000 description 7
238000005984 hydrogenation reaction Methods 0.000 description 7
229910052757 nitrogen Inorganic materials 0.000 description 7
239000007787 solid Substances 0.000 description 7
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
238000013019 agitation Methods 0.000 description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
239000010410 layer Substances 0.000 description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
238000000926 separation method Methods 0.000 description 6
238000006884 silylation reaction Methods 0.000 description 6
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
239000004474 valine Substances 0.000 description 6
KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 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
230000003197 catalytic effect Effects 0.000 description 5
239000007822 coupling agent Substances 0.000 description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
239000002002 slurry Substances 0.000 description 5
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
MTVWFVDWRVYDOR-UHFFFAOYSA-N 3,4-Dihydroxyphenylglycol Chemical compound OCC(O)C1=CC=C(O)C(O)=C1 MTVWFVDWRVYDOR-UHFFFAOYSA-N 0.000 description 4
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
230000002378 acidificating effect Effects 0.000 description 4
229910000147 aluminium phosphate Inorganic materials 0.000 description 4
BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 4
229910052921 ammonium sulfate Inorganic materials 0.000 description 4
235000011130 ammonium sulphate Nutrition 0.000 description 4
150000008064 anhydrides Chemical class 0.000 description 4
125000003118 aryl group Chemical group 0.000 description 4
239000012298 atmosphere Substances 0.000 description 4
238000006482 condensation reaction Methods 0.000 description 4
238000002425 crystallisation Methods 0.000 description 4
230000008025 crystallization Effects 0.000 description 4
230000004048 modification Effects 0.000 description 4
238000012986 modification Methods 0.000 description 4
230000003287 optical effect Effects 0.000 description 4
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
230000006340 racemization Effects 0.000 description 4
150000003254 radicals Chemical class 0.000 description 4
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 4
238000004809 thin layer chromatography Methods 0.000 description 4
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
FJXVYZMGZACQOS-UHFFFAOYSA-N 1-chloro-3-phenylmethoxypropan-2-ol Chemical compound ClCC(O)COCC1=CC=CC=C1 FJXVYZMGZACQOS-UHFFFAOYSA-N 0.000 description 3
125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 3
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 3
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
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 3
125000001931 aliphatic group Chemical group 0.000 description 3
239000000908 ammonium hydroxide Substances 0.000 description 3
239000000010 aprotic solvent Substances 0.000 description 3
SUMDYPCJJOFFON-UHFFFAOYSA-N beta-hydroxyethanesulfonic acid Natural products OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 3
125000001246 bromo group Chemical group Br* 0.000 description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
125000001309 chloro group Chemical group Cl* 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
238000000605 extraction Methods 0.000 description 3
239000012467 final product Substances 0.000 description 3
238000009472 formulation Methods 0.000 description 3
150000004820 halides Chemical class 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
229910000041 hydrogen chloride Inorganic materials 0.000 description 3
239000012442 inert solvent Substances 0.000 description 3
150000007522 mineralic acids Chemical class 0.000 description 3
150000007524 organic acids Chemical class 0.000 description 3
239000002798 polar solvent Substances 0.000 description 3
238000003756 stirring Methods 0.000 description 3
239000000725 suspension Substances 0.000 description 3
FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 3
CANZBRDGRHNSGZ-NSHDSACASA-N (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 CANZBRDGRHNSGZ-NSHDSACASA-N 0.000 description 2
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
WJSVJNDMOQTICG-UHFFFAOYSA-N 2-amino-1-[(2-methyl-4-methylidene-5-oxooxolan-2-yl)methyl]-7h-purin-6-one Chemical compound NC1=NC=2N=CNC=2C(=O)N1CC1(C)CC(=C)C(=O)O1 WJSVJNDMOQTICG-UHFFFAOYSA-N 0.000 description 2
KVFQMAZOBTXCAZ-UHFFFAOYSA-N 3,4-Hexanedione Chemical group CCC(=O)C(=O)CC KVFQMAZOBTXCAZ-UHFFFAOYSA-N 0.000 description 2
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 2
RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
HOOWCUZPEFNHDT-UHFFFAOYSA-N DHPG Natural products OC(=O)C(N)C1=CC(O)=CC(O)=C1 HOOWCUZPEFNHDT-UHFFFAOYSA-N 0.000 description 2
XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
239000004471 Glycine Substances 0.000 description 2
AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
208000009889 Herpes Simplex Diseases 0.000 description 2
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
239000002841 Lewis acid Substances 0.000 description 2
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical group CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
229960000310 isoleucine Drugs 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
239000007788 liquid Substances 0.000 description 1
231100000053 low toxicity Toxicity 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
229960002510 mandelic acid Drugs 0.000 description 1
235000013372 meat Nutrition 0.000 description 1
WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
238000002156 mixing Methods 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 description 1
MXSMRDDXWJSGMC-UHFFFAOYSA-N n-(6-oxo-3,7-dihydropurin-2-yl)acetamide Chemical compound N1C(NC(=O)C)=NC(=O)C2=C1N=CN2 MXSMRDDXWJSGMC-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
239000012454 non-polar solvent Substances 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
150000002941 palladium compounds Chemical class 0.000 description 1
FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
239000002574 poison Substances 0.000 description 1
231100000614 poison Toxicity 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
239000003223 protective agent Substances 0.000 description 1
239000003586 protic polar solvent Substances 0.000 description 1
150000003212 purines Chemical class 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
238000010791 quenching Methods 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
230000009467 reduction Effects 0.000 description 1
239000011369 resultant mixture Substances 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
229930195734 saturated hydrocarbon Natural products 0.000 description 1
UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
229910001488 sodium perchlorate Inorganic materials 0.000 description 1
JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
239000004324 sodium propionate Substances 0.000 description 1
235000010334 sodium propionate Nutrition 0.000 description 1
229960003212 sodium propionate Drugs 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
125000004434 sulfur atom Chemical group 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
238000009901 transfer hydrogenation reaction Methods 0.000 description 1
125000004665 trialkylsilyl group Chemical group 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
OHSJPLSEQNCRLW-UHFFFAOYSA-N triphenylmethyl radical Chemical compound C1=CC=CC=C1[C](C=1C=CC=CC=1)C1=CC=CC=C1 OHSJPLSEQNCRLW-UHFFFAOYSA-N 0.000 description 1
241001529453 unidentified herpesvirus Species 0.000 description 1
230000002485 urinary effect Effects 0.000 description 1
210000002700 urine Anatomy 0.000 description 1
230000009385 viral infection Effects 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000008096 xylene Substances 0.000 description 1
150000003738 xylenes Chemical class 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Epidemiology (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

CA002243650A 1996-01-26 1997-01-21 Process for preparing purine derivatives Expired - Lifetime CA2243650C (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US59207996A	1996-01-26	1996-01-26
US08/592,079		1996-01-26
PCT/EP1997/000262 WO1997027198A1 (en)	1996-01-26	1997-01-21	Process for preparing purine derivatives

Publications (2)

Publication Number	Publication Date
CA2243650A1 CA2243650A1 (en)	1997-07-31
CA2243650C true CA2243650C (en)	2006-08-15

Family

ID=24369197

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002243650A Expired - Lifetime CA2243650C (en)	1996-01-26	1997-01-21	Process for preparing purine derivatives

Country Status (10)

Country	Link
JP (1)	JP4094667B2 (ja)
KR (1)	KR100491941B1 (ja)
CN (1)	CN1064683C (ja)
AT (1)	ATE222909T1 (ja)
AU (1)	AU1543797A (ja)
CA (1)	CA2243650C (ja)
DE (1)	DE69714971T3 (ja)
ES (1)	ES2180923T5 (ja)
MX (1)	MX9805935A (ja)
WO (1)	WO1997027198A1 (ja)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5869493A (en) *	1996-02-16	1999-02-09	Medivir Ab	Acyclic nucleoside derivatives
US6703394B2 (en)	1996-02-16	2004-03-09	Medivir Ab	Acyclic nucleoside derivatives
EP1668022A1 (en) *	2003-09-11	2006-06-14	F.Hoffmann-La Roche Ag	Process for preparing antiviral nucleoside derivatives
ZA200702234B (en) *	2006-03-21	2008-07-30	Cipla Ltd	Preparation of ester of purine derivatives
EP2714691B1 (en) *	2011-05-31	2016-09-07	Pharmathen S.A.	Process for the preparation of 2-amino-9-((2-phenyl-1,3-dioxan-5-yloxy)methyl)-1h-purin-6(9h)-one compound useful in the preparation of valganciclovir

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4816447A (en) *	1981-08-26	1989-03-28	Merck & Co., Inc.	Anti-viral guanine compounds
NL8202626A (nl) *	1982-06-29	1984-01-16	Stichting Rega V Z W	Derivaten van 9-(2-hydroxyethoxymethyl)guanine.
AP55A (en) *	1987-08-15	1989-09-26	The Wellcome Foundation Ltd	Therapeutic Acyclic Nucleosides
ATE123285T1 (de) *	1988-12-19	1995-06-15	Wellcome Found	Antivirale pyrimidin- und purinverbindungen, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische präparate.
JP3225545B2 (ja) *	1991-09-18	2001-11-05	味の素株式会社	非環状ヌクレオシド類の製造法
PE32296A1 (es) *	1994-07-28	1996-08-07	Hoffmann La Roche	Ester de l-monovalina derivado de 2-(2-amino-1,6-dihidro-6-oxo-purin-9-il) metoxi-1,3-propandiol y sus sales farmaceuticamente aceptables

1997
- 1997-01-21 CA CA002243650A patent/CA2243650C/en not_active Expired - Lifetime
- 1997-01-21 AU AU15437/97A patent/AU1543797A/en not_active Abandoned
- 1997-01-21 WO PCT/EP1997/000262 patent/WO1997027198A1/en active IP Right Grant
- 1997-01-21 AT AT97901569T patent/ATE222909T1/de active
- 1997-01-21 CN CN97192606A patent/CN1064683C/zh not_active Expired - Lifetime
- 1997-01-21 ES ES97901569T patent/ES2180923T5/es not_active Expired - Lifetime
- 1997-01-21 KR KR10-1998-0705709A patent/KR100491941B1/ko not_active Expired - Lifetime
- 1997-01-21 JP JP52651797A patent/JP4094667B2/ja not_active Expired - Lifetime
- 1997-01-21 DE DE69714971T patent/DE69714971T3/de not_active Expired - Lifetime
1998
- 1998-07-23 MX MX9805935A patent/MX9805935A/es unknown

Also Published As

Publication number	Publication date
JP2000503977A (ja)	2000-04-04
DE69714971T2 (de)	2003-05-28
MX9805935A (es)	1998-11-30
CN1212693A (zh)	1999-03-31
KR100491941B1 (ko)	2005-08-05
ES2180923T5 (es)	2005-10-16
ES2180923T3 (es)	2003-02-16
ATE222909T1 (de)	2002-09-15
CA2243650A1 (en)	1997-07-31
JP4094667B2 (ja)	2008-06-04
DE69714971T3 (de)	2005-12-15
AU1543797A (en)	1997-08-20
DE69714971D1 (de)	2002-10-02
CN1064683C (zh)	2001-04-18
KR19990081991A (ko)	1999-11-15
WO1997027198A1 (en)	1997-07-31

Publication	Publication Date	Title
US5756736A (en)	1998-05-26	Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative
US6103901A (en)	2000-08-15	Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative
EP0694547B1 (en)	1999-04-21	2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivatives
US20040102462A1 (en)	2004-05-27	2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3-propanediol derivative
US6340756B1 (en)	2002-01-22	Process for preparing a 2-(2-amino-1, 6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative
US5543414A (en)	1996-08-06	Achiral amino acid acyl esters of ganciclovir and its derivatives
EP0877746B1 (en)	2001-09-19	Process for preparing purine derivatives
WO1997027195A9 (en)	1997-10-30	Process for preparing purine derivatives
CA2243650C (en)	2006-08-15	Process for preparing purine derivatives
WO1997027194A1 (en)	1997-07-31	Process for preparing purine derivatives
EP0882050B2 (en)	2005-05-04	Process for preparing purine derivatives
CA2243972C (en)	2006-06-06	Process for preparing purine derivatives
CA2246164C (en)	2006-09-12	Process for preparing ganciclovir derivatives
CA2547307A1 (en)	1997-07-31	Process for preparing ganciclovir derivatives
HK1012339B (en)	2000-04-07	2-(2-amino-1, 6-dihydro-6-oxo-purin-9-yl)methoxy-1, 3-propanediol derivatives

Legal Events

Date	Code	Title	Description
2001-11-08	EEER	Examination request
2017-03-27	MKEX	Expiry	Effective date: 20170123