CA2012096C - Cytosine compounds and a process for the production thereof - Google Patents
Cytosine compounds and a process for the production thereofInfo
- Publication number
- CA2012096C CA2012096C CA 2012096 CA2012096A CA2012096C CA 2012096 C CA2012096 C CA 2012096C CA 2012096 CA2012096 CA 2012096 CA 2012096 A CA2012096 A CA 2012096A CA 2012096 C CA2012096 C CA 2012096C
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- Canada
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- hydrogen
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- Prior art date
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Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title abstract description 16
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- -1 methoxytrityl Chemical group 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims abstract description 9
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims abstract description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 8
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 8
- 125000005251 aryl acyl group Chemical group 0.000 claims abstract description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 8
- 235000021317 phosphate Nutrition 0.000 claims abstract description 8
- 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 claims abstract description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 7
- 125000005257 alkyl acyl group Chemical group 0.000 claims abstract description 7
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 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 claims description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 230000008707 rearrangement Effects 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 3
- 239000012433 hydrogen halide Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 2
- 150000003841 chloride salts Chemical class 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 abstract description 2
- 230000006820 DNA synthesis Effects 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 13
- 229950000242 ancitabine Drugs 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 9
- 229940104302 cytosine Drugs 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- 239000003125 aqueous solvent Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 5
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 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 2
- VLIXZEKAVFLJRY-UJDVCPFMSA-N 4-amino-1-[(2r,3s,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)-4-(4-methylphenyl)sulfonyloxolan-2-yl]pyrimidin-2-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)[C@]1(O)[C@@H](O)[C@H](N2C(N=C(N)C=C2)=O)O[C@@H]1CO VLIXZEKAVFLJRY-UJDVCPFMSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- WCXOOVODAUHPMZ-VDSQZSGCSA-N 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-4-(4-methylphenyl)sulfonyloxolan-2-yl]pyrimidin-2-one ethanol Chemical compound C(C)O.S(=O)(=O)(C1=CC=C(C)C=C1)[C@@]1([C@H]([C@@H](O[C@@H]1CO)N1C(=O)N=C(N)C=C1)O)O WCXOOVODAUHPMZ-VDSQZSGCSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- NIDVTARKFBZMOT-PEBGCTIMSA-N N(4)-acetylcytidine Chemical compound O=C1N=C(NC(=O)C)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NIDVTARKFBZMOT-PEBGCTIMSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical class Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FIQMVMWAWILUDW-KYJNYJMBSA-N n-[1-[(2r,3r,4r,5r)-4-hydroxy-3-trityloxy-5-(trityloxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]acetamide Chemical compound O=C1N=C(NC(=O)C)C=CN1[C@H]1[C@H](OC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)[C@H](O)[C@@H](COC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)O1 FIQMVMWAWILUDW-KYJNYJMBSA-N 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Compounds of Formula I:
(see fig. I) wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-C9 aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, and a process for the production thereof are provided. The compound of Formula I or the corresponding pharmaceutically acceptable salt (or the neutral form of the compound of Formula I) may then be converted to the corresponding compound of Formula V, or pharmaceutically acceptable salts thereof:
(see fig. V) wherein R2 is as defined above. Compounds of Formula I
and V are useful for inhibition of DNA synthesis.
(see fig. I) wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-C9 aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, and a process for the production thereof are provided. The compound of Formula I or the corresponding pharmaceutically acceptable salt (or the neutral form of the compound of Formula I) may then be converted to the corresponding compound of Formula V, or pharmaceutically acceptable salts thereof:
(see fig. V) wherein R2 is as defined above. Compounds of Formula I
and V are useful for inhibition of DNA synthesis.
Description
2 ~
FIELD OF THE INVENTION
The present invention relates to novel cytosine compounds, and a process for the production thereof. More specifically, the present invention relates to the production of 2,3 ' -cyclocytidine, 2,3 ' -cyclocytidine analogues and pharmaceutically acceptable salts thereof. The invention also relates to the production of 1-(~-D-xylofuranosyl)cytosine, 1-(~ -D-xylofuranosyl)cytosine analogues and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Mizuno et al (Tet. Lett., 4579-4584 (1965) ) teach the production of 2,3 ' -cyclocytidine via a six step process which involves the production of 3 ' -mesylcytidine as a crystalline free-base. Specifically, the last step in the process comprises reacting 3 ' -mesylcytidine with an excess of sodium t-butoxide to produce 2,3 ' -cyclocytidine. Unfortunately, the first step in the process involved conversion of N4-acetyl cytidine (NOTE: this was obtained from cytidine in only a 65% yield) to 2 ',5 ' -di-O-trityl-N4-acetylcytidine in only a 20% yield. Accordingly, the process of Mizuno et al is deficient in that it requires an onerous number of steps to produce 2,3 ' -cyclocytidine and, when produced, 2,3 ' -cyclocytidine is obtained in a relatively low yield of less than 8.5% ( even this low yield assumes theoretical yields for two of the six steps where yield was unreported). Further, Doerr et al (J. Org. Chem., 32, 1462-1471 (1967) ) found it surprising that Mizuno et al reported isolating 2,3 ' -cyclocytidine in neutral form.
2 ~
Fox et al (J. Am. Chem. Soc., 29, 5060-5064 (1957)) teaches the production of l-(~-D-xylofuranosyl) cytosine via coupling of a 100% excess of protected xylosyl halide and protected mercuri-cytosine, followed by deprotection of the coupled compound to form l-(~-D-xylofuranosyl)cytosine. Unfortunately, the coupling step provided a product in only 23~ yield which corresponds to an overall yield of 1-(~ -D-xylofuranosyl)cytosine of 18~. It will be appreciated that these yields would be even lower if they were based on xylose and cytosine as starting materials.
Gosselin et al (J. Med. Chem., 1986, 29, 203-213) teach the production of ~-D-xylofuranosyl compounds by glycosylation of purine and pyrimidine aglycons with peracylated l-O-acetyl-~-D-xylofuranoses, followed by removal of the blocking groups.
It would be desirable to have a relatively simple process for the production of 1-(~ -D-xylofuranosyl)cytosine compounds which did not comprise the use of blocking groups followed by removal of such blocking groups. It would also be desirable to to have a more convenient process which provided higher or comparable yields of such l-(~-D-xylofuranosyl)cytosine compounds.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel 2,3'-cyclocytidine compounds.
It is another object of the present invention to provide a novel process for the production of 2,3'-2~e~
cyclocytidine compounds and pharmaceutically acceptable salts thereof.
It is yet another object of the present invention to provide a novel process for the production of 1-(~-D-xylofuranosyl)cytosine compounds.
Accordingly, in one of its aspects, the present invention provides a process in producing a compound of Formula I:
N
0 ~ ~
N ( I ) R2 O-C~,O y H OH
which comprises the step of intramolecular rearrangement of a compound of Formula I I: NH2 N ~\\
0~ J
RZ O-C~O j ( II ) Rl ~2 SO OH
wherein Rl is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-Cg 2~2~
aryl group, and R2 is selected from the group comprising hydrogen, trityl, methyoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, to produce a compound of Formula I.
In another of its aspects, the present invention provides a process for producing a compound of Formula III:
NH.HCl Nl l ¦ N (III) HO-C ~ O
H OH
which comprises the step of intramolecular rearrangement of a compound of Formula IV:
~ I (IV) o ~ /
HO-C ~ O
OTs OH
wherein Ts is a tosyl group, followed by reaction with hydrogen chloride, to produce the compound of Formula III.
5In yet another of its aspects, the present invention provides a compound of Formula I:
N / (I) R2 o-c~o~J
H OH
wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-C9 aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl.
In yet another of its aspects, the present invention provides a process for producing a compound of Formula V, or a pharmaceutically acceptable salt thereof:
2 ~
N
o N
R2 o - C~O ~1 ( V ) ~0 OH
which comprises the step of reacting (i) a compound of Formula VII, or a pharmaceutically acceptable salt thereof:
~ / (VII) H OH
wherein R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2, 2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, with (ii) an amine selected from the group comprising C5-Cl 2 heterocyclic amines and amines having the general formula:
R3R4RsN
2 ~
wherein R3, R4 and Rs can be the same or different and are selected from the group comprising hydrogen, a C1-C6 alkyl group and a C6-Cg aryl group, with the proviso that each of R3, R4 and R5 are not hydrogen.
In yet another of its aspects, the present invention provides a process for producing a compound of Formula VI:
N ~
N (VI) HO-C ~ O ~
'~1 1/
OH
which comprises the step of reacting a compound of Formula III:
NH.HCl Nl l N (III) HO-C ~ O
H OH
with t-butyl amine in the presence of an aqueous solvent.
In yet another of its aspects, the present invention provides a process for producing a compound of Formula V, or a pharmaceutically acceptable salt thereof:
O ~ N / (V) R2 O-C~O~I
~0 ~/ .
OH
wherein R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts 20thereof, tosyl and mesyl, comprising the steps of:
(i) intramolecular rearrangement of a compound of Formula II:
N ~
l l (II) O ~ /
R2 O-C~O~
wherein Rl is selected from the group comprising trifluoromethyl, a Cl-C6 alkyl group and a C6-Cg aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, to produce a compound of Formula VII, or a pharmaceutically acceptable salt thereof:
NH
~ N / (VII) R2 O-c~Oy H OH
wherein R2 has the above-defined meaning; and (ii) reacting the compound of Formula VII with an amine selected from the group comprising C5 -Cl2 heterocyclic amines and amines having the general formula wherein R3 , R4 and R5 can be the same or different and are selected from the group comprising hydrogen, a Cl-C6 alkyl group and a C6-Cg aryl group, with the proviso that each of R3 , R4 and Rs are not hydrogen, to produce a compound of Formula V.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
.
The compound of Formula II:
N
~~ ~
N
R2 O-C~O~
\ / (II) RlO2SO OH
is the subject of our co-pending Canadian patent application number 2,012,095, filed March 13, 1990.
Essentially, the compound of Formula II may be synthesized by reacting a 2',3'-O-dialkylstannylene cytidine compound with an organic sulfonyl compound. Preferably, the starting material is a compound of Formula IV:
~ N ~ (IV) HO-C ~ O \) OTs OH
B
2 ~
known as 3'-tosylcytidine, which can be suitably prepared by reaction of 2',3'-0-dialkylstannylene cytidine with tosyl chloride.
The compound of Formula II undergoes intramolecular rearrangement to produce the compound of Formula I. Preferably, this rearrangement is conducted by refluxing the compound of Formula II in a suitable polar solvent system. Preferably, the solvent system has a boiling point of at least about 100~C. Non-limiting examples of suitable solvent systems include n-butanol, water, dimethylformamide and a mixture comprising from about 55 to about 65 percent by volume of isopropanol and from about 35 to about 45 percent by volume of toluene.
In a preferred embodiment, the compound of Formula I can be converted to the corresponding halide salt by reaction with a hydrogen halide having the general formula HX
wherein X is a halogen. The preferred halogen is chloride thereby defining HX as hydrogen chloride. The reaction of the compound of Formula II with HX may be conducted in any suitable solvent system. Preferably, the reaction is conducted in the presence of a alcohol, more preferably ethanol.
In a preferred embodiment, 3'-tosylcytidine (Formula IV) undergoes intramolecular rearrangement, preferably by refluxing in an organic solvent such as n-butanol, followed by reaction with hydrogen chloride to 2 ~
provide the hydrochloride salt of 2,3'-cyclocytidine (Formula III):
NH.HCl N / ~'\
I N
HO-C ~ O
H OH
To the Applicant's knowledge, the compound of Formula III has not heretofore been known.
The crude 2,3'-cyclocytidine (Formula I) may be separated from the reaction mixture using conventional techniques within the purview of a person skilled in the art. For example, after the reaction is complete, the crude 2,3'-cyclocytidine (Formula I) may be converted to the corresponding halide salt by reaction with a hydrogen halide, preferably hydrogen chloride. Thereafter, the halide salt may be recrystallized from a suitable organic solvent such as an alcohol, preferably ethanol.
In the aspect of the invention involving the production of a compound of Formula V (reaction of compound of Formula I with an amine) described hereinbefore, the amine suitable for use is selected from the group comprising C5 -Cl 2 heterocyclic amines and amines having the general formula 2 ~
wherein R2, R3 and R4 can be the same or different and are selected from the group comprising hydrogen, a C1-C6 alkyl groups and a C6-Cg aryl group, with the proviso that each of R2, R3 and R4 are not hydrogen. Thus, it will be appreciated that the use of ammonia (i.e.
R2=R3=R4=H) is outside the scope of the present invention. Non-limiting examples of suitable heterocyclic amines include pyridine and piperidine.
Non-limiting examples of other amines suitable for use include t-butylamine, trimethylamine, triethylamine, tripropylamine, tributylamine, methylamine, ethylamine, diethylamine and aniline. The most preferred amine suitable for use in the present process is t-butylamine.
Preferably, the aspect of the invention involving the production of a compound of Formula V is conducted in the presence of an aqeous solvent.
Examples of suitable aqueous solvents include water and a mixture of water and at least one other solvent miscible therewith. The most preferred aqueous solvent for use in the production of a compound of Formula V is water.
The starting material for the production of the compound of Formula V is the compound of Formula VII
described hereinbefore. The preferred form of Formula VII is as a sulfonyl salt (Formula I). Alternatively, and most preferably, the starting material is the hydrochloride salt of 2,3'-cyclocytidine (Formula III):
2 ~
NH.HCl I N
HO-C ~ O ~ (III) \~
H OH
Preferably, 2,3'-cyclocytidine hydrochloride is reacted with t-butylamine in the presence of an aqueous solvent to provide l-(~-D-xylofuranosyl)cytosine (Formula (VI):
N /
~ ~ / (VI) HO-C ~ O
~0 /' 'I /
OH
Typically, the reaction can be conducted at room temperature, preferably with agitation (such as stirring) of the reaction mixture. More preferably, the reaction is conducted in the presence of an aqueous solvent system comprising solely water.
The crude product may be separated from the reaction mixture and purified using conventional &
techniques within the purview of a person skilled in the art. For example, after the reaction is complete, the solvents may be evaporated under vacuum and the resulting solid suspended and agitated in a suitable medium to produce a purified product. Examples of such media include alcohol and mixtures containing alcohol and water. The preferred alcohol for use is ethanol.
Aspects of the invention will be described with reference to the following examples, which should not be considered to limit the scope of the invention.
FIELD OF THE INVENTION
The present invention relates to novel cytosine compounds, and a process for the production thereof. More specifically, the present invention relates to the production of 2,3 ' -cyclocytidine, 2,3 ' -cyclocytidine analogues and pharmaceutically acceptable salts thereof. The invention also relates to the production of 1-(~-D-xylofuranosyl)cytosine, 1-(~ -D-xylofuranosyl)cytosine analogues and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Mizuno et al (Tet. Lett., 4579-4584 (1965) ) teach the production of 2,3 ' -cyclocytidine via a six step process which involves the production of 3 ' -mesylcytidine as a crystalline free-base. Specifically, the last step in the process comprises reacting 3 ' -mesylcytidine with an excess of sodium t-butoxide to produce 2,3 ' -cyclocytidine. Unfortunately, the first step in the process involved conversion of N4-acetyl cytidine (NOTE: this was obtained from cytidine in only a 65% yield) to 2 ',5 ' -di-O-trityl-N4-acetylcytidine in only a 20% yield. Accordingly, the process of Mizuno et al is deficient in that it requires an onerous number of steps to produce 2,3 ' -cyclocytidine and, when produced, 2,3 ' -cyclocytidine is obtained in a relatively low yield of less than 8.5% ( even this low yield assumes theoretical yields for two of the six steps where yield was unreported). Further, Doerr et al (J. Org. Chem., 32, 1462-1471 (1967) ) found it surprising that Mizuno et al reported isolating 2,3 ' -cyclocytidine in neutral form.
2 ~
Fox et al (J. Am. Chem. Soc., 29, 5060-5064 (1957)) teaches the production of l-(~-D-xylofuranosyl) cytosine via coupling of a 100% excess of protected xylosyl halide and protected mercuri-cytosine, followed by deprotection of the coupled compound to form l-(~-D-xylofuranosyl)cytosine. Unfortunately, the coupling step provided a product in only 23~ yield which corresponds to an overall yield of 1-(~ -D-xylofuranosyl)cytosine of 18~. It will be appreciated that these yields would be even lower if they were based on xylose and cytosine as starting materials.
Gosselin et al (J. Med. Chem., 1986, 29, 203-213) teach the production of ~-D-xylofuranosyl compounds by glycosylation of purine and pyrimidine aglycons with peracylated l-O-acetyl-~-D-xylofuranoses, followed by removal of the blocking groups.
It would be desirable to have a relatively simple process for the production of 1-(~ -D-xylofuranosyl)cytosine compounds which did not comprise the use of blocking groups followed by removal of such blocking groups. It would also be desirable to to have a more convenient process which provided higher or comparable yields of such l-(~-D-xylofuranosyl)cytosine compounds.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel 2,3'-cyclocytidine compounds.
It is another object of the present invention to provide a novel process for the production of 2,3'-2~e~
cyclocytidine compounds and pharmaceutically acceptable salts thereof.
It is yet another object of the present invention to provide a novel process for the production of 1-(~-D-xylofuranosyl)cytosine compounds.
Accordingly, in one of its aspects, the present invention provides a process in producing a compound of Formula I:
N
0 ~ ~
N ( I ) R2 O-C~,O y H OH
which comprises the step of intramolecular rearrangement of a compound of Formula I I: NH2 N ~\\
0~ J
RZ O-C~O j ( II ) Rl ~2 SO OH
wherein Rl is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-Cg 2~2~
aryl group, and R2 is selected from the group comprising hydrogen, trityl, methyoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, to produce a compound of Formula I.
In another of its aspects, the present invention provides a process for producing a compound of Formula III:
NH.HCl Nl l ¦ N (III) HO-C ~ O
H OH
which comprises the step of intramolecular rearrangement of a compound of Formula IV:
~ I (IV) o ~ /
HO-C ~ O
OTs OH
wherein Ts is a tosyl group, followed by reaction with hydrogen chloride, to produce the compound of Formula III.
5In yet another of its aspects, the present invention provides a compound of Formula I:
N / (I) R2 o-c~o~J
H OH
wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-C9 aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl.
In yet another of its aspects, the present invention provides a process for producing a compound of Formula V, or a pharmaceutically acceptable salt thereof:
2 ~
N
o N
R2 o - C~O ~1 ( V ) ~0 OH
which comprises the step of reacting (i) a compound of Formula VII, or a pharmaceutically acceptable salt thereof:
~ / (VII) H OH
wherein R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2, 2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, with (ii) an amine selected from the group comprising C5-Cl 2 heterocyclic amines and amines having the general formula:
R3R4RsN
2 ~
wherein R3, R4 and Rs can be the same or different and are selected from the group comprising hydrogen, a C1-C6 alkyl group and a C6-Cg aryl group, with the proviso that each of R3, R4 and R5 are not hydrogen.
In yet another of its aspects, the present invention provides a process for producing a compound of Formula VI:
N ~
N (VI) HO-C ~ O ~
'~1 1/
OH
which comprises the step of reacting a compound of Formula III:
NH.HCl Nl l N (III) HO-C ~ O
H OH
with t-butyl amine in the presence of an aqueous solvent.
In yet another of its aspects, the present invention provides a process for producing a compound of Formula V, or a pharmaceutically acceptable salt thereof:
O ~ N / (V) R2 O-C~O~I
~0 ~/ .
OH
wherein R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts 20thereof, tosyl and mesyl, comprising the steps of:
(i) intramolecular rearrangement of a compound of Formula II:
N ~
l l (II) O ~ /
R2 O-C~O~
wherein Rl is selected from the group comprising trifluoromethyl, a Cl-C6 alkyl group and a C6-Cg aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-Cg arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, to produce a compound of Formula VII, or a pharmaceutically acceptable salt thereof:
NH
~ N / (VII) R2 O-c~Oy H OH
wherein R2 has the above-defined meaning; and (ii) reacting the compound of Formula VII with an amine selected from the group comprising C5 -Cl2 heterocyclic amines and amines having the general formula wherein R3 , R4 and R5 can be the same or different and are selected from the group comprising hydrogen, a Cl-C6 alkyl group and a C6-Cg aryl group, with the proviso that each of R3 , R4 and Rs are not hydrogen, to produce a compound of Formula V.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
.
The compound of Formula II:
N
~~ ~
N
R2 O-C~O~
\ / (II) RlO2SO OH
is the subject of our co-pending Canadian patent application number 2,012,095, filed March 13, 1990.
Essentially, the compound of Formula II may be synthesized by reacting a 2',3'-O-dialkylstannylene cytidine compound with an organic sulfonyl compound. Preferably, the starting material is a compound of Formula IV:
~ N ~ (IV) HO-C ~ O \) OTs OH
B
2 ~
known as 3'-tosylcytidine, which can be suitably prepared by reaction of 2',3'-0-dialkylstannylene cytidine with tosyl chloride.
The compound of Formula II undergoes intramolecular rearrangement to produce the compound of Formula I. Preferably, this rearrangement is conducted by refluxing the compound of Formula II in a suitable polar solvent system. Preferably, the solvent system has a boiling point of at least about 100~C. Non-limiting examples of suitable solvent systems include n-butanol, water, dimethylformamide and a mixture comprising from about 55 to about 65 percent by volume of isopropanol and from about 35 to about 45 percent by volume of toluene.
In a preferred embodiment, the compound of Formula I can be converted to the corresponding halide salt by reaction with a hydrogen halide having the general formula HX
wherein X is a halogen. The preferred halogen is chloride thereby defining HX as hydrogen chloride. The reaction of the compound of Formula II with HX may be conducted in any suitable solvent system. Preferably, the reaction is conducted in the presence of a alcohol, more preferably ethanol.
In a preferred embodiment, 3'-tosylcytidine (Formula IV) undergoes intramolecular rearrangement, preferably by refluxing in an organic solvent such as n-butanol, followed by reaction with hydrogen chloride to 2 ~
provide the hydrochloride salt of 2,3'-cyclocytidine (Formula III):
NH.HCl N / ~'\
I N
HO-C ~ O
H OH
To the Applicant's knowledge, the compound of Formula III has not heretofore been known.
The crude 2,3'-cyclocytidine (Formula I) may be separated from the reaction mixture using conventional techniques within the purview of a person skilled in the art. For example, after the reaction is complete, the crude 2,3'-cyclocytidine (Formula I) may be converted to the corresponding halide salt by reaction with a hydrogen halide, preferably hydrogen chloride. Thereafter, the halide salt may be recrystallized from a suitable organic solvent such as an alcohol, preferably ethanol.
In the aspect of the invention involving the production of a compound of Formula V (reaction of compound of Formula I with an amine) described hereinbefore, the amine suitable for use is selected from the group comprising C5 -Cl 2 heterocyclic amines and amines having the general formula 2 ~
wherein R2, R3 and R4 can be the same or different and are selected from the group comprising hydrogen, a C1-C6 alkyl groups and a C6-Cg aryl group, with the proviso that each of R2, R3 and R4 are not hydrogen. Thus, it will be appreciated that the use of ammonia (i.e.
R2=R3=R4=H) is outside the scope of the present invention. Non-limiting examples of suitable heterocyclic amines include pyridine and piperidine.
Non-limiting examples of other amines suitable for use include t-butylamine, trimethylamine, triethylamine, tripropylamine, tributylamine, methylamine, ethylamine, diethylamine and aniline. The most preferred amine suitable for use in the present process is t-butylamine.
Preferably, the aspect of the invention involving the production of a compound of Formula V is conducted in the presence of an aqeous solvent.
Examples of suitable aqueous solvents include water and a mixture of water and at least one other solvent miscible therewith. The most preferred aqueous solvent for use in the production of a compound of Formula V is water.
The starting material for the production of the compound of Formula V is the compound of Formula VII
described hereinbefore. The preferred form of Formula VII is as a sulfonyl salt (Formula I). Alternatively, and most preferably, the starting material is the hydrochloride salt of 2,3'-cyclocytidine (Formula III):
2 ~
NH.HCl I N
HO-C ~ O ~ (III) \~
H OH
Preferably, 2,3'-cyclocytidine hydrochloride is reacted with t-butylamine in the presence of an aqueous solvent to provide l-(~-D-xylofuranosyl)cytosine (Formula (VI):
N /
~ ~ / (VI) HO-C ~ O
~0 /' 'I /
OH
Typically, the reaction can be conducted at room temperature, preferably with agitation (such as stirring) of the reaction mixture. More preferably, the reaction is conducted in the presence of an aqueous solvent system comprising solely water.
The crude product may be separated from the reaction mixture and purified using conventional &
techniques within the purview of a person skilled in the art. For example, after the reaction is complete, the solvents may be evaporated under vacuum and the resulting solid suspended and agitated in a suitable medium to produce a purified product. Examples of such media include alcohol and mixtures containing alcohol and water. The preferred alcohol for use is ethanol.
Aspects of the invention will be described with reference to the following examples, which should not be considered to limit the scope of the invention.
3'-Tosylcytidine ethanol (17.72 g; 0.04 moles) was suspended in 100 mL n-butanol and thereafter reluxed for 3 hours. The reaction mixture was evaporated to a thin syrup weighing 34 g and ethanol (30 mL), to which had been added 6 g of acetyl chloride, was added to the syrup and mixed therewith. The mixture was seeded and scratched to yield a precipitate, and allowed to stand at -20~C for 1.5 hours. The precipitate was filtered and washed with ethanol to afford 8.35 g of off-white crystals which had a melting point of 191~-193~C
(decomposed). The filtrate and washings were concentrated to a thin syrup. The thin syrup was dissolved in water (150 mL) and 6 mL of 32~ aqueous hydrochloric acid was then added. The aqueous solution was extracted with ethyl acetate in a continuous extractor for 18 hours. Thereafter, the aqueous phase was evaporated to about 1.8 g and recrystallized from ethanol to yield 0.59 g of off-white crystals which were combined with the 8.35 g of crystals described above.
The combined batch of off-white crystals (8.94 g) was recrystallized from aqueous ethanol to afford 8.11 g 2 ~ $ ~
(77% yield) of pure 2,3'-cyclocytidine hydrochloride as white crystals having a melting point of 196.5 -199.0 C
(decomposed). Using a 200 MHz NMR spectrometer, an NMR
spectrum of this 2,3'-cyclocytidine hydrochloride was obtained in DMSO-d-6. The following data on peak shift, number of peaks and coupling constants was obtained from the spectrum and confirms the structure of the product:
SHIFT (~) ASSIGNMENT
3.62, ABm 2H; J4 ~ 5; =J4 ~ 5 . =5.6 Hz: H-5 and H-52 4.47, td lH; J3 . 4 . =3.6 Hz: H-4 4.88, bs lH: H-2' 5.12, t lH; J5; O H JSio H
exchangeable: C5'-OH
5.16, m lH: H-3' 5.90, s lH: H-l' 6.50, d lH; J5 6 =7.3 Hz: H-5 6.70, bs lH; exchangeable: C2-OH
8.18, d lH: H-6 9.13, bs 2H: exchangeable: NH2 2 ~ $ ~
2,3'-Cyclocytidine hydrochloride (5.0 g) was dissolved in 50 mL water. t-Butylamine (2.9 g) was added, with stirring, to the 2,3'-cyclocytidine hydrochloride solution. After 1.5 hours, the solvent was evaporated and 25 mL ethanol was added to the resulting oil. The oil was dissolved in the ethanol with gentle heating which subsequently resulted in the spontaneous formation of a mass of crystalline material.
The crystalline material was kept at -20 C for 2 hours and thereafter was filtered, washed with 5 mL ethanol and dried to afford 4.02 g (86.5% yield) pure 1-(~-D-xylofuranosyl)cytosine (Formula VI). The product had a melting point of 239.0 -240.5 C which is in general agreement with the values reported by Fox et al and Gosselin et al described hereinabove. Using a 200 MHz NMR spectrometer, an NMR spectrum of 1-(~ -D-xylofuranosyl)cytosine was obtained in DMS0-d-6. The following data on peak shift, number of peaks and coupling constants was obtained from the spectrum and confirms the structure of the product:
2~2~
SHIFT ( J') ASSIGNMENT
3.68, ABm 2H; J5IOH=JSiOH=5.6 HZ: H 5 and H-52 3.87, ABm 2H: H-2 ~ and H-3 4.07, m 1H: H-4' 4.74, t 1H; exchangeable: C5'-0H
5.30, d 1H; J2 OH=3.66 HZ, exchangeable: C2 l -OH
5. 62, S lH: H-1' 5.67, d 1H; J3 OH=4.76 HZ, exchangeable: C3 ~ -OH
5.68, d 1H; J56=7.47 HZ: H-5 7.09, bd 2H: NH2 7.69, d 1H: H-6
(decomposed). The filtrate and washings were concentrated to a thin syrup. The thin syrup was dissolved in water (150 mL) and 6 mL of 32~ aqueous hydrochloric acid was then added. The aqueous solution was extracted with ethyl acetate in a continuous extractor for 18 hours. Thereafter, the aqueous phase was evaporated to about 1.8 g and recrystallized from ethanol to yield 0.59 g of off-white crystals which were combined with the 8.35 g of crystals described above.
The combined batch of off-white crystals (8.94 g) was recrystallized from aqueous ethanol to afford 8.11 g 2 ~ $ ~
(77% yield) of pure 2,3'-cyclocytidine hydrochloride as white crystals having a melting point of 196.5 -199.0 C
(decomposed). Using a 200 MHz NMR spectrometer, an NMR
spectrum of this 2,3'-cyclocytidine hydrochloride was obtained in DMSO-d-6. The following data on peak shift, number of peaks and coupling constants was obtained from the spectrum and confirms the structure of the product:
SHIFT (~) ASSIGNMENT
3.62, ABm 2H; J4 ~ 5; =J4 ~ 5 . =5.6 Hz: H-5 and H-52 4.47, td lH; J3 . 4 . =3.6 Hz: H-4 4.88, bs lH: H-2' 5.12, t lH; J5; O H JSio H
exchangeable: C5'-OH
5.16, m lH: H-3' 5.90, s lH: H-l' 6.50, d lH; J5 6 =7.3 Hz: H-5 6.70, bs lH; exchangeable: C2-OH
8.18, d lH: H-6 9.13, bs 2H: exchangeable: NH2 2 ~ $ ~
2,3'-Cyclocytidine hydrochloride (5.0 g) was dissolved in 50 mL water. t-Butylamine (2.9 g) was added, with stirring, to the 2,3'-cyclocytidine hydrochloride solution. After 1.5 hours, the solvent was evaporated and 25 mL ethanol was added to the resulting oil. The oil was dissolved in the ethanol with gentle heating which subsequently resulted in the spontaneous formation of a mass of crystalline material.
The crystalline material was kept at -20 C for 2 hours and thereafter was filtered, washed with 5 mL ethanol and dried to afford 4.02 g (86.5% yield) pure 1-(~-D-xylofuranosyl)cytosine (Formula VI). The product had a melting point of 239.0 -240.5 C which is in general agreement with the values reported by Fox et al and Gosselin et al described hereinabove. Using a 200 MHz NMR spectrometer, an NMR spectrum of 1-(~ -D-xylofuranosyl)cytosine was obtained in DMS0-d-6. The following data on peak shift, number of peaks and coupling constants was obtained from the spectrum and confirms the structure of the product:
2~2~
SHIFT ( J') ASSIGNMENT
3.68, ABm 2H; J5IOH=JSiOH=5.6 HZ: H 5 and H-52 3.87, ABm 2H: H-2 ~ and H-3 4.07, m 1H: H-4' 4.74, t 1H; exchangeable: C5'-0H
5.30, d 1H; J2 OH=3.66 HZ, exchangeable: C2 l -OH
5. 62, S lH: H-1' 5.67, d 1H; J3 OH=4.76 HZ, exchangeable: C3 ~ -OH
5.68, d 1H; J56=7.47 HZ: H-5 7.09, bd 2H: NH2 7.69, d 1H: H-6
Claims (12)
1. A process in producing a compound of formula I:
(I) which comprises the step of intramolecular rearrangement of a compound of Formula II:
(II) wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and C6-C9 aryl group, and R2 is selected from the group comprising hydrogen,trityl,methyoxytrityl, dimethoxytrityl, acetyl, a C2-C6-alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphate and salts thereof, tosyl and mesyl, to produce a compound of Formula I.
(I) which comprises the step of intramolecular rearrangement of a compound of Formula II:
(II) wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and C6-C9 aryl group, and R2 is selected from the group comprising hydrogen,trityl,methyoxytrityl, dimethoxytrityl, acetyl, a C2-C6-alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphate and salts thereof, tosyl and mesyl, to produce a compound of Formula I.
2. The process defined in claim 1, wherein R2 is hydrogen.
3. The process defined in claim 2, wherein R1 is
4-methylphenyl.
4. The process defined in claim 1, wherein said step is conducted by refluxing the compound of Formula II in a polar solvent system.
4. The process defined in claim 1, wherein said step is conducted by refluxing the compound of Formula II in a polar solvent system.
5. The process defined in claim 4, wherein the polar solvent system has a boiling point of at least 100°C.
6. The process defined in claim 4, wherein said polar solvent system is selected from the group comprising n-butanol, water, dimethylformamide and a mixture comprising from about 55 to about 65 percent by volume of isopropanol and from about 35 to about 45 percent by volume of toluene.
7. The process defined in claims 1, 2 or 3, wherein said step is conducted by refluxing the compound of Formula II in the presence of n-butanol.
8. The process defined in claims 1, 2 or 3, further comprising the step of reacting the compound of Formula I with a hydrogen halide having the general formula HX
wherein X is a halogen, to produce thereby the corresponding halide salt of the compound of Formula I.
wherein X is a halogen, to produce thereby the corresponding halide salt of the compound of Formula I.
9. The process defined in claims 1, 2 or 3, further comprising the step of reacting the compound of Formula I with hydrogen chloride to produce thereby the corresponding chloride salt of the compound of Formula I.
10. A compound of Formula I:
(I) wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-C9 aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl.
(I) wherein R1 is selected from the group comprising a trifluoromethyl group, a C1-C6 alkyl group and a C6-C9 aryl group, and R2 is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C2-C6 alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-trichloroethyl, phosphates and salts thereof, tosyl and mesyl.
11. The compound defined in claim 1, wherein R2 is hydrogen.
12. The compound defined in claims 12 or 13, wherein R1 is 4-methylphenyl.
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012096 CA2012096C (en) | 1990-03-13 | 1990-03-13 | Cytosine compounds and a process for the production thereof |
| PCT/CA1991/000078 WO1991013901A1 (en) | 1990-03-13 | 1991-03-13 | 3'-o-tosylcytidine and cytosine compounds, and process for production thereof |
| US07/930,605 US5399682A (en) | 1990-03-13 | 1991-03-13 | Process for preparing 2,3'-O-cyclocytidine |
| EP91906308A EP0523080B1 (en) | 1990-03-13 | 1991-03-13 | 2,3'-o-cyclocytidines, and process for production thereof |
| HU9202905A HUT61565A (en) | 1990-03-13 | 1991-03-13 | Process for producing 2,3'-0-cyclocytidine and 1-(beta-d-xylopento-furanosyl)-cytosine derivatives and their analogous compounds, as well as 3'-0-(p-toluenesulfonyl)-cytidine derivatives |
| AU74801/91A AU7480191A (en) | 1990-03-13 | 1991-03-13 | 3'-o-tosylcytidine and cytosine compounds, and process for production thereof |
| BR919106157A BR9106157A (en) | 1990-03-13 | 1991-03-13 | COMPOUNDS AND PROCESS 3'-O-TOSIL CYTIDINE AND CYTOSINE AND PROCESS FOR THE PRODUCTION OF THE SAME |
| AT91906308T ATE125265T1 (en) | 1990-03-13 | 1991-03-13 | 2,3'-O-CYCLOCYTIDINES AND METHOD FOR THE PRODUCTION THEREOF. |
| DE69111438T DE69111438T2 (en) | 1990-03-13 | 1991-03-13 | 2,3'-O-CYCLOCYTIDINE AND METHOD FOR THE PRODUCTION THEREOF. |
| US08/191,192 US5527782A (en) | 1990-03-13 | 1994-02-02 | 5-halo-2,3'-O-cyclocytidines |
| US08/356,498 US5536824A (en) | 1990-03-13 | 1994-12-15 | Organosulfonyl salts of 2,3'-O-cyclocytidine |
| US08/469,506 US5596093A (en) | 1990-03-13 | 1995-06-06 | Process for preparing halogenated 2,3-O-cyclocytidine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012096 CA2012096C (en) | 1990-03-13 | 1990-03-13 | Cytosine compounds and a process for the production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2012096A1 CA2012096A1 (en) | 1991-09-13 |
| CA2012096C true CA2012096C (en) | 1997-10-28 |
Family
ID=4144518
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2012096 Expired - Lifetime CA2012096C (en) | 1990-03-13 | 1990-03-13 | Cytosine compounds and a process for the production thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2012096C (en) |
-
1990
- 1990-03-13 CA CA 2012096 patent/CA2012096C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2012096A1 (en) | 1991-09-13 |
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