CA2012095C - 3'-tosylcytidine compounds and process for production thereof - Google Patents
3'-tosylcytidine compounds and process for production thereofInfo
- Publication number
- CA2012095C CA2012095C CA 2012095 CA2012095A CA2012095C CA 2012095 C CA2012095 C CA 2012095C CA 2012095 CA2012095 CA 2012095 CA 2012095 A CA2012095 A CA 2012095A CA 2012095 C CA2012095 C CA 2012095C
- Authority
- CA
- Canada
- Prior art keywords
- group
- compound
- formula
- compounds
- tosylcytidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- 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 class 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 title description 8
- -1 p-toluenesulfonyl Chemical group 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 150000001412 amines Chemical class 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 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 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 5
- 125000005257 alkyl acyl group Chemical group 0.000 claims abstract description 5
- 125000005251 aryl acyl group Chemical group 0.000 claims abstract description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 4
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 4
- 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 4
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims abstract description 3
- 235000021317 phosphate Nutrition 0.000 claims abstract 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 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 4
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001805 chlorine compounds Chemical group 0.000 claims 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 abstract description 6
- 230000006819 RNA synthesis Effects 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 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 4
- 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 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 240000001414 Eucalyptus viminalis Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HNNLWPATHYVXMO-NMFUWQPSSA-N [(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] 4-methylbenzenesulfonate Chemical class C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@@H](O)[C@H](N2C(N=C(N)C=C2)=O)O[C@@H]1CO HNNLWPATHYVXMO-NMFUWQPSSA-N 0.000 description 2
- VAUJJKNQYHUZFJ-ZOQUXTDFSA-N [(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 VAUJJKNQYHUZFJ-ZOQUXTDFSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 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
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 229910001887 tin oxide Inorganic materials 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Novel compounds of Formula I, or pharmaceutically acceptable salts thereof, are provided:
Description
2~ 95 FIELD OF THE INVENTION
The present invention relates to novel 3'-tosylcytidine compounds and pharmaceutically acceptable salts thereof. Further, the present invention relates to a process for the production of 3'-tosylcytidine compounds.
BACKGROUND OF THE INVENTION
Fromageot et al (Tet. Lett., 3499-3505, (1966)) speculated production of N4 ,o3 ' ,o5 ' -triacetyl-3-O'-tosylcytidine by reacting an equilibrium mixture of N4, o3 ', 05 ' -triacetylcytidine and the corresponding N4 ~ o2 ~ o5 -isomer with a slight excess of p-toluenesulfonyl chloride in an anhydrous pyridine solution. The 3'-O-tosylcytidine derivative was assumed to be a product present in a dichloromethane phase after an arabinofuranosylcytosine derivative had been extracted from the reaction mixture with water.
However, the 3'-O-tosylcytidine derivative was not isolated nor is there any disclosure or suggestion of how to prepare this derivative.
Mizuno et al (Tet. Lett., 4579-4584 (1965)) teach the production of 3'-O-mesylcytidine via a four step process from N4-acetylcytidine. This corresponds to a five step process, overall, if cytidine is used as the starting material. Thus, it is not surprising that the overall yield of 3'-O-mesylcytidine produced in this manner is less that 10~ (even this low yield assumes theoretical yields for two of the five steps where yield was unreported).
2~2~9~
Heretofore, the Applicants are not aware of prior art which teaches the production of 3'-tosylcytidine.
SUMMARY OF THE INVENTION
It is an ob;ect of the present invention to provide novel 3'-tosylcytidine compounds.
It is another object of the present invention to provide a novel process for the production of cytidine compounds, including 3'-tosylcytidine compounds.
Accordingly, in one of its aspects, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:
N /
N (I) 25RZO-C ~ O y Y OH
wherein Y is selected from p-toluenesulfonyl and -SO2CF3, 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, phosphate and salts thereof, tosyl and mesyl.
~_ 2 $ ~
In another of its aspects, the present invention provides a process for producing a compound of Formula II, or a pharmaceutically acceptable salt thereof:
N ~
~ N ~ (II) R2 O-C~O~J
wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-Cg aryl group, which comprises the step of reacting (i) a compound of Formula III:
~ N / (III) R2 O-C~O~) O~ ,0 ,Sn wherein R1 is a C1-C6 alkyl 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, 2,2,2-2 ~ 3 trichloroethyl, phosphate and salts thereof, tosyl and mesyl, with (ii) an amine selected from the group comprising pyridine and amines having the general formula R3R4RsN
wherein R3, R4 and R5 can be the same or different and each of R3, R4 and R5 is selected from the group comprising a Cl-C6 alkyl group and a C6-Cg aryl group, in the presence of (iii) a sulfonyl compound having the general formula wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-C9 aryl group, and X is selected from a halogen and -SO3CF3, to produce a compound of Formula II.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Thus, the invention provides 3'-tosylcytidine compounds such as 3'-tosylcytidine or pharmaceutically acceptable salts thereof.
The compound of Formula III:
-2 ~ 9 5 N
N
R20-C ~ 0 ~
(III) ~Sn R1 `R1 is known. Generally, this compound may be prepared by reacting cytidine with the appropriate dialkyl-tin oxide.
In one preferred embodiment of the compound of Formula III, R1 is butyl and R2 is hydrogen. With these definitions for R1 and R2, the compound of Formula III
is 2',3'-O-dibutylstannylene cytidine.
An example of a suitable "C2-C6 alkylacyl group" for use as R2 is acetyl. Further, an example of a suitable ''C6-Cg arylacyl group" for use as R2 benzoyl.
Provided that it does not contain a hydrogen bonded to nitrogen, the amine suitable for use in the presence process is not particularly restricted and may be selected from the group comprising trimethylamine, triethylamine, pyridine, tripropylamine and tributylamine. The most preferred amine is triethylamine.
The reaction of the compound of Formula III
with the amine is conducted in the presence of a sulfonyl compound, preferably a sulfonyl chloride 2 ~
compound. More preferably, the sulfonyl chloride compound is one of p-toluenesulfonyl chloride and methanesulfonyl chloride. When p-toluene sulfonyl chloride is used, the product of the process is a 3'-tosylcytidine compound of Formula I (i.e. Y is p-toluenesulfonyl).
Typically, the reaction can be conducted at room temperature, preferably with agitation (such as stirring) of the reaction mixture. The reaction may be conducted in a suitable organic solvent system. Non-limiting examples of suitable organic solvents include alcohols, toluene, benzene, chloroform, dichloromethane and the like. The preferred organic solvents are alcohols, more preferably methanol.
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 refluxed in a suitable medium (e.g. water). Thereafter, the crude product may be recrystallized from a suitable solvent, such as ethanol.
Aspects of the present invention will be described with reference to the following example which should not be considered to limit the scope of the invention.
EXAMPLE
A 500 mL flask was charged with 50 mL
methanol, 1.95 g cytidine and 2 g dibutyl tin oxide.
-2 ~
The resulting suspension was refluxed for five hours and then stirred at room temperature for 12 hours. To the mixture was then added triethylamine (7.8 mL) followed by slow addition of p-toluenesulfonyl chloride (10.68 g). The resulting mixture was stirred for 12 hours at room temperature. Thereafter, the solvents were evaporated under vacuum and chloroform (100 mL) was added to the resulting white gum. The chloroform/white gum suspension was refluxed for 15 minutes and then cooled to room temperature. The resulting white precipitate was filtered and set aside. After concentration of the filtrate under vacuum, the resulting residue was suspended in water (15 mL) at room temperature for 3 hours and then at 6C for 12 hours.
The suspension was filtered and the solid was resuspended in 15 mL water and the mixture heated to 90C and then cooled to room temperature (producted remained in solution). The solution was filtered through Celite and the filtrate was stirred at 6C for 12 hours which resulted in precipitation of a solid.
The precipitate was filtered and dried under vacuum to afford 1 g of crude 3'-tosylcytidine tosylate salt. The crude 3'-tosylcytidine tosylate salt was suspended in 25 mL chloroform and stirred for one hour. The suspension was filtered and washed with 5 mL chloroform.
Thereafter, the precipitate was suspended in 25 mL
boiling ethanol, to which was added 1.8 mL t-butylamine (pH = 8-9). The hot mixture was filtered, and the filtrate stirred at 15C for 16 hours. The resulting precipitate was filtered, washed with ethanol and dried to afford 0.53 g (14.9~ yield) of pure 3'-tosylcytidine ethanol, a novel compound which had a melting point of 115-116.5C (bubbles) with decomposition occurring at 160-170.
-2~
A sample of the novel compound was converted to the corresponding hydrochloride salt by reaction with dilute aqueous hydrochloric acid. Using a 200 MHz NMR
spe~Lo".eter, an NMR spectrum of this hydrochloride salt was obtained in DMS0-d-6. The following data on peak shift, number of peaks and coupling constants was obt~neA from the spectrum and confirms the structure of the hydrochloride salt of 3'-tosylcytide:
2~:~2~
SHIFT (~) ASSIGNMENT
2.42, s 3H: CH3 3.37, dd lH; J~ 5; =2-24 Hz, J5; 5i=12.44 Hz: H-51 3.45, bs 3H; exchangeable: NH3 3.54, dd lH; J4 5 =2.59 Hz: H-52' 4.07, m lH; J3 4 =3.17 Hz: H-4' 4.26, t lH; Jl 2 =6-04 Hz, J2 3 4 93 Hz: H-2' 4.85, dd lH: H-3 ' 5.76, d lH: H-l ' 6.19, d lH; J56=7.80 Hz: H-5 7.48, d 2H; JT O 6 y l 23 =8.40: Tosyl H-3 7.84, d 2H: Tosyl H-2 8.13, d lH: H-6 8.75 9.85, 2 x s 2 x lH, exchangeable: C2'-OH
and C5 ' OH
The present invention relates to novel 3'-tosylcytidine compounds and pharmaceutically acceptable salts thereof. Further, the present invention relates to a process for the production of 3'-tosylcytidine compounds.
BACKGROUND OF THE INVENTION
Fromageot et al (Tet. Lett., 3499-3505, (1966)) speculated production of N4 ,o3 ' ,o5 ' -triacetyl-3-O'-tosylcytidine by reacting an equilibrium mixture of N4, o3 ', 05 ' -triacetylcytidine and the corresponding N4 ~ o2 ~ o5 -isomer with a slight excess of p-toluenesulfonyl chloride in an anhydrous pyridine solution. The 3'-O-tosylcytidine derivative was assumed to be a product present in a dichloromethane phase after an arabinofuranosylcytosine derivative had been extracted from the reaction mixture with water.
However, the 3'-O-tosylcytidine derivative was not isolated nor is there any disclosure or suggestion of how to prepare this derivative.
Mizuno et al (Tet. Lett., 4579-4584 (1965)) teach the production of 3'-O-mesylcytidine via a four step process from N4-acetylcytidine. This corresponds to a five step process, overall, if cytidine is used as the starting material. Thus, it is not surprising that the overall yield of 3'-O-mesylcytidine produced in this manner is less that 10~ (even this low yield assumes theoretical yields for two of the five steps where yield was unreported).
2~2~9~
Heretofore, the Applicants are not aware of prior art which teaches the production of 3'-tosylcytidine.
SUMMARY OF THE INVENTION
It is an ob;ect of the present invention to provide novel 3'-tosylcytidine compounds.
It is another object of the present invention to provide a novel process for the production of cytidine compounds, including 3'-tosylcytidine compounds.
Accordingly, in one of its aspects, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:
N /
N (I) 25RZO-C ~ O y Y OH
wherein Y is selected from p-toluenesulfonyl and -SO2CF3, 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, phosphate and salts thereof, tosyl and mesyl.
~_ 2 $ ~
In another of its aspects, the present invention provides a process for producing a compound of Formula II, or a pharmaceutically acceptable salt thereof:
N ~
~ N ~ (II) R2 O-C~O~J
wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-Cg aryl group, which comprises the step of reacting (i) a compound of Formula III:
~ N / (III) R2 O-C~O~) O~ ,0 ,Sn wherein R1 is a C1-C6 alkyl 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, 2,2,2-2 ~ 3 trichloroethyl, phosphate and salts thereof, tosyl and mesyl, with (ii) an amine selected from the group comprising pyridine and amines having the general formula R3R4RsN
wherein R3, R4 and R5 can be the same or different and each of R3, R4 and R5 is selected from the group comprising a Cl-C6 alkyl group and a C6-Cg aryl group, in the presence of (iii) a sulfonyl compound having the general formula wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-C9 aryl group, and X is selected from a halogen and -SO3CF3, to produce a compound of Formula II.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Thus, the invention provides 3'-tosylcytidine compounds such as 3'-tosylcytidine or pharmaceutically acceptable salts thereof.
The compound of Formula III:
-2 ~ 9 5 N
N
R20-C ~ 0 ~
(III) ~Sn R1 `R1 is known. Generally, this compound may be prepared by reacting cytidine with the appropriate dialkyl-tin oxide.
In one preferred embodiment of the compound of Formula III, R1 is butyl and R2 is hydrogen. With these definitions for R1 and R2, the compound of Formula III
is 2',3'-O-dibutylstannylene cytidine.
An example of a suitable "C2-C6 alkylacyl group" for use as R2 is acetyl. Further, an example of a suitable ''C6-Cg arylacyl group" for use as R2 benzoyl.
Provided that it does not contain a hydrogen bonded to nitrogen, the amine suitable for use in the presence process is not particularly restricted and may be selected from the group comprising trimethylamine, triethylamine, pyridine, tripropylamine and tributylamine. The most preferred amine is triethylamine.
The reaction of the compound of Formula III
with the amine is conducted in the presence of a sulfonyl compound, preferably a sulfonyl chloride 2 ~
compound. More preferably, the sulfonyl chloride compound is one of p-toluenesulfonyl chloride and methanesulfonyl chloride. When p-toluene sulfonyl chloride is used, the product of the process is a 3'-tosylcytidine compound of Formula I (i.e. Y is p-toluenesulfonyl).
Typically, the reaction can be conducted at room temperature, preferably with agitation (such as stirring) of the reaction mixture. The reaction may be conducted in a suitable organic solvent system. Non-limiting examples of suitable organic solvents include alcohols, toluene, benzene, chloroform, dichloromethane and the like. The preferred organic solvents are alcohols, more preferably methanol.
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 refluxed in a suitable medium (e.g. water). Thereafter, the crude product may be recrystallized from a suitable solvent, such as ethanol.
Aspects of the present invention will be described with reference to the following example which should not be considered to limit the scope of the invention.
EXAMPLE
A 500 mL flask was charged with 50 mL
methanol, 1.95 g cytidine and 2 g dibutyl tin oxide.
-2 ~
The resulting suspension was refluxed for five hours and then stirred at room temperature for 12 hours. To the mixture was then added triethylamine (7.8 mL) followed by slow addition of p-toluenesulfonyl chloride (10.68 g). The resulting mixture was stirred for 12 hours at room temperature. Thereafter, the solvents were evaporated under vacuum and chloroform (100 mL) was added to the resulting white gum. The chloroform/white gum suspension was refluxed for 15 minutes and then cooled to room temperature. The resulting white precipitate was filtered and set aside. After concentration of the filtrate under vacuum, the resulting residue was suspended in water (15 mL) at room temperature for 3 hours and then at 6C for 12 hours.
The suspension was filtered and the solid was resuspended in 15 mL water and the mixture heated to 90C and then cooled to room temperature (producted remained in solution). The solution was filtered through Celite and the filtrate was stirred at 6C for 12 hours which resulted in precipitation of a solid.
The precipitate was filtered and dried under vacuum to afford 1 g of crude 3'-tosylcytidine tosylate salt. The crude 3'-tosylcytidine tosylate salt was suspended in 25 mL chloroform and stirred for one hour. The suspension was filtered and washed with 5 mL chloroform.
Thereafter, the precipitate was suspended in 25 mL
boiling ethanol, to which was added 1.8 mL t-butylamine (pH = 8-9). The hot mixture was filtered, and the filtrate stirred at 15C for 16 hours. The resulting precipitate was filtered, washed with ethanol and dried to afford 0.53 g (14.9~ yield) of pure 3'-tosylcytidine ethanol, a novel compound which had a melting point of 115-116.5C (bubbles) with decomposition occurring at 160-170.
-2~
A sample of the novel compound was converted to the corresponding hydrochloride salt by reaction with dilute aqueous hydrochloric acid. Using a 200 MHz NMR
spe~Lo".eter, an NMR spectrum of this hydrochloride salt was obtained in DMS0-d-6. The following data on peak shift, number of peaks and coupling constants was obt~neA from the spectrum and confirms the structure of the hydrochloride salt of 3'-tosylcytide:
2~:~2~
SHIFT (~) ASSIGNMENT
2.42, s 3H: CH3 3.37, dd lH; J~ 5; =2-24 Hz, J5; 5i=12.44 Hz: H-51 3.45, bs 3H; exchangeable: NH3 3.54, dd lH; J4 5 =2.59 Hz: H-52' 4.07, m lH; J3 4 =3.17 Hz: H-4' 4.26, t lH; Jl 2 =6-04 Hz, J2 3 4 93 Hz: H-2' 4.85, dd lH: H-3 ' 5.76, d lH: H-l ' 6.19, d lH; J56=7.80 Hz: H-5 7.48, d 2H; JT O 6 y l 23 =8.40: Tosyl H-3 7.84, d 2H: Tosyl H-2 8.13, d lH: H-6 8.75 9.85, 2 x s 2 x lH, exchangeable: C2'-OH
and C5 ' OH
Claims (8)
1. A process for the producing a compound of Formula II, or a pharmaceutically acceptable salt thereof:
(II) wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-C9 aryl group, which comprises the step of reacting (i) a compound of Formula III:
(III) wherein R1 is a C1-C6 alkyl 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, with (ii) an amine selected from the group comprising pyridine and amines having the general formula wherein R3, R4 and R5 can be the same or different and each of R3, R4 and R5 is selected from the group comprising a C1-C6 alkyl group and a C6-C9 aryl group, in the presence of (iii) a sulfonyl compound having the general formula wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-C9 aryl group, and X is selected from a halogen and -SO3CF3, to produce a compound of Formula II.
(II) wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-C9 aryl group, which comprises the step of reacting (i) a compound of Formula III:
(III) wherein R1 is a C1-C6 alkyl 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, with (ii) an amine selected from the group comprising pyridine and amines having the general formula wherein R3, R4 and R5 can be the same or different and each of R3, R4 and R5 is selected from the group comprising a C1-C6 alkyl group and a C6-C9 aryl group, in the presence of (iii) a sulfonyl compound having the general formula wherein R6 is selected from the group comprising -CF3, a C1-C6 alkyl group and a C6-C9 aryl group, and X is selected from a halogen and -SO3CF3, to produce a compound of Formula II.
2. The process defined in claim 1, wherein R2 is hydrogen.
3. The process defined in claim 1, wherein X is chloride.
4. The process defined in claim 2, wherein said sulfonyl compound is selected from p-toluenesulfonyl chloride and methanesulfonyl chloride.
5. The process defined in claim 2, wherein said sulfonyl compound is p-toluenesulfonyl chloride.
6. The process defined in claim 4, wherein said amine is selected from the group comprising trlmethylamine, triethylamine, pyridine, trlpropylamine and trlbutylamlne.
7. The process deflned ln clalm 5, wherein said amlne is triethylamine.
8. The process defined in claim 7, wherein said step is conducted in the presence of methanol.
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012095 CA2012095C (en) | 1990-03-13 | 1990-03-13 | 3'-tosylcytidine compounds and process for production thereof |
| 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. |
| 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 |
| DE69111438T DE69111438T2 (en) | 1990-03-13 | 1991-03-13 | 2,3'-O-CYCLOCYTIDINE AND METHOD 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 |
| 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 2012095 CA2012095C (en) | 1990-03-13 | 1990-03-13 | 3'-tosylcytidine compounds and process for production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2012095A1 CA2012095A1 (en) | 1991-09-13 |
| CA2012095C true CA2012095C (en) | 1996-07-23 |
Family
ID=4144517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2012095 Expired - Fee Related CA2012095C (en) | 1990-03-13 | 1990-03-13 | 3'-tosylcytidine compounds and process for production thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2012095C (en) |
-
1990
- 1990-03-13 CA CA 2012095 patent/CA2012095C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2012095A1 (en) | 1991-09-13 |
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