CA2012093C - Process for producing 2,2'-cyclocytidine and analogues thereof - Google Patents
Process for producing 2,2'-cyclocytidine and analogues thereofInfo
- Publication number
- CA2012093C CA2012093C CA 2012093 CA2012093A CA2012093C CA 2012093 C CA2012093 C CA 2012093C CA 2012093 CA2012093 CA 2012093 CA 2012093 A CA2012093 A CA 2012093A CA 2012093 C CA2012093 C CA 2012093C
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- Prior art keywords
- group
- process defined
- compound
- cyclocytidine
- formula
- Prior art date
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- 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, 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
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- Organic Chemistry (AREA)
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- 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
A novel process for the production of 2,2'-cyclocytidine compounds and pharmaceutically acceptable salts thereof comprises reacting a 2',3'-O-dialkylstannylene cytidine compound with an amine in the presence of a sulfonyl compound. 2,2'-Cyclocytidine is a percursor to cytarabine, a known antineoplastic and antiviral agent.
Description
2 ~ 3 FIELD OF THE INVENTION
The present invention relates to a novel process for producing cyclonucleosides and pharmaceutically acceptable salts thereof. More specifically, the present invention relates to a process for the production of 2,2'-cyclocytidine, 2,2'-cyclocytidine analogues and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INYENTION
The production of cyclonucleosides is known.
For example, Walwick et al (Proc. Chem. Soc., 84 (1959)) teach the production of 2,2'-cyclocytidine hydrochloride from cytidine. The process involved heating cytidine with polyphosphoric acid followed by dephosphorylation of one of the reaction products, 2,2'-cyclocytidine-3',5'-diphosphate.
Doerr et al (J. Org. Chen., 32, 1462 (1967)) teach the production of 2,2'-cyclocytidine chloride from uridine using a process comprising six steps. It is interesting to note that in the final step, 2,2'-cyclocytidine hydrochloride was obtained only in a 57%
yield. Taking into account the fact that each step is not quantitative, the overall yield of 2,2'-cyclocytidine hydrochloride from uridine can be expected to be on the order of from 10% to 20%.
Kikugawa et al (Tet. Lett., 869 (1970)) teach the production of the hydrochloride or the formate salt of 2,2'-cyclocytidine. Specifically, the process comprises reacting cytidine with thionyl chloride and N,N'-dimethylformamide. It is interesting to note that the crude 2,2'-cyclocytidine salt was obtained in a -1- ~
2~ 3 yield of only 30.4%. Kikugawa et al (J. Org. Chem., 37, 284 (1972)) also provide an improved process for preparing 2,2'-cyclocytidine. The improvement appears to relate to an improved yield (55%) of the product using ion exchange and chromatography techniques.
Sowa et al (Bull. Chem. Soc. Jap., 48, 505 (1975)) teach a process for the production of cyclonucleosides which comprises reacting the starting ribonucleoside with thionyl chloride and water and subsequently reflecting the reaction mixture at an acidic pH. It is interesting to note that a yield of about 73% of 2,2'-cyclocytidine hydrochloride was allegedly obtained whereas a yield of about 47% of 2,2'-cyclouridine hydrochloride was alledgedly obtained.
Yamaguchi et al (J. Med. Chem., 19, 654 (1979)) teach the production of 2,2'-cyclocytidine hydrochloride via reaction of cytidine with an organic acid chloride.
The aforementioned prior art techniques for the preparation of 2,2'-cyclonucleosides are deficient in that they require multiple steps with inherent loss of yield and/or they require silica/resin columns for isolation and purification. It would be desirable to have a relatively simple process for producing 2,2'-cyclonucleosides in acceptable and/or comparable yields.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel process for the production of 2,2'-cyclocytidine compounds and pharmaceutically acceptable salts thereof.
~ 2~3 -Accordingly, the present invention provides a process for producing a compound of Formula I, or a pharmaceutically acceptable salt thereof:
NH
,, Nl ~
\ N (I) R~0-C ~ 0~
which comprises the step of reacting (i) a compound of Formula II:
N (II) R2 o-c~o~J
Sn Rl~ `Rl wherein Rl is a Cl-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-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, with (ii) an amine selected from 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 Rs is selected from the group comprising a C1-C6 alkyl group and 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 C6-Cg aryl group, and X is selected from a halogen and S03CF3, to produce a compound of Formula I.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Thus, the present process can be used to produce 2,2'-cycloribosides such as 2,2'-cyclocytidine 20or pharmaceutically acceptable salts thereof.
The compound of Formula II:
I (II) 0~\ /
N
R2 O-C~O~) O~ ~0 ~Sn~
2 ~
is known. Generally, this compound may be prepared by reacting the appropriate nucleoside with the appropriate dialkyl tin oxide.
In one preferred embodiment of the invention, R1 is butyl and R2 is hydrogen. With these definitions for R1 and R2, the compound of Formula II is 2',3'-0-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 is benzoyl.
Provided that it does not contain a hydrogen bonded to nitrogen, the amine suitable for use in the present 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 II
with the amine is conducted in the presence of a sulfonyl compound, preferably a sulfonyl chloride compound. More preferably the sulfonyl chloride compound is one of p-toluenesulfonyl chloride and methanesulfonyl chloride.
Typically, the reaction can be conducted at room temperature, preferably with agitation of the reaction mixture (such as stirring). The reaction may be conducted in any suitable organic solvent system.
Examples of suitable organic solvents include:
alcohols, toluene, benzene, chloroform, dichloromethane 2~
and the like. The preferred organic solvents are alcohols, more preferably methanol.
The crude 2,2'-cyclocytidine 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. chloroform). Thereafter, the crude 2,2'-cyclonucleoside may be purified from water (in which the product is soluble) and alcohol (in which the product is relatively insoluble).
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.
The resulting suspension was refluxed for five hours and then stirred at room temperature for twelve 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 twelve 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 fifteen minutes and then cooled to room temperature. The resulting white precipitate was filtered and washed with chloroform, and dried to yield 1 g of crude 2,2'-cyclocytidine hydrochloride. The crude cyclocytidine hydrochloride 2~2~3 was suspended in 5 mL water and the mixture was heated to 60C. This solution was filtered and the solvent reduced under vacuum to obtain a turbid oil. Ethanol (18 mL) was added and the mixture was stirred at 5C for twelve hours. The resulting precipitate was filtered and dried to provide 0.6 g of pure 2,2'-cyclocytidine hydrochloride (29% yield). The product was characterized by comparison of its melting point, and MMR and IR spectra with those previously reported for 2,2'-cyclocytidine.
The present invention relates to a novel process for producing cyclonucleosides and pharmaceutically acceptable salts thereof. More specifically, the present invention relates to a process for the production of 2,2'-cyclocytidine, 2,2'-cyclocytidine analogues and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INYENTION
The production of cyclonucleosides is known.
For example, Walwick et al (Proc. Chem. Soc., 84 (1959)) teach the production of 2,2'-cyclocytidine hydrochloride from cytidine. The process involved heating cytidine with polyphosphoric acid followed by dephosphorylation of one of the reaction products, 2,2'-cyclocytidine-3',5'-diphosphate.
Doerr et al (J. Org. Chen., 32, 1462 (1967)) teach the production of 2,2'-cyclocytidine chloride from uridine using a process comprising six steps. It is interesting to note that in the final step, 2,2'-cyclocytidine hydrochloride was obtained only in a 57%
yield. Taking into account the fact that each step is not quantitative, the overall yield of 2,2'-cyclocytidine hydrochloride from uridine can be expected to be on the order of from 10% to 20%.
Kikugawa et al (Tet. Lett., 869 (1970)) teach the production of the hydrochloride or the formate salt of 2,2'-cyclocytidine. Specifically, the process comprises reacting cytidine with thionyl chloride and N,N'-dimethylformamide. It is interesting to note that the crude 2,2'-cyclocytidine salt was obtained in a -1- ~
2~ 3 yield of only 30.4%. Kikugawa et al (J. Org. Chem., 37, 284 (1972)) also provide an improved process for preparing 2,2'-cyclocytidine. The improvement appears to relate to an improved yield (55%) of the product using ion exchange and chromatography techniques.
Sowa et al (Bull. Chem. Soc. Jap., 48, 505 (1975)) teach a process for the production of cyclonucleosides which comprises reacting the starting ribonucleoside with thionyl chloride and water and subsequently reflecting the reaction mixture at an acidic pH. It is interesting to note that a yield of about 73% of 2,2'-cyclocytidine hydrochloride was allegedly obtained whereas a yield of about 47% of 2,2'-cyclouridine hydrochloride was alledgedly obtained.
Yamaguchi et al (J. Med. Chem., 19, 654 (1979)) teach the production of 2,2'-cyclocytidine hydrochloride via reaction of cytidine with an organic acid chloride.
The aforementioned prior art techniques for the preparation of 2,2'-cyclonucleosides are deficient in that they require multiple steps with inherent loss of yield and/or they require silica/resin columns for isolation and purification. It would be desirable to have a relatively simple process for producing 2,2'-cyclonucleosides in acceptable and/or comparable yields.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel process for the production of 2,2'-cyclocytidine compounds and pharmaceutically acceptable salts thereof.
~ 2~3 -Accordingly, the present invention provides a process for producing a compound of Formula I, or a pharmaceutically acceptable salt thereof:
NH
,, Nl ~
\ N (I) R~0-C ~ 0~
which comprises the step of reacting (i) a compound of Formula II:
N (II) R2 o-c~o~J
Sn Rl~ `Rl wherein Rl is a Cl-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-trichloroethyl, phosphates and salts thereof, tosyl and mesyl, with (ii) an amine selected from 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 Rs is selected from the group comprising a C1-C6 alkyl group and 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 C6-Cg aryl group, and X is selected from a halogen and S03CF3, to produce a compound of Formula I.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Thus, the present process can be used to produce 2,2'-cycloribosides such as 2,2'-cyclocytidine 20or pharmaceutically acceptable salts thereof.
The compound of Formula II:
I (II) 0~\ /
N
R2 O-C~O~) O~ ~0 ~Sn~
2 ~
is known. Generally, this compound may be prepared by reacting the appropriate nucleoside with the appropriate dialkyl tin oxide.
In one preferred embodiment of the invention, R1 is butyl and R2 is hydrogen. With these definitions for R1 and R2, the compound of Formula II is 2',3'-0-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 is benzoyl.
Provided that it does not contain a hydrogen bonded to nitrogen, the amine suitable for use in the present 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 II
with the amine is conducted in the presence of a sulfonyl compound, preferably a sulfonyl chloride compound. More preferably the sulfonyl chloride compound is one of p-toluenesulfonyl chloride and methanesulfonyl chloride.
Typically, the reaction can be conducted at room temperature, preferably with agitation of the reaction mixture (such as stirring). The reaction may be conducted in any suitable organic solvent system.
Examples of suitable organic solvents include:
alcohols, toluene, benzene, chloroform, dichloromethane 2~
and the like. The preferred organic solvents are alcohols, more preferably methanol.
The crude 2,2'-cyclocytidine 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. chloroform). Thereafter, the crude 2,2'-cyclonucleoside may be purified from water (in which the product is soluble) and alcohol (in which the product is relatively insoluble).
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.
The resulting suspension was refluxed for five hours and then stirred at room temperature for twelve 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 twelve 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 fifteen minutes and then cooled to room temperature. The resulting white precipitate was filtered and washed with chloroform, and dried to yield 1 g of crude 2,2'-cyclocytidine hydrochloride. The crude cyclocytidine hydrochloride 2~2~3 was suspended in 5 mL water and the mixture was heated to 60C. This solution was filtered and the solvent reduced under vacuum to obtain a turbid oil. Ethanol (18 mL) was added and the mixture was stirred at 5C for twelve hours. The resulting precipitate was filtered and dried to provide 0.6 g of pure 2,2'-cyclocytidine hydrochloride (29% yield). The product was characterized by comparison of its melting point, and MMR and IR spectra with those previously reported for 2,2'-cyclocytidine.
Claims (10)
1. A process for producing a compound of Formula I, or pharmaceutically acceptable salt thereof:
(I) which comprises the step of reacting (i) a compound of Formula II:
(II) 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 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 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 C6-C9 aryl group, and X is selected from SO3CF3 and a halogen, to produce a compound of Formula I.
(I) which comprises the step of reacting (i) a compound of Formula II:
(II) 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 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 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 C6-C9 aryl group, and X is selected from SO3CF3 and a halogen, to produce a compound of Formula I.
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 claims 1, 2, 3 or 4, wherein said amine is selected from the group comprising trimethylamine, triethylamine, pyridine, tripropylamine and tributylamine.
7. The process defined in claim 5, wherein said amine is triethylamine.
8. The process defined in claims 1, 2, 3 or 4, wherein said step is conducted in the presence of an organic solvent.
9. The process defined in claims 1, 2, 3 or 4, wherein said step is conducted in the presence of an organic solvent selected from the group comprising alcohols, toluene, benzene, chloroform and dichloromethane
10. The process defined in claim 7, wherein said step is conducted in the presence of methanol.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012093 CA2012093C (en) | 1990-03-13 | 1990-03-13 | Process for producing 2,2'-cyclocytidine and analogues thereof |
| PCT/CA1991/000077 WO1991013900A1 (en) | 1990-03-13 | 1991-03-13 | Process for producing 2,2'-o-cyclonucleosides, nucleosides, and analogs thereof |
| DE69108014T DE69108014T2 (en) | 1990-03-13 | 1991-03-13 | METHOD FOR PRODUCING NUCLEOSIDES AND THEIR ANALOGS. |
| AT91906244T ATE119541T1 (en) | 1990-03-13 | 1991-03-13 | METHOD FOR PRODUCING NUCLEOSIDES AND THEIR ANALOGUES. |
| BR919106158A BR9106158A (en) | 1990-03-13 | 1991-03-13 | PROCESS TO PRODUCE 2,2'-O-CYCLONUCLEOSIDEOS, NUCLEOSIDEOS AND THEIR ANALOGS |
| EP91906244A EP0521923B1 (en) | 1990-03-13 | 1991-03-13 | Process for producing nucleosides, and analogs therof |
| AU74737/91A AU7473791A (en) | 1990-03-13 | 1991-03-13 | Process for producing 2,2'-o-cyclonucleosides, nucleosides, and analogs thereof |
| HU9202906A HUT61566A (en) | 1990-03-13 | 1991-03-13 | Process for producing 2,2'-o-cyclonucleosides, nucleosides and their analogous compounds |
| US08/313,579 US5610292A (en) | 1990-03-13 | 1994-09-27 | Process for producing 2,2'-o-cyclonucleosides nucleosides, and analogs thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012093 CA2012093C (en) | 1990-03-13 | 1990-03-13 | Process for producing 2,2'-cyclocytidine and analogues thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2012093A1 CA2012093A1 (en) | 1991-09-13 |
| CA2012093C true CA2012093C (en) | 1995-12-26 |
Family
ID=4144515
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2012093 Expired - Fee Related CA2012093C (en) | 1990-03-13 | 1990-03-13 | Process for producing 2,2'-cyclocytidine and analogues thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2012093C (en) |
-
1990
- 1990-03-13 CA CA 2012093 patent/CA2012093C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2012093A1 (en) | 1991-09-13 |
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|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |