CA2012094C - Process for producing cytarabine and analogues thereof - Google Patents
Process for producing cytarabine and analogues thereofInfo
- Publication number
- CA2012094C CA2012094C CA 2012094 CA2012094A CA2012094C CA 2012094 C CA2012094 C CA 2012094C CA 2012094 CA2012094 CA 2012094 CA 2012094 A CA2012094 A CA 2012094A CA 2012094 C CA2012094 C CA 2012094C
- Authority
- CA
- Canada
- Prior art keywords
- group
- cytarabine
- hydrogen
- process defined
- amine
- 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
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, 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
Abstract
A novel process for producing cytarabine or a cytarabine analogue comprising the step of reacting 2,2'-cyclocytidine or an analogue thereof with an amine.
Preferably the process is conducted in the presence of an aqueous solvent. Cytarabine is a known antineoplastic and antiviral agent.
Preferably the process is conducted in the presence of an aqueous solvent. Cytarabine is a known antineoplastic and antiviral agent.
Description
FIELD OF THE INVENTION
The present invention relates to a novel process for the production of cytarabine, cytarabine analogues and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Cytarabine is a known antineoplastic and antiviral agent. Cytarabine, which is also known as 4-amino-l-~-D-arabinofuranosyl-2f lN J -pyrimidinone, 1-~-D-arabinofuranosylcytosine and ~-cytosinearabinoside, has the following chemical structure:
~ N
HO-C ~ O
~ HO~
HO
Ogilvie (Carbohyd. Res., 24, 210 (1972)) teaches the production of cytarabine from cytidine.
Specifically, the process comprised reacting cytidine with diphenyl carbonate and sodium hydrogen carbonate at 150C in DMF. The product cytarabine was purified using thin layer chromatography and obt~ineA in a yield of 40%.
Beranek et al (Nucleic Acid Chemistry, Vol. 1, 249, Edited by Townsend and Tipson, Wiley, New York) ~12~
teach the production of cytarabine from cytidine.
Specifically, cytidine is reacted with incremental amounts of diphenyl carbonate in the presence of DMF and water at 120C. The overall yield of pure cytarabine was limited to 31.9%.
Roberts et al (J. Org. Chem., 32, 816 (1967)) teach the production of cytarabine from cytidine (or from 2'(3')-cytidylic acid). Specifically, cytidine is reacted with phosphoric acid at 80C for a period of 30 hours to produce a 2,2'-cyclocytidine analogue intermediate. This intermediate is then hydrolyzed at a pH of 9 utilizing lithium hydroxide to produce the 3',5'-diphosphate of cytarabine. The diphosphate is then treated with magnesium chloride, ammonium chloride and concentrated ammonium hydroxide, and thereafter purified by column chromatography to yield pure cytarabine. The overall yield of pure cytarabine is limited to 53% based on the unrecovered portion of the starting cytidine.
Kikugawa et al (J. Org. Chem., 37, 284-288 (1972)) teach the conversion of 2,2'-cyclocytidine hydrochloride to cytarabine. Specifically, ammonia is added to an aqueous solution of 2,2'-cyclocytidine thereby raising the pH to 9. The solution is thereafter acidified with hydrochloric acid and run through an ion exchange column. Thereafter, cytarabine is crystallized from ethanol in a yield of 90%.
Sowa et al (Bull. Chem. Soc. Jap., 48, 505-507 (1975) teach the production of cytarabine from 2,2'-cyclocytidine. Specifically, sodium hydroxide is added to an aqueous solution of 2,2'-cyclocytidine hydrochloride thereby raising the pH of the solution to 10. Thereafter, the solution is run through a H~ ionic exchange resin followed by recrystallization of pure cytarabine from ethanol.
Unfortunately, the prior art processes for the production of cytarabine and its analogues are deficient in that the purified product is obt~ne~ in a relatively low yield and/or the process is complicated requiring a series of steps including the use of ion exchange resins. Thus, it would be desirable to have a process for the production of cytarabine, cytarabine analogues and pharmaceutically acceptable salts thereof in relatively high yields and by a relatively simply process.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel process for the production of cytarabine, cytarabine analogues and pharmaceutically acceptable salts thereof.
Accordingly, the present invention provides a process for directly preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof:
¦ (I) O ~ N /
Rl O-C~O~
\ HO~
HO
The present invention relates to a novel process for the production of cytarabine, cytarabine analogues and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Cytarabine is a known antineoplastic and antiviral agent. Cytarabine, which is also known as 4-amino-l-~-D-arabinofuranosyl-2f lN J -pyrimidinone, 1-~-D-arabinofuranosylcytosine and ~-cytosinearabinoside, has the following chemical structure:
~ N
HO-C ~ O
~ HO~
HO
Ogilvie (Carbohyd. Res., 24, 210 (1972)) teaches the production of cytarabine from cytidine.
Specifically, the process comprised reacting cytidine with diphenyl carbonate and sodium hydrogen carbonate at 150C in DMF. The product cytarabine was purified using thin layer chromatography and obt~ineA in a yield of 40%.
Beranek et al (Nucleic Acid Chemistry, Vol. 1, 249, Edited by Townsend and Tipson, Wiley, New York) ~12~
teach the production of cytarabine from cytidine.
Specifically, cytidine is reacted with incremental amounts of diphenyl carbonate in the presence of DMF and water at 120C. The overall yield of pure cytarabine was limited to 31.9%.
Roberts et al (J. Org. Chem., 32, 816 (1967)) teach the production of cytarabine from cytidine (or from 2'(3')-cytidylic acid). Specifically, cytidine is reacted with phosphoric acid at 80C for a period of 30 hours to produce a 2,2'-cyclocytidine analogue intermediate. This intermediate is then hydrolyzed at a pH of 9 utilizing lithium hydroxide to produce the 3',5'-diphosphate of cytarabine. The diphosphate is then treated with magnesium chloride, ammonium chloride and concentrated ammonium hydroxide, and thereafter purified by column chromatography to yield pure cytarabine. The overall yield of pure cytarabine is limited to 53% based on the unrecovered portion of the starting cytidine.
Kikugawa et al (J. Org. Chem., 37, 284-288 (1972)) teach the conversion of 2,2'-cyclocytidine hydrochloride to cytarabine. Specifically, ammonia is added to an aqueous solution of 2,2'-cyclocytidine thereby raising the pH to 9. The solution is thereafter acidified with hydrochloric acid and run through an ion exchange column. Thereafter, cytarabine is crystallized from ethanol in a yield of 90%.
Sowa et al (Bull. Chem. Soc. Jap., 48, 505-507 (1975) teach the production of cytarabine from 2,2'-cyclocytidine. Specifically, sodium hydroxide is added to an aqueous solution of 2,2'-cyclocytidine hydrochloride thereby raising the pH of the solution to 10. Thereafter, the solution is run through a H~ ionic exchange resin followed by recrystallization of pure cytarabine from ethanol.
Unfortunately, the prior art processes for the production of cytarabine and its analogues are deficient in that the purified product is obt~ne~ in a relatively low yield and/or the process is complicated requiring a series of steps including the use of ion exchange resins. Thus, it would be desirable to have a process for the production of cytarabine, cytarabine analogues and pharmaceutically acceptable salts thereof in relatively high yields and by a relatively simply process.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel process for the production of cytarabine, cytarabine analogues and pharmaceutically acceptable salts thereof.
Accordingly, the present invention provides a process for directly preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof:
¦ (I) O ~ N /
Rl O-C~O~
\ HO~
HO
2 ~
which comprises the step of reacting (i) a compound of Formula II or a pharmaceutically acceptable salt thereof:
N~
I
\ N (II) 10R1O-C ~ ~
Y
HO H
wherein Rl is selected for 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 wherein RZ, R3 and R4 can be the same or different and are is selected from the group comprising hydrogen, a C1-C6 alkyl group and a C6-Cg aryl group, with the proviso that the each of R2, R3 and R4 are not hydrogen.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compound of Formula II:
2~ 1 2094 NH
N
R'0-C ~ ~ (II) is known and may be prepared in a number of dlfferent manners.
Preferably, this compound $s prepared by reacting a cytldine compound-tin oxide con~ugate of Formula III:
0 ~ N /
R10-C ~ 0 ~ (III) Sn Rs `R~
wherein Rl is as defined hereinbefore and Rs is a C1-C6 alkyl group with an amine in the pr~ce~ce of a sulfonyl compound. Thl~ process of producing the starting compound for the present process (i.e. the compound of Formula III) is the subject of our copending Canadian patent application number 2,012,093, filed March 13, 1990.
It will of course be understood that the manner in which starting compound of 2 ~
Formula III is made is not particularly restricted as regards the present process.
The most preferred starting material for the present process is 2,2'-cyclocytidine. In this embodiment R1 of Formula II is hydrogen.
An example of a suitable "C2-C6 alkylacyl group" for use as R1 is acetyl. Further, an example of a suitable "C6-Cg arylacyl group" for use as R1 is benzoyl.
The amine suitable for use in the present process is selected from the group comprising Cs-C1 2 heterocyclic amines and amines having the general formula R2R3R~N
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 present process is conducted in the presence of an aqueous solvent. Examples of 2 ~
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 present comprises solely water.
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 any polar solvent for the starting compound of Formula I. Preferably, the solvent is water.
The crude cytarabine, cytarabine analogue or pharmaceutically acceptable salt thereof 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 present invention will be described with reference to the following example which should not be considered to limit the scope of the invention.
EXAMPLE
2,2'-Cyclocytidine hydrochloride (6.5 g) was dissolved in 35 mL water at 80C. The solution was cooled to room temperature and t-butylamine (2.8 g) was added and the mixture stirred for 2 hours. Thereafter, the solvent was evaporated under vacuum and ethanol (16 2 ~
g) was added. The mixture was stirred at room temperature for 12 hours. Filtration of the resulting precipitate yielded 5 g of pure cytarabine after drying, which corresponds to a yield of 83~. The product was characterized by comparison of its melting point, and MMR and IR spectra with those previously reported for cytarabine.
which comprises the step of reacting (i) a compound of Formula II or a pharmaceutically acceptable salt thereof:
N~
I
\ N (II) 10R1O-C ~ ~
Y
HO H
wherein Rl is selected for 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 wherein RZ, R3 and R4 can be the same or different and are is selected from the group comprising hydrogen, a C1-C6 alkyl group and a C6-Cg aryl group, with the proviso that the each of R2, R3 and R4 are not hydrogen.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compound of Formula II:
2~ 1 2094 NH
N
R'0-C ~ ~ (II) is known and may be prepared in a number of dlfferent manners.
Preferably, this compound $s prepared by reacting a cytldine compound-tin oxide con~ugate of Formula III:
0 ~ N /
R10-C ~ 0 ~ (III) Sn Rs `R~
wherein Rl is as defined hereinbefore and Rs is a C1-C6 alkyl group with an amine in the pr~ce~ce of a sulfonyl compound. Thl~ process of producing the starting compound for the present process (i.e. the compound of Formula III) is the subject of our copending Canadian patent application number 2,012,093, filed March 13, 1990.
It will of course be understood that the manner in which starting compound of 2 ~
Formula III is made is not particularly restricted as regards the present process.
The most preferred starting material for the present process is 2,2'-cyclocytidine. In this embodiment R1 of Formula II is hydrogen.
An example of a suitable "C2-C6 alkylacyl group" for use as R1 is acetyl. Further, an example of a suitable "C6-Cg arylacyl group" for use as R1 is benzoyl.
The amine suitable for use in the present process is selected from the group comprising Cs-C1 2 heterocyclic amines and amines having the general formula R2R3R~N
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 present process is conducted in the presence of an aqueous solvent. Examples of 2 ~
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 present comprises solely water.
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 any polar solvent for the starting compound of Formula I. Preferably, the solvent is water.
The crude cytarabine, cytarabine analogue or pharmaceutically acceptable salt thereof 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 present invention will be described with reference to the following example which should not be considered to limit the scope of the invention.
EXAMPLE
2,2'-Cyclocytidine hydrochloride (6.5 g) was dissolved in 35 mL water at 80C. The solution was cooled to room temperature and t-butylamine (2.8 g) was added and the mixture stirred for 2 hours. Thereafter, the solvent was evaporated under vacuum and ethanol (16 2 ~
g) was added. The mixture was stirred at room temperature for 12 hours. Filtration of the resulting precipitate yielded 5 g of pure cytarabine after drying, which corresponds to a yield of 83~. The product was characterized by comparison of its melting point, and MMR and IR spectra with those previously reported for cytarabine.
Claims (7)
1. A process for directly preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof:
(I) which comprises the step of reacting (i) a compound of Formula II or a pharmaceutically acceptable salt thereof:
(II) wherein R1 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 C5 -C1 2 heterocyclic amines and amines having the general formula wherein R2, R3 and R4 can be the same or different and are selected from the group comprising hydrogen, a C1-C6 alkyl group and a C6-C9 aryl group, with the proviso that each of R2, R3 and R4 are not hydrogen.
(I) which comprises the step of reacting (i) a compound of Formula II or a pharmaceutically acceptable salt thereof:
(II) wherein R1 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 C5 -C1 2 heterocyclic amines and amines having the general formula wherein R2, R3 and R4 can be the same or different and are selected from the group comprising hydrogen, a C1-C6 alkyl group and a C6-C9 aryl group, with the proviso that each of R2, R3 and R4 are not hydrogen.
2. The process defined in claim 1, wherein R1 is hydrogen.
3. The process defined in claim 1, wherein said amine is selected from the group comprising t-butylamine, trimethylamine, triethylamine, pyridine, tripropylamine, tributylamine, methylamine, ethylamine, diethylamine, aniline and piperidine.
4. The process defined in claim 2, wherein the amine is t-butylamine.
5. The process defined in claim 1, wherein said step is conducted in the presence of an aqueous solvent.
6. The process defined in claims 2, 3 or 4, wherein said step is conducted in the presence of an aqueous solvent selected from water and a mixture of water with at least one other solvent miscible therewith.
7. The process defined in claim 4, wherein said step is conducted in the presence of an aqueous solvent comprising solely water.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012094 CA2012094C (en) | 1990-03-13 | 1990-03-13 | Process for producing cytarabine and analogues 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 |
| HU9202906A HUT61566A (en) | 1990-03-13 | 1991-03-13 | Process for producing 2,2'-o-cyclonucleosides, nucleosides and their analogous compounds |
| PCT/CA1991/000077 WO1991013900A1 (en) | 1990-03-13 | 1991-03-13 | Process for producing 2,2'-o-cyclonucleosides, nucleosides, and analogs thereof |
| 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 |
| 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 2012094 CA2012094C (en) | 1990-03-13 | 1990-03-13 | Process for producing cytarabine and analogues thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2012094A1 CA2012094A1 (en) | 1991-09-13 |
| CA2012094C true CA2012094C (en) | 1996-07-23 |
Family
ID=4144516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2012094 Expired - Fee Related CA2012094C (en) | 1990-03-13 | 1990-03-13 | Process for producing cytarabine and analogues thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2012094C (en) |
-
1990
- 1990-03-13 CA CA 2012094 patent/CA2012094C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2012094A1 (en) | 1991-09-13 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |