U.S. patent application number 09/895317 was filed with the patent office on 2002-01-10 for process for preparing 2,6-dichloropurine.
This patent application is currently assigned to Sumika Fine Chemicals Co., Ltd.. Invention is credited to Hayashi, Taketo, Kumazawa, Hiroharu, Nishikawa, Junichi.
Application Number | 20020004598 09/895317 |
Document ID | / |
Family ID | 26595711 |
Filed Date | 2002-01-10 |
United States Patent
Application |
20020004598 |
Kind Code |
A1 |
Hayashi, Taketo ; et
al. |
January 10, 2002 |
Process for preparing 2,6-dichloropurine
Abstract
A process for preparing 2,6-dichloropurine including
chlorinating 2-amino-6-chloropurine with a chlorine source in the
presence of a diazotizating agent.
Inventors: |
Hayashi, Taketo; (Osaka,
JP) ; Kumazawa, Hiroharu; (Osaka, JP) ;
Nishikawa, Junichi; (Osaka, JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
Sumika Fine Chemicals Co.,
Ltd.
Osaka
JP
|
Family ID: |
26595711 |
Appl. No.: |
09/895317 |
Filed: |
July 2, 2001 |
Current U.S.
Class: |
544/264 |
Current CPC
Class: |
C07D 473/40
20130101 |
Class at
Publication: |
544/264 |
International
Class: |
C07D 473/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 10, 2000 |
JP |
2000-208450 |
Jun 13, 2001 |
JP |
2001-179050 |
Claims
1. A process for preparing 2,6-dichloropurine comprising
chlorinating 2-amino-6-chloropurine with a chlorine source in the
presence of a diazotizating agent.
2. The process according to claim 1, wherein the diazotizating
agent is chosen from the group consisting of alkali metal nitrites,
alkyl esters of nitrous acid, nitrosyl chloride, nitrosylsulfuric
acid and nitrogen monoxide.
3. The process according to claim 1, wherein the diazotizating
agent is sodium nitrite.
4. The process according to claim 1, wherein the diazotizating
agent is an alkyl ester of nitrous acid.
5. The process according to claim 1, wherein the diazotizating
agent is present in an amount of 1 to 5 mol per one mol of
2-amino-6-chloropurine.
6. The process according to claim 1, wherein the diazotizating
agent is present in an amount of 1 to 2 mol per one mol of
2-amino-6-chloropurine.
7. The process according to claim 1, wherein the chlorine source is
a metal chloride.
8. The process according to claim 1, wherein the chlorine source is
a chlorinating agent.
9. The process according to claim 1, wherein the chlorine source is
a metal chloride and a chlorinating agent.
10. The process according to claim 7, wherein the metal chloride is
lithium chloride.
11. The process according to claim 8, wherein the chlorine source
is hydrochloric acid.
12. The process according to claim 11, wherein the concentration of
hydrochloric acid is not less than 10%.
13. The process according to claim 9, wherein the metal chloride is
lithium chloride and the chlorinating agent is one of the group
consisting of chlorine, N-chlorosuccimide and thionyl chloride.
14. The process according to claim 9, wherein the metal chloride is
lithium chloride and the chlorinating agent is chlorine.
15. The process according to claim 7, further comprising adding an
acid to the metal chloride.
16. The process according to claim 15, wherein the acid is acetic
acid.
17. The process according to claim 15, wherein the metal chloride
is lithium chloride and the acid is acetic acid.
18. The process according to claim 1, wherein the chlorine source
is a metal chloride or a chlorinating agent.
19. The process according to claim 18, wherein the chlorine source
is present in an amount of from 1 to 90 mol per one mol of
2-amino-6-chloropurine.
20. The process according to claim 18, wherein the chlorine source
is present in an amount of from 5 to 20 mol per one mol of
2-amino-6-chloropurine.
21. The process according to claim 9, wherein the molar ratio of
the metal chloride to the chlorinating agent is from 1:1 to
10:1.
22. The process according to claim 9, wherein the molar ratio of
the metal chloride to the chlorinating agent is from 2:1 to
6:1.
23. The process according to claim 22, wherein the amount of the
chlorine source is from 1 to 10 mol per one mol of
2-amino-6-chloropurine.
24. The process according to claim 22, wherein the amount of the
chlorine source is 3 to 6 mol per one mol of
2-amino-6-chloropurine.
25. The process according to claim 1, further comprising suspending
or dissolving the 2-amino-6-chloropurine in a solvent.
26. The process according to claim 25, further comprising adding an
alkali metal hydroxide to the solvent.
27. The process according to claim 1, wherein the reaction
temperature is -20.degree. C. to 100.degree. C.
28. The process according to claim 1, wherein the reaction
temperature is -10.degree. C. to 60.degree. C.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a process for preparing
2,6-dichloropurine. More specifically, the present invention
relates to a process for preparing 2,6-dichloropurine, which can be
suitably used as a raw material for nucleoside and nucleotide
analogues which are useful as pharmaceuticals.
[0003] 2. Discussion of the Related Art
[0004] As a process for preparing 2,6-dichloropurine, there have
been known the following processes:
[0005] (A) a process comprising chlorinating xanthine with
pyrophosphoryl chloride as disclosed in J. Am. Chem. Soc. 78,
3508-10 (1956);
[0006] (B) a process comprising chlorinating hypoxanthine or
N-oxide of 6-chloropurine with phosphorus oxychloride as disclosed
in Japanese Examined Patent Publication Sho 45-11508 and U.S. Pat.
No. 3,314,938;
[0007] (C) a process comprising four steps using a barbituric acid
derivative as a starting material as disclosed in J. Org. Chem. 19,
930(1954) and J. Am. Chem. Soc. 80, 404-8(1958);
[0008] (D) a process comprising cyclizing
2,4-dichloro-5,6-diaminopyrimidi- ne as disclosed in U.S. Pat. No.
2,844,576; and the like.
[0009] However, there are some defects in process (A) in that the
pyrophosphoryl chloride used as a chlorinating agent is complicated
to prepare. In process A, pyrophosphoryl chloride is obtained from
phosphorous oxychloride via a complicated procedure requiring a
high reaction temperature of 165.degree. C., a corrosion resistant
reaction vessel and a 19-hour reaction time.
[0010] In addition, all of the processes (A) to (D) have long
preparation steps and require complicated preparation
procedures.
[0011] An object of the present invention is to provide a process
capable of conveniently preparing 2,6-dichloropurine by using an
inexpensive starting material.
[0012] These and other objects of the present invention will be
apparent from the following description.
SUMMARY OF THE INVENTION
[0013] According to the present invention, there is provided a
process for preparing 2,6-dichloropurine comprising the step of
chlorinating 2-amino-6-chloropurine with a chlorine source in the
presence of a diazotizating agent.
DETAILED DESCRIPTION OF THE INVENTION
[0014] One of the features of the present invention is that the
process for preparing 2,6-dichloropurine comprises the step of
chlorinating 2-amino-6-chloropurine with a chlorine source in the
presence of a diazotizating agent.
[0015] 2-amino-6-chloropurine is used as a starting material and is
readily available, since 2-amino-6-chloropurine has been
industrially widely prepared.
[0016] The diazotizating agent includes, for instance, alkali metal
nitrites, such as sodium nitrite and potassium nitrite; alkyl
esters of nitrous acid of which the alkyl moiety has 2 to 6 carbon
atoms, such as t-butyl nitrite and isoamyl nitrite; nitrosyl
chloride; nitrosylsulfuric acid; nitrogen monoxide; and the like.
Among them, sodium nitrite is preferable because it is inexpensive
and easily available. In addition, the alkyl esters of nitrous acid
are preferable, because they increase the reactivity. The alkali
metal nitrite can be dissolved in water before use since the alkali
metal nitrite is solid at room temperature.
[0017] The amount of the diazotizating agent is 1 to 5 mol,
preferably 1 to 2 mol per one mol of 2-amino-6-chloropurine, from
the viewpoints of increasing reactivity and economics.
[0018] Representative examples of the chlorine source include metal
chlorides, chlorinating agents, and the like. These chlorine
sources can be used alone or in an admixture including at least two
kinds of sources.
[0019] The metal chloride includes lithium chloride, potassium
chloride, sodium chloride, calcium chloride, magnesium chloride,
zinc chloride, nickel chloride, cuprous chloride, cupric chloride,
and the like. Among them, lithium chloride is preferable from the
viewpoints of increasing reactivity and improving yield.
[0020] The chlorinating agent includes chlorine, hydrochloric acid,
thionyl chloride, alkyl chlorides such as methyl chloride,
N-chlorosuccinimide, and the like. Among them, hydrochloric acid is
preferable from the viewpoints of cost and improving yield. The
concentration of hydrochloric acid is preferably not less than
10%.
[0021] It is preferable that the chlorine source is a combination
of the metal chloride and the chlorinating agent, from the
viewpoints of increasing reactivity and improving yield.
[0022] Among the combinations of the metal chloride and the
chlorinating agent, it is preferable that the metal chloride is
lithium chloride and the chlorinating agent is chlorine,
N-chlorosuccimide or thionyl chloride, from the viewpoints of
increasing reactivity, improving yield and suppressing the
generation of by-products. It is more preferable that the metal
chloride is lithium chloride and the chlorinating agent is
chlorine.
[0023] When the metal chloride is used as the chlorine source, an
acid can be added to the metal chloride. The acid includes acetic
acid, propionic acid, formic acid, phosphoric acid and the like.
Among them, acetic acid is preferable, from the viewpoints of
increasing reactivity and suppressing the generation of
by-products. As to the combination of the metal chloride and the
acid, it is preferable that the metal chloride is lithium chloride
and the acid is acetic acid, from the viewpoints of increasing
reactivity, improving yield and suppressing the generation of
by-products.
[0024] When the chlorine source is composed of the metal chloride
alone or the chlorinating agent alone, it is desired that the
amount of the chlorine source is 1 to 50 mol, preferably 5 to 20
mol per one mol of 2-amino-6-chloropurine, from the viewpoint of
increasing reactivity, suppressing the generation of by-products
and increasing economic advantages.
[0025] When the combination of the metal chloride and the
chlorinating agent is used as the chlorine source, the ratio of the
metal chloride to the chlorinating agent (molar ratio of the metal
chloride/the chlorinating agent), is preferably 1/1 to 10/1, more
preferably 2/1 to 6/1. In this case, it is desired that the amount
of the chlorine source is 1 to 10 mol, preferably 3 to 6 mol per
one mol of 2-amino-6-chloropurine.
[0026] In the present invention, first 2-amino-6-chloropurine can
be suspended or dissolved in a solvent.
[0027] The solvent includes, for instance, water, organic solvents
such as N,N-dimethylformamide and N,N-dimethylacetamide, and the
like. The amount of the solvent is not limited to that which is
specified, and can be altered by proper adjustment. In the case
where hydrochloric acid or the combination of the metal chloride
and the acid is used as the chlorine source, a solvent is not used,
since the acid acts as a solvent. Therefore, when the acid is
employed, 2-amino-6-chloropurine can be suspended in the acid.
[0028] Also, an alkali metal hydroxide, ammonia or the like can be
added to the solvent in order to increase the solubility of
2-amino-6-chloropurine, and thereby 2-amino-6-chloropurine can be
partly or completely dissolved.
[0029] 2-Amino-6-chloropurine can be chlorinated by properly mixing
the suspension or solution of 2-amino-6-chloropurine with the
chlorine source and a diazotizating agent.
[0030] The reaction temperature during the chlorination depends
upon the kinds of the chlorine source and the diazotizating agent.
It is desired that the reaction temperature is -20.degree. to
100.degree. C., preferably -10.degree. to 60.degree. C., from the
viewpoints of increasing reactivity and suppressing formation of
the by-products.
[0031] The reaction time depends upon the reaction conditions and
the like. The reaction time is usually from 1 to several hours.
[0032] The resulting reaction solution can be subjected to an
after-treatment in an ordinary method to collect the resulting
2,6-dichloropurine.
[0033] The 2,6-dichloropurine can be collected by, for instance, a
method comprising neutralizing the reaction solution with a base
such as sodium hydroxide, potassium hydroxide, potassium carbonate
or sodium carbonate or its aqueous solution to cause precipitation,
and collecting precipitated crystals by filtration; or a method
comprising extracting 2,6-dichloropurine with acetonitrile or ethyl
acetate.
[0034] After the extraction, the formed 2,6-dichloropurine can be
collected as crystals by concentrating the extract. Thereafter,
2,6-dichloropurine can be purified by an ordinary method.
[0035] Thus, a desired compound 2,6-dichloropurine can be
conveniently prepared from an inexpensive compound as a starting
material.
EXAMPLES
[0036] The present invention will be more specifically described on
the basis of the following examples, without intending to limit the
present invention thereto.
Example 1
[0037] To 209.4 g of a 35% aqueous hydrochloric acid (2.00 mol) was
added 33.9 g (0.20 mol) of 2-amino-6-chloropurine. A solution
prepared by dissolving 17.9 g (0.26 mol) of sodium nitrite in 30 mL
of water was added to the above mixture in a thin stream. The
mixture was stirred at 15.degree. to 20.degree. C. for 1 hour.
[0038] After the termination of the reaction, the resulting
reaction solution was diluted with 300 mL of water, and 229 g of an
about 40% aqueous sodium hydroxide was added in a thin stream to
adjust its pH to 13.
[0039] Next, the reaction solution was extracted seven times with
400 mL of acetonitrile. The resulting extracts were combined, and
the combined extracts were dried over anhydrous sodium sulfate.
After drying, the residual solution was filtered, and the filtrate
was concentrated under reduced pressure. 300 mL of water was added
to the concentrated residue, and the mixture was neutralized with
acetic acid to precipitate crystals. Thereafter, the mixture was
heated to 75.degree. to 80.degree. C., and stirred for 1 hour.
Next, the mixture was cooled to 0.degree. to 10.degree. C. and
stirred for 1 hour. Subsequently, the precipitated crystals were
collected by filtration, washed with 50 mL of water, and dried
under reduced pressure, to give 12.2 g of white crystals of
2,6-dichloropurine (yield: 32.4%).
[0040] Melting point: 180.degree. C. (literature value: 179.degree.
to 181.5.degree. C.)
[0041] .sup.1H-NMR (400 MHZ, DMSO-d.sub.6): .delta. (ppm)=8.74 (s,
1H), 14.15 (s, 1H)
Example 2
[0042] In 500 g of N,N-dimethylformamide was dissolved 100 g (2.36
mol) of lithium chloride. Thereafter, the mixture was cooled, 100 g
(0.590 mol) of 2-amino-6-chloropurine was added thereto, and the
mixture was stirred. To the resulting suspension was added 43.0 g
(0.607 mol) of chlorine gas and 76.8 g (0.708 mol) of t-butyl
nitrite at the same time at 10.degree. to 40.degree. C. over a
period of 1 hour. After the termination of the addition, the
chlorination reaction was carried out by stirring the mixture at
10.degree. to 40.degree. C. for 2 hours.
[0043] After the termination of the reaction, 500 g of water was
added in a thin stream to the reaction solution, and the reaction
solution was analyzed by high-performance liquid chromatography. As
a result, it was found that 78.7 g of 2,6-dichloropurine was
contained in the reaction solution. The reaction yield was
70.6%.
[0044] Next, the resulting reaction solution was extracted four
times with 541 g of ethyl acetate. The extracts were combined, and
thereafter washed with 200 g of water and 228 g of a 12% aqueous
sodium thiosulfate. Subsequently, the washed extracts were
re-extracted once with 150 g of 4N-aqueous sodium hydroxide and
twice with 150 g of 2N-aqueous sodium hydroxide. The resulting
alkali extracts were combined, and thereafter its pH was adjusted
to 5 with a 35% hydrochloric acid to precipitate crystals. After
the filtration, the resulting crystals were washed with 200 g of
water, and thereafter dried at 60.degree. C. under reduced
pressure, to give 59.0 g of pale yellowish crystals of
2,6-dichloropurine (yield: 52.9%). The physical properties of the
resulting 2,6-dichloropurine were the same as those in Example
1.
Example 3
[0045] The reaction was carried out in the same manner as in
Example 2 except that 88.5 g (0.708 mol) of isoamyl nitrite was
used in place of 76.8 g (0.708 mol) of tert-butyl nitrite.
[0046] The resulting reaction solution was analyzed. As a result,
it was found that the reaction yield of 2,6-dichloropurine was
57.0%.
Example 4
[0047] The reaction was carried out in the same manner as in.
Example 3 except that 500 g of N,N-dimethylacetamide was used in
place of 500 g of N,N-dimethylformamide.
[0048] The resulting reaction solution was analyzed. As a result,
it was found that the reaction yield of 2,6-dichloropurine was
65.8%.
Example 5
[0049] The reaction was carried out in the same manner as in
Example 2 except that 88.5 g (0.708 mol) of isoamyl nitrite was
used in place of 76.8 g (0.708 mol) of tert-butyl nitrite, and that
97.2 g (0.728 mol) of N-chlorosuccimide was used in place of 43.0 g
(0.607 mol) of chlorine gas.
[0050] The resulting reaction solution was analyzed. As a result,
it was found that the reaction yield of 2,6-dichloropurine was
63.8%.
Example 6
[0051] The reaction was carried out in the same manner as in
Example 2 except that 75.8 g (0.637 mol) of thionyl chloride was
used in place of 43.0 g (0.607 mol) of chlorine gas, and that 88.5
g (0.708 mol) of isoamyl nitrite was used in place of 76.8 g (0.708
mol) of tert-butyl nitrite.
[0052] The resulting reaction solution was analyzed. As a result,
it was found that the reaction yield of 2,6-dichloropurine was
60.6%.
Example 7
[0053] To 40 mL of glacial acetic acid were added 5.1 g (30.0 mmol)
of 2-amino-6-chloropurine and 6.4 g (150 mmol) of lithium chloride,
and thereafter 3.11 g (45.0 mmol) of sodium nitrite was added
thereto, and the reaction solution was stirred at 50.degree. to
55.degree. C. for 4 hours.
[0054] After the termination of the reaction, the resulting
reaction solution was cooled to room temperature, and 100 mL of
water was added in a thin stream to precipitate the crystals. The
precipitated crystals were separated by filtration.
[0055] The resulting filtrate was neutralized with 122.5 g of a 20%
aqueous sodium hydroxide, and thereafter the neutralized mixture
was extracted twice with 300 mL of ethyl acetate. The extracts were
combined and concentrated under reduced pressure.
[0056] To the concentrated residue was added 37 mL of water to
re-crystallize the product. The precipitated crystals are collected
by filtration, washed with 5 mL of water, and thereafter dried
under reduced pressure, to give 1.5 g of white crystals of
2,6-dichloropurine (yield: 27.2%).
[0057] The resulting 2,6-dichloropurine crystals were identical in
melting point and NMR to those of the product obtained in Example
1.
Example 8
[0058] To 75 mL of water were added 17.0 g (0.10 mol) of
2-amino-6-chloropurine, 4.4 g (0.11 mol) of sodium hydroxide, and
10.4 g (0.15 mol) of sodium nitrite.
[0059] The resulting solution was added in a thin stream to 104.2 g
(1.00 mol) of a 35% hydrochloric acid at a temperature of 0.degree.
to 5.degree. C. over one hour.
[0060] Thereafter, the mixture was stirred at the same temperature
for one hour. After the termination of the reaction, the mixture
was treated in the same manner as in Example 1, to give 6.6 g of
white crystals of 2,6-dichloropurine (yield: 35.0%).
[0061] The resulting 2,6-dichloropurine crystals were identical in
melting point and NMR to those of the product obtained in Example
1.
[0062] It can be seen from the above results that according to the
process of Examples 1 to 8, a desired compound, 2,6-dichloropurine
can be conveniently prepared from an inexpensive compound,
2-amino-6-chloropurine.
[0063] Numerous modifications and variations of the present
invention are possible in light of the above teachings. It is
therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise than as
specifically described herein.
* * * * *