GB2109369A - Process for purifying guanine - Google Patents
Process for purifying guanine Download PDFInfo
- Publication number
- GB2109369A GB2109369A GB08227127A GB8227127A GB2109369A GB 2109369 A GB2109369 A GB 2109369A GB 08227127 A GB08227127 A GB 08227127A GB 8227127 A GB8227127 A GB 8227127A GB 2109369 A GB2109369 A GB 2109369A
- Authority
- GB
- United Kingdom
- Prior art keywords
- guanine
- solution
- purifying
- alkali metal
- crude
- 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.)
- Granted
Links
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 title claims abstract description 124
- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 6
- 239000002184 metal Substances 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 8
- 239000002253 acid Substances 0.000 abstract description 7
- -1 alkali metal salt Chemical class 0.000 abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 4
- 230000003472 neutralizing effect Effects 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- SYEYEGBZVSWYPK-UHFFFAOYSA-N 2,5,6-triamino-4-hydroxypyrimidine Chemical compound NC1=NC(N)=C(N)C(O)=N1 SYEYEGBZVSWYPK-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A process for purifying guanine comprises dissolving crude guanine in a concentrated aqueous solution of an alkali metal hydroxide at an elevated temperature, cooling the resulting solution, thereby causing guanine to precipitate in the form of an alkali metal salt which is slightly soluble in the concentrated aqueous alkali solution, and neutralizing the metal salt with an acid.
Description
SPECIFICATION
Process for purifying guanine
The present invention relates to a process for purifying guanine which provides high quality guanine in high yield from crude guanine.
Guanine is one of the so-called nucleic acid bases and can be utilized in various fields, including production of pharmaceuticals. Guanine is prepared, for instance, by a process which comprises cyclizing 2,4,5-triamino-6oxy-pyrimidine with formic acid or the like as disclosed in Berichte, 33, 1371, 3035(1900), a process in which guanine is synthesized from an arylazocyanoacetyl derivative and urea, thiourea, formic acid or a derivative of formic acid as disclosed in Japanese Examined Patent Publication (Tokkyo Kokoku) No. 20067/1967, and a process in which a 2-arylazocyanoacetylguanidine is reacted with formic acid or a formic acid derivative under reducing conditions as disclosed in
Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 141894/1976.However, in any of these known processes, the product contains a small amount of by-products as impurities and, therefore, must be further purified.
However, there has been no profitable process for purifying guanine and no pure product has been available on a commercial scale.
For guanine, there are no suitable solvents other than strong acids and strong bases.
Therefore, purification of guanine has been generally conducted by adsorption of impurities on an adsorbent such as active carbon in these solvents or recrystallization in the form of a mineral acid salt. However, an improved purity can be achieved only at the cost of a reduced yield and it has been impossible to
obtain high quality guanine at economical
cost.
It is an object of the present invention to provide a process for purifying guanine.
A further object of the invention is to provide a process for economically purifying guanine in high purities and high yields by
recovering guanine in the form of a metal salt from crude guanine.
These and other objects will become apparent from the description hereinafter.
The present inventors have found that gu
anine has a property to crystallize as a sparingly soluble salt from a highly concentrated aqueous alkali solution. On the basis of this finding, it has now been found that by dis
solving crude guanine in a concentrated aqueous alkali solution under heating and then cooling the solution, a metal salt of guanine
containing a far less amount of impurities than in a conventional purification process can
be precipitated as crystals to thereby achieve a purification of crude guanine.
In accordance with the present invention, there is provided a process for purifying guanine which comprises dissolving crude guanine in a concentrated aqueous solution of an alkali metal hydroxide at an elevated temperature, and cooling the resulting solution to precipitate a crystalline metal salt of guanine.
Pure guanine is obtained by, for instance, dissolving the alkali metal salt in water and neutralizing the solution with an inorganic or organic acid.
Bases which are effectively employed in the present invention are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. It is desirable that the concentration of an aqueous solution of an alkali metal hydroxide used as a solvent is at least 1 5 % by weight. When the concentration is less than 15% by weight, the solubility of an alkali metal salt of guanine in the aqueous alkali solution increases and the yield is lowered.
Crude guanine is dissolved in an aqueous alkali solution at an elevated temperature, usually at a temperature of about 50 to about 90"C., preferably not less than about 60"C. The solution of guanine is then cooled to crystallize guanine in the form of the alkali metal salt.
The process of the present invention can be practiced by conducting dissolution of crude guanine and cooling of the solution in a batchwise operation. It is also possible to conduct the process of the invention in a continuous operation. When the dissolution and the precipitation are conducted by a multi-stage recrystallation process, high quality guanine can be obtained in a very high yield without using any other purification aids such as active carbon.
It is also possible to practice the present invention in combination with a known purification procedure involving the use of an adsorbent such as active carbon. Thus, depending on the quality grade of crude guanine, these procedures can be used in various combinations.
The metal salts of guanine can be easily converted into guanine, for instance, by dissolving the salts in water or a low concentration of an aqueous alkali solution and neutral
izing with an acid, e.g. mineral acids such as sulfuric acid, and organic acids such as acetic acid.
In accordance with the process of the present invention, high purity guanine can be obtained in a high yield. The purified guanine
has a high whiteness. Since the solvent used
in the invention is an aqueous alkali solutiion, the equipment may be made of common
metal materials and this is also an advantage
in industrial application of the process.
The present invention is more specifically
described and explained by means of the
following Examples. It is to be understood
that the present invention is not limited to the
Examples and various changes and modifications may be made in the invention without departing from the spirit and scope thereof.
Example I {Synthesis of guanine)
In 200 g. of formamide, 80 g. of 2,4,5 triamino-6-oxy-pyrimidine sulfate was cyclized by heating at 160"C. for 8 hours to give 49 g. of crude guanine having a purity of 98 % (measured by liquid chromatography) and a whiteness of 70 %.
(Purification of guanine)
To 100 ml. of a 20 % by weight aqueous solution of sodium hydroxide was added 10 g. of the crude guanine synthesized above and was dissolved by heating at 70"C. The solution was then gradually cooled to a temperature below 15"C. to precipitate the sodium salt of guanine (hereinafter referred to as ''guanine salt"). After separation of the crystals by filtration, the filtrate contained 0.4 g.
of guanine. This filtrate was discarded. The above procedure is referred to as the first crystallization.
The guanine salt separated in the first crystallization was dissolved again in a 20 % by weight aqueous solution of sodium hydroxide under heating and the solution was cooled to give crystals of the guanine salt (the second crystallization). The crystals were separated and the filtrate was used as a solvent for the first crystallization.
A third crystallization was carried out in the same manner as above, and the filtrate was used as a solvent for the second crystallization. The above crystallization procedures were carried out in six stages in total. The guanine salt recovered in the 6th crystallization stage was neutralized with 30 % sulfuric acid to give pure guanine.
When the above recrystallization procedure in six stages was repeated several times, the composition of the crystallization solvent in each stage became a steady state. The sixstage crystallization conducted in the steady state yielded 9.1 g. of the pure guanine. The yield was 92 %. The purified guanine had a purity of 99.6 % (measured by liquid chromatography) and a whiteness of 94 % (measured by a spectrophotometer at 480 nm).
Example 2
In 100 ml. of a 20 % by weight aqueous solution of sodium hydroxide was dissolved under heating 10 g. of crude guanine synthesized in the same manner as Example 1, and the solution was cooled to give crystals of the guanine salt. The guanine salt crystals were recovered by filtration and dissolved in 200 ml. of a 1 % by weight aqueous solution of sodium hydroxide. The solution was decolorized by addition of 0.3 g. of activated carbon and the carbon was filtered off. The filtrate was neutralized with an acid to give 8.4 g. of pure guanine. The purity was 99.5 % and the whiteness was 89 %. The yield was 85 %.
Comparative Example
In 200 ml. of a 1 % by weight aqueous solution of sodium hydroxide was dissolved 10 g. of crude guanine synthesized in the same manner as in Example 1, and the solution was decolorized with 1 g. of activated carbon with stirring. The activated carbon was removed and the solution was neutralized with an acid to give 7.5 g. of purified guanine. The yield was 76 %. The purity was 99.3 % and the whiteness was 81 %.
Example 3 (Synthesis of guanine)
To 550 g. of formamide were added 93 g.
of 2-phenylazocyanoacetylguanine, a Raney nickel catalyst prepared from 14 g. of an alloy containing 48 % of nickel and 14 g. of activated carbon. In an autoclave with a hydrogen pressure of 30 kg/cm2., the reaction was conducted at 150"C. for 5 hours. The formamide was distilled away under reduced pressure and the residue was treated with an alkali to give 52 g. of crude guanine.
(Purification of guanine)
Ten grams of the obtained crude guanine was subjecfed to 8 stages of crystallization under the same conditions as in Example 1 to give 8.0 g. of pure guanine. The purity was 99.6 % and the whiteness was 87 %.
In addition to the ingredients used in the
Examples, other ingredients can be used in the Examples as set forth in the specification to obtain substantially the same results.
Claims (3)
1. A process for purifying guanine which comprises dissolving crude guanine in a concentrated aqueous solution of an alkali metal hydroxide at an elevated temperature, and cooling the resulting solution to precipitate a crystalline metal salt of guanine.
2. The process of Claim 1, wherein the concentration of the aqueous solution of an alkali metal hydroxide is at least 1 5 % by weight.
3. A process for purifying guanine substantially as described in any one of the examples disclosed herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15215581A JPS5855485A (en) | 1981-09-28 | 1981-09-28 | Purification of guanine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2109369A true GB2109369A (en) | 1983-06-02 |
| GB2109369B GB2109369B (en) | 1985-06-12 |
Family
ID=15534220
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08227127A Expired GB2109369B (en) | 1981-09-28 | 1982-09-23 | Process for purifying guanine |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5855485A (en) |
| CH (1) | CH651834A5 (en) |
| DE (1) | DE3235372A1 (en) |
| GB (1) | GB2109369B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6207650B1 (en) * | 1989-05-15 | 2001-03-27 | Bristol-Myers Squibb Company | Antiviral, highly water soluble, stable, crystalline salts of 2′, 3′-dideoxyinosine, 2′, 3′-dideoxy-2′, 3′-didehydrothymidine and 2′, 3′-dideoxy-2′-fluoroinosine |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3727508A1 (en) * | 1987-08-18 | 1989-03-02 | Boehringer Ingelheim Kg | METHOD FOR PRODUCING SODIUM PURINE |
| DE3729471A1 (en) * | 1987-09-03 | 1989-03-16 | Huels Troisdorf | Process for the preparation of guanine |
| DE3928365A1 (en) * | 1989-08-28 | 1991-03-07 | Huels Chemische Werke Ag | METHOD FOR PRODUCING PURE GUANINE |
| DE4022314A1 (en) * | 1990-07-13 | 1992-01-16 | Boehringer Ingelheim Kg | METHOD FOR PRODUCING 2-CHLORINE-1,7-DIHYDROPURIN-6-ON AND METHOD FOR CLEANING IT |
| DE4136114C2 (en) * | 1991-11-02 | 1995-05-24 | Boehringer Ingelheim Kg | Improved process for the production of guanine and its alkali metal salts |
| DE4422587C2 (en) * | 1994-06-28 | 2000-11-30 | Sueddeutsche Kalkstickstoff | Process for the production of purines |
-
1981
- 1981-09-28 JP JP15215581A patent/JPS5855485A/en active Pending
-
1982
- 1982-09-23 GB GB08227127A patent/GB2109369B/en not_active Expired
- 1982-09-24 DE DE19823235372 patent/DE3235372A1/en active Granted
- 1982-09-24 CH CH565682A patent/CH651834A5/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6207650B1 (en) * | 1989-05-15 | 2001-03-27 | Bristol-Myers Squibb Company | Antiviral, highly water soluble, stable, crystalline salts of 2′, 3′-dideoxyinosine, 2′, 3′-dideoxy-2′, 3′-didehydrothymidine and 2′, 3′-dideoxy-2′-fluoroinosine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5855485A (en) | 1983-04-01 |
| CH651834A5 (en) | 1985-10-15 |
| DE3235372C2 (en) | 1990-09-06 |
| GB2109369B (en) | 1985-06-12 |
| DE3235372A1 (en) | 1983-04-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0208948B1 (en) | A method for optical resolution of phenylacetic acid derivative | |
| JPH0813801B2 (en) | Method for purifying tryptophan | |
| US5264624A (en) | Process for the recovery of adipic acid | |
| GB2109369A (en) | Process for purifying guanine | |
| HUP0302530A2 (en) | Process for the purification of 2-nitro-4-methylsulphonylbenzoic acid | |
| JP7730912B2 (en) | Methods for the preparation of nitric oxide-donating prostaglandin analogs | |
| MXPA03004775A (en) | A process for the preparation of 1-(aminomethyl) cyclohexaneacetic acid. | |
| EP0611369B1 (en) | Process for preparing (s) (+)-4,4'-(1-methyl-1,2-ethanediyl)-bis(2,6-piperazinedione) | |
| US3397231A (en) | Refining of alpha-6-deoxy-5-oxytetracycline | |
| JPH0546332B2 (en) | ||
| JP3291991B2 (en) | Purification method of O, S-dimethyl N-acetyl phosphoramidothioate | |
| US5349074A (en) | Process for pharmaceutical grade high purity hyodeoxycholic acid preparation | |
| KR910006125B1 (en) | How to prepare acetamecin | |
| US3341587A (en) | Process for the preparation of n-acetyl-p-aminophenol (apap) | |
| WO1998056750A1 (en) | A process for the preparation of diacerein | |
| GB2048858A (en) | Spectinomycin recovery process | |
| EP1951657B1 (en) | Process for the manufacture of iohexol | |
| US3860607A (en) | Process for preparing hydroxy-l-proline or n-acetyl-hydroxy-l-proline from hydrolyzed gelatin | |
| JP3291987B2 (en) | Purification method of O, S-dimethyl-N-acetylphosphoramidothioate | |
| US2361576A (en) | Method of refining a crude 1-naphthylacetic acid | |
| SU725562A3 (en) | Method of preparing maleic acid salts of 2-phenyl-6-(1-oxy-2-tert-butylaminoethyl)-4h-pyrido(3,2-d)-1,3-dioxine | |
| US2958692A (en) | S-carboxymethylmercapto-g- | |
| JP2505687B2 (en) | Process for producing pure 3,3'-4,4'-tetraaminobiphenyl | |
| US4418016A (en) | Method for recovering omega-amino-dodecanoic acid from crystallization mother liquors | |
| US4973752A (en) | Novel process to prevent formation of chlorinated by-products in APAP production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19950923 |