GB2107309A - Preparation of 2-amino-4- hydroxy-5-halo-substituted pyrimidine derivatives - Google Patents
Preparation of 2-amino-4- hydroxy-5-halo-substituted pyrimidine derivatives Download PDFInfo
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- GB2107309A GB2107309A GB08223902A GB8223902A GB2107309A GB 2107309 A GB2107309 A GB 2107309A GB 08223902 A GB08223902 A GB 08223902A GB 8223902 A GB8223902 A GB 8223902A GB 2107309 A GB2107309 A GB 2107309A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
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- Plural Heterocyclic Compounds (AREA)
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Abstract
2-Amino-4-hydroxy-5-halo- substituted pyrimidine derivatives of the formula (I), <IMAGE> wherein R is a C1-4 alkyl or a phenyl group, and X is bromine or iodine, are prepared from the corresponding 2-amino-4-hydroxypyrimidine derivatives by halogenation carried out with an acidic solution of a haloid complex of an interhalogen. The new method of the invention is economic and advantageous also on an industrial scale.
Description
SPECIFICATION
Process for the preparation of 2-amino-4-hydroxy-5-halo-substituted pyrimidine derivatives
This invention relates to a new process for the preparation of 2-amino-4-hydroxy-5-halosubstituted pyrimidine derivatives possessing valuable antiviral and interferon inducing properties.
The compounds prepared according to the invention are encompassed by the general formula (I),
wherein
R represents a C14 alkyl or a phenyl group, and
X is a bromine or iodine.
The compounds of the general formula (I) are known from literature. The bromo derivatives of the general formula (I), wherein R is phenyl group, was prepared by brominating the unsubstituted pyrimidine ring with elementary bromine (J. Chem. Soc. Perkin Trans. 1. (1975) 1023; J. Chem. Soc.
41(1947) 46). According to another method, the halo derivatives of the general formula (I) can be produced by halogenation carried out with a halosuccinimide (German Patent Specifications Nos.
2,522,090 and 2,522,047; U.S. Patent Specification No. 3,956,302).
Due to its amino and hydroxyl groups, the pyrimidine derivative to be halogenated is highly sensitive to oxidation, so the side-reactions, which take place when brominating with an elementary bromine, result in a poor yield, and the product thus obtained is contaminated. The pyrimidine is less reactive by reason of hindrances caused by the substituents in positions 4 and 6. When using the corresponding succinimides as halogenating agent, the desired compound is obtained in low (about 3040%) yields.
Now it has been found that the disadvantages of the known processes can be mitigated by carrying out the halogenation with an acidic solution of a haloid complex of an interhalogen.
The interhaloids as analytical reagents used for the halogenation of aromatic compounds are described in MTA Kem. Tud. Oszt. Kozl. 12, 1 5 (1959). The preparation of the interhaloid complexes is described in Talanta 7, 41 (1960). In the process according to the invention these complexes are used for preparative purposes, namely, for the halogenation of 2-amino-4-hydroxypyrimidine derivatives.
According to the novel process of the invention the 2-amino-4-hydroxy-5-halo-substituted pyrimidine derivatives of the general formula (I), wherein Rand X have the above defined meanings, are prepared from the 2-amino-4-hydroxy-pyrimidine derivatives of the general formula (II),
wherein
R is as defined above, by halogenation carried out with an acidic solution of a haloid complex of an interhalogen.
The halogenation according to the invention is carried out in an aqueous medium containing organic and/or mineral acid. It is preferable to perform the process in an aqueous medium containing acetic acid and hydrochloric acid.
The process according to the invention provides the derivatives of the general formula (I) in a good yield. The electron-attracting effect of the halogen cation being present in the interhaloid complex surpasses that of any other reagent. The pyrimidine ring is attacked by the reactive cation, that is why the key reaction of the process according to the invention takes place quickly and quantitatively, without side-reactions.
The method according to the invention is economic and can be carried out readily and advantageously also on an industrial scale. The new method of the invention is surprising to a person skilled in the art, as till now the haloid complexes of interhalogens have not been used for industrial processes.
The main advantages of this new process over the methods known in the art are as follows: the reaction is complete within a short time;
the compounds of the general formula (I) can be obtained in a good yield;
the halogenation is carried out in an aqueous medium;
the halogen is utilized more advantageously than at the reactions performed with elementary halogen;
the halogenating agent is easy to handle and store.
The process according to the invention is illustrated by the following Examples of non-limiting character.
Example 1
Preparation of 2-amino-4-hydroxy-5-bromo-6-phenylpyrimidine 3.74 g (0.02 moles) of 2-amino-4-hydroxy-6-phenylpyrimidine are dissolved in a mixture of 30 ml of acetic acid and 8 ml of 6 N hydrochloric acid solution.
A bromochloride reagent solution is prepared as follows:
1.66 g (0.011 moles) of sodium bromate are dissolved in 13 ml of water, and a solution of 2.5 ml (0.022 moles) of 48% hydrogen bromide or 2.62 g of potassium bromide in 30 ml of concentrated hydrochloric acid solution is added within half an hour, at a temperature not exceeding 300 C.
The thus-prepared bromochloride solution is added to the acidic solution of 2-amino-4-hydroxy6-phenylpyrimidine at 700 C, within half an hour. Then the reaction mixture is stirred for further one hour at the same temperature. The solution is neutralized while hot with concentrated ammonium hydroxide solution (pH=7), the crystalline product thus obtained is cooled and filtered with water and dried.
In this way 4.8 g (90%) of 2-amino-4-hydroxy-5-bromo-6-phenylpyrimidine are obtained. It can be recrystallized from 90% aqueous ethanol solution with a yield of 8090%.
M.p.: 278-2820C.
Analysis: C'OH8N3OBr Mol. weight: 266.11
Calculated: C%=45.40 H%=3.00 N%=15.70 Br%=30.03
Found: C%=45.85 H%=3.67 N%=1 5.12 Br%=29.79
UV A (ethanol): 310 nm, 1 g=3.95; 233 nm 19=4.22.
lRi'(KBr):3420,3310, 1670, 1620, 1580, 1450, 1345, 1225 cm-l.
1H-NMR: S (DMSO-d6) 6.55 (2H, 5,-NH2), 7.02 (5H, s, phenyl-H) 11.5 (1 H, s, --OH).
Example 2
Preparation of 2-amino-4-hydroxy-5-bromo-6-methylpyrlmidine 2.5 g (0.02 moles) of 2-amino-4-hydroxy-6-methylpyrimidine are dissolved in a mixture of 30 ml
of acetic acid and 8 ml of 6 N hydrochloric acid solution. Then a solution of bromochloride reagent
prepared as described in the previous Example is added within half an hour at 700 C, under stirring. The
reaction mixture is stirred for further one hour at the same temperature. The hot solution is neutralized
with concentration ammonium hydroxide solution (pH=7), the crystalline product thus obtained is
cooled and filtered, washed with water and dried.
3.87 g (95%) of 2-amino-4-hydroxy-5-bromo-6-methylpyrimidine are obtained. The product can
be recrystallized from 80% aqueous ethanol solution with a yield of 70 to 80%.
M.p.: 242-2470C.
Analysis: C5H6N3OBr Mol. weight: 204.04.
Calculated: C%=29.43 H%=2.96 N%=20.60 Br%=39.17
Found: C%=29.54 H%=3.20 N%=20.48 Br%=39.33
UV A (ethanol): 295 nm 19=3.90.
lRz;(KBr):3480,3330,3160, 1670, 1640, 1600, 1465, 1390, 1215 cm~'.
'H-NMR: S (DSMO-de): 2.15 (3H, s,-OH3); 6.45 (2H, s,-NH2); 11.5 (1 H, s,-0H).
Example 3
Preparation of 2-amino-4-hydroxy-5-bromo-6-ethylpyrimidine
2.78 g (0.02 moles) of 2-amino-4-hydroxy-6-ethylpyrimidine are dissolved in the mixture of 30
ml of acetic acid and 8 ml of 6 N hydrochloric acid solution. Then a bromochloride solution prepared as
described in Example 1 is added under stirring at 300C.
The reaction mixture is stirred for further one hour at the same temperature, then neutralized with
concentrated ammonium hydroxide solution (pH=7). The thus-obtained crystalline product is cooled
and filtered, washed with water and dried.
4.14 g (95%) of 2-amino-4-hydroxy-6-ethylpyrimidine are obtained. The product can be
recrystallized from 50% aqueous acetic acid solution with a yield of 80 to 90%.
M.p.: 233-2360C.
Analysis: C6HRN3OBr Mol. weight: 218.06.
Calculated: C%=33.05 H%=3.70 N%=19.27 Br%=36.64
Found: C%=33.37 H%=3.56 N%=1 9.64 Br%=36.45
UV A (ethanol): 297 nm 1 g=4.00.
lRv(KBr):3390,3330,3140, 1660, 1640, 1620, 1460, 1395, 1210 cm-l.
'H-NMR 6 (DMSO-d,): 1.1 (3H,t, -CH2-CH3) 2.45 (2H,q,-CH2-) 11.5 (1H, 5,-OH).
Example 4
Preparation of 2-amino-4-hydroxy-5-iodo-6-ethylpyrimidine
2.78 g (0.02 moles) of 2-amino-4-hydroxy-5-ethylpyrimidine are dissolved in a mixture of 30 ml
of acetic acid and 8 ml of 6 N hydrochloric acid solution.
An iodochloride reagent solution is prepared as follows:
1.71 g (0.008 moles) of potassium iodate are dissolved in the mixture of 30 ml of water and 8 ml of concentrated hydrochloric acid. Then a solution of 1.19 g (0.016 moles) of potassium iodide in 25 ml of water and 8 ml of concentrated hydrogen chloride solution is added within 30 minutes, under stirring, at a temperature not exceeding 200 C.
The iodochloride solution thus obtained is added to the acidic 2-amino-4-hydroxy-5ethylpyrimidine solution at room temperature, under stirring. The reaction mixture is stirred at room temperature for 24 hours, then neutralized with 20% ammonium hydroxide solution (pH=7). The crystalline product thus obtained is filtered off, washed with water and dried.
2.15 g (81%) of 2-amino-4-hydroxy-5-iodo-6-ethylpyrimidine are obtained. The product can be recrystallized from 95% ethanol with a yield of 70-80%.
M.p.: 232-2340C.
Analysis: C6H8N3OI Mol. weight: 265.07.
Calculated: C%=27.19 H%=3.04 N%=1 5.85 l%=47.88 Found: C%=27.38 H%=3.42 N%=15.62 1%=47.46 UV A (ethanol): 300 nm.
IRv(KBr): 3450, 3400, 1640, 1605, 1455, 1310, 1210.
1H-NMR a (DMSO-d6): 11.3 (1 H, s,-OH), 6.50 (2H, s,-NH2), 2.40 (2H, q, H2), 1.05 (3H, t, -CH3).
Claims (5)
1. A process for the preparation of 2-amino-4-hydroxy-5-halo-substituted pyrimidine derivatives of the general formula (I),
wherein
R represents a C14 alkyl group or a phenyl group, and
X is bromine or iodine, by halogenating a 2-amino-4-hydroxypyrimidine derivative of the general formula (II),
wherein
R has the same meaning as above, characterised by carrying out the halogenation with an acidic solution of a haloid complex of an interhalogen.
2. A process as claimed in claim 1, characterised by carrying out the halogenation in an aqueous medium containing organic and/or mineral acid.
3. A process as claimed in claim 1, characterised by carrying out the halogenation in an aqueous medium containing acetic acid and hydrochloric acid.
4. A process of making the compound of formula (I) substantially as hereinbefore described in any one of Examples 1 to 4.
5. A compound of the general formula (I) prepared by the process claimed in any one of claims 1 to 4.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU812482A HU187355B (en) | 1981-08-28 | 1981-08-28 | Process for preparing 2-amino-4-hydroxy-5-halo-substituted pyrimidine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2107309A true GB2107309A (en) | 1983-04-27 |
GB2107309B GB2107309B (en) | 1985-05-30 |
Family
ID=10959594
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08223902A Expired GB2107309B (en) | 1981-08-28 | 1982-08-19 | Preparation of 2-amino-4-hydroxy-5-halo-substituted pyrimidine derivatives |
Country Status (10)
Country | Link |
---|---|
JP (1) | JPS5874671A (en) |
BE (1) | BE894193A (en) |
CH (1) | CH648833A5 (en) |
ES (1) | ES515190A0 (en) |
FI (1) | FI822818L (en) |
FR (1) | FR2512021B1 (en) |
GB (1) | GB2107309B (en) |
HU (1) | HU187355B (en) |
IT (1) | IT1190971B (en) |
SU (1) | SU1132789A3 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000043373A2 (en) * | 1999-01-22 | 2000-07-27 | Amgen Inc. | Kinase inhibitors |
US6495558B1 (en) | 1999-01-22 | 2002-12-17 | Amgen Inc. | Kinase inhibitors |
-
1981
- 1981-08-28 HU HU812482A patent/HU187355B/en not_active IP Right Cessation
-
1982
- 1982-08-12 FI FI822818A patent/FI822818L/en not_active Application Discontinuation
- 1982-08-19 GB GB08223902A patent/GB2107309B/en not_active Expired
- 1982-08-23 ES ES515190A patent/ES515190A0/en active Granted
- 1982-08-25 BE BE1/10578A patent/BE894193A/en not_active IP Right Cessation
- 1982-08-26 IT IT22986/82A patent/IT1190971B/en active
- 1982-08-27 CH CH5100/82A patent/CH648833A5/en not_active IP Right Cessation
- 1982-08-27 FR FR8214695A patent/FR2512021B1/en not_active Expired
- 1982-08-27 JP JP57149042A patent/JPS5874671A/en active Pending
- 1982-08-28 SU SU823484882A patent/SU1132789A3/en active
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000043373A2 (en) * | 1999-01-22 | 2000-07-27 | Amgen Inc. | Kinase inhibitors |
WO2000043373A3 (en) * | 1999-01-22 | 2000-12-28 | Kinetix Pharmaceuticals Inc | Kinase inhibitors |
US6495558B1 (en) | 1999-01-22 | 2002-12-17 | Amgen Inc. | Kinase inhibitors |
Also Published As
Publication number | Publication date |
---|---|
HU187355B (en) | 1985-12-28 |
FR2512021A1 (en) | 1983-03-04 |
FI822818A0 (en) | 1982-08-12 |
BE894193A (en) | 1983-02-25 |
JPS5874671A (en) | 1983-05-06 |
IT1190971B (en) | 1988-02-24 |
SU1132789A3 (en) | 1984-12-30 |
ES8306479A1 (en) | 1983-06-01 |
FI822818L (en) | 1983-03-01 |
FR2512021B1 (en) | 1985-08-09 |
GB2107309B (en) | 1985-05-30 |
CH648833A5 (en) | 1985-04-15 |
ES515190A0 (en) | 1983-06-01 |
IT8222986A0 (en) | 1982-08-26 |
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Legal Events
Date | Code | Title | Description |
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PCNP | Patent ceased through non-payment of renewal fee |