GB2104508A - Improved process for the preparation of 2,4,-diamino-5-(3',4',5'-trimethoxy-benzyl) pyrimidine - Google Patents
Improved process for the preparation of 2,4,-diamino-5-(3',4',5'-trimethoxy-benzyl) pyrimidine Download PDFInfo
- Publication number
- GB2104508A GB2104508A GB08218310A GB8218310A GB2104508A GB 2104508 A GB2104508 A GB 2104508A GB 08218310 A GB08218310 A GB 08218310A GB 8218310 A GB8218310 A GB 8218310A GB 2104508 A GB2104508 A GB 2104508A
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- United Kingdom
- Prior art keywords
- general formula
- trimethoxy
- compound
- reacting
- guanidine
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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
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to an improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine of the general formula I <IMAGE> by reacting a compound of the general formula II <IMAGE> (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said compound of the general formula II by reacting alpha -(3,4,5-trimethoxy-benzal)- beta -methoxy-propionitrile of the formula III <IMAGE> with ethylene glycol monoalkylether of the general formula IV HO-CH2-CH2-OR (IV> (wherein R as as stated above) in the presence of an alkali metal alkoxide at a temperature between 60 DEG and 90 DEG and reacting the compound of the general formula II thus obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms. The advantage of the process is that it is economical and can be carried out with high yields even on industrial scale and provides a product of high purity. The compound of the formula I obtained is a known chemotherapeutical drug.
Description
SPECIFICATION
Improved process for the preparation of 2,4-diamino-5-(3' 4' 5'-trimethoxy-benzyl)-pyrimidine
This invention relates to an improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine by reacting a compound of the general formula II
(wherein R is an alkyl group having 1-4 carbon atoms) with guanidine.
The 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine of the formula I
is a well known chemotherapeutical drug (referred to further on as Trimethoprim).
Several procedures are known for the preparation of the compound of the formula I; some of the said processes take place viaa-(3,4,5,-trimethoxy-benzyl)-ss-(substituted)-acrylonitriles.
According to Hungarian Patent No. 149,799 3,4,5-trimethoxy-benzaldehyde is condensed with B-alkoxy- propionitrile. The yield of the condensation reaction is higher than 80 % and the condensation product thus obtained consists of about 80 % of a-(3,4,5-trimethoxy-benzal)-ss-alkoxy-propionitrile and 20 % of a-(3,4,5-trimethoxy-benzyl)-ss-alkoxy-acrylonitrile. The condensation product is subsequently reacted with guanidine. However only the benzyl derivative participates in the reaction with guanidine, while the benzal compound isomerises to the benzyl derivative practically but to a very small extent.Thus the yield of
Trimethoprim does not exceed 28 % and the total yield related to 3,4,5-trimethoxy-benzaldehyde is not higher than 20-24 %.
According to Hungarian Patent No. 162,316 the above known process is rendered more economical by condensing 3,4,5-trimethoxy-benzaldehyde with a ss-alkoxy-propionitrile, reacting the condensation product thus obtained with an amine, isomerising the a-(3,4,5-trimethoxy-benzal)-$-amino-prnpionitrile derivative thus obtained into the corresponding benzyl derivative and reacting the latter compound with guanidine.
The total yield of Trimethoprim related to the 3,4,5-trimethoxy-benzaldehyde starting material is, however, moderate.
According to Hungarian patent No. 174,318 3,4,5-trimethoxy-benzaldehyde is reacted with a alkoxyethoxy)-propionitrile. Thus a a-(3,4,5-trimethoxy-benzal)-ss-(2-alkoxy-ethoxy)-propionitrile of the general formula Ia
is obtained (wherein R is as stated above) with a yield of above 80%, which is then isolated, thoroughly purified, subjected to isomerisation at 90-95 C in the presence of a base into the corresponding benzyl isomer of the general formula II which is then reacted with guanidine to give Trimethoprim with a yield of about 80 %. Thus the total yield of the laboratory scale Trimethoprim production is about 64-72 %.
Although the above process is significantly more economical than the previously described methods, the industrial scale use thereof is liable to serious problems. In the reaction of 3,4,5-trimethoxy-benzaldehyde and ss-(2-alkoxy-ethoxy)-propionitrile water is formed which is distilled off at a high temperature of about 1 200C. At this high temperature hydrolysis of the a-(3,4,5-trimethoxy-benzal)-ss-(2-alkoxy-ethoxy)- propionitrile with the water being present takes place.
According to our experiments the nitrile group hydrolyses and the corresponding carboxylic acid is formed in an amount of some per cents. This side reaction gives rise to the formation of tarry side products which come particularly into prominence as the batch size is increase. Thus the laboratory scale total yield of 64-72 % decreases to about 50-55 % already when the batch size is of about a 10 molar amount. It can be stated that the above known process is unsatisfactory from economic point of view.
The aim of the present invention is the elaboration of an economical industrial scale process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine.
It has been found that the a-(3,4,5-trimethoxy-benzal)-ss-methoxy-propionitrile of the formula III
can be trans-etherified into the corresponding benzal isomer of the general formula Ila almost with quantitative yields by reacting with an ethylene glycol monoalkyl-ether of the general formula IV HO-CH2-CH2-OR (IV) (wherein R is as stated above) and the compound of the general formula Ila can be converted easily into the corresponding benzyl isomer of the general formula II almost at theoretical yields. The benzvl isomer of the general formula II is so pure that it can be reacted without isolation and purification with guanidine to give
Trimethoprim.
According to the present invention there is provded a process for the preparation of 2,4-diamino-5-(3',4',5'trimethoxy-benzyl)-pyrimidine of the general formula I by reacting a compound of the general formula II (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said compound of the general formula II by reacting a-(3,4,5-trimethoxy-benzal)-ss-methoxy-propionitrile of the formula lil with an ethylene glycol monoalkylether of the general formula IV (wherein R is as stated above) in the presence of an alkyl metal alkoxide at a temperature between 60"C and 90"C and reacting the compound of the general formula II thus obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms.
As compound of the general formula IV preferably ethylene glycol monomethylether can be used. The compound of the general formula IV is preferably used in an excess and plays the role of the solvent, too.
As alkali metal alkoxide preferably sodium methoxide can be used.
It is not necessary to isolate the benzal isomer of the general formula lla obtained in the reaction of the a-(3,4,5-trimethoxy-benzal)-p-methoxy-propionitrile of the formula Ill and the ethylene glycol monoal kylether of the general formula IV. Under the reaction conditions used at 60-90"C - preferably at 80-90"C - the benzyl isomer is quantitatively formed within a few hours. The benzyl isomer of the general formula II can be isolated or, if desired, reacted with guanidine without isolation.
The benzyl isomer of the general formula ll is reacted with guanidine in the presence of an alcohol having 4-8 carbon atoms. For this purpose preferably tertiary butanol or isobutanol can be used. The reaction between the benzyl isomer and guanidine can be carried out in the presence of a further organic solvent (e.g.
another alcohol, such as methanol) in addition to the alcohol having 4-8 carbon atoms.
If according to a preferred embodiment of the process of the present invention the compound of the general formula II is reacted with guanidine without isolation, the compound of the general formula IV is always present in the ring closure stage of the reaction, provided it was used in an excess in the preparation of the benzyl derivative.
It is preferred to add guanidine in the form of an acid addition salt - e.g. the hydrochloride - to the benzyl derivative and set free the guanidine from its acid addition salt in the reaction mixture with the aid of a base, preferably an alkali metal alkoxide.
The reaction of the benzyl isomer and guanidine is carried out preferably at 70-1 00 C, advantageously at the boiling point of the reaction mixture.
The a-(3,4,5-trimethoxy-benzal)-ss-methoxy-propionitrile of the formula Ill may be prepared in a known manner by reacting 3,4,5-trimethoxy-benzaldehyde with p-methoxy-propionitrile. The latter -methoxy- propionitrile is prepared by reacting acrylonitrile with methanol in alkaline medium.
The process of the present invention enables the economical industrial scale manufacture of Trimethoprim. The drawbacks of the process according to Hungarian patent No. 174,318 are eliminated.
The total yield related to 3,4,5-trimethoxy-benzaldehyde is about 80 %. According to the process of the present invention Trimethoprim can be manufactured from the compound of the formula Ill by a one-step technology. The purity of the product obtained meets the therapeutical requirements.
Further details of processes in accordance with the present invention are to be found in the following non-limiting Examples.
Example 1
Preparation of the starting material
1.75 g. of potassium hydroxide are dissolved in 115 ml of methanol. To the solution 55 g of acrylic nitrile are added within 20 minutes at a temperature below 40"C. The mixture is stirred at 40"C for an hour, whereupon 100 g. of 3,4,5-trimethoxy-benzaldehyde are added. The reaction mixture is stirred at 60"C for 8 hours whereupon it is cooled to 30"C. 55 ml of methanol and in portions 30 g. of potassium hydroxide are added. The suspension formed is stirred for 5 hours, cooled to 20"C and 500 ml of water are added within 15 minutes. The product is crystallized at 5-10DC, filtered, washed three times with 15 ml of methanol and three times with 100 ml of water each and dried.Thus 116 g. of a-(3,4,5-trimethoxy-benzal)-,8-methoxy- propionitrile are obtained. Mp.: 81-83"C. Yield: 86 %.
Example 2
Preparation of 2,4diamino-5-(3 ,4' 5'-trimethoxy-benzyl)-pyrimidine A mixture of 100 g. of α-(3,4,5-trimethoxy-benzal)-ss-methoxy-prnpionitrile, 100 ml. of anhydrous ethylene glycol monomethylether and 5 g. of sodium methoxide is stirred at 82-840C for 3 hours. The reaction mixture is cooled to 30 C, then 160 ml. of isobutanol, 40 ml. of methanol, 85 g. of guanidine-hydrochloride and 50 g.
of powdered sodium methoxide are added. The reaction mixture is stirred at 35-40"C for an hour and at 90-92"C for 7 hours. The crystal suspension is cooled to 20"C, filtered and washed on the filter three times with 20 ml. of methanol each. The moist substance thus obtained is washed with 500 ml. of lukewarm water (30-35 C) and dried. Thus 102.5 9. of the title compound are obtained, yield: 93.6 %, mp.:198-201 C.
Claims (6)
1. An improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine of the general formula I
by reacting a compound of the general formula II
(wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said compound of the general formula II by reacting a-(3,4,5-trimethoxy-benzal)-,-methoxy-propionitrile of the formula Ill
with an ethylene glycol monoalkylether of the general formula IV
HO-CH2-CH2-OR (IV) (wherein R is as stated above) in the presence of an alkali metal alkoxide at a temperature between 60"C and 90"C and reacting the compound of the general formula II thus obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms.
2. A process according to claim 1, which comprises carrying out the reaction of the compounds of the formulae Ill
and IV HO-CH2-CH2-OR (IV) at a temperature between 80"C and 90"C.
3. A process according to claim 1 or claim 2, which comprises using sodium methoxide as the alkali metal alkoxide.
4. A process as claimed in any of claims 1 to 3 as herein described, with reference to Example 2.
5. A process as claimed in any one of claims 1 to 4, wherein the compound of the formula III is produced substantially as hereinbefore described with reference to Example 1.
6. 2,4-diamine-5-13',4',5 trimethoxybenzyl/-pyrimidine produced by a process as claimed in any one of claims 1 to 5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU811869A HU187370B (en) | 1981-06-26 | 1981-06-26 | Improved process for producing 2,4-diamino-5-bracket-3-comma above, 4-comma above,5-comma above-trimethoxy-benzyl-bracket closed-pyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2104508A true GB2104508A (en) | 1983-03-09 |
| GB2104508B GB2104508B (en) | 1985-01-16 |
Family
ID=10956594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08218310A Expired GB2104508B (en) | 1981-06-26 | 1982-06-24 | Improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5838266A (en) |
| AT (1) | AT387961B (en) |
| AU (1) | AU547823B2 (en) |
| BE (1) | BE893611A (en) |
| CA (1) | CA1174679A (en) |
| CH (1) | CH648834A5 (en) |
| CS (1) | CS244908B2 (en) |
| DD (1) | DD202703A5 (en) |
| DK (1) | DK155434C (en) |
| ES (1) | ES513482A0 (en) |
| FI (1) | FI76790C (en) |
| FR (1) | FR2508450B1 (en) |
| GB (1) | GB2104508B (en) |
| GR (1) | GR76159B (en) |
| HU (1) | HU187370B (en) |
| IE (1) | IE53466B1 (en) |
| IL (1) | IL66132A (en) |
| IT (1) | IT1190889B (en) |
| SE (1) | SE451133B (en) |
| SU (1) | SU1145929A3 (en) |
| YU (1) | YU42774B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2602507B1 (en) * | 1986-08-08 | 1989-06-09 | Sanofi Pharma | PROCESS FOR THE PREPARATION OF 2,4-DIAMINO-BENZYL-5 PYRIMIDINES |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB743221A (en) * | 1953-05-26 | 1956-01-11 | Wellcome Found | Improvements in or relating to the manufacture of acrylonitriles |
| DE1303727B (en) * | 1959-09-03 | 1976-02-05 | Ausscheidung aus: 14 45 176 The Wellcome Foundation Ltd., London | Alpha-arylidene-substituted propioni-iriles |
| NL122146C (en) * | 1960-09-02 | |||
| US4033962A (en) * | 1975-06-26 | 1977-07-05 | Hoffman-La Roche Inc. | 2,4-Diamino-pyrimidine derivatives and processes |
| DE2635765C3 (en) * | 1976-08-09 | 1979-02-08 | Ludwig Heumann & Co Gmbh, 8500 Nuernberg | Process for the preparation of 2,4-EMamino-5- (3 ', 4'r5'-trimethoxybenzyl) -pyrimidine |
| US4115650A (en) * | 1976-11-17 | 1978-09-19 | Hoffmann-La Roche Inc. | Process for preparing 2,4-diamino-5-(substituted benzyl)-pyrimidines |
| DE2730467A1 (en) * | 1977-07-06 | 1979-01-18 | Basf Ag | BENZYLPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THE SAME |
-
1981
- 1981-06-26 HU HU811869A patent/HU187370B/en not_active IP Right Cessation
-
1982
- 1982-06-23 BE BE1/10544A patent/BE893611A/en not_active IP Right Cessation
- 1982-06-23 SE SE8203914A patent/SE451133B/en not_active IP Right Cessation
- 1982-06-24 AT AT0244982A patent/AT387961B/en not_active IP Right Cessation
- 1982-06-24 CS CS824717A patent/CS244908B2/en unknown
- 1982-06-24 IT IT22035/82A patent/IT1190889B/en active
- 1982-06-24 SU SU823456294A patent/SU1145929A3/en active
- 1982-06-24 FI FI822268A patent/FI76790C/en not_active IP Right Cessation
- 1982-06-24 GR GR68560A patent/GR76159B/el unknown
- 1982-06-24 GB GB08218310A patent/GB2104508B/en not_active Expired
- 1982-06-24 IL IL66132A patent/IL66132A/en unknown
- 1982-06-25 IE IE1520/82A patent/IE53466B1/en not_active IP Right Cessation
- 1982-06-25 ES ES513482A patent/ES513482A0/en active Granted
- 1982-06-25 DD DD82241097A patent/DD202703A5/en not_active IP Right Cessation
- 1982-06-25 AU AU85346/82A patent/AU547823B2/en not_active Ceased
- 1982-06-25 DK DK288082A patent/DK155434C/en not_active IP Right Cessation
- 1982-06-25 CA CA000406060A patent/CA1174679A/en not_active Expired
- 1982-06-25 YU YU1385/82A patent/YU42774B/en unknown
- 1982-06-25 JP JP57109647A patent/JPS5838266A/en active Pending
- 1982-06-25 CH CH3908/82A patent/CH648834A5/en not_active IP Right Cessation
- 1982-06-25 FR FR8211151A patent/FR2508450B1/en not_active Expired
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19920624 |