IE53347B1 - A process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine - Google Patents
A process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidineInfo
- Publication number
- IE53347B1 IE53347B1 IE1521/82A IE152182A IE53347B1 IE 53347 B1 IE53347 B1 IE 53347B1 IE 1521/82 A IE1521/82 A IE 1521/82A IE 152182 A IE152182 A IE 152182A IE 53347 B1 IE53347 B1 IE 53347B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- trimethoxybenzyl
- beta
- alpha
- diethylene glycol
- Prior art date
Links
Classifications
-
- 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
Abstract
2,4-Diamino-5-/3',4',5'-trimethoxybenzyl/pyrimidine is prepared by reacting alpha-/3,4,5-trimethoxy-benzal/-beta-methoxypropionitrile with a diethylene glycol monalkyl ether of the formula HO-CH2-CH2-O-CH2-CH2-OR (wherein R is an alkyl group having 1 to 4 carbon atoms) at 60 to 90 DEG C in the presence of an alkali metal alkoxide, and reacting the obtained benzyl isomer of the formula (optionally without separation) with guanidine in the presence of an alkanol having 4 to 8 carbon atoms.
Description
This invention relates to a novel process for the preparation of 2,4-diamino-5-/3’»4*,5’-trimethoxybenzyl/pyrimidine of the formula I
through the reaction of an alpha-/3 ,4 »5 -trimethoxybenzyl/beta - / eubstituted/-acrylonitrile with guanidine.
The 2,4-diamino-5-/3’,4*»5’-trimethoxybenzyl/pyrimidine, known as trimethoprim, is a valuable pharmaceutical having very high antibacterial activity.
io Several processes for the preparation of trimethoprim have been described, a part of which proceeds through alpha/ 3, 4 ,5 -trimethoxybenzyl/-beta-/substituted/-acrylonitrile.
Thus, in British patent specification No. 957,797
3,4,5-trimethoxybenzaldehyde is condensed with beta-alkoxy15 propionitrile to produce a condensation product with a yield of above 80 per cent. The reaction product consists of about 80 per cent of alpha-/3 ,4 ,5 -trimethoxybenzal/-beta-alkoxyacrylonitrile and about 20 per cent of alpha-/3 ,4 ,5 -trimethoxybenzyl/-beta-alkoxyacrylonitrile. In the following step, the condensation product is cyclized with guanidine. However, only the benzyl compound takes part in the cyclisation reaction, meanwhile practically no isomerization of the benzal compound into the benzyl one takes place. As a result, not more than a yield of 28 per cent of trimethoprim can be obtained, i.e. the total yield calculated for 3,4,5trimethoxybenzaldehyde is equivalent to 20 to 24 per cent, at the best.
According to British patent specification No. 1,261,455, the condensation product of 3,4,5-trimethoxybenzaldehyde and beta-alkoxypropionitrile is reacted with an amine to give alpha-/3 ,4 ,5 -trimethoxybenzal/-beta-aminopropionitrile that can be isomerized into the corresponding benzyl isomer with a yield of 40 to 50 per cent. The latter isomer can be cyclized with guanidine to obtain trimethoprim with a yield of 80 per cent. However, the total yield of trimethoprim calculated for 3,4,5-trimethoxybenzaldehyde is, even in this process, lower than 40 per cent.
According to British patent specification No. 1,554,493,
3,4,5-trimethoxybenzaldehyde is reacted with a beta-/2-alkoxyethoxy/propionitrile to produce alpha-/3’,4’,5*-trimethoxybenzal/-beta-/2-alkoxyethoxy/propionitrile with a yield of above 80 per cent. After separation and a thorough purification, the latter compound is isomerized into the corresponding benzyl isomer in the presence of a base at 90 to 95 °C. The benzyl isomer produced is reacted with guanidine to give trimethoprim with a yield of about 80 per cent. Thus, the total yield is 64 to 72 per cent on a laboratory scale.
Although the latter known process is, in fact, more economical than the earlier ones, some difficulties are met when using it on a plant scale. The water formed in the condensation reaction of 3,4,5-trimethoxybenzaldehyde and beta53347 /2- alkoxyethoxy/propionitrile is distilled off at a high temperature, e.g, about 120 °C. At such a high temperature the alpha-/3,4,5-trimethoxybenzal/-beta-/2-alkoxyethoxy/propionitrile is hydrolyzed by the water present. In accordance with our experiences, the hydrolysis of the nitrile group takes place as a concurrent reaction and the corresponding carboxylic acid is produced. As a result of this reaction tarry by-products are formed, the quantity of which is enhanced when using higher batch sizes. Thus, the total yield of 64 to 72 per cent,on a laboratory scale, becomes as low as 50 to 55 per cent with a batch size of about 10 moles.
As a consequence, the process of British patent specification No. 1,554,493 is not economical enough on an industrial scale.
Thia invention aims at an economical Industrial process for the preparation of 2,4-diamino-5-/3*,4’,5’-trimethoxybenzyl/pyrimidine.
It waa found that if the alpha-/3,4,5-trimethoxybenzal/beta -methoxypropionitrile of the formula III
CHCN
CH=C ι
CH2-0CH3 /hi/ is reacted with a diethylene glycol monoalkyl ether of the formula IV,
HO-CHgCHg-O-CHgCI^-OR /IV/ wherein R is an alkyl group having 1 to 4 carbon atoms, the benzal isomer of the formula Ila,
CHSO
CHiO
CN
CH=C /Ila/
CH2-0-CH2CH2-02CHrOft wherein R is as stated above, formed with theoretical yield isomerizes into the corresponding benzyl isomer of the formula II,
CHjO
CN
CH30
io wherein R is as stated above, already at a temperature of as low as 60 to 90 °C with a nearly theoretical yield. The benzyl isomer thus obtained is of such a purity that it can be - optionally without separation and purification - cyclized with guanidine to give trimethoprim.
According to the invention, 2,4-diamino-5-/3’>4*,5’trimethoxybenzyl/pyrimidine of the formula I is prepared through the reaction of an alpha-/3 ,4 ,5 -trimethoxybenzyl/beta-/ substituted/acrylonitrile with guanidine, in which an alpha-/3 ,4 ,5 -trimethoxybenzal/-beta~methoxypropionitrile of the formula III is reacted with a diethylene glycol monoalkyl ether of the formula IV at 60 to 90 °C in the presence of an alkali metal alkoxide, and the obtained benzyl isomer of the formula II is reacted - optionally without separation with guanidine in the presence of an alkanol having 4 to 8 carbon atoms.
Preferably, diethylene glycol monomethyl ether is employed as the compound of the formula IV» In general, this compound is used in excess, and in this caee no separate solvent is required.
Preferably, the alkali metal alkoxide is sodium methoxide, sodium ethoxide, potassium methoxide etc.
The benzyl isomer of the formula II as well as the benzal isomer of the formula Ila are novel compounds. The benzal isomer need not be separated, and, in the procese of the invention, it transforms into the benzyl” isomer quantitatively, in general, in 1 to 2 hours. Thebenzyl isomer formed can be separated; however, if desired, it is cyclized with guanidine without separation.
The benzyl isomer of the formula II is cyclized with guanidine in the presence of an alkanol having 4 to 8 carbon atoms, such as tertiary butanol or isobutanol. Of course, other organic solvents may be present in the cyclization reaction, too, for example a further alkanol, such as methanol.
If the compound of the formula II is not separated prior to the cyclization with guanidine, then any excess of the diethylene glycol monoalkyl ether of the formula IV used in the former reaction is also present in the cyclization.
Preferably, guanidine is used as an acid addition salt, such as hydrochloride. In this case, guanidine is liberated from the acid addition salt in the reaction mixture with a base, suitably alkali metal alkoxide.
The cyclization of the benzyl isomer is performed generally at 70 to 100 °C, especially at the boiling point of
5334 the reaction mixture.
The alpha-/3 ,4 ,5 -trimethoxybenzal/-beta-methoxypropionitrile of the formula 111 used as the starting substance is prepared from 3,4»5-trimethoxybenzaldehyde with beta-methoxy propionitrile. The latter compound is obtained from the reaction of acrylonitrile with methanol in alkaline medium.
The process of the invention allows the economical production of trimethoprim. The total yield calculated for
3,4,5-trimethoxybenzaldehyde being about 80 per cent is not detrimentally influenced by the enhancement of the batch size. Trimethoprim of very high purity suitable for pharmaceutical purposes may be produced from the compound of the formula III in a single step.
The invention is further elucidated by means of the following non-limiting Examples.
Preparation of the starting compound
1.75 g of potassium hydroxide are dissolved in 115 ml of methanol in a flask having 4 litres capacity» 55 g of acrylonitrile are added to the solution in 20 minutes under cooling to avoid temperatures of above 40°C. The reaction mixture is stirred at 40 °C for 1 hour, then 100 g of 3»4,5-trimethoxybenzaldehyde are added. The mixture is heated to SO °C and stirred for 8 hours at this temperature, then cooled to 30 °C.
ml of methanol and 30 g of potassium hydroxide are added, the latter in several portions· The suspension formed ie stirred for 5 hours, then cooled to 20 °C and 500 ml of water are added in 15 minutes· The product is crystallized at 5 to 10 °C, filtered, washed with 3 x 15 ml portions of methanol and 3 x 100 ml portions of water, then dried.
116 g /86 %/ of alpha-/3 »4 ,5 -trimethoxybenzal/-betamethoxypropionitrile are obtained, m.p. 81 to 83 °C.
Example 1
120 ml of anhydrous diethylene glycol monomethyl ether,
100 g /0.38 moles/ of alpha-/3 .4 ,5 -trimethoxybenzal/-betamethoxypropionitrile and 5 g of powdered sodium methoxide are transferred into a flask of 1 litre capacity. The reaction mixture is heated to 74 to 76 °C, stirred for 3 hours at this temperature, then cooled to 30 °C. 160 ml of isobutanol, 40 ml of methanol, 85 g of guanidine hydrochloride and 50 g of powdered sodium methoxide are added. The mixture is stirred at 35 to 40 °C for 1 hour, then heated to 90 to 92 °C and stirred for 7 hours at the boiling point. The suspension formed is cooled under 20 °C, then filtered, washed with 3 x 20 ml portions of methanol, then with 500 ml of water at 30 to 35 °C and dried.
5334
102 g /93 %/ of 2,4-diamino-5-/3’,4’,5’-trimethoxybenzyl/pyrimidine are obtained, m.p. 198 to 201 °C.
Example 2
A. alpha-/3 ,4 ,5 -Trimethoxybenzyl/-beta-jf2-/2’-methoxyethoxy /ethoxy_7acrylonitrile
The mixture of 120 ml of anhydrous diethylene glycol monomethyl ether, 100 g of alpha-/3 ,4 ,5 -trimethoxybenzal/-betamethoxypropionitrile and 5 g of sodium methoxide is heated at 74 to 76 °C for 3 hours, then cooled to 20 °C. The mixture is poured into a mixture of 300 ml of benzene and 500 ml of water.
The organic phase is separated, washed with 2x 200 ml portions of water and evaporated. The residual 110 g of crude product is distilled for purification. The pure compound has a boiling point of 208 to 214 °C at 0.02 mm Hg.
B. 2,4-Diamino-5-/3*,4’,5’-trimethoxybenzyl/-pyrimidine
To the mixture of 200 ml of isobutanol, 80 ml of methanol, 190 g of guanidine hydrochloride and 100 g of sodium methoxide, 200 g of alpha-/3 ,4 ,5 -trimethoxybenzy1/-beta-/”2-/2'-methoxyethoxy/ethoxy_7acrylonitrile dissolved in 120 ml of isobutanol are added. The reaction mixture is heated and boiled under reflux for 7 hours, then cooled to 20 °C. The crystalline product is filtered, washed with 3x 20 ml portions of methanol, then suspended in 500 ml of water, filtered, washed with water and dried.
174.5 g /95 %/ of 2,4-diamino-5-/3’,4’,5’-trimethoxybenzyl/pyrimidine are obtained, m.p. 198 to 201 °C.
Example 3
The mixture of 350 kg anhydrous diethylene glycol monomethyl ether, 300 kg alpha-/3 ,4 ,5 -trimethoxybenzal/-betamethoxypropionitrile and 20 kg of powdered sodium methoxide is heated at 73 to 80 °C for 4 hours· The mixture is cooled to 30 °C and 540 litres of isobutanol, 120 litres of methanol,
275 kg of guanidine hydrochloride and 160 kg of powdered sodium methoxide are added. The reaction mixture is stirred at 35 to 40 °C for 1 hour, then at 90 to 92 °C for 7 hours under reflux. The suspension formed 1b cooled to 20 °C, centrifuged and washed with 200 litres of methanol. The wet product obtained is suspended in 1500 litres of water at 30 to 35 °C, centrifuged, washed with 500 litres of water and dried.
300 kg /91 %/ of 2,4-diamino-5-/3*,4’,5’-trimethoxybenzyl/ pyrimidine are obtained, m.p. 198 to 201 °C.
Claims (9)
1· A process for the preparation of
2. ,4-diamino-5/3' , 4’ ,5’-trimethoxybenzyl/pyrimidine of the formula I through the reaction of an alpha-/3 ,4 ,5 -trimethoxybenzyl/5 beta -/substituted/acrylonitrile with guanidine, in which an alpha-/3 ,4 ,5 -trimethoxybenzal/-beta-methoxypropionitrile of the formula III /111/ is reacted with a diethylene glycol monoalkyl ether of the io formula IV» HO-CHgCHg-O-CHgCHg-OR /IV/ wherein R is an alkyl group having 1 to 4 carbon atone, at 60 to 90 °C in the presence of an alkali metal alkoxide, and the obtained benzyl isomer of the formula II, IS CN CH r C CH -0-CH 2 CHi- 0-CH 2 CH 2 -OR /11/ wherein S is as stated above, is reacted - optionally without separation - with guanidine in the presence of an alkanol having 4 to 8 carbon atoms· 5 2. A process as claimed in Claim 1, in which the diethylene glycol monoalkyl ether is diethylene glycol monomethyl ether.
3. A process as claimed in Claim 1 or 2, in which the alkali metal alkoxide is sodium methoxide. io
4. A process as claimed in any of Claims 1 to 3, in which the reaction of the alpha-/3 ,4 ,5 -trimethoxybenzal/-beta-methoxypropionitrile of the formula III with the diethylene glycol monomethyl ether is performed at 70 to 80 °C.
5. A process as claimed in any one of Claims 1 to 4 15 substantially as herein described with reference to any one of Examples 1 to 3.
6. 2,4-Diamino-5-/3 1 ,4 1 ,5 1 -trimethoxybenzyl/pyrimidine produced by a process as claimed in any one of the preceding claims.
7. A compound of formula II, in which R is an alkyl group having 1 to 4 carbon atoms.
8. A compound of formula II, in which R is a methyl group.
9. A compound of formula II given and defined in Claim 1, which is any one of those specifically hereinbefore 5 mentioned.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU811868A HU186413B (en) | 1981-06-26 | 1981-06-26 | 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 |
---|---|
IE821521L IE821521L (en) | 1982-12-20 |
IE53347B1 true IE53347B1 (en) | 1988-10-26 |
Family
ID=10956590
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE1521/82A IE53347B1 (en) | 1981-06-26 | 1982-06-25 | A process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine |
Country Status (22)
Country | Link |
---|---|
JP (1) | JPS5838265A (en) |
AT (1) | AT385033B (en) |
AU (1) | AU547822B2 (en) |
BE (1) | BE893609A (en) |
CA (1) | CA1164458A (en) |
CH (1) | CH651828A5 (en) |
CS (1) | CS244907B2 (en) |
DD (1) | DD202702A5 (en) |
DK (1) | DK155668C (en) |
ES (1) | ES8304948A1 (en) |
FI (1) | FI76789C (en) |
FR (1) | FR2508449B1 (en) |
GB (1) | GB2106098B (en) |
GR (1) | GR76158B (en) |
HU (1) | HU186413B (en) |
IE (1) | IE53347B1 (en) |
IL (1) | IL66131A (en) |
IT (1) | IT1190888B (en) |
RO (1) | RO85316B (en) |
SE (1) | SE451134B (en) |
SU (1) | SU1147252A3 (en) |
YU (1) | YU42264B (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 | |||
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 HU811868A patent/HU186413B/en not_active IP Right Cessation
-
1982
- 1982-06-18 DK DK275682A patent/DK155668C/en not_active IP Right Cessation
- 1982-06-23 BE BE1/10542A patent/BE893609A/en not_active IP Right Cessation
- 1982-06-23 SE SE8203913A patent/SE451134B/en not_active IP Right Cessation
- 1982-06-24 IL IL66131A patent/IL66131A/en unknown
- 1982-06-24 GR GR68559A patent/GR76158B/el unknown
- 1982-06-24 CS CS824716A patent/CS244907B2/en unknown
- 1982-06-24 FI FI822267A patent/FI76789C/en not_active IP Right Cessation
- 1982-06-24 RO RO107980A patent/RO85316B/en unknown
- 1982-06-24 AT AT0244882A patent/AT385033B/en not_active IP Right Cessation
- 1982-06-24 SU SU823456105A patent/SU1147252A3/en active
- 1982-06-24 DD DD82241053A patent/DD202702A5/en not_active IP Right Cessation
- 1982-06-24 GB GB08218309A patent/GB2106098B/en not_active Expired
- 1982-06-24 IT IT22034/82A patent/IT1190888B/en active
- 1982-06-25 IE IE1521/82A patent/IE53347B1/en not_active IP Right Cessation
- 1982-06-25 CA CA000405973A patent/CA1164458A/en not_active Expired
- 1982-06-25 ES ES513481A patent/ES8304948A1/en not_active Expired
- 1982-06-25 YU YU1384/82A patent/YU42264B/en unknown
- 1982-06-25 JP JP57109646A patent/JPS5838265A/en active Pending
- 1982-06-25 CH CH3907/82A patent/CH651828A5/en not_active IP Right Cessation
- 1982-06-25 AU AU85345/82A patent/AU547822B2/en not_active Ceased
- 1982-06-25 FR FR8211150A patent/FR2508449B1/en not_active Expired
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