GB2106098A - Preparation of 2,4-diamino-5-/3',4',5'- trimethoxybenzyl/pyrimidine - Google Patents
Preparation of 2,4-diamino-5-/3',4',5'- trimethoxybenzyl/pyrimidine Download PDFInfo
- Publication number
- GB2106098A GB2106098A GB08218309A GB8218309A GB2106098A GB 2106098 A GB2106098 A GB 2106098A GB 08218309 A GB08218309 A GB 08218309A GB 8218309 A GB8218309 A GB 8218309A GB 2106098 A GB2106098 A GB 2106098A
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- benzyl
- diamino
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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)
- Liquid Crystal Substances (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
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 <IMAGE> (optionally without separation) with guanidine in the presence of an alkanol having 4 to 8 carbon atoms.
Description
SPECIFICATION
A process for the preparation of 2,4-diamino-5-/3',4',5'-trimethoxybenzyl/pyrimidine 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-/substituted/-acrylonitrile with guanidine.
The 2,4-diamino-5-/3',4',5'-trimethoxybenzyl/pyrimidine, known as trimethoprim, is a valuable phamaceutical having very high antibacterial activity.
Several processes for the preparation of trimethoprim have been described, a part of which proceeds through alpha-/ 3,4, 5-trimethoxybenzyl /-beta-/substituted/-acylonitrile.
Thus, in British patent specification No. 957, 97 3,4,5-trimethoxybenzaldehyde is condensed with beta-alkoxy-propionitrile to produce a condensation product with a yeild of above 80 per cent. The reaction product consists of about 80 per cent of alpha-/3,4,5-trimethoxy-benzal/- beta-alkoxy-acrylonitrile and about 20 per cent of alpha-/3,4,5-trimethoxybenzyl/-beta-alkoxy acrylonitrile. In the following step, the condensation produce is cyclized with guanidine.
However, only the "benzyl" compound takes part in the cyclization 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 3,4,5-trimethoxybenzaldehyde is equivalent to 20 to 24 per cent, at the best.
According to British patent specification No. 1,261,455 the condensation product of 3,4,5trimethoxybenzaldehyde and beta-alkoxypropionitrile is reacted with an amine to give alpha /3,4, 5-trimethoxybenzal /-beta-amino-propionitrile 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 yeild of trimethoprim calculated for 3,4,5-trimethoxybenzaldehyde is, even in this proces, lower than 40 per cent.
According to British patent specification No. 1,554,493 3,4,5-trimethoxybenzaldehyde is reacted with a beta-/2-alkoxy-ethoxy/-propionitrile to produce alpha-/3',4',5'-trimethoxybenzal/-beta-/2-alkoxyethoxy/-propionitrile with a yield of above 80 per cent. After separation and 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 percent. 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 beta-/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 trimethoxy-benzal/-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 byproducts 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 to on an industriai scale.
This invention aims at an economical industrial process for the preparation of 2,4-diamino-5 /3',4', 5'-trimethoxybenzyl/pyrimidine.
It was found that if the alpha-/3,4,5-trimethoxybenzal-/beta-methoxypropionitrile of the formula Ill
is reacted with a diethylene glycol monoalkyl ether of the formula IV,
HO-CH2CH2-O-CH2CH2-OR (lV) wherein R is an alkyl group having 1 to 4 carbon atoms, the "benzal" isomer of the formula Ila,
wherein R is as stated above, formed with theoretical yield isomerizes into the corresponding "benzyl" isomer of the formula II,
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 beoption- ally without separation and purificationcyclized 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-trimethoxy-benzyl/-beta-/substi- tuted /acrylonitrile with guanidine in which an alpha-/3,4,5-trimethoxybenzal/-beta-methoxy propionitrile of the formula Ill is reacted with a diethylene glycol monalkyl 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 case 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 "benzel" isomer need not be separated, and in the process of the invention, it transforms into the "benzyl" isomer quantatitively, in general, in 1 to 2 hours. The 'benzyl" 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 preferably in the presence of an aikanol 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 the reaction mixture.
The alpha-/3,4,5-trimethoxybenzal/-beta-methoxy-propionitrile of the formula Ill used as the starting substance is prepared from 3,4,5-trimethoxybenzaldehyde with beta-methoxy-propionitrile. The latter compound is obtained from the reacton 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-trimethoxybenzaldenhyde 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 Ill 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 11 5 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 about 40"C. The reaction mixture is stirred at 40"C for 1 hour, then 100 9 of 3,4,5-trimethoxybenzaldehyde are added. The mixture is heated to 60"C and stirred for 8 hours at this temperature, then cooled to 30"C. 55 ml of methanol and 30 g of potassium hydroxide are added, the latter in several portions. The suspension formed is stirred for 5 hours then cooled to 20"C and 500 ml of water are added in 1 5 minutes.The product is crystallized at 5 to 10"C, filtered, washed, with 3 X 1 5 ml portions of methanol and 3 X 100 ml portions of water, then dried.
116 9/86%/ of alpha-/3,4,5-trimethoxy-benzal/-beta-methoxypropionitriíe are obtained, m.p. 81 to 83"C.
Example 1 1 20 ml of anhydrous diethylene glycol monomethyl ether, 100 g /0.38 moles/ of alpha /3,4,5tnmethoxy-benzal/-beta-methoxyprnpionitflle 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. 1 60 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.
102 g/93 %/ of 2,4-diamino-5-/3',4',5'-trimethoxy-benzyl/-pyrimidine are obtained m.p.
198 to 201 C.
Example 2
A. alpha-/3,4, 5-trimethoxybenzyl /-beta-[2-/21-methoxy-ethoxy/-ethoxy] acrylonitrile.
The mixture of 1 20 ml of an hydros diethylene glycol monomethyl ether, 100 g of alpha /3,4,5trimethoxy-benzal/-beta-methoxyprnpionitrile 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 2 x 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, 1 90 g of guanidine hydrochloride and 100 g of sodium methoxide, 200 g of alpha-/3,4,5-trimethoxy-benzyl/-beta-[2-/methoxy- ethoxy/-ethoxy] acrylonitrile dissolved in 1 20 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 3 X 20 ml portions of methanol, then suspended in 500 ml of water, filtered washed with water and dried.
174.5 g/95 %/ of 2,3-diamino-5-/3',4t,5'-trimethoxy-benzyl/-pyrimidine are obtained, m.p.
198 to 201 C.
Example 3
The mixture of 350 kg anhydrous diethylene glycol monomethyl ether, 300 kg alpha-/3,4,5trimethoxybenzal/-beta-methoxypropionitrile and 20 kg of powdered sodium methoxide is heated 78 to 80"C for 4 hours. The mixture is cooled to 30"C to 540 litres of isobutanol, 1 20 litres of methanol, 275 kg of guanidine hydrochloride and 1 60 kg of powdered sodium methoxide are added. The reaction mixture was stirred at 35 to 40"C for 1 hour, then at 90 to 92"C for 7 hours under reflux. The suspension formed is cooled to 20do, centrifuged and washed with 200 litres of methanol. The wet product obtained is suspended in 1 500 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'-trimethoxy-benzyl/-pyrimidine are obtained, m.p.
198 to 201"C.
Claims (8)
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,-trimethoxy-benzyl-beta-/substituted/acrylonitrile with guanidine, in which an alpha-/3,4,5-trimethoxybenzal/-beta-methoxypropionitrile of the formula (Ill)
is reacted with a diethylene glycol monoalkyl ether of the formula IV,
HO-CH2CH2-O-CH2-OR (IV) wherein R is an alkyl group having 1 to 4 carbon atoms at 60 to 90"C in the presence of an alkali metal alkoxide, and the obtained benzyl isomer of the formula II,
wherein R is as stated above, is reacted---optionally without separation-- with guanidine in the presence of an alkanol having 4 to 8 carbon atoms.
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.
4. A process as claimed in any of Claims 1 to 3, in which the reaction of the alpha-/3,4,5trimethoxy-benzal/-beta-methoxypropionitrile of the formula Ill 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 substantially as herein described with reference to any one of examples 1 to 3.
6. 2,4-diamino-5-/3',4',5'-trimethoxy-benzyl/-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.
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 |
|---|---|
| GB2106098A true GB2106098A (en) | 1983-04-07 |
| GB2106098B GB2106098B (en) | 1984-12-19 |
Family
ID=10956590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08218309A Expired GB2106098B (en) | 1981-06-26 | 1982-06-24 | 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) | ES513481A0 (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 SE SE8203913A patent/SE451134B/en not_active IP Right Cessation
- 1982-06-23 BE BE1/10542A patent/BE893609A/en not_active IP Right Cessation
- 1982-06-24 DD DD82241053A patent/DD202702A5/en not_active IP Right Cessation
- 1982-06-24 FI FI822267A patent/FI76789C/en not_active IP Right Cessation
- 1982-06-24 CS CS824716A patent/CS244907B2/en unknown
- 1982-06-24 GB GB08218309A patent/GB2106098B/en not_active Expired
- 1982-06-24 IT IT22034/82A patent/IT1190888B/en active
- 1982-06-24 AT AT0244882A patent/AT385033B/en not_active IP Right Cessation
- 1982-06-24 RO RO107980A patent/RO85316B/en unknown
- 1982-06-24 IL IL66131A patent/IL66131A/en unknown
- 1982-06-24 SU SU823456105A patent/SU1147252A3/en active
- 1982-06-24 GR GR68559A patent/GR76158B/el unknown
- 1982-06-25 YU YU1384/82A patent/YU42264B/en unknown
- 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
- 1982-06-25 IE IE1521/82A patent/IE53347B1/en not_active IP Right Cessation
- 1982-06-25 ES ES513481A patent/ES513481A0/en active Granted
- 1982-06-25 JP JP57109646A patent/JPS5838265A/en active Pending
- 1982-06-25 CA CA000405973A patent/CA1164458A/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 |