CA1164458A - Process for the preparation of 2,4-diamino-5-(3',4', 5'-trimethoxybenzyl)pyrimidine - Google Patents
Process for the preparation of 2,4-diamino-5-(3',4', 5'-trimethoxybenzyl)pyrimidineInfo
- Publication number
- CA1164458A CA1164458A CA000405973A CA405973A CA1164458A CA 1164458 A CA1164458 A CA 1164458A CA 000405973 A CA000405973 A CA 000405973A CA 405973 A CA405973 A CA 405973A CA 1164458 A CA1164458 A CA 1164458A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- beta
- alpha
- diethylene glycol
- guanidine
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 title abstract description 10
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract description 21
- MTHSVFCYNBDYFN-UHFFFAOYSA-N anhydrous diethylene glycol Natural products OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 12
- -1 diethylene glycol monoalkyl ether Chemical class 0.000 claims abstract description 12
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 6
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 5
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 4
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical group COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 claims 3
- 239000003513 alkali Substances 0.000 claims 1
- 150000004703 alkoxides Chemical class 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 229960001082 trimethoprim Drugs 0.000 abstract description 9
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 6
- 229960004198 guanidine Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 3
- CBQYNPHHHJTCJS-UHFFFAOYSA-N Alline Chemical compound C1=CC=C2C3(O)CCN(C)C3NC2=C1 CBQYNPHHHJTCJS-UHFFFAOYSA-N 0.000 description 2
- 241000237074 Centris Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000001701 trimethoxybenzyl group Chemical group 0.000 description 2
- UCTUXUGXIFRVGX-UHFFFAOYSA-N 2,3,4-trimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1OC UCTUXUGXIFRVGX-UHFFFAOYSA-N 0.000 description 1
- 101100113686 Clitocybe nebularis clt4 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 101150019895 thiE gene Proteins 0.000 description 1
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
Landscapes
- 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)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Abstract The invention relates to a novel process for the preparation of 2,4-diamino-5-/3',4',5'-trimethoxybenzyl/-pyrimidine of the formula I
/I/
through the reaction of an alpha-/3 ,4 ,5 -trimethoxybenzyl/--beta-/substituted/-acrylonitrile with guanidine.
According to the invention an alpha-/3 ,4 ,5 -trimethoxy-benzal/-beta-methoxypropionitrile of the formula III
/III/
is reacted with a diethylene glycol monoalkyl ether of the formula 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, /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.
The process of the invention allows the economical production of trimethoprim having very high antibacterial activity. The total yield calculated for 3,4,5-trimethoxy-benzaldehyde being about 80 per cent is not detrimentally influenced by the enhancement of the batch size. Trimethoprim of very high purity is produced from the compound of the formula III in a single step.
/I/
through the reaction of an alpha-/3 ,4 ,5 -trimethoxybenzyl/--beta-/substituted/-acrylonitrile with guanidine.
According to the invention an alpha-/3 ,4 ,5 -trimethoxy-benzal/-beta-methoxypropionitrile of the formula III
/III/
is reacted with a diethylene glycol monoalkyl ether of the formula 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, /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.
The process of the invention allows the economical production of trimethoprim having very high antibacterial activity. The total yield calculated for 3,4,5-trimethoxy-benzaldehyde being about 80 per cent is not detrimentally influenced by the enhancement of the batch size. Trimethoprim of very high purity is produced from the compound of the formula III in a single step.
Description
5 ~
A PROCESS E'0~ T~-E PREPARATIO~J ~JF 2~ ~- DI~rlNo-5~/3~ A 4~ ~ 5 ~TRIMETMOXYBh'NZYL/PYRI:~.lDINE
~hi~ invention reLatee to a novel proce~ ~or tha preparation o~ 2,4-diamino~5-/3~,4~,5' -tri.~etho~ybenz.yl~
pyrimidine of -the formula I
CH30 ~CH.~ NH
CH.30 through the reaction of an alpha-/3 ,4 ,5 ~trisnethoxybeIlzyl/--beta-/~ubstituted/-acrylonitrile with guanidineO
The 294-diamino-5-/3',4',5'-trimethoxybenzyl/pyrimidine~
known a~ trimethoprim9 ie a valuable pharmaceutical havin~
very high antibacterial activity~
Several proce~ee~ for the preparation of trimethoprim have been de~cribed, a part o~ which procee~ through alpha~
-/3 ,4 ,5 -trimethoxybenzylJ-beta-/eub~tituted~acrylonit~iLe.
Thue, in Briti~h patent epecification No. 957,797 394~5~trimethoxybenzaldehyd~ i~ condensed with bet~alko~y~
propionitrile to produce a condensation product with a yleld o~ abov~ 80 per cen-t~ The reaction product con9i~t~ of abou-t 80 per cent of alpha~/3 9 4 g 5 ~trimethoxybenzal/-beta~alkoxy~
acrylonitrile and abou-t 20 per cent o~ alpha J3 ,4 ,5 ~tri-methoxybenzylJ~beta alkoxyacrylonitrile4 In the :Eollowing ~tep, -th~ conden~ation product i8 cyclized wi-th guanidineO ~o~ever~
only the "ben~yl" compound take~ part in -the cyclization ~ 2 ~
reaction, melnwhile prac-t-icall~y nv :lso~erlæatioxl OI the 'ibenzal" coi~pound into t,he "~enz~yl;' one take~ place~ A~ a re~ult, not more than a yiald of ~ per cent of trimethoprim can be obtain~d! i~e. the to-tal .yield calculated ~or 3~495 trimetho}:yben~aldehytle i~ equivaient to 20 to 24 per eent~
~t the b~E~ t~
Accor~ing -to Bri-ti~h pa terlt ~3peci:~ication ~o. 11261,455, the condenaation produc~ of 3,4,5--trimethoxybenzaLdehyde end beta~alkcxypropionitrile i,q reacted with an amine to giv~
alpha-/3 94 ~5 -trimethoxybenzal/~-beta-aminopropionitrile that can be isomerized into the corre~pondin~ "b~nzyl" ieomer with a yiel~ o~ 40 to 50 per cent. ~he latter i~omer ca~ be cyclized with guanidine to obtain trimethoprim with a yield of 80 per cent. However, -the total yield of trim~thoprim calculated ~or 3,4,5-trime-thoxybenzaldehyde i~, even in thi~ proce~, lower than 40 per cent.
According to ~riti~h patent speci~ication No~ 1,554,493, 3,4,5~trimethoxybenzaldehyde i~ reacted with a beta-/2~1koxy-ethoxy~propionitrile to produce alpha-/37,4~,5)-trlmethoxy-~0 benzal~-beta-/2-alkoxyethoxy~propioni-trile with a yield o~
above 80 per cent, A~ter ~eparation and a thorough purification, the latter compound i~ i~omerized into the corre~ponding "benzyl"
i~omer in the pre~ence o~ a ba~e at 90 to 95 C. The "benzyl"
i~o~er produced ia reacted with guanidine to ~i~e trimethoprim ~ith a yield of about 80 per cent~ ~huH, th~ total yield i~
64 to 72 per cent on l~boratory ~c~leO
Although the latter known procea~ i~? in ~act9 more economical than the earlier onss, some di~ficultiea are met when u~ing it on plant ~cale. The water ~ormed in the co~denoation reaction o~ 3,4,5-trimethoxyben~aldehyde and beta-i 8 ~J2~alkoxyethoxy~-prop~ionitril.e i.~ di~-tilled o~ a-t ~ hi~,h temperature~ e~gO about 120 C., At f3uch ~ high temperature the alpha~3, 4, 5- trimethoxyberlza~ beta~ alko~et;ho~
propionitrile i~3 hydrolyzed by the water pre~ent9 ïn accordance with our experience~ -lhe hydroly~i~ o:f' the nitrile group talces place a~ u concur:rent re~ tlO~ and ~he correspon~ g carboxylic acld i8 producedO A~ a re~ult of thiE reactiorl -tarry by product~ ar~, Iormed~ the quantity o:E which i~ enhanced when using higher batch ~ize~ hus, -the to-tal yield o~ 64 to lû 72 per cent, on a laboratory scale, become~ a~ low a~ 50 to 55 per cen t wi th a batch ~lize OI about 10 mole~,, .AB a con~equence; the proce~3s o~ Briti~3h patent opeciflcation No. 1,554,493 i8 :rlot economicai enough on industrial ~ale~
Thie invention aim~ at a~ economical indu~trial proce~
for the preparation of 2,4-diamino~5-/3',4',5'-trimethoxy-be~zyl/pyrimidine~
It wae found that if the alpha-/3,4,5-trimethox~bellzal/--beta-methoxypropionitrile of the formula III
C~3 ~
clt3~ ,) C1~= C JIII~
Cll~() Cl 12-OC1~3 i~ reacted with a diethylene glycol monoalkyl ether of the formul.a IV~
~ I0-CH2~H2_0~C~2CH2_0R /IVJ
wherein R i9 an alkyl group having 1 to 4 carbon atom~
the ~Iben~al~ isomer of the formula IIa~
~i ~
~}~3~ C~
Ct~ a/
A PROCESS E'0~ T~-E PREPARATIO~J ~JF 2~ ~- DI~rlNo-5~/3~ A 4~ ~ 5 ~TRIMETMOXYBh'NZYL/PYRI:~.lDINE
~hi~ invention reLatee to a novel proce~ ~or tha preparation o~ 2,4-diamino~5-/3~,4~,5' -tri.~etho~ybenz.yl~
pyrimidine of -the formula I
CH30 ~CH.~ NH
CH.30 through the reaction of an alpha-/3 ,4 ,5 ~trisnethoxybeIlzyl/--beta-/~ubstituted/-acrylonitrile with guanidineO
The 294-diamino-5-/3',4',5'-trimethoxybenzyl/pyrimidine~
known a~ trimethoprim9 ie a valuable pharmaceutical havin~
very high antibacterial activity~
Several proce~ee~ for the preparation of trimethoprim have been de~cribed, a part o~ which procee~ through alpha~
-/3 ,4 ,5 -trimethoxybenzylJ-beta-/eub~tituted~acrylonit~iLe.
Thue, in Briti~h patent epecification No. 957,797 394~5~trimethoxybenzaldehyd~ i~ condensed with bet~alko~y~
propionitrile to produce a condensation product with a yleld o~ abov~ 80 per cen-t~ The reaction product con9i~t~ of abou-t 80 per cent of alpha~/3 9 4 g 5 ~trimethoxybenzal/-beta~alkoxy~
acrylonitrile and abou-t 20 per cent o~ alpha J3 ,4 ,5 ~tri-methoxybenzylJ~beta alkoxyacrylonitrile4 In the :Eollowing ~tep, -th~ conden~ation product i8 cyclized wi-th guanidineO ~o~ever~
only the "ben~yl" compound take~ part in -the cyclization ~ 2 ~
reaction, melnwhile prac-t-icall~y nv :lso~erlæatioxl OI the 'ibenzal" coi~pound into t,he "~enz~yl;' one take~ place~ A~ a re~ult, not more than a yiald of ~ per cent of trimethoprim can be obtain~d! i~e. the to-tal .yield calculated ~or 3~495 trimetho}:yben~aldehytle i~ equivaient to 20 to 24 per eent~
~t the b~E~ t~
Accor~ing -to Bri-ti~h pa terlt ~3peci:~ication ~o. 11261,455, the condenaation produc~ of 3,4,5--trimethoxybenzaLdehyde end beta~alkcxypropionitrile i,q reacted with an amine to giv~
alpha-/3 94 ~5 -trimethoxybenzal/~-beta-aminopropionitrile that can be isomerized into the corre~pondin~ "b~nzyl" ieomer with a yiel~ o~ 40 to 50 per cent. ~he latter i~omer ca~ be cyclized with guanidine to obtain trimethoprim with a yield of 80 per cent. However, -the total yield of trim~thoprim calculated ~or 3,4,5-trime-thoxybenzaldehyde i~, even in thi~ proce~, lower than 40 per cent.
According to ~riti~h patent speci~ication No~ 1,554,493, 3,4,5~trimethoxybenzaldehyde i~ reacted with a beta-/2~1koxy-ethoxy~propionitrile to produce alpha-/37,4~,5)-trlmethoxy-~0 benzal~-beta-/2-alkoxyethoxy~propioni-trile with a yield o~
above 80 per cent, A~ter ~eparation and a thorough purification, the latter compound i~ i~omerized into the corre~ponding "benzyl"
i~omer in the pre~ence o~ a ba~e at 90 to 95 C. The "benzyl"
i~o~er produced ia reacted with guanidine to ~i~e trimethoprim ~ith a yield of about 80 per cent~ ~huH, th~ total yield i~
64 to 72 per cent on l~boratory ~c~leO
Although the latter known procea~ i~? in ~act9 more economical than the earlier onss, some di~ficultiea are met when u~ing it on plant ~cale. The water ~ormed in the co~denoation reaction o~ 3,4,5-trimethoxyben~aldehyde and beta-i 8 ~J2~alkoxyethoxy~-prop~ionitril.e i.~ di~-tilled o~ a-t ~ hi~,h temperature~ e~gO about 120 C., At f3uch ~ high temperature the alpha~3, 4, 5- trimethoxyberlza~ beta~ alko~et;ho~
propionitrile i~3 hydrolyzed by the water pre~ent9 ïn accordance with our experience~ -lhe hydroly~i~ o:f' the nitrile group talces place a~ u concur:rent re~ tlO~ and ~he correspon~ g carboxylic acld i8 producedO A~ a re~ult of thiE reactiorl -tarry by product~ ar~, Iormed~ the quantity o:E which i~ enhanced when using higher batch ~ize~ hus, -the to-tal yield o~ 64 to lû 72 per cent, on a laboratory scale, become~ a~ low a~ 50 to 55 per cen t wi th a batch ~lize OI about 10 mole~,, .AB a con~equence; the proce~3s o~ Briti~3h patent opeciflcation No. 1,554,493 i8 :rlot economicai enough on industrial ~ale~
Thie invention aim~ at a~ economical indu~trial proce~
for the preparation of 2,4-diamino~5-/3',4',5'-trimethoxy-be~zyl/pyrimidine~
It wae found that if the alpha-/3,4,5-trimethox~bellzal/--beta-methoxypropionitrile of the formula III
C~3 ~
clt3~ ,) C1~= C JIII~
Cll~() Cl 12-OC1~3 i~ reacted with a diethylene glycol monoalkyl ether of the formul.a IV~
~ I0-CH2~H2_0~C~2CH2_0R /IVJ
wherein R i9 an alkyl group having 1 to 4 carbon atom~
the ~Iben~al~ isomer of the formula IIa~
~i ~
~}~3~ C~
Ct~ a/
2~ .c~ C ~2~2~
wherein R i~3 a~ ~atecl above3 for~d wi. I;h theQ:ra-kical yield ieomeri~e0 into -the co~re~pondi~ be~zJ~ 3omer: ~f th~
10 :~ormula II ~
CH~ ~ ~ ct~i C~ C
~ ~ cl~-a-cH~c~ -o-c~ c~ aR flI~
wherein R i~ as atated above, already at a temperature of ae low a~ 60 to 90 ~ with a noarly theora-tical yieldO The "benzyl"
icomer thu8 obtained io of euch a purity tha-t it can be - optionally without oepar~tion and purifica-tion - cyclized with guanidine -to give trimethoprim.
According to the invention, 2,4~diamino-5~3 ? ~ 4 9 ~ 5-~trimethoxybenzyl~pyrimidine o~ the ~ormula I :l~ prepared through the reaction o~ an alpha-l3 ,4 y5`-trimethoxybe~zyl~-beta~ub~tituted/acrylonitrile with gua~idl~e9 i~ whichan alpha-~3 ,4 ,5 -trimethoxybenzal~beta-metho~ypropionitrile of the formula III i9 reacted with ~ diethylene glycol mono alkyl ether o~ the ~ormula IV at 60 to 90 C in tho pre~enc~
o~ an alkali metal alkoxide ? andthe obtained benzyl i~omer o~
~0 the ~ormula II i~ reacted optio~ally ~ithout ~eparatiorl -~ 5 --with g~ani~ine in the pre~ence of an alkanol havi~g 4 to 8 carbon atom~.
~refer~bly, die~hylene glycol monometh~l ether i~
employed a~ the compound of the formula IV, In general, thi~
compound i8 used in e~ce~9 and in this caae no ~eparate 80 lvent i~ required.
Pre~erably, the alkali metal alko~ide ie sodium methoxide, ~odium ethoxide, pota~ium methoxide etc~
The "benzylll isomer of the formula II a~ well a~ the "benzal" isomer of the *ormula IIa are novel compound~. The "benz.al" isomer need not be separated, and, i~ -the procese o~
the invention, it tran~form~ into the "benzyl" i~omer quanti-tatively, in general, in 1 to 2 hour~, rhe"be~zyl"
i80mer ~ormed can be separated; however, i~ denired, it ie cyclized with guanidine without separation.
~he "benzyl" i~omer of the formula II i~ cyclized with guanidine pre~erably in the presence of an alkanol having 4 to 8 carbon atom~, ~uch a~ tertiary butanol or i~obutanol~ Of cour~e, other organic ~olvents may be present in the cyclization reaction, too, for example a further alkanol,~uch a~ me-thanol.
II the compound o~ the formula II i8 not ~eparated prior to the cyclization with guanidins, then any excess of the di-ethylene glycol mo~oalkyl ether of the formula IV used in the ~o~mer reaction is also pre~ent in the cycli~ation, Pre~erably, guanidi~e i~ u~ed as an acid addition salt, such as hydrochlorideg In t~is ca~e, guanidille is liberated ~rom the acid addition salt in the reaction mixture with a base, suitably alkali metal all~oxideO
The cyclization of the "benzyl" isomer i0 performed generaLly a t 70 to 100 C, egpeciall~r at the boili~g point OI
~6~r~8 the reaction mixture4 The alpha~J3 ,4 /5 -trimetho~ybenzal~-beta-m~hoæy~
propioni-trile of the formula III u~ed a~ th~ etar-tirl~ ~ub~tance i8 prepared ~ro~ 3,4,5-trimethoxybe~zaldehyde with beta-methoxy~
propionitrile. The lat-ter compound ia obtained from the re-aCtiQn of acrylonitrile with methanol in alkaline mediumO
The proce~ of -the invention alLow~ the econo~ical production of trime-thoprim~ The total yield cslculated for
wherein R i~3 a~ ~atecl above3 for~d wi. I;h theQ:ra-kical yield ieomeri~e0 into -the co~re~pondi~ be~zJ~ 3omer: ~f th~
10 :~ormula II ~
CH~ ~ ~ ct~i C~ C
~ ~ cl~-a-cH~c~ -o-c~ c~ aR flI~
wherein R i~ as atated above, already at a temperature of ae low a~ 60 to 90 ~ with a noarly theora-tical yieldO The "benzyl"
icomer thu8 obtained io of euch a purity tha-t it can be - optionally without oepar~tion and purifica-tion - cyclized with guanidine -to give trimethoprim.
According to the invention, 2,4~diamino-5~3 ? ~ 4 9 ~ 5-~trimethoxybenzyl~pyrimidine o~ the ~ormula I :l~ prepared through the reaction o~ an alpha-l3 ,4 y5`-trimethoxybe~zyl~-beta~ub~tituted/acrylonitrile with gua~idl~e9 i~ whichan alpha-~3 ,4 ,5 -trimethoxybenzal~beta-metho~ypropionitrile of the formula III i9 reacted with ~ diethylene glycol mono alkyl ether o~ the ~ormula IV at 60 to 90 C in tho pre~enc~
o~ an alkali metal alkoxide ? andthe obtained benzyl i~omer o~
~0 the ~ormula II i~ reacted optio~ally ~ithout ~eparatiorl -~ 5 --with g~ani~ine in the pre~ence of an alkanol havi~g 4 to 8 carbon atom~.
~refer~bly, die~hylene glycol monometh~l ether i~
employed a~ the compound of the formula IV, In general, thi~
compound i8 used in e~ce~9 and in this caae no ~eparate 80 lvent i~ required.
Pre~erably, the alkali metal alko~ide ie sodium methoxide, ~odium ethoxide, pota~ium methoxide etc~
The "benzylll isomer of the formula II a~ well a~ the "benzal" isomer of the *ormula IIa are novel compound~. The "benz.al" isomer need not be separated, and, i~ -the procese o~
the invention, it tran~form~ into the "benzyl" i~omer quanti-tatively, in general, in 1 to 2 hour~, rhe"be~zyl"
i80mer ~ormed can be separated; however, i~ denired, it ie cyclized with guanidine without separation.
~he "benzyl" i~omer of the formula II i~ cyclized with guanidine pre~erably in the presence of an alkanol having 4 to 8 carbon atom~, ~uch a~ tertiary butanol or i~obutanol~ Of cour~e, other organic ~olvents may be present in the cyclization reaction, too, for example a further alkanol,~uch a~ me-thanol.
II the compound o~ the formula II i8 not ~eparated prior to the cyclization with guanidins, then any excess of the di-ethylene glycol mo~oalkyl ether of the formula IV used in the ~o~mer reaction is also pre~ent in the cycli~ation, Pre~erably, guanidi~e i~ u~ed as an acid addition salt, such as hydrochlorideg In t~is ca~e, guanidille is liberated ~rom the acid addition salt in the reaction mixture with a base, suitably alkali metal all~oxideO
The cyclization of the "benzyl" isomer i0 performed generaLly a t 70 to 100 C, egpeciall~r at the boili~g point OI
~6~r~8 the reaction mixture4 The alpha~J3 ,4 /5 -trimetho~ybenzal~-beta-m~hoæy~
propioni-trile of the formula III u~ed a~ th~ etar-tirl~ ~ub~tance i8 prepared ~ro~ 3,4,5-trimethoxybe~zaldehyde with beta-methoxy~
propionitrile. The lat-ter compound ia obtained from the re-aCtiQn of acrylonitrile with methanol in alkaline mediumO
The proce~ of -the invention alLow~ the econo~ical production of trime-thoprim~ The total yield cslculated for
3,4,5~trimethoæybenzaldehyde belng about ao per cent ia not detrimen-tally in~luenced by the enhancement of the batch ~lze.
Trimethoprim of very high purity ~uitabl~ for pharmaceutical purpo~ee i~ produced from the compound of the formula III in a ~ingle ~tep, The invention i~ further elucidated b~ mean~ o~ the following EXample~
3o ~ 3. ~ 5 8 .=~ I
~ra-tlon s~ e the ~1ta .r~ ~
l~rl5 g nJ~ puta~-J~3:ium hydrox:i.de are di~3~01~Ted in 115 ml of methallol irl a fl~lc ht.-r:ing ~ litre~ capacity~ 55 g of acrylo~
ni1;rile are added to t;he ~301ution în 20 mirlute~ under C401i~1g to avoid temperR ~ure~bove ~o ~c~ The reaction mi~tllre ia ~tirred at 40 (~ or 1 hour, then 100 g OI 3,4,5-trimethoxy-ben~aldeh;yde are adùed~ The mi~ture i~ heated to 60 C and ~tirred for 8 hour~ at th.i~ tempeYature, -then cooled 1;o 30 C., 55 ml OI methaIlol ~nd 30 g of pota~ium }~droxide are added9 the la t ter in ~everal portion~., The ~uapen~ion formed i~
~tirred for 5 hour~, then cooled to 20 C and 5ûO ml of water are added in 15 minutea. T:he product i8 crye-tallized at 5 to lQ C t filtered, w~shed with 3 ,~ 15 ml portione o:f methan~l and 3 x 100 ml portlon~ of water, then dried~
116 g /86 %~ of alpha-/3 ,4 ,5 trimethoxybenzal/-beta-methoxypropionitrile are obtainedl m.p, 81 to 83 C.
120 ml of anhydroll~ diet,hylene glycol ~onomethyl ether, 100 g /0~38 mole~/ of alpha~/3 ~4 ,5 ~trimethoxybenzal/-beta--metho~ypropionitrile and S ~ o~ powdered ~odium metho~ide sre transferred into a flaek o~ 1 lit.re capacity. The reaction mixture i~ heated to 74 to 76 C 9 ~tirred for 3 hour~ at thi~
tempe.rature~ then cooled to 30 C, 160 ~1 o~ i~obutanol~ 40 ml of methanol, 85 g of guanidine hydrochloride and 50 g o~
powdered ~odium methoxide ar~ added~ ~he mixture io ~ti.rred at 35 to 40 C for 1 hour, then heated to 90 to 92 C and ~tirred for 7 hour~ at the boiling point~ ~h~ euepeneion ~ormed i8 cooled under ~0 C, then filtered, wa~hed with 3 x 20 ml portion~ of' methanol, then with 500 ml of water ~t 30 to 35 C
and dried.
`- ~3 P'`
102 g J93 %~ O.~t.~ [3iam-.irlo~5~5~ ,47 ~5'~kximetho~yb~nzylJ-pyriiuidine ar* obtai~ed, m~p~ 198 to 201 ~)CO
~ 2 A9 alpha~03 ,4 ,5 ~TrirrJethcxybenzyl~-beta~ r ? /2 9 -metho~y-e-thoxy~e^thv~y 7aorylollitri.1e q`he mix~tllre oX 120 ml o~ ant~drou~ diet~ylene glycol mono-methyl ether9 100 ~ o~ alpha-~3 ~4 ,5 -trimethoxybenzalJ-beta-~methoxypropionitril~ and 5 g o~ ~odium m~thoxid~ i~ heated at 74 to 76 ~ ~or 3 hour~, then cooled to 20 CO l'he mixture i9 poured to the mixture of 300 ml~)~nzene and 500 ml o:~ ~ater"
~he organ:ic phaee i~ ~eparated, wa~hed ~ith 2x 200 ml po.rtione o~ water and evaporatedl The re~idual 110 g o~ crude product ie di~tilled for puriXicati.onr ~he pure compound hae a boiling point o~ 20~ to 214 C at 0~02 mm Hg~
~0 ~,4-Diamino 5~/3194~ trimethoxybenz~l~pyrimidine ~o the mixture o~ 200 ml o~ i~obutanol, 80 ml o~ methanol, 190 g o~ guanidlne hydrochloride and 100 g of sodium methoxide, 200 g of alpha-~3 ,4 ,5 -trimethoxybenzyl/-beta-r 2-Jmethoxy-ethoxy~etho~y 7acryloni.trile dia~olved in 120 ml of i~obutanol are added. The reaction mixture i~ heated and boiled under re~lux for 7 houre, -then cooled to 20 C~ The crys~alline product i~ ~iltered, wa~hed with 3x 20 ml portion~ O:e meth~nol, then ~uspended in 500 ml of water, ~ilteredS waE3hed with water and driedO
174.5 g /95 ~oJ o~ 2,4 diamino-5 ~31,4',57-trimetho~y benzyl~pyrimidine are obtained, m.p. 198 to 2~1 C4 ~e~
~he mi~ture of 350 kg anhydrous diethylene glycol mono-methyl ether9 300 kg alpha~3 ,~ ,5 trimethoxybe~zal3-beta--metho~ypropioni~rile and 20 kg o~ powdered aodium methoxide ~ 9 ~
i~ heated a-t 78 to 80 C for 4 hour~. ~he mixture i~ cooled to 30 C and 5~0 lltrea of isobutanol, 120 litre~ of me-thanol, 275 kg of guanidin~ hyd~ochloride ~d 160 kg o~ powdered ~odium metho~ide are added0 ~he :reaction mixture i8 stirred at 35 to 40 C for 1 hour~ then at 90 to 92 C ~or 7 houro under re~lux~ ~he ~u~pen~ion ~ormed i~ cooled to 20 C, centri~uged and wa~hed with 200 litre~ o~ methanol. Th~ wet product obtained ia 3u~pendad in 1500 litree of water at 30 to 35 C, centri~uged, wa~hed with 500 litre~ of wate.r and dried.
300 kg /91 %/ of 294-diamino-5-J3~,4',5'~trimethoxybenzyl/-pyrimidine a.re obtained, m9p. 198 -to 201 C~
Trimethoprim of very high purity ~uitabl~ for pharmaceutical purpo~ee i~ produced from the compound of the formula III in a ~ingle ~tep, The invention i~ further elucidated b~ mean~ o~ the following EXample~
3o ~ 3. ~ 5 8 .=~ I
~ra-tlon s~ e the ~1ta .r~ ~
l~rl5 g nJ~ puta~-J~3:ium hydrox:i.de are di~3~01~Ted in 115 ml of methallol irl a fl~lc ht.-r:ing ~ litre~ capacity~ 55 g of acrylo~
ni1;rile are added to t;he ~301ution în 20 mirlute~ under C401i~1g to avoid temperR ~ure~bove ~o ~c~ The reaction mi~tllre ia ~tirred at 40 (~ or 1 hour, then 100 g OI 3,4,5-trimethoxy-ben~aldeh;yde are adùed~ The mi~ture i~ heated to 60 C and ~tirred for 8 hour~ at th.i~ tempeYature, -then cooled 1;o 30 C., 55 ml OI methaIlol ~nd 30 g of pota~ium }~droxide are added9 the la t ter in ~everal portion~., The ~uapen~ion formed i~
~tirred for 5 hour~, then cooled to 20 C and 5ûO ml of water are added in 15 minutea. T:he product i8 crye-tallized at 5 to lQ C t filtered, w~shed with 3 ,~ 15 ml portione o:f methan~l and 3 x 100 ml portlon~ of water, then dried~
116 g /86 %~ of alpha-/3 ,4 ,5 trimethoxybenzal/-beta-methoxypropionitrile are obtainedl m.p, 81 to 83 C.
120 ml of anhydroll~ diet,hylene glycol ~onomethyl ether, 100 g /0~38 mole~/ of alpha~/3 ~4 ,5 ~trimethoxybenzal/-beta--metho~ypropionitrile and S ~ o~ powdered ~odium metho~ide sre transferred into a flaek o~ 1 lit.re capacity. The reaction mixture i~ heated to 74 to 76 C 9 ~tirred for 3 hour~ at thi~
tempe.rature~ then cooled to 30 C, 160 ~1 o~ i~obutanol~ 40 ml of methanol, 85 g of guanidine hydrochloride and 50 g o~
powdered ~odium methoxide ar~ added~ ~he mixture io ~ti.rred at 35 to 40 C for 1 hour, then heated to 90 to 92 C and ~tirred for 7 hour~ at the boiling point~ ~h~ euepeneion ~ormed i8 cooled under ~0 C, then filtered, wa~hed with 3 x 20 ml portion~ of' methanol, then with 500 ml of water ~t 30 to 35 C
and dried.
`- ~3 P'`
102 g J93 %~ O.~t.~ [3iam-.irlo~5~5~ ,47 ~5'~kximetho~yb~nzylJ-pyriiuidine ar* obtai~ed, m~p~ 198 to 201 ~)CO
~ 2 A9 alpha~03 ,4 ,5 ~TrirrJethcxybenzyl~-beta~ r ? /2 9 -metho~y-e-thoxy~e^thv~y 7aorylollitri.1e q`he mix~tllre oX 120 ml o~ ant~drou~ diet~ylene glycol mono-methyl ether9 100 ~ o~ alpha-~3 ~4 ,5 -trimethoxybenzalJ-beta-~methoxypropionitril~ and 5 g o~ ~odium m~thoxid~ i~ heated at 74 to 76 ~ ~or 3 hour~, then cooled to 20 CO l'he mixture i9 poured to the mixture of 300 ml~)~nzene and 500 ml o:~ ~ater"
~he organ:ic phaee i~ ~eparated, wa~hed ~ith 2x 200 ml po.rtione o~ water and evaporatedl The re~idual 110 g o~ crude product ie di~tilled for puriXicati.onr ~he pure compound hae a boiling point o~ 20~ to 214 C at 0~02 mm Hg~
~0 ~,4-Diamino 5~/3194~ trimethoxybenz~l~pyrimidine ~o the mixture o~ 200 ml o~ i~obutanol, 80 ml o~ methanol, 190 g o~ guanidlne hydrochloride and 100 g of sodium methoxide, 200 g of alpha-~3 ,4 ,5 -trimethoxybenzyl/-beta-r 2-Jmethoxy-ethoxy~etho~y 7acryloni.trile dia~olved in 120 ml of i~obutanol are added. The reaction mixture i~ heated and boiled under re~lux for 7 houre, -then cooled to 20 C~ The crys~alline product i~ ~iltered, wa~hed with 3x 20 ml portion~ O:e meth~nol, then ~uspended in 500 ml of water, ~ilteredS waE3hed with water and driedO
174.5 g /95 ~oJ o~ 2,4 diamino-5 ~31,4',57-trimetho~y benzyl~pyrimidine are obtained, m.p. 198 to 2~1 C4 ~e~
~he mi~ture of 350 kg anhydrous diethylene glycol mono-methyl ether9 300 kg alpha~3 ,~ ,5 trimethoxybe~zal3-beta--metho~ypropioni~rile and 20 kg o~ powdered aodium methoxide ~ 9 ~
i~ heated a-t 78 to 80 C for 4 hour~. ~he mixture i~ cooled to 30 C and 5~0 lltrea of isobutanol, 120 litre~ of me-thanol, 275 kg of guanidin~ hyd~ochloride ~d 160 kg o~ powdered ~odium metho~ide are added0 ~he :reaction mixture i8 stirred at 35 to 40 C for 1 hour~ then at 90 to 92 C ~or 7 houro under re~lux~ ~he ~u~pen~ion ~ormed i~ cooled to 20 C, centri~uged and wa~hed with 200 litre~ o~ methanol. Th~ wet product obtained ia 3u~pendad in 1500 litree of water at 30 to 35 C, centri~uged, wa~hed with 500 litre~ of wate.r and dried.
300 kg /91 %/ of 294-diamino-5-J3~,4',5'~trimethoxybenzyl/-pyrimidine a.re obtained, m9p. 198 -to 201 C~
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 2,4-diamino-5-/3',4',5'-trimethoxyben-xyl/-pyrimidine of the formula I
(I) through the reaction of an alpha-/3,4,5-trimethoxybenæyl/-beta-/substituted/acryl-onitrile with guanidine, in which an alpha-/3,4,5-trimethoxybenzyl/-beta-methoxy-propionitrile of the formula III
(III) is reacted with a diethylene glycol monoalkyl ether of the formula IV, HO-CH2CH2-O-CH2CH2-OR (IV) wherein R is an alkyl group having 1 to 4 carbon atoms, at 60 to 90°C in the pre-sence of an alkali me-tal alkoxide, and the obtained benzyl isomer of the formula II, (II) wherein R is as stated above, is reacted with guanidine in the presence of an alk-anol having 4 to 8 carbon atoms.
(I) through the reaction of an alpha-/3,4,5-trimethoxybenæyl/-beta-/substituted/acryl-onitrile with guanidine, in which an alpha-/3,4,5-trimethoxybenzyl/-beta-methoxy-propionitrile of the formula III
(III) is reacted with a diethylene glycol monoalkyl ether of the formula IV, HO-CH2CH2-O-CH2CH2-OR (IV) wherein R is an alkyl group having 1 to 4 carbon atoms, at 60 to 90°C in the pre-sence of an alkali me-tal alkoxide, and the obtained benzyl isomer of the formula II, (II) wherein R is as stated above, is reacted with guanidine in the presence of an alk-anol having 4 to 8 carbon atoms.
2. A process as claimed in claim 1, in which the diethylene glycol mono-alkyl ether is diethylene glycol monomethyl ether.
3. A process as claimed in claim 1, in which the alkali metal alkoxide is sodium methoxide.
4. A process as claimed in claim 1, in which the diethylene glycol mono-alkyl ether is diethylene glycol monomethyl ether and the alkali metal alkoxide is sodium methoxide.
5. A process as claimed in claim 1, 2 or 3, in which the reaction of the alpha-/3,4,5-trimethoxybenzyl/-beta-methoxypropionitrile of the formula III with the diethylene glycol monomethyl ether is performed at 70 to 80°C.
6. A process as claimed in claim 1 or 4, in which the reaction mixture containing the benzyl isomer of formula II is reacted with guanidine without iso-lation of the benzyl isomer of formula II.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1868/81 | 1981-06-26 | ||
| 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 (1)
| Publication Number | Publication Date |
|---|---|
| CA1164458A true CA1164458A (en) | 1984-03-27 |
Family
ID=10956590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000405973A Expired CA1164458A (en) | 1981-06-26 | 1982-06-25 | 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 GB GB08218309A patent/GB2106098B/en not_active Expired
- 1982-06-24 IT IT22034/82A patent/IT1190888B/en active
- 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 IL IL66131A patent/IL66131A/en unknown
- 1982-06-24 GR GR68559A patent/GR76158B/el unknown
- 1982-06-24 DD DD82241053A patent/DD202702A5/en not_active IP Right Cessation
- 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 RO RO107980A patent/RO85316B/en unknown
- 1982-06-25 CH CH3907/82A patent/CH651828A5/en not_active IP Right Cessation
- 1982-06-25 YU YU1384/82A patent/YU42264B/en unknown
- 1982-06-25 IE IE1521/82A patent/IE53347B1/en not_active IP Right Cessation
- 1982-06-25 FR FR8211150A patent/FR2508449B1/en not_active Expired
- 1982-06-25 AU AU85345/82A patent/AU547822B2/en not_active Ceased
- 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 JP JP57109646A patent/JPS5838265A/en active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3341541A (en) | Processes and intermediates for pyrimidine derivatives | |
| RU2017736C1 (en) | 5,6-dihydro-2-(substituted phenyl)-1,2,4-triazine-3,5-(2h,4h)-diones showing anticoxidial and coxidiostatic activity | |
| US4670559A (en) | 2-amino-4-cyclopropyl-1,3,5-triazines as intermediates for the production of herbicidally active N-(cyclopropyl-triazinyl)-N'-arylsulfonyl ureas | |
| US5166358A (en) | Process for 1-phenyl-imidazoline-2,5-diones | |
| JPS6383079A (en) | Manufacture of 2-chloro-5-chloromethlthiazole | |
| FR2492383A1 (en) | SPIRO-QUATERNARY AMMONIUM HALIDES, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN PROCESS FOR PRODUCING N- (2-PYRIMIDINYL) PIPERAZINYL-ALKYLAZOSPIRO-ALKANEDIONES | |
| MC894A1 (en) | Benzil-pyrimidines and their preparations | |
| JPWO1993002046A1 (en) | Nitrile manufacturing method | |
| EP0079447B1 (en) | Deazapurine derivatives | |
| CA1164458A (en) | Process for the preparation of 2,4-diamino-5-(3',4', 5'-trimethoxybenzyl)pyrimidine | |
| JP5289331B2 (en) | Synthesis of 4-amino-pyrimidine | |
| CA1091673A (en) | Diamino-benzylpyrimidines | |
| ES2188816T5 (en) | PROCEDURE TO PREPARE 4,6-DIHYDROXIPIRIMIDINE. | |
| US4143227A (en) | Process for substituted 5-benzyl-2,4-diamino-pyrimidines | |
| KR100697737B1 (en) | Method for preparing 5-[(4-chlorophenyl) methyl] -2,2-dimethylcyclopentanone | |
| US3018305A (en) | Alpha-phenylben-zoyl-alpha-arylaminocarbinol derivatives | |
| US4658035A (en) | Preparation of 2-alkyl-4,5-dihydroxymethylimidazoles | |
| US5543541A (en) | Method of preparing aryl triazolinones with trialkyl orthoacetates | |
| RU2089539C1 (en) | Method of preparing 2,5-n,n′-(dimethylaminomethyl)-1-4- hydroquinone | |
| Mustafa et al. | Trifluoropyruvic acid hydrate in heterocyclic synthesis: a facile synthesis of 5-hydroxy-5-trifluoromethylhydantoin derivatives | |
| GB1579859A (en) | Process for the production of 2,4-diamino-5-benzylpyrimidines | |
| EP0067593A1 (en) | Process for the preparation of trimethoprim and novel intermediates for use therein | |
| FI76790B (en) | FORM OF FRAMSTAELLNING AV 2,4-DIAMINO-5- (3 ', 4', 5'-TRIMETOXYBENYL) PYRIMIDINE. | |
| US4786736A (en) | Preparation of diaziridines and products therefrom | |
| US4789743A (en) | Process for the preparation of 2,4-diamino-5-benzylpyrimidines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |