CA2002757A1 - Process for the preparation of 3,5-dimethyl-4-methoxy-pyridine derivatives and novel intermediate for said preparation - Google Patents

Process for the preparation of 3,5-dimethyl-4-methoxy-pyridine derivatives and novel intermediate for said preparation

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Publication number
CA2002757A1
CA2002757A1 CA002002757A CA2002757A CA2002757A1 CA 2002757 A1 CA2002757 A1 CA 2002757A1 CA 002002757 A CA002002757 A CA 002002757A CA 2002757 A CA2002757 A CA 2002757A CA 2002757 A1 CA2002757 A1 CA 2002757A1
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Canada
Prior art keywords
methoxy
dimethyl
preparation
give
aminomethylpyridine
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.)
Abandoned
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CA002002757A
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French (fr)
Inventor
Karl Baumann
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Cl Pharma AG
Hafslund Nycomed Pharma AG
Original Assignee
Karl Baumann
Cl Pharma Aktiengesellschaft
Hafslund Nycomed Pharma Aktiengesellschaft
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Filing date
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Application filed by Karl Baumann, Cl Pharma Aktiengesellschaft, Hafslund Nycomed Pharma Aktiengesellschaft filed Critical Karl Baumann
Publication of CA2002757A1 publication Critical patent/CA2002757A1/en
Abandoned legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/63One oxygen atom
    • C07D213/68One oxygen atom attached in position 4

Abstract

Abstract of the Disclosure A process for the preparation of compounds of formula I

I

in which X is the radical OH or Cl, by the catalytic hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine, subsequent reaction of the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine to give 3,5-dimethyl-4 methoxy-2-hydroxymethylpyridine and, if desired, chlorin-ation to give 3,5-dimethyl-4-methoxy-2-chloromethylpyri-dine, and the novel intermediate 3,5-dimethyl- 4-methoxy-2-aminomethylpyridine.

Description

Process ~or th~ preparation o~ 3,5-d~methyl-4-me~hoxy-pyridine derivatives and novel intermedlate for ~aid preparation The inven~ion relates to a novel process fvr the S preparation of 3,5-dimethyl-4-methoxy-2-hydroxymethyl-pyridine or 3,5-dimethyl-4-methoxy-2-chloromethylpyxidine, to th~ novel intermediate, 3,5-dimethyl-4- methoxy-2-amino-methylpyridine, formed in thi~ process and to the use of said intermediate.
3,5-DLmethyl-4-methoxypyridine derivatives are valuable intermediates for the preparation of ATPa~e in-hibitors, as described for instance in US-A 4,255,4~1, US-A 4,337 257 and US-A 4,508905.
US Pate~t US ~ 4,472,409 discloses the preparation of 3,5-dimethyl-4-methoxy-2-hydrox~nethyl-pyridine or 3,5-dimethyl-4-me~hoxy-2-chloromethylpyridine from 2,3,5-trime~hylpyridine, the first step being to react this compound ~ith HzO2 to give the N- oxidet after which this N-oxide is nitrated to give 2,3,S-trimethyl-4-nitro-pyridine N-oxide and the N02 group i~ exchanged for a metho~y group by treatment with sodium methoxide. The 2~3,5-trimethyl-4-methoxypyrldine N-oxide ~onmed is then treated with acetic anhydride, ~he resulking acetyl dexiv~-ative i~ ~aponiied to give 3,5- dlme~hyl-4-methoxy-2-hydroxymethylpyridine and, if desired, ~he latter is reacted wlth thlonyl chloride to give 3,5-dimethyl-4-meth-oxy-2-chloromethylpyridine.
Fur~ r US-A 4,62n,008 ! discloses another process whereby 1,4-dimethoxy-3,5-dLmethylpyri-~dinium methylsulphate i8 obtained first by reacting 3,5-di-methyl-4methoxypyridine N-oxide, prepared as described .
in US - A 4 472 409 with dimethyl-~ulphate, and 3,5-dimethyl-4-methoxy-2- hydroxymethyl-pyridine is then obtained by rearrangement.
Th~ starting compound for ths~e processes, 2,3,5-trimethylpyridine, is obtainable only wi~h difficulty and in poor yield, for instance by reacting 3,5-dLmethylpyri-dine with methyl-lithium at low temperatures.

;21[111:11;2~5~

US - A 4,785,113 di~close~
the preparation of the title compounds from ethyl 2-methyl-acetoacetate by reaction with N~ to give ethyl 3-amino-2-methylcrotonate, ~eaction wlth diethyl monomethylmalcnats S to give 2,3,5-trimethyl-4,6-dihydroxypyridine, chlorination to giv~e 2,4-dichloro-3,5,6-~rimethylpyridine, ~elective cleavage of the 2~Cl sub~tikuent and exchange of the 4-Cl ~ubstituent for a metho~y group, and then oxidation to give the N-oxid~ e subsequent reaction~ are carried out anal.o~ously to the process degcribed in . US-A 4,472l409 In thi~ process, the 2,3,5-trimethyl-4-methoxy-pyridine N-oxide required for the rearrangements to modify the methyl group bonded in the 2-position has to be prepar-ed from aliphatic compounds in a complicated 7-step pro-cs~ss.
It has now been possible to find a ~Lmple proces~
fo~ the preparation of 3,5-dimethyl-4-methoxy-2-hydroxy-meth~lpyridine or 3,5-dLmethyl-4-methoxy-2-chloromethyl-pyridine fxom 3,5-dimethyl-4-methoxy~2-cyanopyridinel which i~ described in Chemical Abstracts, vol. 106, 1020928 (1987).
The invention accordingly relates to a proce~ for the preparation of compounds o for~ula I..

CH3 ~ 51~3 ~ ~ ~ CH2X

~(~0;~75~

in which X is the radical OH or Cl , comprising cakalytical hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine of formula II
OCH~
3 ~ 3 .
, ~ II
N CN

.
in the presence of an lnert diluent, the resulting 3,5-dimethyl~4-methoxy-2-aminomethylpyridine of formula III

3 ~, CH3 . I I . '.

~ N / CH2NH2 III

being then reac~ed with sodlum nltrite ln aqueou~-acldia solu~ n to give 3~5-di~e~hy~ me~hoxy-2-hydroxymothylp~ri~lne and, i.~ de~ired, the la~ter being then reacted wl~h thiollyl chloride to glve 3,5-dimethyl-4-me~hoxy-2-chlormethylpyridine.

: ~The intermediate formed in ~hi3 proce~, 3,5 dimethyl-4-methoxy-2-amLno~ethylpyridine, i8 novel and reprssents a further ~ub~ec~ of the invention. ~
The starting matarial or this process,~ 3,5-dLmethyl-4-methoxy-2-cyanopyxLdine, can be prepared in a :

~W~
- 4 ~
simple manner from 3,5-dLmethylpyridine by oxidation to give 3,5-dimethylpyridine N-oxide, nitr~tion and reaction with dLmethyl ~ulphate to gi~e 1,4-dumethoxy-3,5- dimethyl-pyridinium methylsulphate, treatment with KCN and subse-S quent exchange o~ the nitro group for a methoxy group ~ith sodium methoxide.
In a first step, the cyano group is hydrogenated to the aminomethyl group. The hydrogenation is carried out in the presence of a hydrogenation catalyst and a diluent which is inert under the reaction conditions.
Examples of catalysts which can be used are Raney nickel or Pd on active charcoal. To prevent the formation of the secondary amine, it is preferred to add a base, such as NH3, or an acid, for example a ~ineral acid or toluene-sulphonic acid, up to 2 equivalents being used in the case where an acid i added.
It is preferred to use Raney nickel in cowbination with NH3 or Pd/C in combination with an acid, Raney nickel with NH3 being e~pecially preferred~
Examples of suitable diluents which are inert under the reaction conditions are alcohols, such as methanol or e~hanol, ethers, such a~ dioxane or tetrahydrofuran, or mixtures o~ diluents with water. Mekhansl i~ pref0rably used. Dapending on the other reaction conditiorl~, the hydrogena~ion take~ place a~ about 20 - lOOqC, pre~er~bly a~ room temparature, and under a pres~ure of about 1 to 5 bar, proferably at normal pressure.
When the xeaction iz complete, the catalyst is ~ilterad of~ and the solvent i~ removed in order to isolate the intermediat~ formed in the hydrogena~ion, 3,5~dimethyl-4-methoxy-2-aminome~hylpyridine. The remaining residue can be purified further by conventional methods, for example by vacuum distillation, and cry~tallized.
The reaction of the novel intermediate to give 3,5-dLmethyl-4-methoxy-2-hydroxymethylpyridine i5 carried out by diazotization of the amino group under hydrolyzing conditions.
The reac~ion is carried out in aqueous-acidic solution. Suitable acids are mineral acids or acetic acid.

~;?~7~7 ~ 5 -The acid u~ed is preferably glacial acetic acid. The ratio o~ water to acid can vary within wide limits and is preer-ably about 9:1 to 1:1. The diazotization is carried out ~ith sodium nitrite, it being possible for the sodium nitrite to be used in solid form or in solution. The reaction is carried out in the temperature range from about -20 to 50C, preferably from about -S to 10C.
When the reaction is complete, the aqueous solution is rendered alkaline, the product is extracted with an organic solvent, for example methylene chloride, and the organic phase is dried.
The product is isolated by filtration of the or~anic phase and purified, for example by bulb-tube distillation.
If desired, the 3,5-dimethyl-4-methoxy-2-hydroxy-methylpyridine prepared in this way i5 then reacted with thionyl chloride to give 3,5-dimethyl-4-metho~y-2-chloro-methylpyridine.
The reaction is carried out in the presence of a diluent which is inert under the reaction conditions, for example in dichloroethane, methylene chloride, chloroform, diox~ne or tetrahydrofuran.
Depending on the other reaction conditions, tha reaction is carried out in the temperature r~nge ~ro~ about -30 to 50~C, preerably ~rom about -20 to 0C.
When the reaction is complete, the diluent is evaporated off, the residue i~ dlgested, for example in i-propanol, and 3,5-dimethyl~4-methoxy-2-chloromethyl-pyridine hyd~ochloride is isolated.
The process i~ preferably carried out stsrting from 3,5-dLmethyl-4-methoxy-2-cyanopyridine, but withou~ i501-ation of the intermediates up to 3,5-dimethyl-4- methoxy-2 chloromethylpyridine.
In this process, the catalyst is filtered off after 3S the hydrogenation and the diluent is removed. The residue i~ then taken up in aqueous-acidic solution and the diazot-ization is carried out under hydrolyzing conditions.
The 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine which is present in an organic solvent after the ex~raction 2~i~57 is then reacted with thionyl chloride to give 3,5 ~imethyl-4-methoxy-2-chloromethylpyridine, which is isolated as described above.
The process affords a good total yield. I~ general, yields of 40 - 50% are achieved, based on 3,5- dim~thyl-4-methoxy-2-cyanopyridine.

Example 1:

3,5-Dimethyl~4-methoxy-2-aminomethylpyridin~
A mixture of 20 g of Raney nickel and 20 g of 3,5-dimethyl-4-methoxy-2-cyanopyridine in 650 ml of NH3-saturated methanol, prepared by the passage of dry NH3 gas, was hydrogenated for 3 days at room tempera~ure and normal pressure. After flushing with Ar, the catalyst was fil-tered off and the solvent was removed on a rotary evaporat-or. The remaining violet-coloured liquid residue was purified by bulb-tube distillation.
T: 120C air bath temperature, p: 0~05 bar 13.5 g (65.9~ o~ theory) of the title compound were obtained as a colourless oil.
~H NMR (300 MHz/TMS) (ppm) ~ 1.9~ (sb, 2~, -NHz), 2.21 (3, 3H, -CH3), 2.24 (~, 3H, -CH3j, 3.75 (g, 3~, -OCH3), 3.90 (~, 2H, -CM2), 8.X1 (8, lH, pyr-H) Exampl~ 2:

3,5-Dimethyl-4-methoxy-2-hydroxymethylpyridine A solution of 3.61 g of NaNO2 in 20 ml of H20 was added in portions, at 0C, to a solution of 2.9 g of 3,5-dimethyl-4-methoxy-2-aminomethylpyridine in 50 ml of 10%
aqueous acetic acid and the mixture was stirred for 1 h.
It was then partitioned between 30 ml of 4 N NaO~ and 50 ml of CH2Cl2, the organic phase was ~eparated off and the aqueous phase was extracted again with 3 times 50 ml of CH2Cl~. The combined or~anic phases were dried over Na2SO4/
filtered and evaporated. The bro~n crystalline crude 3s prod~ct was purified by bulb-tube distillation.

.
- ~

~2~57 -- 7 --..

T: 115 - 135C air bath temperaturer p: 0.01 bar 2.57 g (88.3~ of theory) of the title compound were obtained as a colourless oil, which solidifies at room temperature.
lH NMR (300 ~Hz/TMS/CDCl3) ~ppm) = 2.12 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.77 (s, 3H, OCH3~, 4~62 (2, 2H, -CH2~, 4-9 (sb, 1~, -OH), 8.19 (s, lH, pyr-H) ~xample 3:

Preparation of the starting compound, 3,5-dLmethyl-4-meth-oxy 2-cyanopyridine a) 3,5-DLmethylpyridine N-oxide ~ 8 ml of glacial acetic acid were added dropwise, at 2SC~ to 350 g of 3,5-dimethylpyridine. The mixture was heated to 50C and 870.3 g of 40~ peracetic acid ~ere metered in such that the temperature could be képt at 50~C
by cooling. About 1 hour after the addition of the per-acetic acid had ended, the reaction mixture was cooled to 25C and 230 g o~ Na2SO3 in 1 1 o~ water were added drop~
wise, with cooling, AEter the excess peraaetic acid had beQn de5troyed (KI-~tarch te~t), 1330 ml o~ water w~re added, the mixturo wa~ rendered alkaline with 730 ml o~ 50 NaO~ and the solution was extracted .in sevoral portion~
with a total o~ about 4500 ml o~ ahloro~orm. The co~ined organic phases were dried with Na2SO~ and the solvent was evaporated off to about 740 ml.
b) 3,5-D~methyl-~-nitropyridine ~-oxide The solution obtained from a) was added dropwise to 577.5 ml of concentrated sulphuric acid at a tempera~ure of 40C and a pressure o~ about 0.26 bar, the solvent beinq stripped off at the same time. The solution was subse-quently kept at 45~C for 1 h under a ~ater-je~ vacuum and then heated to 70C and 577.5 ml of fuming HNO3 were added dropwise, with cooling, such that the temperature did not exceed 80 - 85C. The mixture was lef~ to cool overnight and added dropwise ~o a mixture of 3 kg of ice and 2 l of water, with cooling. The resultin~ mixture was then , ~ .

. .

~o~

rendered alkaline with about 720 ml of 50~ NaOH and ex-tracted in several portions with about 9 1 o~ chloroform.
The combined organic phases were dried ~ith Na2SO4 and concentrated to about 900 ml, 500 ml of diisopropyl ether S were added at room temperature and the pr~cipikate ~ormed was filtered off and dried to give 427 g (77.7~ of theory) of the ti~le compound. M.p.: 180 - 183C (subl.) c) 1,4-Dimethoxy-3,$-dimethylpyridinium methylsulphate 4050 ml of ethyl acetate, 400 g of the product from b) and 390 g of dLmethyl sulphate were refluxed for 4 h, cooled overnight and extra~ted in several portions with about 1600 ml of water.
d) 3,5-Dimethyl-4-nitro-~-cyanopyridine 464.9 g of KCN were dissolved in 3500 ml of water, the solution was cooled to 5C and 1600 ml vf the aqueous solution from c) were added dropwise, with cooling. About 1 h after the dropwise addition had ended, the precipitate w~s filtered off, washed with water and dried over P2Q5 to give 377.4 g of the title comp4und (89.3% of theory, based on b). M.p.: 66 - 71C 1H NMR (300 MHZ/T~S/CDCl3) (ppm) ~ 2.40 (s, 3H, CH3), 2~53 ~s, 3H, CH3), 8.59 (s, lH, pyr-H) e) 3,5-D~methyl-4-methoxy-2-cyanopyridine 350 g of the product from d~ were dissolvad in 2100 ml o~ methanol, the solutLon wa8 he~ted to the reflux temperature and a ~o~u~ion o~ 391 g of NaOC~3 in lS00 ml o methanol wa~ added dropwi~e. When the reaction wa~ com-plete, 10 g of active charcoal were added, the mixture was cooled to 30C and filtered and the solution was concentra-ted to about l.S l under vacuum. The mixture was poured int~ 7.S l of ice water and the precipitate formed was filtered off w~th suction, washed with water and dried over P205 .
288.4 g of the title compound (90% of theory, based on d) were obtained. M.p.: S9 - 61C
H NMR (300 MHz/TMStCDCl3) ~ppm) = 2.34 (s, 3H, CH3), 2.47 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 8.32 (s, lH, pyr-H) , g Example 4:

3,5-Dimethyl-4-methoxy 2-chloromethylpyridine hydro chloride 20 g of 3,5-dimethyl-4-methoxy-2-cyanopyridine were dissolved in 650 ml of NH3-saturated methanol, 20 g of Raney nic~el were added under an N2 atmosphere and the mixture was hydrogenated. The catalyst was then filtered off and the ~olution w~s evaporated under vacuum.
The residue, consisting of 21.3 g of a violet oil, was dissolved in 100 ml of water and 100 ml of glacial acetic acid, the solution was cooled to 0C and 25.4 g of NaNO2 in 50 ml of water were added drowise, with cooling.
The mixture was then rendered alkaline with 500 ml of 4 N
NaOH and about 30 ml of 50~ NaOH and extracted with 600 ml of CH2Cl2 and the combined organic phases were dried over NazSO4 .
The dried CH2Cl~ solution was cooled to -10C and 50.11 g of SOC12 were added dropwise. The solution wa then evaporated at 45~C under vacuum and the residue was ~tirred with i-propanol and filtered off with suction.
11.25 g (41.07% of theory) of the title compound were obtained.
H NNR ~300 MHz/TMS/CDCl3) (ppm) = 2.46 t~, 3H, CH3), 2.48 (s, 3H, CH3), 4.09 (8 3Hr OCH3), 5~12 ~s, 2H, C~2)~ ~-39 (~ lH, pyr-H) .
.
, ,

Claims (9)

1. A process for the preparation of compounds of formula I

I

in which X is the radical OH or Cl , comprising catalytical hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine of formula II

II

in the presence of an inert diluent, the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine of formula III

III

being then reacted with sodium nitrite in aqueous-acidic solution to give 3,5-dimethyl-4-methoxy-2 hydroxymethylpyridine and, if desired, the latter being then reacted with thionyl chloride to give 3,5-dimethyl-4-methoxy-2-chlormethylpyridine.
2. A process according to claim 1, comprising the catalytic hydrogenation being carried out with Raney nickel or Pd on active charcoal as catalyst.
3. A process according to claim 1 comprising carrying out the catalytic hydrogenation with Raney nickel in combination with NH3 or with Pd on active charcoal in combination with mineral acids or toluence-sulphonic acid.
4. A process according to claim 1 comprising carrying out the catalytic hydrogenation with Raney nickel in combination with NH3.
5. A process according to claim 1, comprising carrying out the hydrogenation in the presence of methanol as the diluent.
6. A process according to claim 1, comprising carrying out the reaction of 3,5-dimethyl-4-methoxy-2-aminomethylpyridine in the presence of water and glacial acetic acid in a ratio of 9:1 to 1:1.
7.A process according to claim 1, comprising recting the intermediates formed in the reaction, 3,5-dimethyl-4-methoxy-2-aminomethylpyridine and 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine without isolation, to give a compound of formula I in which X is the radical Cl.
8. 3,5-Dimethyl-4-methoxy-2 aminomethylpyridine
9. Use of 3,5-dimethyl-4-methoxy-2 aminomethylpyridine for the preparation of 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine and 3,5-dimethyl-4-methoxy-2-chloromethylpyridine.
CA002002757A 1988-11-15 1989-11-10 Process for the preparation of 3,5-dimethyl-4-methoxy-pyridine derivatives and novel intermediate for said preparation Abandoned CA2002757A1 (en)

Applications Claiming Priority (2)

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AT0278988A AT391693B (en) 1988-11-15 1988-11-15 METHOD FOR PRODUCING 3-5-DIMETHYL-4METHOXYPYRIDINE DERIVATIVES AND NEW INTERMEDIATE PRODUCT THEREFOR
ATA2789/88 1988-11-15

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NO894410L (en) 1990-05-16
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HU895899D0 (en) 1990-02-28
DE58903808D1 (en) 1993-04-22
AU4465789A (en) 1990-05-24
JPH02180868A (en) 1990-07-13
IL92152A0 (en) 1990-07-12
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KR900007803A (en) 1990-06-02
US5066810A (en) 1991-11-19
ATA278988A (en) 1990-05-15
PT92307B (en) 1995-07-18
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ATE86978T1 (en) 1993-04-15
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DK568989A (en) 1990-05-16
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IL92152A (en) 1993-05-13
DD284877A5 (en) 1990-11-28
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EP0369208A1 (en) 1990-05-23
CS643889A3 (en) 1992-01-15
SU1745121A3 (en) 1992-06-30
AU628100B2 (en) 1992-09-10
PH25813A (en) 1991-11-05
HU207995B (en) 1993-07-28
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GR3007391T3 (en) 1993-07-30
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