EP1005457A1 - Preparation of pyridine derivatives - Google Patents
Preparation of pyridine derivativesInfo
- Publication number
- EP1005457A1 EP1005457A1 EP98940348A EP98940348A EP1005457A1 EP 1005457 A1 EP1005457 A1 EP 1005457A1 EP 98940348 A EP98940348 A EP 98940348A EP 98940348 A EP98940348 A EP 98940348A EP 1005457 A1 EP1005457 A1 EP 1005457A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- process according
- carried out
- preparation
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/89—Heterocyclic 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 with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/04—Heterocyclic 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
- C07D213/60—Heterocyclic 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/04—Heterocyclic 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
- C07D213/60—Heterocyclic 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
Definitions
- EP103553-A is concerned with the preparation of a particular pyridine intermediate, 4-methoxy-3,5-lutidine-N-oxide.
- the process for the preparation of this intermediate involves nitration of 3,5-lutidine-N-oxide in the 4-position followed by substitution of the nitro group by a methoxy group. It is stated that it is an advantage to prepare this intermediate by processing both the nitration and the substitution step without isolation of the intermediate nitro-pyridine.
- R is NO,, Cl. Br or OH.
- R is H or HOCH
- R is HOCH 2 .
- Compound IV may be used as an intermediate in the preparation of omeprazole according to reaction schemes illustrated in Figures 1 to 3 of the accompanying drawings. Pyridine derivative IX is reacted with a benzimadazole derivative to form omeprazole as disclosed in EP5129-A.
Abstract
The invention provides pyridine derivatives used for in the preparation of materials having pharmaceutical applications, having formula (I) where R1 is NO2, C1, Br or OH, R2 is H or HOCH2, R3 is HOCH2, ClCH2 or Br CH2, or the N-oxide of the compound of formula (I) in the case where R2 is H and R3 is HOCH2, provided that where R1 is OH, then R2 is H and R3 is C1 CH2 or Br CH2. A process for the preparation of compounds of formula (I) is also disclosed.
Description
PREPARATION OF PYRIDINE DERIVATIVES
FIELD OF THE INVENTION
This invention is concerned with pyridine derivatives, and their methods of preparation. The pyridine derivatives of the present invention are useful in the preparation of materials having pharmaceutical applications.
By way of example, a material which may be prepared from one of the pyridine derivatives of the present invention is omeprazole which is used as a gastric acid secretion inhibiting drug and can also provide gastro intestinal cytoprotective effects in mammals and animals. Reference will be made below to other materials which can be prepared from the pyridine derivatives of the present invention.
EP103553-A is concerned with the preparation of a particular pyridine intermediate, 4-methoxy-3,5-lutidine-N-oxide. The process for the preparation of this intermediate involves nitration of 3,5-lutidine-N-oxide in the 4-position followed by substitution of the nitro group by a methoxy group. It is stated that it is an advantage to prepare this intermediate by processing both the nitration and the substitution step without isolation of the intermediate nitro-pyridine.
According to the process described in EP103553-A, two consecutive reactions are performed on the pyridine nucleus at the 4-position. To produce the pyridine derivative required to react with the benzimidazole derivative, further reactions are then performed on the pyridine nucleus at the 1-and 2-positions.
STATEMENTS OF INVENTION
It has now been surprisingly found that other pyridine derivatives can be used in the preparation of omeprazole and other pharmaceuticals as a result of a process involving the subjection of 3,5-lutidine-N-oxide to reaction sequence involving nitration followed by alkoxylation at the 4-position but in which these 4-position reactions are not carried out consecutively.
According to the present invention there is provided a compound of the formula
where R, is NO,, Cl. Br or OH. R, is H or HOCH,, R, is HOCH2. C1CH2 or Br CH,, or the N-oxide of the compound of formula I in the case where R, is H and R3 is HOCH2, provided that where R, is OH. then R, is H and R, is Cl CH, or Br CH,.
Preferably R, is NO,. In one alternative R, is then preferably H and R3 is HOCH, or the N-oxide thereof. In another preferred alternative R, and R-, are both HOCH,.
The present invention also provides a process for the preparation of a compound of formula I comprising subjecting a compound of the formula
to alkylation or arylation of the N-oxygen atom and nitration or halogenation at the 4-position of the pyridine ring to produce a compound of the formula
where R, is as defined above, R4 is alkyl or aryl and A" is a suitable counter ion, subjecting the compound of formula III to hydroxymethylation to produce compounds of the formula
and. optionally, subjecting the compound of formula IV to alkoxylation at the 4- position, halogenation of the hydroxymethyl group and hydroxylation at the 4- positon to produce a compound of the formula
C H
where Hal is Cl or Br.
Preferably R4 is C,-C6 alkyl or benzyl. More preferably R4 is methyl or ethyl and the alkylation is carried out by means of dimethyl sulphate or diethyl sulphate. Optionally this step is carried out in the presence of a solvent such as dichloromethane.
In the case where, in the conversion of compound II to compound III. nitration is effected at the 4-position of the pyridine ring, then this may be carried out by means of, for instance, nitric acid or a nitric acid/sulphuric acid mixture. For instance, the nitric acid may be concentrated nitric acid used together with concentrated sulphuric acid.
Where halogenation is effected at the 4-position of the pyridine ring, this may be carried out by means of bromine or chlorine used in elemental form or generated in situ. For instance, bromine may be added to the substrate dissolved in a solvent such as carbon tetrachloride.
The compound of formula II may be prepared by oxidation of a compound of the formula
This oxidation may be carried out by, for instance, hydrogen peroxide. The compound of formula II may be dissolved in. for instance, acetic acid and the hydrogen peroxide added to the resulting solution. Alternatively, it may be oxidised without solvent, under catalytic conditions. This approach allows removal of small amounts of unreacted lutidine by distillation during water removal.
The mixture of compounds IV, V and VI may be formed by subjecting the compound of formula III to hydroxymethylation using, for instance, methanol together with a radical initiator. The radical initiator may be, for instance, ammonium persulphate or benzoyl peroxide.
Depending on the reaction conditions used, the proportion of each of compounds IV. V and VI in the product mixture may vary. Any one or more of the compounds IV, V and VI may be isolated from the product mixture.
Compound IV may be used as an intermediate in the preparation of omeprazole according to reaction schemes illustrated in Figures 1 to 3 of the accompanying drawings. Pyridine derivative IX is reacted with a benzimadazole derivative to form omeprazole as disclosed in EP5129-A.
Compound V may be used in the preparation of aza-sugars having a variety of biological activities.
Compound IV and VI may be converted to compounds such as 2-chloromethyl-4- hydroxy-3,5-butidine hydrochloride which in turn may be used to prepare omeprazole derivatives in which the 4-pyridine position is substituted by groups such as benzyloxy and aryloxy.
The compound of formula IV may be reacted further by subjecting it to alkoxy lation at the 4-position. Preferably the alkoxylation is methoxylation by, for instance, a methoxide such as sodium methoxide to form a compound of the formula
The sodium methoxide may be prepared by adding sodium to methanol and may be added to the substrate dissolved in a solvent such as dimethylformamide, the latter promoting the reaction. In addition the reaction may be catalysed by a catalyst such as copper bromide.
Where the group in the 4-position is NO,, then this group may be made more susceptible to substitution by an alkoxy group by activating the 4-position of the pyridine. Preferably, activation may be carried out by quaternisation with appropriate activating agents. Examples of such agents are acrylamide, acrylic esters and chloropropionic acid esters.
The halogenation of the hydroxymethyl group of compound IX may be carried out by means of, for instance, a chlorinating agent such as thionyl chloride or oxalyl chloride to form a compound of the formula
or a salt thereof.
The thionyl chloride may be added to the substrate which is dissolved in a solvent such as dry toluene.
The 4-alkoxy group may be converted to a hydroxyl group by any suitable method including, for instance, subjecting the 4-alkoxy compound to prolonged refluxing in a solvent such as toluene.
It should be appreciated that references to a compound in this specification, including the claims, are intended to refer, where appropriate, to a corresponding salt of that compound.
EMBODIMENTS OF THE PRESENT INVENTION
The preparation of various compounds of use in the present invention will now be described by way of examples only:
1. Synthesis of 3,5-lutidine-N-oxide 34% Hydrogen peroxide (2312.5g, 21.1.mol) was added slowly to a slurry of 3,5 lutidine (1983.2g, 18.5 mol) and ammonium molybdenum oxide (37. Og, 1.8%w/w) whilst maintaining the temperature of the reaction mixture between 70-80°C. The reaction was followed by GC until <4%w/w of 3,5-lutidine was detected. The reaction mixture was then heated under reduced pressure to remove the untreated 3,5- lutidine and water from the product. The product was then either transferred hot to a suitable container to give catalyst contaminated product (2096.8g, 90.5% yield) or was charged to toluene (16-18 kg) and the precipitated catalyst slurried with dicalite (21.0g, l%w/w). The insoluble material was then filtered and the solvent removed in vacuo to yield a pale yellow-orange product. Recrystallisation from toluene gave white microcrystals of 3,5-lutidine-N-oxide (m.p 104.5 °C, 98.8% area by GC, 0.05%w/wash).
2. Methylation of 3,5-Lutidine-N-Oxide
3,5-Lutidine-N-oxide (4) (15g, 0.12 mol) was heated in a 250ml 2-necked round bottom flask to 95°C, at which temperature the solid began to melt. The resulting liquid was carefully stirred and dimethyl sulphate (15.2g, 0.12 mol) was added dropwise from a dropping funnel over a 30 minute period. The mixture was then heated at 100°C for 3 hours, to yield a dark brown oil which solidified on cooling.
The crude product was recrystallised from acetone as a white crystalline solid which was identified by 'H-NMR analysis as being the N-methoxyammonium salt (8).
Crude yield
Purified yield = 23. lg
% yield = 77% δH (500MHZ, DMSO-D6) 2.51 (6H.s. 2x - CH- .3.38 (3H. s. S04CH?) 4.42 (3H. S. NOCH3), 8.35 (ih, S, 4-h) and 9.22 (2H. s. 2-H. 6-H).
Mpt (from acetone) 11 1°C. m/z (%) 138 (M - SO4Me 6%), 123 (96%). 95 ( 100%)
3. Synthesis of 4-Nitro-3,5-Lutidine-N-Oxide 3,5-Lutidine-N-Oxide (4) (20g, 0.16 mol), dissolved in cone sulphuric acid (20 ml), was added to a 250 ml 3-necked round bottom flask equipped with reflux condenser and dropping funnel. This reaction mixture was cooled to 0°C in an ice bath to which concentrated nitric acid (10ml) was added dropwise with stirring over a 30 minute period. The clear solution was then heated to 90°C and stirred for 16 hours during which time a brown gas was generated. On cooling, the pH of the solution was adjusted to 10 by addition of sodium hydroxide solution (10M, 100ml). Acetonitrule (80ml) was then added and the mixture stirred for 30 minutes. The orange organic layer was separated and concentrated under vacuum to yield an orange solid. 'H-NMR analysis indicated that the nitration had taken place primarily at the para-position (95%) with a small amount of the ortho isomer also being formed
(5%). The crude product was recrystallised from CH2CI,/hexane yielding the purified para-isomer as a single compound in the form of a pale yellow solid. Crude yield = 25. Og Purified yield = 21.5g (of4-nitro-3,5-lutidine-N-oxide % yield = 79% δH (500MHZ, CDCI3) 2.32 (6H.s, 2x - CH,),7.99 (2H. s. 2-H. 6-H) m/z (%) 168 (W. 100%)
4. Synthesis of 4-Bromo-3,5-Lutidine-N-Oxide
To a solution of 3,5-lutidine-N-oxide (lO.Og, 0.08 mol) dissolved in dry carbon tetrachloride (150ml) in a 250ml round bottom flask, was added bromine (26. Og, 0.16 mol) and anhydrous potassium carbonate (22.4g, O. lόmol . This mixture was refluxed for 3 hours and then filtered. The solvent was removed under vacuum to yield a sticky orange solid. 'H-NMR analysis indicated that a 9:1 ratio of para to ortho brominated products had been formed. These isomers were separated and purified by flash chromatography (CHC1, - 5% C OH/CHCl-,)
Crude yield = 21.5g
Purified yield = 11.8g (of 4-bromo-3,5-lutιdine-N-oxide % yield = 72%
4-bromo isomer : δH (500MHz. CDCI3) 2.37 (6H, s, 2 x - CH3), 8.05 (2H, s, 2-H. 6-H) m/z (%) 203 (M"+2, 94%),201 (M+, 100%), 123 (M+-Br, 60%). vmax (KBr) 1240cm"1 (N-O). 2-Bromo isomer : δH (500MHz. CDC1 2.33 (3H, s, -CH,), 2.46 (3H, s, -CH3), 7.18 (1H, s. 4-H) and
8.38 (1H. s, 6-H) m/z (%) 203 (M+2, 98%), 201 (M+, 100%), 123 (M+ - Br, 10%).
5. Methylation of 4-Nitro-3,5-Lutidine - N-Oxide
4-Nitro-3,5-lutidine-N-oxide (lO.Og, 0.06 mol) was dissolved in dry dichloromethane (100ml) in a 250ml 2-necked round bottom flask equipped with reflux condenser and
drying tube. The solution was refluxed and dimethyl sulphate (7.5g, 0.06 mol) was added dropwise from a dropping funnel over a period of 15 minutes. After refluxing for 3 hours, the reaction mixture was cooled and a white solid crystallised out of the solution. Η-NMR analysis showed that this solid was the required N- methoxyammonium salt.
Yield = 17.3 g
% yield = 89% δH (500MHz. CDC13) 2.57 (6H. s. 2 x - CH,). 3.63 (3H. s. -SO4CH3), 4.62 (3H. s. N- OCH,) and 9.51 (2H. s. 2-H. 6-H)
m/z (%) 183 (Mτ-SO4Me. 10%), 168 ( 100%).
6. Methylation of 4-Bromo-3,5-Lutidine-N-Oxide
4-Bromo-3.5-lutidine-N-oxide (10. Og, 0.05 mol) was dissolved in dry dichloromethane ( 100ml) in a 2-necked round flask equipped with reflux condenser and drying tube. The solution was refluxed and dimethyl sulphate (6.3g, 0.05 mol) was added dropwise from a dropping funnel over a 15 minute period followed by refluxing for 3 hours. On cooling, the solvent was removed under vacuum to yield a light purple solid which was recrystallised from acetone as a white solid. 'H-NMR analysis indicated that the methoxy salt had been formed. Crude yield = 19.4g Purified yield = 12.7g % yield = 78% δH (500MHz. DMSO-d6) 2.65 (6H, s, 2 x - CH3), 3.72 (3H, s. -SO4CH3), 4.51 (3H. s, NOCH3), and 9.09 (2H. s. 2-H, 6-H).
m/z (%) 218 ((M+2)-SO4Me. 8%), 216 (NT - SO4Me, 14%), 201 (100%).
7. Synthesis of 2-HydroxymethyI-4-Nitro-3,5-Lutidine and other compounds
The methoxy salt (lOg, 0.03mol) was dissolved in methanol (150ml) in a 2-necked round bottom flask and heated to reflux. Ammonium persulphate (7.8g, 0.03mol)
dissolved in water (10ml) was added dropwise over a period for 1 hour. The reaction mixture was then stirred at room temperature overnight. The pH of the resulting solution (1.0) was adjusted to 10 by dropwise addition of sodium hydroxide solution (10M, 25ml). The methanol was removed under vacuum and the residual aqueous solution was extracted with dichloromethane (3 x 80ml). The combined organic extracts were dried (MgSO4) and concentrated to yield an orange oil.
'H-NMR analysis showed that a mixture of products had been formed along with the desired title compound. Separation and purification of these compounds was carried out by flash chromatography (CHC1, - 5% CH,OH/CHCl,).
These products, which were identified by 'H-NMR. MS. GC-MS and IR spectral data, are listed in order of increasing polarity:
4-nitro-3.5-lutidine 2-hydroxymethyl-4-nitro-3.5-lutidine. 2-hydroxymethyl-4-nitro- 3.5-lutidine-N-oxide. 4-nitro-3.5-lutidine-N-oxide and 2.6-dihydroxymethyl-4-nitro-
3.5-lutidine-N-oxide.
Crude yield = 7.1 g
Purified yield = 32g (of 2-hydroxymethyl-4-nιtro-3.5-lutidine)
% yield = 55% δH (500MHz, CDC7) 2.16 (3H, s,-CH,), 2.30 (3H. s. CH,), 4.73 (2H, s, CH,OH) and 8.42 (1H, s. 6-H) m/z (%) 183 (IVT, 100%, 165 (M+-H2O, 90%) 153 (84%), 107 (76%).
4-nitro-3,5-lutidine: δH (500MHz. CDCI3) 8.50 (2H, s. 2-H, 6-H) and 2.38 (6H, s. 2 x - CH3).
2-hydroxymethyl-4-nitro-3.5-lutidine-N-oxide: δH (500MHz, CDCI3) 2.29 (6H, s, 2 x -CH,), 4.84 (2H, s. CH.OH) and 8.10 (1H, s.
6-H) m/z (%) 198 (M\ 10%), 135 (100%)
4-nitro-3 ,5 -lutidine-N-oxide :
'H-NMR spectral data as previously detailed
2, 6-dihydroxymethyl-4-nitro-3 ,5-lutidine-N-oxide:
δH (500MHz, CDCl,) 2.16 (6H, s, 2x-CH,) 4.84) (4H, S, 2xCH,OH) vmax (neat)/cm-' 1230 (N-O).
Variation of the reaction conditions can have a marked effect on the relative yields of the various products of the reaction. For instance, a reaction carried out on 0.5g methoxy salt using 50ml MeOH and a, 2M excess of persulphate in water give yields of 67%, 9% and zero for 2-hydroxymethyl-4-nitro-3.5-lutidine. 2-hydroxymethyl-4- nitro-3.5-lutidine-N-oxide and 2.6-dihydroxymethyl-4-nitro-3.5-lutidine whereas a reaction carried out on 5g methoxy sale using 100ml of 1 : 1 MeOH/H,0 with persulphate added first gave yields of 64%. 2% and 19% of the same compounds (in the same order).
8. Synthesis of 2-Hydroxymethyl-4-bromo-3,5-Lutidine
The N-methoxyammonium salt (9g. 0.027mol) was dissolved in methanol (150ml) in a 2-necked round bottom flask and heated to reflux. Ammonium persulphate (6.3g, 0.027mol) dissolved in water (8ml) was added dropwise over a period of 1 hour. The reaction mixture was then stirred at room temperature overnight. The pH of the resulting solution (1.0) was adjusted to 10 by dropwise addition of sodium hydroxide solution (10M. 20ml). The methanol was removed under vacuum and the residual aqueous solution was extracted with dichloromethane (3 x 80ml). The combined organic extracts were dried (MgSO4) and concentrated to yield an orange oil.
'H-NMR analysis showed that a mixture of products had been formed along with the desired title compound. Separation and purification of these compounds was carried out by flask chromatography (CHC13 - 5% CH,OH CHCl,). The title compound was however obtained in a slightly impure form due the presence of an impurity which could not be removed by chromato graphic methods.
Crude yield = 61 g
Purified yield = 3.3g (of 2-hydroxymethyl-4-bromo-3, 5 -lutidine
% yield = 55%
δH (500MHz. CDCl,) 2.19 (3H, s,-CH3), 2.33 (3H, s, -CH3), 4.64 (2H, s, CH2OH), and 8.17 (1H, s, 6-H).
9. Synthesis of 2-Hydroxymethyl-4-methoxy-3,5-Lutidine
2-Hydroxymethyl-4-nitro-3, 5 -lutidine (9.0g, 49mmol), dissolved in dry DMF (30ml), was added dropwise to a refluxing solution of freshly prepared sodium methoxide (5.3, 98mmol) sodium in methanol) in dry DMF (150ml) with a trace of copper (1) bromide as catalyst. This reaction mixture was refluxed overnight, cooled and the solvent removed under vacuum to yield a brown solid. This crude product was stirred with dichloromethane and activated charcoal for 30 min. This mixture was then filtered and concentrated to yield a crude brown oil. 'H-NMR analysis of this product indicates that the nucleophilic substitution had taken place.
The product was purified by flash chromatography (CHC13 - 5% MeOH/CHCl,) as an off white solid.
Crude yield = 4.4g
Purified yield = 1.3g
% yield = 16% δH (500MHz. CDCI3) 2.1 1 (3H, s,-CH3), 2.26 (3H, s, CH,), 3.77 (3H, s. OCH3), 4.63 (2H, s, CH,OH) and 8.201 (1H, s, 6-H).
10. Synthesis of 2-Hydroxymethyl-4-methoxy-3,5-Lutidine
2-Hydroxymethyl-4-bromo-3,5-lutidine (3.3g, 15mmol), dissolved in dry DMF (15ml), was added dropwise to a refluxing solution of freshly prepared sodium methoxide (1.6g, 30mmol) (sodium in methanol) in dry DMF (100ml) with a trace of copper (1) bromide as catalyst. This reaction mixture was refluxed overnight, cooled and the solvent removed under vacuum to yield a brown solid. This crude product was stirred with dichloromethane and activated charcoal for 30 min. This mixture was then filtered and concentrated to yield a crude brown oil. Η-NMR analysis of this product indicates that the nucleophilic substitution had taken place.
The product was purified by flash chromatography (CHC13 - 5% MeOH/CHCl3) as an off white solid.
Crude yield = 2.1g
Purified yield = l.lg % yield = 44% δH (500MHz, CDC13) 2.11 (3H, s,CH3), 2.26 (3H, s, CH3), 3.77 (3H, s, OCH3), 4.63 (2H, s, CH2OH) and 8.201 (1H. s, 6-H).
11. Synthesis of 2-Chloromethyl-4-methoxy-3,5-lutidine hydrochloride 2-Hydroxymethyl-4-methoxy-3.5-lutidine (1.3g, 7.7mmol) was dissolved in dry toluene (50ml) in a 100ml 3 necked round bottom flask under a flow of dry nitrogen. To this solution was added thionyl chloride (0.67ml, 9.24mmol) which immediately resulted in the formation of a white precipitate. This mixture was then stirred for 1.5 hours and a white solid was filtered off. 'H-NMR analysis showed that the title compound had been formed but there were also some impurities present.
The required compound was purified and isolated as a white solid by flask chromatography (3% MeOH/CHCl,).
Crude yield = 1.6g Purified yield = l.lg
% yield = 76% δH (500MHz, CDCI3) 2.45 (3H, s,-CH,), 2.46 (3H, s, CH3), 4.09 (3H, s, OCH3), 5.10 (2H, s, CH2OH) and 8.35 (1H, s, 6-H).
12. Formation of 2-chloromethyl-4-hydroxy-3,5-lutidine hydrochloride (4-OH CMML)
2-Chloromethyl-4-methoxy-3,5-lutidine hydrochloride (CMML) (10g) was suspended in toluene (50ml) and refluxed in an oil bath for 18 hr (overnight). The mixture was cooled and the solid was filtered in vacuo, to give a 88% yield of solid.
HPLC analysis of the solid was as follows: 2.216min, 25.47%, unknown; 3.176min, 73.26%, 4-OH CMML; 21.505min, 0.08%, CMML.
4-OH CMML was purified to give a beige solid using the following method. 4-OH CMML (80.2g) was charged to a 500ml flask and IMS (320g) was added. The contents of the flask were heated to 40°C to dissolve the 4-OH CMML. To this solution was charged charcoal (3g) and celite (3g). The slurry was stirred and filtered and the filtrate was added to ethyl acetate (1500g) in a salt ice bath. The solution was stirred to precipitate out tar which adheres to the side of the flask.. The liquor was decanted from the tars and the solvent removed in vacuo. The yield of the 4-OH CMML was 59.3g, 74%.
Claims
A compound of the formula
where R, is NO,, Cl. Br or OH. R2 is H or HOCH,, R, is HOCH,. CICH, or Br CH,, or the N-oxide of the compound of formula I in the case where R, is H and R, is HOCH2, provided that where R, is OH. then R, is H and R, is Cl CH, or Br CH,
2. A compound according to Claim 1 wherein R, is NO,.
3. A compound according to Claim 2 wherein R2 is H and R3 is HOCH, or the
N-oxide thereof.
4. A compound according to Claim 2 wherein R, and R, are HOCH,.
5. A process for the preparation of a compound of formula I in Claim 1 comprising subjecting a compound of the formula
to alkylation or arylation of the N-oxygen atom and nitration or halogenation at the 4-position of the pyridine ring to produce a compound of the formula
OR.t where R, is as defined in Claim 1 , R4 is alkyl or aryl and A- is a suitable counter ion, subjecting the compound of formula III to hydroxymethylation to produce compounds of the formula
and, optionally, subjecting the compound of formula IV to alkoxylation at the 4- position, halogenation of the hydroxymethyl group and hydroxylation at the 4- position to produce a compound of the formula
where Hal is Cl or Br.
6. A process according to Claim 5 wherein R4 is C,-C6 alkyl or benzyl.
7. A process according to Claim 5 or Claim 6 wherein R4 is methyl or ethyl and the alkylation is carried out by means of dimethyl sulphate or diethyl sulphate.
8. A process according to any of Claims 5 to 7 wherein the nitration is carried out by means of nitric acid or a nitric acid/sulphuric acid mixture.
9. A process according to any of Claims 5 to 7 wherein the halogenation is carried out by means of chlorine or bromine which is elemental or generated in situ.
10. A process according to any of Claims 5 to 9 wherein the compound of the formula II is prepared by oxidation of a compound of formula
11. A process according to Claim 10 wherein the oxidation is carried out by means of hydrogen peroxide.
12. A process according to any of Claims 5 to 11 wherein the compounds of formulae IV, V and VI are formed by reaction of the compound of formula III with methanol and a radical initiator.
13. A process according to any of Claims 5 to 12 wherein the compound of formula IV is subjected to alkoxylation carried out by means of a methoxide to form a compound of formula
CMe.
14. A process according to Claim 13 wherein the reaction with methoxide is carried out in the presence of a catalyst.
15. A process according to Claims 13 or Claim 14 wherein said halogenation is chlorination to form a compound of the formula
or a salt thereof.
16. A process according to Claim 15 wherein the chlorinating agent is thionyl chloride or oxalyl chloride.
17. The use of the compound of formula IV, as set out in Claim 5, in the preparation of omeprazole or an omeprazole derivative.
18. The use of the compound of formula V, as set out in Claim 5, in the preparation of an aza sugar.
19. The use of the compound of formula VI, as set out in Claim 5. in the preparation of an omeprazole derivative.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9717849.5A GB9717849D0 (en) | 1997-08-23 | 1997-08-23 | Preparation of pyridene derivatives |
| GB9717849 | 1997-08-23 | ||
| PCT/GB1998/002465 WO1999010326A1 (en) | 1997-08-23 | 1998-08-24 | Preparation of pyridine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1005457A1 true EP1005457A1 (en) | 2000-06-07 |
Family
ID=10817902
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98940348A Withdrawn EP1005457A1 (en) | 1997-08-23 | 1998-08-24 | Preparation of pyridine derivatives |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1005457A1 (en) |
| AU (1) | AU8869098A (en) |
| GB (1) | GB9717849D0 (en) |
| WO (1) | WO1999010326A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245913B1 (en) * | 1999-06-30 | 2001-06-12 | Wockhardt Europe Limited | Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole |
| EA009590B1 (en) | 2001-05-11 | 2008-02-28 | Тиботек Фармасьютикалз Лтд. | Broadspectrum 2-amino-benzoxazole sulfonamide hiv protease inhibitors |
| KR20060070572A (en) | 2003-09-18 | 2006-06-23 | 콘포마 세러퓨틱스 코포레이션 | Novel heterocyclic compounds as hsp90-inhibitors |
| CN104557693B (en) * | 2015-01-16 | 2017-01-04 | 江苏中邦制药有限公司 | A kind of synthetic method of 3,5-Dimethyl-4-nitropyridine-N-oxide |
| CN111303018A (en) * | 2020-03-16 | 2020-06-19 | 浙江华洲药业有限公司 | Synthetic method of omeprazole intermediate |
| CN114805193B (en) * | 2022-04-19 | 2023-06-20 | 南京红太阳医药研究院有限公司 | Preparation method of omeprazole intermediate |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8204879D0 (en) * | 1982-08-26 | 1982-08-26 | Haessle Ab | NOVEL CHEMICAL INTERMEDIATES |
| ES2026761A6 (en) * | 1990-10-31 | 1992-05-01 | Genesis Para La Investigacion | A process for the preparation of omeprazol. |
| ES2035767B1 (en) * | 1991-04-05 | 1994-02-01 | Genesis Para La Investigacion | PROCEDURE FOR OBTAINING 2-HYDROXIMETIL-3,5-DIMETILPIRIDINAS 4-SUBSTITUTED. |
| JP3026238B2 (en) * | 1991-07-17 | 2000-03-27 | 三菱東京製薬株式会社 | Novel 4-methoxy-2- (2-tetrahydropyranyloxymethyl) pyridine compounds, intermediates for producing the same, and methods for producing them |
| JP3029901B2 (en) * | 1991-08-28 | 2000-04-10 | 三菱東京製薬株式会社 | Method for producing 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine by a novel methoxy group introduction method |
| JP3029894B2 (en) * | 1991-09-17 | 2000-04-10 | 三菱東京製薬株式会社 | Method for producing novel 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine, intermediates for producing the same, and methods for producing them |
| JP3158599B2 (en) * | 1992-02-12 | 2001-04-23 | 三菱東京製薬株式会社 | Method for producing novel 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5-b] pyridine, intermediate for producing the same and method for producing the same |
| ES2097089B1 (en) * | 1995-02-01 | 1997-12-16 | Esteve Quimica Sa | PROCEDURE FOR THE PREPARATION OF 2-HYDROXIMETIL-3,5-DIMETIL-4-METOXIPIRIDINA. |
-
1997
- 1997-08-23 GB GBGB9717849.5A patent/GB9717849D0/en not_active Ceased
-
1998
- 1998-08-24 EP EP98940348A patent/EP1005457A1/en not_active Withdrawn
- 1998-08-24 AU AU88690/98A patent/AU8869098A/en not_active Abandoned
- 1998-08-24 WO PCT/GB1998/002465 patent/WO1999010326A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9910326A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999010326A1 (en) | 1999-03-04 |
| AU8869098A (en) | 1999-03-16 |
| GB9717849D0 (en) | 1997-10-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0107866B1 (en) | Trihalomethylpyridine compounds | |
| SG192094A1 (en) | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates | |
| HUE029528T2 (en) | A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and synthetic intermediates thereof | |
| JP2019520305A (en) | Method for producing tyrosine kinase inhibitor and derivative thereof | |
| SK280466B6 (en) | 5,6-disubstituted-3-pyridylmethyl ammonium halide compounds and process for their preparation | |
| EP0246669B1 (en) | Halopyridones | |
| WO2006035459A1 (en) | An improved process for the production of derivatives of thiozolidinediones and their precursors | |
| EP1005457A1 (en) | Preparation of pyridine derivatives | |
| US4260766A (en) | Preparation of (dichloromethyl) pyridines by reductive dechlorination | |
| RU2090558C1 (en) | 5,6-disubstituted 3-pyridylmethylammonium halogenides, method of their synthesis and methods of synthesis 5-(substituted methyl)-2,3-pyridine carboxylic acids | |
| KR0143987B1 (en) | Process for the preparation of 2-chloro-5-chloromethyl-pyridine and new intermediates | |
| JP3145822B2 (en) | Method for producing 5-substituted 2-chloropyridines | |
| US6271418B1 (en) | Process for preparing (hetero) aromatic substituted benzene derivatives | |
| JP2771994B2 (en) | Method for producing propenoic acid derivative | |
| EP0591624B1 (en) | Process for the preparation of pure 2,5-dichloropyridine and the isolation of 2,3-dichloropyridine which is formed as a by-product | |
| US5726315A (en) | Certain 3-hydroxy-6-hydroxymethyl-pyridine intermediates | |
| HU199798B (en) | Process for producing 2-substituted-5-methyl-pyridine derivatives | |
| JPS6343389B2 (en) | ||
| EP0894784B1 (en) | 4-fluorosalicylic acid derivatives and process for producing the same | |
| EP0882713B1 (en) | Process for preparing halogenopyridine derivatives | |
| US4973736A (en) | Diethers of m- or p-hydroxyphenol | |
| CN110483383B (en) | Preparation method of pyridine derivative | |
| EP0016978B1 (en) | Process for preparing nitriles | |
| JP3346011B2 (en) | Method for producing pyridines having chlorine atom at α-position | |
| US6197962B1 (en) | Method for producing 2-sulfonylpyridine derivatives and method for producing 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20000316 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20020301 |