CA2168939A1 - Synthesis of pharmaceutically useful pyridine derivatives - Google Patents

Synthesis of pharmaceutically useful pyridine derivatives

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Publication number
CA2168939A1
CA2168939A1 CA 2168939 CA2168939A CA2168939A1 CA 2168939 A1 CA2168939 A1 CA 2168939A1 CA 2168939 CA2168939 CA 2168939 CA 2168939 A CA2168939 A CA 2168939A CA 2168939 A1 CA2168939 A1 CA 2168939A1
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Canada
Prior art keywords
group
alkyl
acid esters
cyano
carboxyl acid
Prior art date
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Abandoned
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CA 2168939
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French (fr)
Inventor
Michel Bekhazi
Michel Zoghbi
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PDI Research Laboratories Inc
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PDI Research Laboratories Inc
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Priority to CA 2168939 priority Critical patent/CA2168939A1/en
Priority to PCT/CA1997/000081 priority patent/WO1997029103A2/en
Priority to AU15383/97A priority patent/AU1538397A/en
Publication of CA2168939A1 publication Critical patent/CA2168939A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
    • C07C329/02—Monothiocarbonic acids; Derivatives thereof
    • C07C329/04—Esters of monothiocarbonic acids
    • C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D211/86—Oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/28—Sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process is provided of reacting:

(see fig.I) (see fig.II) (see fig.III) (see fig.IV) wherein R, R1, R2, R3 and X are selected from:

(see fig.V)

Description

-TITLE OF INVENTION
Synthesis of Pharmaceutically Useful Pyridine Derivatives.

FIELD OF INVENTION
This invention relates to the manufacture of Omeprazole, intermediates suitable for the manufacture of Omeprazole and the use thereof to manufacture Omeprazole. This invention in its broadest aspects is directed to the manufacture of medicines such as Omeprazole, Pantoprazole, and Lansoprazole, intermediates suitable for the use to manufacture each of the medicines and the processes using those intermediates to manufacture the medicines.

BACKGROUND OF INVENTION
Omeprazole was discovered by Hassel chemists, and is derived from the oxidation of intermediate 1'.

S--<~ ~OCH3 H3~S--<~ ~OCH3 T - '- 1' O

Intermediates 2' and 3' are coupled to give 1.

~` ~OCH3 IntPnnPAi~tP 2' IntermPtli~tP 3 (See for example Canadian Letters Patent No. 1,127,158) -2- 216g9~,~
-Because the intermediates leading to the pyridine entity were very unstable, Hassel came up with the following starting intermediate, w~ere the oxygen on the nitrogen is eliminated at the stage when X is converted from methyl to hydroxymethyl.

~\~X
o Tn~ , 4 (See Canadian Letters Patent No. 1,234,118) EP 484,265 (Esteve) on the other hand, carried the synthesis with either of chloro or nitro at the 4 position. Once the skeleton was built, Esteveeither substituted at the 4 position with methoxy and then reduced the nitroso or vice-versa.
US 5,374,730 (Torcan) purports to teach the manufacture of 15 Omeprazole free from highly coloured impurities. Torcan achieves that result by making a solid intermediate, that can be crystallized. To this end, Torcan oxidized their substituted thioether and obtained a water soluble crystalline intermediate which upon decarboxylation yielded pure water insoluble Omeprazole.
Applicant is also aware of new and efficient oxidizing agents used for converting the thioether to S=O purportedly taught by recent Takeda (CA
1,263,119) and Hassel's (U.S. 5,386,032) patents.
Applicant has now discovered a novel method for the manufacture of Omeprazole, Pantoprazole and Lansoprazole and related medicines which Applicant believes is efficient and suitable to produce these medicines.
3 21 6~9~
-These methods are to be used to build substituted pyridines (useful pharmaceutical intermediates), which could be used as ~recursors for the synthesis of Omeprazole, Pantoprazole or Lansoprazole and related medicines.
In all the published synthesis covering Omeprazole or 5 Lansoprazole, the appropriately substituted pyridine was reacted with A, B or C
synthons.

R I ~f NH~_OCH3 N A
cB

Applicant believes that the following approach would be highly suitable for use to make pyridines which are intermediates that could be used tomake medicines. Applicant proposes that the following pyridine compound:

x~ ~R2 ~N R3 A' B' 20 could be prepared by the following scheme of reaction (in suitable solvents):
4 2 i 6g~,9~
-Scheme 1:

+ ~;~R R~R3 n ~ III

Rl~R2 R~N~R3 IV

(Intermediate II is available. Intermediate I is generally known and may be prepared using methods known in the literature such as:
1. Lou, J.-D.; Lou, W.-X. Synthesis, 1987, 179 (and references cited therein).2. E. Breitmaier; S. Gassenmann, Chem. Ber., 1971, 104, 665.
3. Kalina, N.N.; Klimko, V.T.; Protopopova, T.-V; Skoldinor, A.P. Z h .
Obshch. Khim. 1962, 32, 2146, C.A., 58, 7825 g.
4. Klimko, V.T.; Protopopova, T.-V.; Smirnova, N.V.; Skoldinov, A.P. Zh.
Obshch. Khim. 1962, 32, 2961.
5. Kalinina, N.N.; Klimko, V.T.; Protopopova; Skoldinov, A.P. J. Gen. Chem.
USSR (Engl. Transl.), 1962, 32, 2116.
6. Klimko, V.T.; Protopopova, N.V.; Smirnova, N.V.; Skoldinov, A.P. J. Gen.
Chem. USSR (Engl. Transl.), 1962, 32, 2913.
7. Wang, Chia-Lin J.; Salvino, J.M., Tetrahedron Lett. 1984, 25(46), 5243-6.
8. Seebach D., Chem. Ber. 1972, 102, 487.

-9. Solladié, G.; Ruiz, P.; Colobert, F.; Carreno, M.C.; Garcia Ruano, J.L.
Synthesis 1991, 1011.
10. Thummel, R.P.; Kohli, D.K. J. Org. Chem. 1977, 42, 2742.
11. Moller, R.; Engel, N.; Steglich, W. Synthesis, 1978, 621.
12. Ullrich, F.-W.; Breitmaier Synthesis, 1983, 641.
13. Menicagli, R.; Malanga, C.; Guidi, M.; Lardicci, L. Tetrahedron, 1987, 43(1), 171 (and rererellces cited therein).
14. Breitmaier, E.; Ullrich, F.W.; Potthoff, B.; Bohme, R.; Bastian, H. Synthesis, 1987, 1 (Ubersicht).
15. Hertenstein, U.; Hunig, S.; Oller, M. Chem. Ber 1980, 113, 3783.
16. Ruegg, R.; Lindlar, H.; Montavon, M.; Saucy, G.; Schaeren, S.F.; Schwieter, U.; Isler, O. Helv. Chim. Acta 1959, 42, 847.
17. Nair, V.; Vietti, D.E.; Cooper, C.S. J. Am. Chem. Soc., 1981, 103, 3030.
18. Gagan, J.M.F.; Lloyd, D. Chem. Comm. 1967, 1043.
19. Weibenfels, M.; Schurig, H.; Huhsam, G. Chem. Ber., 1967, 100, 584.
20. Todoriki, R.; Ono, M.; Tamura, S. Heterocycles, 1986, 24(3), 775.
21. Eskenazi, P.C.; Maitte, P. Bull. Soc. Chim. 1976, 995.
22. Farina, F.; Gomez, M.J.; Martin, M.V. An. Quim. 1974, 70(12), 900-4.
23. Farina, F.; Victory, P. Tetrahedron Lett. 1969, 38, 3219-22.) Intermediates I and II are selected to form A' and B' (the halves of the pyridine molecule). III is converted to the final product IV by oxidation [O].
The substituents R, Rl, R2, R3 and X are chosen having regard to the substituents on the medicines. Thus, the following combinations present themselves:

R R1 R2 R3 X Medicine OCH
H CH3 _~ ~3/ OCH3 Omeprazole HN

- 6 - 2 1 ~
-H H S~ OCH2F OCH3 Pantoprazole H H S--</ ~/OCH3 OCH2CF3 Lansoprazole H

or R may be selected from:
H

Alkyl (1-3C) Carboxyl acid Esters Cyano Rl may be selected from:
H

Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano 20 R3 may be selected from:
Alkoxy Hydroxy 7 2 l 6~3q Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
Compound III is novel and the precursor for the medicines identified above (Omeprazole, Pantoprazole and Lansoprazole).

Compound III may also be an intermediate where R3 is a leaving group such as Halogen (for example chlorine, bromine, fluorine and the like) or a protected oxygen (OP where P is a protecting group). In this regard, intermediate "A"", useful to make the above medicines, may be made from intermediate IIIA where R3 is OP (where P= a protecting group).

The following synthesis based on building intermediate "A"" set out below presents itself:

-X
~H ~, Base ~ ~

P_P~olecting Group mA
IIA

[O]

X X
Rl~R2 chlorinatingRl~R2 RJ~N~ ~ agentRJ~Nl~OH
IVA
A"

(Wherein the process X is eliminated during the reaction(s), X may be added to Intermediate "A" or to the intermediates during the final stages of preparing the 5 medicine by methods known to persons skilled in the art.) Compound IIA may be prepared from the corresponding alcohol and a suitable protecting group (e.g. tetrahydropuranyl, tert-butyldimethyl silyl, etc.). Other protecting groups like esters, carbonates and substituted methyl, 10 ethyl, benzyl or silyl esters can also be used.

Intermediate A" is then used to manufacture one of the three medicines, as follows:

g ~ q3~

R~ + HS~

Rl~ N~

R N

~ N~

wherein R, Rl, R2 and X are defined above in the chart and L is selected from OCH3 and 0CH2F.

Additionally, the pyridine may be built last so that all constituents of the molecules are attached to a skeleton first, and ~hen the pyridine is completed last. For example, the following scheme presents itself. (Synthesis based on building the pyridine last):

-lo- 2168~3~

HS--<' ~L
~R2 TsCl ~R2 H

o~OH Chloride) o + ~S~

VI

~5 ~NH~L

~NH VII

~[o]

~S~

N

wherein R, Rl, R2, X and L are defined as previously.

In another scheme, the Benzimidazole is built last:

2 t 6~39 R2 R2 J' R2 OEt KS OEt ~ S~ (Et is ethyl) ~OH ~OTs ~/ S
V VII

R~ H
H~O
~ I

X R2 ~ OEt X R2 OEt ~/ ~ ~ [] R ~ ~S

R X R IX

H2N ~3~L

Rl~ NH~L
N
R

wherein R, Rl, R2, X and L are as previously described.
Compounds IIA, III, IIIA, VI, VII, VIl[I, IX and X following, are new:

o~P
P=Protecting Group IIA

-12- 21 68~3~
Rl ~R2 R)~N~R3 III

Rl~R2 R N~
H IIIA

o~S~\

VI

Rl~ ~NH~L

NH VII

R2 OEt ~S~s o vm X R2 OEt Rl~/S~`s ~NH
R IX

-13- 2 1 68~39 Rl ~ ~, ~SOEt R N X

R, Rl, R2, R3, and X are as defined above.

The invention will now be illustrated with reference to the following proposed examples.

Example 1:
Synthesis of the chloro pyridine (scheme relating to building intermediate "A") A base (e.g. Potassium t-Butoxide) (1.0 eq) will be added to a cooled solution (-20 to OC) of the protected hydroxy ketone (1.0 eq) in dry tetrahydrofuran (THF). A THF solution of the a"~ unsaturated carbonyl (1.0 eq), would then be added dropwise. At the end of the reaction, ammonium chloride/ammonia (3.0 eq) will be added and the reaction mixture stirred at room temperature. Water may then be added to the mixture and the organic product extracted in toluene. The crude dihydropyridine will then be extracted with an acidic aqueous solution (sulfuric acid).
To the aqueous solution, nitric acid will be added and the mixture heated to reflux until the oxidation is complete. The solution will then be slowly cooled to OC. Crushed ice will then be added followed by ammonium hydroxide until the mixture is alkaline. The solid is then isolated and washed with cold water. The crude product will be recrystallized from alcohol.
Other oxidizing agents could be used to oxidize the dihydropyridine to the pyridine, e.g. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

-The 2-Chloromethyl pyridine "Intermediate A" can be prepared by reacting the 2-hydroxymethylpyridine with thionylchloride (according to Arch.
Pharm. Vol. 26 pp. 448-451 (1956)).

5 Example 2:
Based on the scheme for building the pyridine last.
Tosylchloride (1.0 eq) is added to a solution of the hydroxy ketone (1.0 eq) and base (e.g. triethylamine) (1.0 eq) in a suitable solvent (e.g. toluene, methylene chloride). The mercaptobenzimidazole sodium salt (1.0 eq) will be 10 added to the tosylate solution. At the end of the reaction, the mixture will be washed successively with water, a saturated solution of sodium bicarbonate and brine. The organic extract will be dried over sodium sulfate, filtered and will be rotary evaporated to yield the crude product.

15 Example 3:
Benzimidazole formation (synthesis based on building the imidazole last) Xanthate (1.0 eq) and the tosylate (1.0 eq) will be reacted in a solvent (e.g. ethanol) at reflux. When the reaction is complete, the solvent will be replaced with toluene and the organic layer will be washed with water and brine.20 The toluene is then rotary evaporated, THF will be added, and the solution cooled (-20 to OC).
A base (e.g. Potassium t-Butoxide) (1.0 eq) is added to the cooled solution of the xanthate adduct. A THF solution of the oc,~ unsaturated carbonyl(1.0 eq), is then added dropwise. At the end of the reaction, ammonium 25 chloride/ammonia (3.0 eq) will be added and the reaction mixture stirred at room temperature. Water will be added to the mixture and the organic product extracted in toluene. Toluene will be rotary evaporated and the crude product will be used for the next step.

- 15- ~ 9 ~
-m-Chloroperbenzoic acid (2.0 eq) will be dissolved in chloroform, cooled to OC and added to the cooled chloroform solution (OC) of the dihydropyridine. The mixture will be stirred overnight at room temperature, filtered, and washed with 10% NaHCO3, and dried over sodium sulfate.
Filteration and rotary evaporation afford the crude product.
The crude product and 5-substituted phenylenediamine (1.0 eq) will be dissolved in toluene that contained TFA (1.0 eq). The mixture will be refluxed until the reaction is complete. At the end of the reaction, the mixture will be cooled, 10% NaOH will then be slowly added until the mixture is just alkaline.
The crude benzimidazole will be then filtered, washed with water and recrystallized from alcohol.

Example 4:
Intermediate I which is 3-methoxy, 2-methyl, 2-propenal, where X is methoxy, R1 is methyl and R is hydrogen, may be prepared as follows:
Methanesulfonyl chloride (1 eq.) will be added to a solution of methylmalondialdehyde sodium salt (prepared by a literature procedure involving the Vilsmeier-Haack-Arnold acylation of propionaldehyde diethyl acetal: Nair, V.; Vietti, D.E.; Cooper, C.S. J. Am. Chem. Soc. 1981, 103, 3030-3036) (1 eq.) in a suitable solvent (e.g. methylene chloride, toluene). The mixture will be stirred at room temperature until the reaction is complete. At the end of the reaction, the product will be concentrated on the rotary evaporator and dissolved in anhydrous methanol. The mesylate methanol solution will then be added to a sodium methoxide (1-5 eq.) solution in the same solvent. The mixture will be stirred at room temperature until the reaction is complete. The product will be concentrated on the rotary evaporator, dissolved in methylene chloride (or other suitable solvent, e.g. toluene) and washed consecutively with saturated aqueous ammonium chloride, water, and Z 1 ~ 9 brine. The solution will then be dried over anhydrous sodium sulfate, filtered, and rotary evaporated to yield the crude 3-methoxy, 2-methyl, 2-propenal (I).
Other specific intermediate (I) compounds can be prepared by persons skilled in 5 the art having regard to the articles referred to herein and the above teachings.
As many changes can be made to the invention without departing from the scope of the invention, it is intended that all material herein be inl~l~reled as illustrative of the invention and not in a limiting sense.

Claims (34)

1. A process of reacting:

I II III

IV

wherein R, R1, R2, R3 and X are selected from:

or R may be selected from the group consisting of:

H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
2. The process of:

I II III

wherein R, R1, R2, R3 and X are selected from the following group:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
3. The process of reacting:

III

to produce:

IV

wherein the substituents R, R1, R2, R3 and X are selected as follows:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano Rl may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
4. The process of claim 1 or 3 wherein the medicine Omeprazole is produced.
5. The process of claim 1 or 3 wherein the medicine Pantoprazole is produced.
6. The process of claim 1 or 3 wherein the medicine Lansoprazole is produced.
7. The process of reacting:

Base I P=Protecting Group IIIA
IIA

chlorinating A" agent IVA

wherein R, R1, R2, R3 and X are selected from:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
8. The process of reacting:

+ Base I P=Protecting Group IIIA
IIA

wherein R, R1, R2, R3 and X are selected from:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
9. The process of reacting:
[O] IIIA IVA

wherein R, R1, R2, R3 and X are selected from:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H

Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
10. The process of reacting:

chlorinating A"
agent wherein R, R1, R2, R3 and X are selected from:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
11. The process of reacting:

TsCl + I VI

VII

[O]

wherein R, R1, R2 and X are selected from:

and L is selected from OCH3 and OCH2F.
12. The process of reacting:
TsCl V
VI

wherein R2 is selected from:

To produce the Medicine identified below:
and L is selected from OCH3 and OCH2F.
13. The process of reacting:

+ I VI

VII

wherein R, R1, R2 and X are selected from:

and L is selected from OCH3 and OCH2F.
14. The process of reacting:

VII

[O]

wherein R, R1, R2 and X are selected from:

and L is selected from OCH3 and OCH2F.
15. The process of claim 14 wherein wherein the medicine Omeprazole is produced.
16. The process of claim 14 wherein the medicine Pantoprazole is produced.
17. The process of claim 14 wherein the medicine Lansoprazole is produced.
18. The process of reacting:

VIII

[O] X IX

wherein R, R1, R2 and X are selected from:

and L is selected from OCH3 and OCH2F.
19. The process of reacting:

V VIII

wherein R2 is selected from:

To produce the Medicine identified below:
20. The process of reacting:

VIII

IX

wherein R, R1, R2 and X are selected from:

21. The process of reacting:

[O] IX X

wherein R, R1, R2 and X are selected from:

22. The process of reacting:

X

wherein R, R1, R2 and X are selected from:

and L is selected from OCH3 and OCH2F.
23. The process of claim 18 or 22 wherein the medicine Omeprazole is produced.
24. The process of claim 18 or 22 wherein the medicine Pantoprazole is produced.
25. The process of claim 18 or 22 wherein the medicine Lansoprazole is produced.
26. The product:

III

wherein R, R1, R2, R3 and X are selected from:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R3 may be selected from the group consisting of:
Alkoxy Hydroxy Halogen Activated Ester Tosylate Mesylate Thiol Xanthyl and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
27. The product:

P=Protecting Group IIA

wherein R2 is selected from:

To produce the Medecine identified below:

R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano and P is a protecting group.
28. The product:

IIIA

wherein R, R1, R2 and X are selected from:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H

and P is a protecting group.
29. The product:

wherein Ts is Tosylate and R2 is selected from:

or R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano Thiol Xanthyl
30. The product:

VI

wherein R2 and L are selected from:

or R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano
31. The product:

VII

wherein R, R1, R2, X and L are selected from:

To produce the Medicine identified below:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Carboxyl acid Esters Cyano and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H
32. The product:

VIII

wherein R2 is selected from:

or R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano
33. The product:

IX

wherein R, R1, R2 and X are selected from:

or R may be selected from the group consisting of:

H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano and X may be selected from the group consisting of:

Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H

and Et is ethyl
34. The product:

wherein R, R1, R2 and X are selected from:

or R may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R1 may be selected from the group consisting of:
H
Alkyl (1-3C) Carboxyl acid Esters Cyano R2 may be selected from the group consisting of:
H

Alkyl (1-3C) Carboxyl acid Esters Cyano and X may be selected from the group consisting of:
Alkoxy Halogen Nitro Cyano Carboxyl Alkyl H

and Et is ethyl.
CA 2168939 1996-02-06 1996-02-06 Synthesis of pharmaceutically useful pyridine derivatives Abandoned CA2168939A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA 2168939 CA2168939A1 (en) 1996-02-06 1996-02-06 Synthesis of pharmaceutically useful pyridine derivatives
PCT/CA1997/000081 WO1997029103A2 (en) 1996-02-06 1997-02-05 Synthesis of omeprazole-type pyridine derivatives and intermediates thereof
AU15383/97A AU1538397A (en) 1996-02-06 1997-02-05 Synthesis of omeprazole-type pyridine derivatives and intermediates thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CA 2168939 CA2168939A1 (en) 1996-02-06 1996-02-06 Synthesis of pharmaceutically useful pyridine derivatives

Publications (1)

Publication Number Publication Date
CA2168939A1 true CA2168939A1 (en) 1997-08-07

Family

ID=4157512

Family Applications (1)

Application Number Title Priority Date Filing Date
CA 2168939 Abandoned CA2168939A1 (en) 1996-02-06 1996-02-06 Synthesis of pharmaceutically useful pyridine derivatives

Country Status (1)

Country Link
CA (1) CA2168939A1 (en)

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