WO1997029103A2 - Synthesis of omeprazole-type pyridine derivatives and intermediates thereof - Google Patents
Synthesis of omeprazole-type pyridine derivatives and intermediates thereof Download PDFInfo
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- WO1997029103A2 WO1997029103A2 PCT/CA1997/000081 CA9700081W WO9729103A2 WO 1997029103 A2 WO1997029103 A2 WO 1997029103A2 CA 9700081 W CA9700081 W CA 9700081W WO 9729103 A2 WO9729103 A2 WO 9729103A2
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- 0 *CC(CON)O Chemical compound *CC(CON)O 0.000 description 2
- WAUOFAUQPRDCLP-UHFFFAOYSA-N CC(c(cc1)cc(N2)c1NC2S(Cc1c(C)c(OC)c(C)cn1)=O)=O Chemical compound CC(c(cc1)cc(N2)c1NC2S(Cc1c(C)c(OC)c(C)cn1)=O)=O WAUOFAUQPRDCLP-UHFFFAOYSA-N 0.000 description 1
- OTZKORDIZPUQRB-UHFFFAOYSA-N Cc(cnc(CSC1Nc(cc(cc2)OC)c2N1)c1C)c1OC Chemical compound Cc(cnc(CSC1Nc(cc(cc2)OC)c2N1)c1C)c1OC OTZKORDIZPUQRB-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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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- 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
Definitions
- 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.
- Omeprazole was discovered by Hassel chemists, and is derived from the oxidation of intermediate 1'.
- Hassel came up with the following starting intermediate, where the oxygen on the nitrogen is eliminated at the stage when X is converted from methyl to hydroxymethyl.
- 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, Esteve either substituted at the 4 position with methoxy and then reduced the nitroso or vice-versa.
- 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.
- 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).
- R may be selected from:
- R 1 may be selected from:
- R 2 may be selected from:
- Cyano R 3 may be selected from:
- X may be selected from:
- Compound III is novel and the precursor for the medicines identified above (Omeprazole, Pantoprazole and Lansoprazole).
- Compound III may also be an intermediate where R 3 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).
- R 3 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).
- Compound IIA may be prepared from the corresponding alcohol and a suitable protecting group (e.g. tetrahydropuranyl, tert-butyldimethyl silyl, etc.).
- a suitable protecting group e.g. tetrahydropuranyl, tert-butyldimethyl silyl, etc.
- Other protecting groups like esters, carbonates and substituted methyl, ethyl, benzyl or silyl esters can also be used.
- Intermediate A is then used to manufacture one of the three medicines, as follows:
- R, R 1 , R 2 and X are defined above in the chart and L is selected from OCH 3 and OCH 2 F.
- the pyridine may be built last so that all constituents of the molecules are attached to a skeleton first, and then the pyridine is completed last.
- the following scheme presents itself. (Synthesis based on building the pyridine last):
- R, R1, R2, R 3 , and X are as defined above.
- a base e.g. Potassium t-Butoxide (1.0 eq) will be added to a cooled solution (-20 to O C) of the protected hydroxy ketone (1.0 eq) in dry tetrahydrofuran (THF).
- THF dry tetrahydrofuran
- ammonium chloride/ammonia 3.0 eq
- the crude dihydropyridine will then be extracted with an acidic aqueous solution (sulfuric acid).
- nitric acid will be added and the mixture heated to reflux until the oxidation is complete.
- the solution will then be slowly cooled to O C. 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.
- oxidizing agents could be used to oxidize the dihydropyridine to the pyridine, e.g. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
- DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
- 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)).
- 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).
- a suitable solvent e.g. toluene, methylene chloride.
- the mercaptobenzimidazole sodium salt (1.0 eq) will be added to the tosylate solution.
- 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.
- Xanthate (1.0 eq) and the tosylate (1.0 eq) will be reacted in a solvent (e.g. ethanol) at reflux.
- a solvent e.g. ethanol
- the solvent will be replaced with toluene and the organic layer will be washed with water and brine.
- the toluene is then rotary evaporated, THF will be added, and the solution cooled (-20 to O C).
- 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 ⁇ , ⁇ unsaturated carbonyl (1.0 eq) is then added drop wise.
- ammonium chloride /ammonia 3.0 eq
- 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.
- 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.
- 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.
- 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.
- a suitable solvent e.g. methylene chloride, toluene
- 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 brine.
- the solution will then be dried over anhydrous sodium sulfate, filtered, and rotary evaporated to yield the crude 3-methoxy,
- the product from example 2 will be oxidized (route I, found at page 12 of the application) by reaction with MCPBA in methylene chloride.
- the product will be isolated after pH adjustment by extraction and evaporation.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process of reacting (a) is provided wherein R, R1, R2, R3 and X are selected from (b).
Description
TITLE OF INVENTION
SYNTHESIS OF OMEPRAZOLE-TYPE PYRIDINE DERIVATTVES AND INTERMEDIATES THEREOF
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'.
Intermediates 2' and 3' are coupled to give 1.
(See for example Canadian Letters Patent No. 1,127,158) Because the intermediates leading to the pyridine entity were very unstable, Hassel came up with the following starting intermediate, where the oxygen on the nitrogen is eliminated at the stage when X is converted from methyl to hydroxymethyl.
(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, Esteve either 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 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.
These methods are to be used to build substituted pyridines (useful pharmaceutical intermediates), which could be used as precursors for the synthesis of Omeprazole, Pantoprazole or Lansoprazole and related medicines.
In all the published synthesis covering Omeprazole or
Lansoprazole, the appropriately substituted pyridine was reacted with A, B or C synthons.
Applicant believes that the following approach would be highly suitable for use to make pyridines which are intermediates that could be used to make medicines. Applicant proposes that the following pyridine compound:
Scheme 1:
2. E. Breitmaier; S. Gassenmann, Chem. Ber., 1971, 104, 665.
3. Kalina, N.N.; Klimko, V.T.; Protopopova, T.-V; Skoldinor, A.P. Zh.
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. Solladie, 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 references cited therein).
14. Breitmaier, E.; Ullrich, F.W.; Potthoff, B.; Bohme, R.; Bastian, H.
Synthesis, 1987, 1 (Ubersicht).
15. Hertenstein, U.; Hunig, S.; Oiler, 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). Ill is converted to the final product IV by oxidation [O]. The substituents R, R1, R2, R3 and X are chosen having regard to the substituents on the medicines. Thus, the following combinations present themselves:
or R may be selected from:
H
Alkyl (1-3C)
Carboxyl acid
Esters
Cyano
R1 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 R3 may be selected from:
Alkoxy Hydroxy 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:
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, ethyl, benzyl or silyl esters can also be used.
Intermediate A" is then used to manufacture one of the three medicines, as follows:
wherein R, R1, R2 and X are defined above in the chart and L is selected from OCH3 and OCH2F.
Additionally, the pyridine may be built last so that all constituents of the molecules are attached to a skeleton first, and then the pyridine is completed last. For example, the following scheme presents itself. (Synthesis based on building the pyridine last):
wherein R, R1, R2, X and L are defined as previously.
In another scheme, the Benzimidazole is built last:
)
wherein R, R1, R2, X and L are as previously described.
According to other aspects of the invention, the processes may be carried out as follows:
Thus the following processes in schematic form are established:
Compounds I, IIA, III, IIIA, VI, VII, VIII, IX, X, XI, XII and XIII following, are new:
10
R, R1, 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 O C) of the protected hydroxy ketone (1.0 eq) in dry tetrahydrofuran (THF). A THF solution of the α,β 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 O C. 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)).
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 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.
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. The toluene is then rotary evaporated, THF will be added, and the solution cooled (-20 to O C).
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 α, β unsaturated carbonyl (1.0 eq), is then added drop wise. At the end of the reaction, ammonium 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.
m-Chloroperbenzoic acid (2.0 eq) will be dissolved in chloroform, cooled to O C and added to the cooled chloroform solution (O C) 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, 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 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 the art having regard to the articles referred to herein and the above teachings.
Example 5:
The product from example 2 will be oxidized (route I, found at page 12 of the application) by reaction with MCPBA in methylene chloride. The product will be isolated after pH adjustment by extraction and evaporation.
The Michael, aminolysis, cyclization and oxidation of the resulting dihydropyridine will be then achieved as in example 1.
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 interpreted as illustrative of the invention and not in a limiting sense.
Claims
THE EMBODIMENTS OF THE INVENΗON IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:
1. A process of reacting:
is provided 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
The process of:
wherein R, R1, R2, R3 and X are selected from the following group:
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:
to produce:
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
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
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:
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:
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:
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:
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:
and L is selected from OCH3 and OCH2F.
12. The process of reacting:
wherein R2 is selected from:
and L is selected from OCH3 and OCH2F.
13. The process of reacting:
wherein R, R1, R2 and X are selected from:
and L is selected from OCH3 and OCH2F.
14. The process of reacting:
wherein R, R1, R2 and X are selected from:
15. The process of claim 14 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:
wherein R, R1, R2 and X are selected from:
and L is selected from OCH3 and OCH2F.
19. The process of reacting:
wherein R2 is selected from:
20. The process of reacting:
wherein R, R1, R2 and X are selected from:
21. The process of reacting:
wherein R, R1, R2 and X are selected from:
22. The process of reacting:
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:
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:
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:
wherein R, R1, R2 and X are selected from:
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:
H
Alkyl (1-3C)
Carboxyl acid
Esters
Cyano
Thiol
Xanthyl
30. The product:
H
Alkyl (1-3C)
Carboxyl acid
Esters
Cyano
31. The product:
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
32. The product:
H
Alkyl (1-3C)
Carboxyl acid
Esters
Cyano
33. The product:
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:
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.
35. The process:
36. The process:
37. The process:
38. The process:
39. The process:
40. The process:
41. The process:
42. The product:
43. The product:
44. The product:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU15383/97A AU1538397A (en) | 1996-02-06 | 1997-02-05 | Synthesis of omeprazole-type pyridine derivatives and intermediates thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2168939 CA2168939A1 (en) | 1996-02-06 | 1996-02-06 | Synthesis of pharmaceutically useful pyridine derivatives |
| CA2,168,939 | 1996-02-06 | ||
| CA2,173,820 | 1996-04-10 | ||
| CA 2173820 CA2173820A1 (en) | 1996-04-10 | 1996-04-10 | Synthesis of pharmaceutically useful pyridine derivatives and intermediates for such pyridine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1997029103A2 true WO1997029103A2 (en) | 1997-08-14 |
| WO1997029103A3 WO1997029103A3 (en) | 1997-10-23 |
Family
ID=25678329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA1997/000081 WO1997029103A2 (en) | 1996-02-06 | 1997-02-05 | Synthesis of omeprazole-type pyridine derivatives and intermediates thereof |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU1538397A (en) |
| WO (1) | WO1997029103A2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0931790A2 (en) * | 1998-01-26 | 1999-07-28 | Kuraray Co., Ltd. | Method for producing 2-sulfonylpyridine derivates and method for producing 2-( (2-pyridyl)methyl)thio)-1H-benzimidazole derivates |
| US6350876B2 (en) | 1998-01-26 | 2002-02-26 | Kuraray Co., Ltd. | 4-chloro-3,5-dimethyl-2-sulfonyl pyridines |
| US7435825B2 (en) | 2001-08-17 | 2008-10-14 | Grunenthal Gmbh | Hydrates of optionally substituted 2-(2-pyridinyl) methylthio-1H-benzimidazoles and process for the production thereof |
| US7683177B2 (en) | 2003-06-10 | 2010-03-23 | Teva Pharmaceutical Industries Ltd | Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole |
| US8691995B2 (en) | 2004-12-16 | 2014-04-08 | Cipla Limited | Process |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0005129B1 (en) * | 1978-04-14 | 1981-04-29 | Aktiebolaget Hässle | Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation |
| EP0484265A1 (en) * | 1990-10-31 | 1992-05-06 | Centro Genesis Para La Investigacion, S.L. | A process for the preparation of omeprazol |
| US5292885A (en) * | 1989-08-11 | 1994-03-08 | Isochem | Pyranone, process for its preparation, its use in the preparation of a new pyridinone and a process for the preparation of same |
| US5374730A (en) * | 1993-11-04 | 1994-12-20 | Torcan Chemical Ltd. | Preparation of omeprazole and lansoprazole |
-
1997
- 1997-02-05 WO PCT/CA1997/000081 patent/WO1997029103A2/en active Application Filing
- 1997-02-05 AU AU15383/97A patent/AU1538397A/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0005129B1 (en) * | 1978-04-14 | 1981-04-29 | Aktiebolaget Hässle | Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation |
| US5292885A (en) * | 1989-08-11 | 1994-03-08 | Isochem | Pyranone, process for its preparation, its use in the preparation of a new pyridinone and a process for the preparation of same |
| EP0484265A1 (en) * | 1990-10-31 | 1992-05-06 | Centro Genesis Para La Investigacion, S.L. | A process for the preparation of omeprazol |
| US5374730A (en) * | 1993-11-04 | 1994-12-20 | Torcan Chemical Ltd. | Preparation of omeprazole and lansoprazole |
Non-Patent Citations (2)
| Title |
|---|
| J.ORG.CHEM., vol. 47, no. 12, 1982, pages 2487-2489, XP000653641 KOSER ET AL: "One-step alpha-tosylation of ketones with ÄHydroxytosyloxy)iodoÜbenzene" * |
| TETRAHEDRON, vol. 42, no. 19, 1986, pages 5365-5368, XP000652161 LEY ET AL: "Ultrasonic formation and reactions of sodium phenylselenide" * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0931790A2 (en) * | 1998-01-26 | 1999-07-28 | Kuraray Co., Ltd. | Method for producing 2-sulfonylpyridine derivates and method for producing 2-( (2-pyridyl)methyl)thio)-1H-benzimidazole derivates |
| EP0931790A3 (en) * | 1998-01-26 | 1999-08-18 | Kuraray Co., Ltd. | Method for producing 2-sulfonylpyridine derivates and method for producing 2-( (2-pyridyl)methyl)thio)-1H-benzimidazole derivates |
| US6197962B1 (en) | 1998-01-26 | 2001-03-06 | Kuraray Co., Ltd. | Method for producing 2-sulfonylpyridine derivatives and method for producing 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives |
| US6350876B2 (en) | 1998-01-26 | 2002-02-26 | Kuraray Co., Ltd. | 4-chloro-3,5-dimethyl-2-sulfonyl pyridines |
| US7435825B2 (en) | 2001-08-17 | 2008-10-14 | Grunenthal Gmbh | Hydrates of optionally substituted 2-(2-pyridinyl) methylthio-1H-benzimidazoles and process for the production thereof |
| US7557218B2 (en) | 2001-08-17 | 2009-07-07 | Grunenthal Gmbh | Hydrates of optionally substituted 2-(2-pyridinyl) methylthio-1H-benzimidazoles and process for the production thereof |
| US7683177B2 (en) | 2003-06-10 | 2010-03-23 | Teva Pharmaceutical Industries Ltd | Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole |
| US8691995B2 (en) | 2004-12-16 | 2014-04-08 | Cipla Limited | Process |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997029103A3 (en) | 1997-10-23 |
| AU1538397A (en) | 1997-08-28 |
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