WO1999033807A2 - Synthesis of pharmaceutically useful pyridine derivatives (intermediates) employing free radical substitution reactions to functionalize the 2-position of the pyridine - Google Patents
Synthesis of pharmaceutically useful pyridine derivatives (intermediates) employing free radical substitution reactions to functionalize the 2-position of the pyridine Download PDFInfo
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- WO1999033807A2 WO1999033807A2 PCT/CA1998/001153 CA9801153W WO9933807A2 WO 1999033807 A2 WO1999033807 A2 WO 1999033807A2 CA 9801153 W CA9801153 W CA 9801153W WO 9933807 A2 WO9933807 A2 WO 9933807A2
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- compound
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- 0 *c1cncc(*)c1* Chemical compound *c1cncc(*)c1* 0.000 description 4
- SUBDBMMJDZJVOS-UHFFFAOYSA-N Cc1cnc(CS(c2nc(ccc(OC)c3)c3[nH]2)=O)c(C)c1OC Chemical compound Cc1cnc(CS(c2nc(ccc(OC)c3)c3[nH]2)=O)c(C)c1OC SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- HWWYDZCSSYKIAD-UHFFFAOYSA-N Cc1cncc(C)c1 Chemical compound Cc1cncc(C)c1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 description 1
- NBZVILUCDBYYIE-UHFFFAOYSA-N Cc1cncc(C)c1OC Chemical compound Cc1cncc(C)c1OC NBZVILUCDBYYIE-UHFFFAOYSA-N 0.000 description 1
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
- C07D213/04—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
- This invention relates to the manufacture of intermediates suitable for use in the manufacture of Omeprazole and other medicines and the use thereof to manufacture Omeprazole and other medicines.
- This invention in its broadest aspects is directed to the manufacture of intermediates useful in the manufacture of medicines such as Omeprazole, Pantoprazole, and Lansoprazole, intermediates suitable for the use to manufacture medicines and the processes for manufacturing the intermediates and for using those intermediates to manufacture medicines.
- Omeprazole basically involves the coupling of intermediates A and B to form intermediate C which is oxidized to the sulfinyl or sulfoxy compound, Omeprazole.
- Hassle used the N-oxide form of intermediate A:
- N-Oxide form may be considered necessary to prepare the precursor 4- nitro compound and it is essential for the alkylation/functionalization of the 2-position (X ), according to Hassle's process.
- R 2 -Cl, -N0 2 , or -OCH3
- Torcan reported a method that offers advantages involving the oxidation and the purification of the final product. Their method comprises oxidizing the amide of Intermediate C to the corresponding amide sulfinyl compound followed by hydrolysis and decarboxylation to form Omeprazole. Torcan did not report processes for the manufacture of the pyridinyl moiety.
- Nitropyridines and their N-oxides are suspected carcinogens and therefore are unsafe to handle. Also, the above processes employ the nitropyridines and their N- oxides in the early or late stages of the manufacture. In both cases the suspected carcinogens are potential impurities.
- Taiwanese method does not employ nitropyridines or N- oxides, it suffers from the disadvantage that it employs a large number of steps (approximately 10 steps) and the low availability of the starting material. Both are factors that affect the manufacturing yield and cost. It is therefore an object of the invention to provide a method of manufacturing intermediates useful in preparing medicines where said intermediates avoid N-oxides that are suspected carcinogens. It is also another object of the invention to provide methods of manufacturing intermediates useful in preparing medicines where said method employs intermediates that are safe to handle. It is also another object of the invention to provide methods of manufacturing intermediates useful in preparing medicines wherein the number of steps are minimal in number.
- R 3 Alkoxy (1-4C), OCH2CF3, Cyano, Hydrogen, Halogen, Acetoxy or Aryloxy, any electron withdrawing group or salts (organic or inorganic) of electron donating groups
- R 1 , R 2 CH 3 using intermediate HI.
- An exemplary process may be by carrying out the following reaction step or steps which are obvious chemical equivalents of the following steps:
- a process of manufacturing Omeprazole by using the intermediate formed by the process above described with the appropriate substituents or an obvious chemical equivalent there is provided a process of manufacturing Pantoprazole by using the intermediate formed by the process above described with the appropriate substituents or an obvious chemical equivalent.
- a process of manufacturing Lansoprazole by using the intermediate formed by the process above described with the appropriate substituents or an obvious chemical equivalent there is provided a process of manufacturing Omeprazole by using the intermediate formed by the process above described with the appropriate substituents or an obvious chemical equivalent.
- R 1 , R 2 and R 3 as previously defined, with a radical • alkyl under free radical reaction conditions or an obvious chemical equivalent.
- R 1 , R 2 and R 3 as previously defined, with a radical • aryloxycarbonyl under free radical reaction conditions or obvious chemical equivalent.
- R 1 , R 2 and R 3 as previously defined, with a radical • aryloxymethyl (for example, •phenoxymethyl) under free radical reaction conditions or obvious chemical equivalent.
- the inventors propose that their approach would be highly suitable for use to make pyridines which are intermediates that could be used to make medicines.
- R 3 Alkoxy (1-4C), OCH2CF3, Cyano, Hydrogen, Halogen, Acetoxy or Aryloxy, any electron withdrawing group or salts (organic or inorganic) of electron donating groups
- R Alkoxy, Hydroxy, Halogen, Activated ester, Tosylate,
- Compound I may then be manufactured using intermediate III.
- intermediate III For the synthesis of an intermediate useful in the manufacture of
- This reaction could be carried out in an inert solvent such as toluene, dimethylbenzene, chlorobenzene or could be carried out neat with no solvent, with the halogenating reagent used in excess (2-5 eq.), to be the solvent.
- the mode of addition of reagents is not important, i.e. pyridine to the halogenating reagent or the halogenating reagent to pyridine.
- the addition is done dropwise, under nitrogen, at a temperature range of 0- 70°C.
- the product is obtained as a salt.
- the free base could be obtained by typical procedures known to a person skilled in the art.
- Method in subparagraph (i) is preferred method because it provides simple conditions and good yields.
- the pyridine used in this reaction could be in the free base or the salt form.
- the salt could be prepared prior to the reaction or formed in situ and it is the result of reacting the pyridine with an organic or inorganic acid, preferably sulfuric acid.
- An inert solvent such as Toluene or Xylene could be added to form a two-phase reaction. If an organic solvent is added, it is preferable in a volume equal to or higher than that of water.
- 2-alkoxycarbonyl-4-Halopyridine could be reacted with an appropriate reagent to effect reduction of the ester moiety to an alcohol.
- Reducing agents such as Diisobutylaluminum Hydride (e.g. Syn 1975, 617) in an appropriate solvent such as toluene, tetrahydrofuran, hexane or a combination of those solvents could be used.
- sodium bis[2-methoxyethoxy] aluminum hydride e.g. /. Heterocyclic chem., 1990, 27, 2125; Syn., 1976, 526
- borohydrides such as Sodium or Lithium borohydride, (e.g. /. Org. Chem. 1963.
- Nucleophilic substitution of the halogen on the 4-position by a nucleophile such as a -OCH3 radical can be performed using methoxide salts such as sodium, potassium or copper methoxide (e.g. see Chem & Ind.,, 1967, 1784). Also, sodium or potassium methoxide could be used in the presence of a copper salt such as cuprous iodide, cuprous bromide or cuprous chloride. The reaction can be carried out in an inert solvent such as dimethylformamide, dimethylacetamide, dimethylsufoxide, diglyme, methanol, or a combination of those solvents. The methoxide salt is used in excess (2-7 eq.) and the reaction temperature could be between 65°C and reflux. e) Nucleophilic substitution of the OH radical by a Halogen:
- Ester Reducing agent e.g. NaBH 4
- step "d” could be performed before step “c” (Scheme-2).
- step "d" could be performed before step “c” (Scheme-2).
- the steps may be carried out in different orders as would be understood by persons skilled in the art. It is preferred to have an electron withdrawing group at the 4-position before functionalizing the 2-position.
- the unreacted starting material in the free radical reaction could easily be recovered by alkaline treatment and extraction with an organic solvent.
- the 2-alkoxycarbonyl product is obtained in purity higher or equal to 90%.
- Analytically pure product could be obtained by hydrolysis of the ester to the acid according to methodologies generally known in the art.
- the hydrolysis of III to the acid (IV) could be accomplished using aqueous sodium hydroxide or aqueous hydrochloric acid.
- the acid obtained (IV) could then be converted back to the ester using methods generally known in the art. For example, reaction of the acid with thionyl chloride followed by an alcohol such as methanol.
- the acid could be reduced directly to the alcohol using carboxylic acid reducing agents that are generally known to persons skilled in the art.
- carboxylic acid reducing agents that are generally known to persons skilled in the art.
- Diborane, diborane complexes e.g. Syn. 1979, 704; /. Org. Chem. 1973. 38, 2786
- lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, lithium borohydride can be used pure or with catalysts and additives (e.g. /. Org. Chem. 1982. 47, 4702; Tet. 1992. 48, 4623).
- 4-nucleophilic substitution reaction can be geared to provide the ether cleavage product, such as (V) and (VI), as the major products. This could be achieved by, for example, employing longer reaction times (over 15 hours).
- the synthesis of 4-hydroxy products such as compounds (V) and (VI)
- (VI) is also within the scope of this invention. These products are inorganic salts of 4-hydroxypyridines.
- the 4-hydroxypyridines may also take the form of these organic salts.
- Compound (V) may be a mono organic /inorganic salt.
- Compound (VI) may be a mono- or di- organic/ inorganic salt (such as the sodium or potassium salt).
- the alkylation of the 4-hydroxy compounds could be accomplished employing methods that are generally known to a person skilled in the art. For example, compounds (V) or (VI) could be methylated by treatment with 1 equivalent (for compound V) or 2-5 equivalents (for compound VI) of a methylating agent such as lodomethane, in an inert aprotic solvent such as dimethylformamide.
- R 3 is hydrogen with SOCI2 or any other halogenating agent to form 4-halopyridine derivatives.
- the halogenating agent can be used neat, and in another embodiment it can be used in the presence of solvents such as toluene, xylene, chlorobenzene or any other suitable inert solvent.
- solvents such as toluene, xylene, chlorobenzene or any other suitable inert solvent.
- the reaction occurs substantially solvent free.
- 3,5-Dimethylpyridine (1 eq.) was added dropwise to thionyl chloride (1 -5 eq.); either neat or in a solvent (2-10 volumes), (such as toluene, 4- chlorobenzene, xylene etc.) at a temperature ranging from 0-703C. At the end of the addition the mixture was heated to reflux for 12 - 20 hours. At the end of the reaction the solvent (1 - 5 volumes) was added (if not already present). A fraction of the solvent was distilled to get rid of the excess thionyl chloride. The precipitated solid was filtered, washed with toluene followed by methanol, a brown solid was obtained.
- Example 3 Pyridinecarboxylic acid, 3.5-dimethyl-4-methoxy-, methyl ester:
- the aqueous layers were free based with NaOH (30%) and extracted with toluene.
- Example 11 Synthesis of 4-Methoxylutidine: Sodium methoxide (2 eq.) was dissolved in methanol (1.5 volumes) and dry dimethylformamide (2 volumes). The solution was heated to (95- 1003 C) and while stirring under a stream of nitrogen, 4-chlorolutidine (1 eq.) was added dropwise. At the end of the reaction (about 2 hours), the mixture was cooled in an ice bath and cold water (10 volumes) was added. The product was extracted with dichloromethane (3 x 2 volumes). The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. Light yellow oil was obtained in 72% yield.
- Example 12 Synthesis of 2-carboxy-4-chloro-3,5-lutidine:
- Example 13 Synthesis of 4-Chloro-2-hydroxymethyl-3,5-Lutidine from 2-carboxy-4- chloro-3 ,5-lutidine: 2-carboxy-4-chloro-3,5-lutidine (1 eq.) was suspended in dry dimethylformamide and BH3.THF solution (1M in tetrahydrofuran, 3.5 eq.) was added. The mixture was heated to 603 C and stirred under a nitrogen atmosphere until completion (1.5 hours). The mixture was cooled in an ice bath and THF/H2O (1:1) mixture (10 volumes) was added slowly. The aqueous layer was saturated with sodium chloride and the tetrahydrofuran layer was separated. The aqueous layer was extracted with ether. The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The 4-Chloro-2- hydroxymethyl-3,5-Lutidine product was obtained in 51% yield.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/582,345 US6437139B1 (en) | 1997-05-06 | 1998-12-11 | Synthesis of pharmaceutically useful pyridine derivatives |
AU16566/99A AU1656699A (en) | 1997-12-24 | 1998-12-11 | Synthesis of pharmaceutically useful pyridine derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2,225,863 | 1997-12-24 | ||
CA 2225863 CA2225863A1 (en) | 1997-05-06 | 1997-12-24 | Synthesis of pharmaceutical useful pyridine derivatives |
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WO1999033807A2 true WO1999033807A2 (en) | 1999-07-08 |
WO1999033807A3 WO1999033807A3 (en) | 1999-10-21 |
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PCT/CA1998/001153 WO1999033807A2 (en) | 1997-05-06 | 1998-12-11 | Synthesis of pharmaceutically useful pyridine derivatives (intermediates) employing free radical substitution reactions to functionalize the 2-position of the pyridine |
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WO (1) | WO1999033807A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105153023A (en) * | 2015-10-10 | 2015-12-16 | 成都同创源医药科技有限公司 | Synthetic method of 2-amino-4-bromopyridine |
CN105153024A (en) * | 2015-10-10 | 2015-12-16 | 成都同创源医药科技有限公司 | Synthetic method of 3,4-substituted 2-picolinic acid |
CN113797968A (en) * | 2021-08-19 | 2021-12-17 | 万华化学集团股份有限公司 | Preparation of 2-chloroisonicotinic acid-phosphomolybdic acid catalyst and preparation method of polyglycerol fatty acid ester |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD29611A (en) * | ||||
EP0103553A1 (en) * | 1982-08-26 | 1984-03-21 | Aktiebolaget Hässle | Intermediates for the preparation of omeprazole |
EP0172595A1 (en) * | 1984-08-20 | 1986-02-26 | SOLVAY & Cie (Société Anonyme) | Process for the preparation of chlorinated derivatives of pyridine, and radical initiators used in this process |
EP0357103A1 (en) * | 1988-07-15 | 1990-03-07 | Solvay | Process for the preparation of 2,6-dichloropyridine and the use of bis(trichloromethyl)sulphone in this process |
EP0533131A1 (en) * | 1991-09-19 | 1993-03-24 | Hoechst Aktiengesellschaft | Process for selectively mono-ortho-hydroxy alkylation of 4-substituted pyridine derivatives |
WO1998050361A2 (en) * | 1997-05-06 | 1998-11-12 | Pdi-Research Laboratories, Inc. | Synthesis of pharmaceutically useful pyridine derivatives |
Family Cites Families (2)
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SU330737A1 (en) * | 1970-03-20 | 1973-05-22 | METHOD OF JOINT PREPARATION OF 2,3-DICHLOR-, 2,3,6-TRICHLOR-2, 3, 4, 5-TETRACHLOR- AND PENTAL CHRORINE | |
CA2027220A1 (en) * | 1989-11-02 | 1991-05-03 | Rajal M. Kusumgar | Impact resistant polyacetal compositions exhibiting excellent antistaticity |
-
1998
- 1998-12-11 WO PCT/CA1998/001153 patent/WO1999033807A2/en active Application Filing
- 1998-12-11 AU AU16566/99A patent/AU1656699A/en not_active Abandoned
Patent Citations (6)
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EP0103553A1 (en) * | 1982-08-26 | 1984-03-21 | Aktiebolaget Hässle | Intermediates for the preparation of omeprazole |
EP0172595A1 (en) * | 1984-08-20 | 1986-02-26 | SOLVAY & Cie (Société Anonyme) | Process for the preparation of chlorinated derivatives of pyridine, and radical initiators used in this process |
EP0357103A1 (en) * | 1988-07-15 | 1990-03-07 | Solvay | Process for the preparation of 2,6-dichloropyridine and the use of bis(trichloromethyl)sulphone in this process |
EP0533131A1 (en) * | 1991-09-19 | 1993-03-24 | Hoechst Aktiengesellschaft | Process for selectively mono-ortho-hydroxy alkylation of 4-substituted pyridine derivatives |
WO1998050361A2 (en) * | 1997-05-06 | 1998-11-12 | Pdi-Research Laboratories, Inc. | Synthesis of pharmaceutically useful pyridine derivatives |
Non-Patent Citations (8)
Title |
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BERNARDI R ET AL: "NUCLEOPHILIC CHARACTER OF CARBON FREE RADICALS. A NEW CONVENIENT, SELECTIVE CARBOXYLATION OF HETEROAROMATIC BASES" TETRAHEDRON LETTERS, no. 9, 1973, pages 645-648, XP002073298 * |
CHOU S -Y ET AL: "SYNTHESIS OF 2-HYDROXYMETHYL-3,5-DIMETHYL-4-METHOXYPYRI DINE: A KEY INTERMEDIATE FOR OMEPRAZOLE" HETEROCYCLES, vol. 45, no. 1, 1997, pages 77-85, XP002073301 cited in the application * |
CITTERIO A ET AL: "NUCLEOPHILIC CHARACTER OF THE ALKYL RADICALS. 19. ABSOLUTE RATE CONSTANTS IN THE HOMOLYTIC ALKYLATION OF PROTONATED HETEROAROMATIC BASES BY N-BUTYL AND TERT-BUTYL RADICALS" JOURNAL OF ORGANIC CHEMISTRY, vol. 45, 1980, pages 4752-4757, XP002073300 * |
DATABASE WPI Section Ch, Week 674 Derwent Publications Ltd., London, GB; Class C02, AN 74-10791v XP002073303 & SU 330 737 A (N-CAUCASUS PHYTOPATH), 30 January 1973 (1973-01-30) * |
DATABASE WPI Section Ch, Week 9250 Derwent Publications Ltd., London, GB; Class B03, AN 92-412945 XP002073302 & KR 9 109 817 A (CHOONG-WAE-PHARM CO), 3 November 1991 (1991-11-03) * |
FONTANA F ET AL: "HOMOLYTIC ACYLATIONS OF PROTONATED PYRIDINES AND PYRAZINES WITH ALPHA-KETO ACIDS: THE PROBLEM OF MONOACYLATION" JOURNAL OF ORGANIC CHEMISTRY, vol. 56, 1991, pages 2866-2869, XP002073299 * |
MINISCI F: "NOVEL APPLICATIONS OF FREE-RADICAL REACTIONS IN PREPARATIVE ORGANIC CHEMISTRY" SYNTHESIS, no. 1, 1973, pages 1-24, XP002073297 * |
MINISCI,F. ET AL.: "Advances in Homolytic Substitution of Heteroaromatic Compounds" ADV.HETEROCYCL.CHEM., vol. 16, 1974, pages 123-180, XP002101509 NEW YORK * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105153023A (en) * | 2015-10-10 | 2015-12-16 | 成都同创源医药科技有限公司 | Synthetic method of 2-amino-4-bromopyridine |
CN105153024A (en) * | 2015-10-10 | 2015-12-16 | 成都同创源医药科技有限公司 | Synthetic method of 3,4-substituted 2-picolinic acid |
CN105153023B (en) * | 2015-10-10 | 2018-04-13 | 成都同创源医药科技有限公司 | The synthetic method of 2 amino, 4 bromopyridine |
CN113797968A (en) * | 2021-08-19 | 2021-12-17 | 万华化学集团股份有限公司 | Preparation of 2-chloroisonicotinic acid-phosphomolybdic acid catalyst and preparation method of polyglycerol fatty acid ester |
CN113797968B (en) * | 2021-08-19 | 2022-08-05 | 万华化学集团股份有限公司 | Preparation of 2-chloroisonicotinic acid-phosphomolybdic acid catalyst and preparation method of polyglycerol fatty acid ester |
Also Published As
Publication number | Publication date |
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WO1999033807A3 (en) | 1999-10-21 |
AU1656699A (en) | 1999-07-19 |
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