WO1991018895A1 - Improved method for synthesis - Google Patents

Improved method for synthesis Download PDF

Info

Publication number
WO1991018895A1
WO1991018895A1 PCT/SE1991/000402 SE9100402W WO9118895A1 WO 1991018895 A1 WO1991018895 A1 WO 1991018895A1 SE 9100402 W SE9100402 W SE 9100402W WO 9118895 A1 WO9118895 A1 WO 9118895A1
Authority
WO
WIPO (PCT)
Prior art keywords
omeprazole
methoxy
reaction mixture
phase
synthesis
Prior art date
Application number
PCT/SE1991/000402
Other languages
French (fr)
Inventor
Arne Elof BRÄNDSTRÖM
Original Assignee
Aktiebolaget Astra
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to RU9192016535A priority Critical patent/RU2061693C1/en
Priority to EP91910929A priority patent/EP0533752B1/en
Priority to JP3510790A priority patent/JP2993122B2/en
Priority to DE69128832T priority patent/DE69128832T2/en
Priority to RO92-01512A priority patent/RO111366B1/en
Priority to UA93004176A priority patent/UA32524C2/en
Priority to PL91297169A priority patent/PL165433B1/en
Application filed by Aktiebolaget Astra filed Critical Aktiebolaget Astra
Publication of WO1991018895A1 publication Critical patent/WO1991018895A1/en
Priority to BG97146A priority patent/BG61265B1/en
Priority to NO924682A priority patent/NO300541B1/en
Priority to FI925529A priority patent/FI102967B/en
Priority to LVP-93-1020A priority patent/LV10271B/en
Priority to HK98102920A priority patent/HK1003831A1/en
Priority to GR980400843T priority patent/GR3026642T3/en

Links

Classifications

    • 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

  • the present invention relates to an improved method for the synthesis of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)-methyl]sulfin ⁇ l-lH-benizimidazole, referred to under its generic name omeprazole throughout the following specification and claims.
  • US-A-4 255 431 discloses a process for the synthesis of omeprazole comprising the steps of reacting 5-methoxy-2- [ (4-methoxy-3 ,5-dimethyl-2-pyridinyl)-methylthio]-1H- benzi idazole in a methylene chloride solution with m- chloroperoxybenzoic acid resulting in the formation of omeprazole and m-chlorobenzoic acid, omeprazole is highly sensitive to acids, and the reaction mixture has to be maintained at a low temperature to prevent excessive decomposition in the reaction mixture.
  • the product is worked-up by filtering-off of m-chloro ⁇ benzoic acid formed during the reaction.
  • the filtrate is diluted with methylene chloride, is extracted with Na-CC solution, dried and evaporated.
  • the resulting omeprazole product is contaminated with starting materials and by ⁇ products.
  • the object of the present invention is to provide an improved method for the synthesis of omeprazole, which eliminates the drawbacks of previously known methods.
  • the m-chloroperoxybenzoic acid is suitably used in an amount of 0.7 - 1.4 molar equivalents of Compound I, and preferably in an amount of 0.9 - 1.2 molar equivalents.
  • the alkyl formate is methylformate or ethylformate, methylformate being preferred.
  • the alkyl formate is suitably used in an amount of 1.2 - 2.0 molar equivalents of Compound I, and preferably in an amount of 1.5 - 1.8 molar equivalents.
  • One important feature of the method according to the invention is that unreacted sulfide is not transferred into the aqueous phase upon the extraction with aqueous NaOH. Another important feature is that m-chlorobenzoic acid does not crystallize upon the addition of methyl ⁇ formate to the aqueous phase, thereby eliminating the need of filtering-off of m-chlorobenzoic acid in a previous step.
  • the pH of the reaction mixture may be maintained within the pH range of 8.0 - 8.6 with the aid of pH static titration with NaOH or with the use of a buffer.
  • Preferred buffers are sodium bicarbonate and potassium bicarbonate.
  • the pH of the aqueous NaOH phase is kept at above about 12.
  • the crystallization of omeprazole is performed at a pH of above 9.
  • Diluted NaOH is added to a pH above 12 and the CH 2 C1 2 phase is separated off.
  • Methylformate (4.7 g) is charged to the water phase and the pH is kept above 9, whereupon omeprazole crystallizes.
  • the crystals are filtered off and are washed with water and methanol at a temperature of about 0°C.
  • the washed crystals are dried under vacuum. Yield: 15.6 g (92 %).

Abstract

The present invention relates to an improved method for the synthesis of omeprazole, comprising the steps of reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole with m-chloroperoxy-benzoic acid in a methylene chloride solution at a substantially constant pH of about 8.0 to 8.6; extracting the reaction mixture with aqueous NaOH; separating the aqueous phase from the organic phase; and adding an alkyl formate to the aqueous phase, resulting in crystallization of omeprazole.

Description

Improved method for synthesis
Technical field
The present invention relates to an improved method for the synthesis of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)-methyl]sulfinγl-lH-benizimidazole, referred to under its generic name omeprazole throughout the following specification and claims.
Prior art
US-A-4 255 431 discloses a process for the synthesis of omeprazole comprising the steps of reacting 5-methoxy-2- [ (4-methoxy-3 ,5-dimethyl-2-pyridinyl)-methylthio]-1H- benzi idazole in a methylene chloride solution with m- chloroperoxybenzoic acid resulting in the formation of omeprazole and m-chlorobenzoic acid, omeprazole is highly sensitive to acids, and the reaction mixture has to be maintained at a low temperature to prevent excessive decomposition in the reaction mixture.
The product is worked-up by filtering-off of m-chloro¬ benzoic acid formed during the reaction. The filtrate is diluted with methylene chloride, is extracted with Na-CC solution, dried and evaporated. The resulting omeprazole product is contaminated with starting materials and by¬ products.
Summary of the invention
The object of the present invention is to provide an improved method for the synthesis of omeprazole, which eliminates the drawbacks of previously known methods.
This object is achieved according to the present inven- tion, which is characterized by the steps of reacting 5- methoxy-2-[ (4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl¬ thio]-lH-benzimidazole (below denoted Compound I) with m- chloroperoxybenzoic acid in a methylene chloride solution at a substantially constant pH of about 8.0 to 8.6; extracting the reaction with aqueous NaOH; separating the aqueous phase from the organic phase; and adding an alkyl formate to the aqueous phase, resulting in crystallization of omeprazole.
The m-chloroperoxybenzoic acid is suitably used in an amount of 0.7 - 1.4 molar equivalents of Compound I, and preferably in an amount of 0.9 - 1.2 molar equivalents.
According to one embodiment of the invention, the alkyl formate is methylformate or ethylformate, methylformate being preferred.
The alkyl formate is suitably used in an amount of 1.2 - 2.0 molar equivalents of Compound I, and preferably in an amount of 1.5 - 1.8 molar equivalents.
One important feature of the method according to the invention is that unreacted sulfide is not transferred into the aqueous phase upon the extraction with aqueous NaOH. Another important feature is that m-chlorobenzoic acid does not crystallize upon the addition of methyl¬ formate to the aqueous phase, thereby eliminating the need of filtering-off of m-chlorobenzoic acid in a previous step.
The pH of the reaction mixture may be maintained within the pH range of 8.0 - 8.6 with the aid of pH static titration with NaOH or with the use of a buffer. Preferred buffers are sodium bicarbonate and potassium bicarbonate. A great advantage of the method according to the invention is that the reaction takes place in the organic methylene chloride phase while the m-chlorobenzoic acid formed during the reaction goes into the aqueous phase containing the buffer, in the case a buffer is used. Because of this, omeprazole formed does not stay in contact with the acid and the reaction may be performed at a temperature above 0βC.
According to one embodiment of the invention the pH of the aqueous NaOH phase is kept at above about 12.
According to another embodiment of the invention the crystallization of omeprazole is performed at a pH of above 9.
The invention will be further illustrated below with a non-limiting example.
Example
5-methoxy-2-[ (4-methoxy-3,5-dimethyl-2-pyridinyl)- methylthio]-lH-benzimidazole (16.2 g; 0.0492 mol) is reacted with m-chloroperoxybenzoic acid (13.6 g; 0.0537 mol) in CH-C^ act n9 as a solvent at a pH of 8.6, which is maintained by the presence of KHC03 (5.6 g; 0.056 mol) acting as a buffer. The temperature is maintained at about 0°C during the addition.
Diluted NaOH is added to a pH above 12 and the CH2C12 phase is separated off.
Methylformate (4.7 g) is charged to the water phase and the pH is kept above 9, whereupon omeprazole crystallizes. The crystals are filtered off and are washed with water and methanol at a temperature of about 0°C. The washed crystals are dried under vacuum. Yield: 15.6 g (92 %).

Claims

C l a i m s
1. An improved method for the synthesis of omeprazole, c h a r a c t e r i z e d by the steps of reacting 5- methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl- thio]-lH-benzimidazole (Compound I) with m-chloroperoxy- benzoic acid in a methylene chloride solution at a substantially constant pH of about 8.0 to 8.6; extracting the reaction mixture with aqueous NaOH; separating the aqueous phase from the organic phase; and adding an alkyl formate to the aqueous phase, resulting in the crystal¬ lization of omeprazole.
2. Method according to claim 1, c h a r a c t e r i - z e d in that the m-chloroperoxybenzoic acid is used in an amount of 0.7 - 1.4, preferably 0.9 - 1.2, molar equi¬ valents of Compound I.
3. Method according to claim 1 or 2, c h a r a c t e - r i z e d in that the alkyl formate is methylformate.
4. Method according to claims 1 - 3, c h a r a c t e ¬ r i z e d in that pH of the reaction mixture is main¬ tained within the pH range of 8.0 - 8.6 with the aid of pH static titration with NaOH.
5. Method according to claims 1 - 4, c h a r a c t e ¬ r i z e d in that pH of the reaction mixture is main¬ tained within the pH range of 8.0 - 8.6 with the use of a buffer.
6. Method according to claim 5, c h a r a c t e r i ¬ z e d in that the buffer is sodium bicarbonate or potassium bicarbonate.
7. Method according to claims 1 - 6, c h a r a c t e ¬ r i z e d in that the pH of the aqueous NaOH phase is kept at above about 12.
8. Method according to claims 1 - 7, c h a r a c t e ¬ r i z e d in that the alkyl formate is added in an amount of 1.2 - 2.0, preferably 1.5 - 1.8, molar equivalents of Compound I.
9. Method according to claims 1 - 8, c h a r a c t e ¬ r i z e d in that the crystallization of omeprazole is performed at a pH of above 9.
PCT/SE1991/000402 1990-06-07 1991-06-05 Improved method for synthesis WO1991018895A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
UA93004176A UA32524C2 (en) 1990-06-07 1991-06-05 A process for preparation of omeprazole
EP91910929A EP0533752B1 (en) 1990-06-07 1991-06-05 Improved method for synthesis
JP3510790A JP2993122B2 (en) 1990-06-07 1991-06-05 Synthetic method of omeprazole
DE69128832T DE69128832T2 (en) 1990-06-07 1991-06-05 IMPROVED METHOD OF SYNTHESIS
RO92-01512A RO111366B1 (en) 1990-06-07 1991-06-05 Omeprazole preparation process
RU9192016535A RU2061693C1 (en) 1990-06-07 1991-06-05 Method for production of omeprazole
PL91297169A PL165433B1 (en) 1990-06-07 1991-06-05 Method of synthetizing 5-methoxy-2-[(4-methoxy-3,5-dimethylopyridinyl-2)methyl]sulfinyl-1h-benzimidazole
BG97146A BG61265B1 (en) 1990-06-07 1992-12-04 Improved method for synthesis
FI925529A FI102967B (en) 1990-06-07 1992-12-04 An improved method for the synthesis of omeprazole
NO924682A NO300541B1 (en) 1990-06-07 1992-12-04 Improved synthesis procedure in the preparation of omeprazole
LVP-93-1020A LV10271B (en) 1990-06-07 1993-08-10 Improved method for synthesis
HK98102920A HK1003831A1 (en) 1990-06-07 1998-04-08 Improved method for synthesis
GR980400843T GR3026642T3 (en) 1990-06-07 1998-04-14 Improved method for synthesis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9002043A SE9002043D0 (en) 1990-06-07 1990-06-07 IMPROVED METHOD FOR SYNTHESIS
SE9002043-9 1990-06-07

Publications (1)

Publication Number Publication Date
WO1991018895A1 true WO1991018895A1 (en) 1991-12-12

Family

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Application Number Title Priority Date Filing Date
PCT/SE1991/000402 WO1991018895A1 (en) 1990-06-07 1991-06-05 Improved method for synthesis

Country Status (42)

Country Link
US (1) US5386032A (en)
EP (1) EP0533752B1 (en)
JP (1) JP2993122B2 (en)
KR (1) KR0178045B1 (en)
CN (1) CN1040536C (en)
AP (1) AP216A (en)
AT (1) ATE162790T1 (en)
AU (1) AU640246B2 (en)
BG (1) BG61265B1 (en)
CA (1) CA2083605C (en)
CZ (1) CZ279928B6 (en)
DE (1) DE69128832T2 (en)
DK (1) DK0533752T3 (en)
DZ (1) DZ1504A1 (en)
EG (1) EG19392A (en)
ES (1) ES2113378T3 (en)
FI (1) FI102967B (en)
GR (1) GR3026642T3 (en)
HK (1) HK1003831A1 (en)
HR (1) HRP920770B1 (en)
HU (1) HU214323B (en)
IE (1) IE911845A1 (en)
IL (1) IL98274A (en)
IS (1) IS1752B (en)
LT (1) LT3584B (en)
LV (1) LV10271B (en)
MA (1) MA22171A1 (en)
NO (1) NO300541B1 (en)
NZ (1) NZ238224A (en)
PL (1) PL165433B1 (en)
PT (1) PT97873B (en)
RO (1) RO111366B1 (en)
RU (1) RU2061693C1 (en)
SA (1) SA91120027B1 (en)
SE (1) SE9002043D0 (en)
SG (1) SG48053A1 (en)
SK (1) SK278505B6 (en)
TN (1) TNSN91042A1 (en)
UA (1) UA32524C2 (en)
WO (1) WO1991018895A1 (en)
YU (1) YU47570B (en)
ZA (1) ZA913779B (en)

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Cited By (24)

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US5958955A (en) * 1995-12-15 1999-09-28 Astra Aktiebolag Method for the synthesis of a benzimidazole compound
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