LANSOPRAZOLE

• Molecular FormulaC₁₆H₁₄F₃N₃O₂S
• Average mass369.362 Da

Lansoprazole, AG-1749, ABT-006, CG-4801, A-65006, Ogast, Lanzor, Lanzo, Agopton, Opiren, Bamalite, Takepron, Lansox, Lansox, Ogastro, Monolitum, Prevacid, Zoton

Lansoprazole, sold under the brand name Selanz SR among others, is a medication which reduces stomach acid.^[2] It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome.^[3] Effectiveness is similar to other proton pump inhibitors (PPIs).^[4] It is taken by mouth.^[2] Onset is over a few hours and effects last up to a couple of days.^[2]

Common side effects include constipation, abdominal pain, and nausea.^[2][5] Serious side effects may include osteoporosis, low blood magnesium, Clostridium difficile infection, and pneumonia.^[2][5] Use in pregnancy and breastfeeding is of unclear safety.^[1] It works by blocking H⁺/K⁺-ATPase in the parietal cells of the stomach.^[2]

Lansoprazole was patented in 1984 and came into medical use in 1992.^[6] It is available as a generic medication.^[3] In 2017, it was the 188th most commonly prescribed medication in the United States, with more than three million prescriptions.^[7][8]

Medical uses

Lansoprazole is used for treatment of:^[5]

• Ulcers of the stomach and duodenum, and NSAID-induced ulcers
• Helicobacter pylori infection, alongside antibiotics (adjunctive treatment), treatment to kill H. pylori causing ulcers or other problems involves using two other drugs besides lansoprazole known as “triple therapy“, and involves taking twice daily for 10 or 14 days lansoprazole, amoxicillin, and clarithromycin
• Gastroesophageal reflux disease
• Zollinger-Ellison syndrome^[9]

There is no good evidence that it works better than other PPIs.^[4]

Side effects

Side effects of PPIs in general^[10] and lansoprazole in particular^[11] may include:^[5]

• Common: diarrhea, abdominal pain^[12]
• Infrequent: dry mouth, insomnia, drowsiness, blurred vision, rash, pruritus
• Rarely and very rarely: taste disturbance, liver dysfunction, peripheral oedema, hypersensitivity reactions (including bronchospasm, urinary, angioedema, anaphylaxis), photosensitivity, fever, sweating, depression, interstitial nephritis, blood disorders (including leukopenia, leukocytosis, pancytopenia, thrombocytopenia), arthralgia, myalgia, skin reactions^[13] including (erythroderma^[14] Stevens–Johnson syndrome, toxic epidermal necrolysis, bullous eruption)

PPIs may be associated with a greater risk of hip fractures and Clostridium difficile-associated diarrhea.^[5]: 22

Interactions

Lansoprazole interacts with several other drugs, either due to its own nature or as a PPI.^[15]

• PPIs reduce absorption of antifungals (itraconazole and ketoconazole) ^[16] and possibly increase digoxin in plasma
• Increases plasma concentrations of cilostazol (risk of toxicity)

Lansoprazole possibly interacts with, among other drugs:

• sucralfate
• ampicillin
• bisacodyl
• clopidogrel
• delavirdine
• fluvoxamine
• iron salts
• voriconazole
• aminophylline and theophylline
• astemizole

Chemistry

It is a racemic 1:1 mixture of the enantiomers dexlansoprazole and levolansoprazole.^[17] Dexlansoprazole is an enantiomerically pure active ingredient of a commercial drug as a result of the enantiomeric shift. Lansoprazole’s plasma elimination half-life (1.5 h) is not proportional to the duration of the drug’s effects to the person (i.e. gastric acid suppression).^[18]

History

Lansoprazole , available in the name of Selanz SR, was originally synthesized at Takeda and was given the development name AG 1749.^[19] Takeda patented it in 1984 and the drug launched in 1991.^[20] In the United States, it was approved for medical use in 1995.^[21]

Society and culture

Patents

The lansoprazole molecule is off-patent and so generic drugs are available under many brand names in many countries;^[22] there are patents covering some formulations in effect as of 2015.^[23] Patent protection expired on 10 November 2009.^[24][25]

Availability

Since 2009, lansoprazole has been available over the counter (OTC) in the U.S. as Prevacid 24HR^[26][27] and as Lansoprazole 24HR.^[28] In Australia, it is marketed by Pfizer as Zoton.^{[citation needed]}

Research

In vitro experiments have shown that lansoprazole binds to the pathogenic form of tau protein.^[29] As of 2015 laboratory studies were underway on analogs of lansoprazole to explore their use as potential PET imaging agents for diagnosing tauopathies including Alzheimer’s disease.^[29]

SYN

English: doi: 10.1248/cpb.38.2853

SYN

Method of synthesis

i. 2,3-dimethyl-4-nitropyridine-1-oxide is reacted with 2,2,2-trifluoroethanol in presence of potassium carbonate to give 2,3-dimethyl-4-(2,2,2-trifluoro-ethoxy)pyridine-1-oxide.

ii. The compound so formed is treated with acetic anhydride in acidic conditions followed by nutrilizing with sodium hydroxide solution to get 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)-pyridine

iii. Last is treated with thionyl chloride followed by reaction with 2-mercaptobenzimidazole to get 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-ylmethylthio]benzimidazole.

iv. Above formed compound is reacted with m-chloro-perbenzoic acid to get lansoprazole.[2]

SYN

Proton Pump Inhibitors

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

Lansoprazole–Prevacid

Lansoprazole (37.3) is the second approved gastric acid pump inhibitor. The common approach for the synthesis of lansoprazole involves coupling of mercapto-benzimidazole (37.24) with a new 2-chloromethylpyridine derivative (37.32) followed by oxidation of the prochiral sulfide group with m-chloroperbenzoic acid or hydrogen peroxide was first disclosed by Nohara and Maki [73], with followed improvements in patents [74-78] and briefly summed up in papers [79-80].

Lansoprazole synthesis is represented on the Scheme 37.4.

Scheme 37.4. Synthesis of lansoprazole.

In principle it repeats the synthesis Scheme of omeprazole, differing in details and characteristics, for example, in place of 2,3,5-collidine (37.15) as a starting material, 2,3-lutidine (37.27) was selected, and the methoxy group in the fourth position of pyridine ring was replaced by the 2,2,2-trifluoroethoxy group.

Another interesting approach has been demonstrated [81]. In this case, 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (37.32) was prepared starting with 3-picoline (37.34), which was oxidized using peracids (i.e., m-chloroperoxybenzoic acid) to produce 3-methylpyridineN-oxide (37.35). The obtained product was nitrated with fuming nitric acid to produce 3-methyl-4-nitropyridine N-oxide (37.36). The prepared N-oxide was treated with dimethylsulfate at 65 to 70°C to form N-methoxypyridinium salt (37.37), the aqueous solution of which on cooling was treated with sodium cyanide to produce an after formation of intermediate (37.38) and elimination of methanol 2-cyano-3-methyl-4-nitropyridine (37.39). This method for the synthesis of 2-cyanopyridines via addition of cyanide ion to N-alkoxy-quaternary salts of pyridines, supplements the plethora of Reissert-Kaufmann reactions in the quinoline and isoquinoline series previously described [82]. The nitro group in (37.39) was replaced by the 2,2,2-trifluoroethoxy group by a direct reaction with sodium trifluoroethoxide in trifluoroethanol that produced ether (37.40). The next step—transformation of nitrile group in prepared 2-cyanopyridine (37.40) to 2-carboxypyridine (37.41)—was carried out in a one-pot procedure by heating the 2-cyano compound in the presence of concentrated sulfuric acid followed by reaction of the intermediate amide with sodium nitrite under aqueous acidic conditions [83,84]. The obtained acid was esterified in methanol with a catalytic amount of sulfuric acid to produce ester (37.42). The ester (37.42) was reduced by NaBH₄, producing the above-described 2-hydroxymethyl- pyridine derivative (37.31) followed by a reaction with thionyl chloride in dioxane that produced the required 2-chloromethylpyridine compound (37.32). Direct reaction of the last with 2-mercaptobenzimidazole (37.34) in methanol, even without use of any base, produced a sulfide (37.33) in high yield. The oxidation of the last to lansoprazole (37.3) has been carried out by various oxidants and catalysts, which, together with the desired sulfoxide, produced a certain amount of overoxidized product. Oxidizing sulfide (37.33) with a new oxidation method made up of the use of the composite metal oxide catalyst, LiNbMoO₆, in methanol and 35% H₂O₂ as an oxidant sulfide (37.33) was successfully oxidized to desired lansoprazole (37.3) (Scheme 37.5.).

Scheme 37.5. Synthesis of lansoprazole.

Lansoprazole is the second inhibitor of the gastric H+/K+-ATPase to be marketed for the treatment of peptic ulcer disease and reflux esophagitis, erosive esophagitis, and Zollinger-Ellison syndrome. It is an inhibitor of gastric acid secretion and also exhibits antibacterial activity against H. pylori in vitro. More common side effects of lansoprazole are diarrhea and skin rash or itching. Less-common side effects are abdominal pain, joint pain, nausea, vomiting, and increased or decreased appetite [85-91].

SYN

AU 8545895; EP 0174726; ES 8607288; JP 1986050978; US 4628098; US 4689333

The condensation of 2,3-dimethyl-4-nitropyridine N-oxide (I) with 2,2,2-trifluoroethanol (II) by means of K2CO3 in hot HMPT gives 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine N-oxide (III), which by isomerization in acetic anhydride at 100 C is converted to 2-(hydroxymethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (IV). The reaction of (IV) with SOCl2 in refluxing CHCl3 affords the corresponding chloromethyl derivative (V), which is condensed with 2-mercaptobenzimidazole (VI) by means of sodium methoxide in refluxing methanol to yield 2-(2-benzimidazolylthiomethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridin (VII). Finally, this compound is oxidized with m-chloroperbenzoic acid in CHCl3.

SYN

SYN

Chemical Synthesis

Similar to the synthesis of the chiral sulfoxide of armodafinil vide supra, the preparation of the chiral sulfoxide of lansoprazole utilized the catalytic oxidation method developed by Kagan and co-workers (the Scheme). Two routes have been reported that describe the preparation of dexlansoprazole on large scale. The first route developed by Takeda reacts commercially available thioether 29, also used to make lansoprazole, under the Kagan asymmetric oxidation conditions and the alternative route utilizes the cheaper commercial intermediate nitrosulfide 30 in the analogous asymmetric oxidation by Kagan). Thus, the catalyst complex consisting of (+)-DET, Ti(OiPr)4 and water was formed in the presence of thioether 29 in toluene at 30–40°C. The reaction mixture was then cooled to 5 °C and DIPEA and cumene hydroperoxide (CMHP) were added to give, after aqueous work-up and in situ crystallization from the organic layer, dexlansoprazole (VI) in 98% ee. No yield was given in the patent. An alternate, but similar, sequence was also described wherein the nitrosulfide intermediate 30 was subjected to similar oxidative conditions that gave intermediate nitro compound 31 in 80% yield and 98% ee. Compound 31 was treated with KOH and trifluoroethanol to provide dexlansoprazole (VI).

R-(+)-Lansoprazole Preparation Products And Raw materials

PATENT

https://patents.google.com/patent/WO2008087665A2/en

A number of substituted 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole derivatives are reported as gastric proton pump inhibitors. These benzimidazole derivatives include lansoprazole, omeprazole, pantoprazole, and rabeprazole. The Lansoprazole is generally represented by the following chemical formula I

US 4,628,098 & 4,689,333 describes lansoprazole having its chemical name (2-[[[3-methyl-4-(2, 2, 2-trifluoro-ethoxy)-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole. As a characteristic shared with other benzimidazole derivatives (e.g., omeprazole and pantoprazole), lansoprazole can inhibit gastric acid secretion, and thus commonly used as an antiulcer agent. Several methods for preparing Lansoprazole are known. The majority of these methods involve the use of a lansoprazole precursor that contains a thioether group. The thioether group is oxidized in the last step of preparation to form the lansoprazole. These patents (‘098 and ‘333) further describes the oxidation of the thioether group using m-chloroperbenzoic acid, per acid, sodium bromite, sodium hypochlorite, or hydrogen peroxide as the oxidizing agent and the reaction solvent is halogenated hydrocarbon, ether, amide, alcohol, or water.

US 6,002,011 describe the crystallization of Lansoprazole from the same ethanol: water system, containing traces of ammonia. This patent discloses a reslurry method in water, which permits to obtain more stable “solvent free” Lansoprazole. This patent fails to disclose the level of purity for Lansoprazole. In addition, the ethanol and water are difficult to eliminate. Even after intensive drying, Lansoprazole still contains solvent and is unstable under storage. US 6,180,652 describe the presence of sulfone derivative. Formation of sulfone derivative brings about the drawback of low yield of the desired sulfoxide. Although attempts have been made to separate the sulfone derivative from Lansoprazole, it is not a simple task, given their very similar structures and physicochemical properties. This patent also describes a method for separation of Lansprazole from its sulfone derivative, by converting to an acetone complex of the Lansoprazole salt & hence is purified in this method. Lansoprazole and other 2-(2- pyridylmethyl) sulfinylbenzimidazole derivatives tend to lose stability and undergo decomposition when contaminated with traces of a solvent, particularly water, in their crystal structure. It is desirable that the benzimidazole crystals be solvent free (i.e., residual solvent should be reduced to a minimum).

US 6,909,004 describes the method of purifying Lansoprazole, comprising the steps of: a) providing a solution of lansoprazole in a solvent selected from an organic solvent or a mixture of organic solvent and water in the presence of an amine compound; b) combining the provided solution with an acid, and c)isolating the purified Lansoprazole. The amine compound is present in 1:1, mole: mole, ratio relative to the lansoprazole. Solution is in an organic solvent selected from the group consisting of alcohols, acetone, 2-butanone, dimethylformamide and tetrahydrofuran. The alcohol consisting of ethanol, methanol, n-propanol, & iso-propanol.

US 7022859 & US 7060837 provides a method for preparing a substantially pure Lansoprazole containing less than about 0.2% (wt/wt) impurities including sulfone/sulfide derivatives. The present invention also provides a process for recrystallizing Lansoprazole to obtain a Lansoprazole containing less than about 0.1% (wt/wt) water.

US 2004/010151 disclose a method of preparing crystalline Lansoprazole form A, comprising the steps of: a) preparing a solution of Lansoprazole in a solvent selected from the group consisting of methanol, n-butanol, acetone, methylethylketone, ethyl acetate, dimethyl sulfoxide, dimethylforniamide and their mixtures optionally with water; and b) isolating crystalline Lansoprazole form A.

US 2005/020638 describe the process of preparing a stable Lansoprazole, comprising the steps of: a) crystallizing a Lansoprazole from an organic solvent or a mixture of organic solvent and water in the presence of a weak base; and b) isolating a stable Lansoprazole. An amorphous form of Lansoprazole prepared by spray drying method has been described (Farm. Vest. vol. 50, p. 347 (1999)). Curin et al. describe an ethanole solvate form and an ethanole-hydrate form of Lansoprazole (Farm. Vest. vol. 48, pp. 290-291 (1997). Kotar et al. describe two lansoprazole polymorphs, designated as crystalline Lansoprazole forms A and B, (Eur. J. Pharm. Sci. vol. 4, p. 182 (1996 Supp). According to Kotar, each of the crystalline Lansoprazole forms A and B exhibits a different DSC curve. In fact, crystalline Lansoprazole form B is unstable and can undergo a solid-solid transition to form crystalline Lansoprazole form A. No XRD data for crystalline Lansoprazole forms A and B, and fails to disclose processes for preparing these crystalline forms. No indication was found in the literature regarding the existence of other crystalline Lansoprazole forms other than the known forms A, B, ethanolate and ethanolate- hydrate.

WO 00/78729 is discloses a phenomenon of polymorphism in Lansoprazole. The crystalline forms , I and II. The form I find application as an active ingredient of pharmaceutical compositions.

WO 03/082857 disclose a method of preparing crystalline Lansoprazole form A, comprising the steps of: a) preparing a solution of Lansoprazole in a solvent selected from the group consisting of methanol, n-butanol, acetone, methylethylketone, ethyl acetate, dimethyl sulfoxide, dimethylformamide and their mixtures optionally with water; and b) isolating crystalline Lansoprazole form A.

WO 2004/046135 describe the process for preparing a stable Lansoprazole compound, comprising the steps of: a) crystallizing a Lansoprazole from an organic solvent or a mixture of organic solvent and water in the presence of an amine; and b) isolating a stable Lansoprazole compound, wherein the stable Lansoprazole compound comprises greater than 500 ppm and not more than about 3,000 ppm water.

Since proton pump inhibitors of the benzimidazole-type are very susceptible to degradation under acidic or neutral conditions, the reaction mixture is usually worked-up under basic conditions. These basic conditions may decompose any unwanted oxidizing agent still present in the reaction mixture and may also neutralize any acid formed when the oxidizing agent is consumed in the oxidation reaction. The main problem with the oxidation reaction to convert the sulfide intermediates of formula (II) into the sulfoxide compounds of formula (I) is over- oxidation, i.e. oxidation from sulfoxides of formula (I) to sulfones of formula (III) ; N-oxide of formula (IV) & chlorinating impurities ( V).

The formation of sulfones of formula (III) due to over-oxidation is almost impossible to avoid and can be kept to a minimum by performing the oxidation reaction at a low temperature and restricting the amount of oxidizing agent. Typically the amount of oxidizing agent is less than 1 molar equivalent of the starting material, i.e. sulfide intermediates of formula (II), which inevitably results in a less than 100% conversion of starting material. Usually the amount of oxidizing agent is a compromise between maximum conversion of starting material, maximum formation of sulfoxides of formula (I) and minimum formation of unwanted sulfones of formula (III). Chlorinating impurities (V) are observed when chlorinating oxidizing agent such as sodium hypochlorite is used for oxidation reaction. Furthermore removal of the sulfones of formula (III) & chlorinating impurities (V) has often proved to be difficult, time-consuming and costly, in particular when high performance chromatography on an industrial scale is needed. Another problem with the benzimidazole-type is very susceptible to degradation when exposed to high temperatures for removal of solvents during distillation.

Thus, there is continuing need to obtain 2-(2-pyridylmethyl) sulfϊnyl-lH-benzirnidazoles (e.g., Lansoprazole) that are free of contaminants including sulfone and sulfide derivatives. There has also -been a long-felt need for a method to prepare Lansoprazole having reduced water content (<0.1% wt/wt water).

SCHEME : ]

LANSOPRAZOLE (I) SULPHONE (III)

N-OXIDE (IV)

SULPHIDE (II)

+ Chlorinated Impurities

(V)

General Example

10 g of 2- [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methylthio-lH-benzimidazole was suspended in 100 ml chloroform and cooled to -10⁰C. To the above suspension 3.4 g m- chloroperbenzoic acid solution in chloroform was added over a period of 2 hrs at -10 C. After completion of reaction, reaction mass was added to sodium bicarbonate solution (500 ml) and both layers were separated. Organic layer was washed with 2 x 50 ml of hypo solution followed by washing with 3 x 200 ml sodium bicarbonate solution. Both the layers were separated. Chloroform layer was washed with sodium bicarbonate solution (0.5%; 500 ml) at room temperature. Various co-solvents mentioned in Table- 1 were added to organic layer cool slowly to -10 to 10⁰C. Filtered and washed with chilled chloroform (10 ml) followed by sodium bicarbonate solution (0.5%, 100 ml) & dried to get pure Lansoprazole.

SYN

http://www.ijmca.com/File_Folder/116-120.pdf

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Literatures:
Chemical and Pharmaceutical Bulletin, , vol. 38, # 10 p. 2853 – 2858

Literatures:
KRKA, tovarna zdravil, d.d., Novo mesto Patent: EP2030973 A1, 2009 ; Location in patent: Page/Page column 11 ;

Literatures:
RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA SPA Patent: WO2008/77866 A1, 2008 ; Location in patent: Page/Page column 16-17; 19 ;
Yield: ~92%

Patent

Publication numberPriority datePublication dateAssigneeTitle

US4628098A *1984-08-161986-12-09Takeda Chemical Industries, Ltd.2-[2-pyridylmethylthio-(sulfinyl)]benzimidazoles

WO2004018454A1 *2002-08-212004-03-04Teva Pharmaceutical Industries Ltd.A method for the purification of lansoprazole

US20040049045A1 *2000-12-012004-03-11Hideo HashimotoProcess for the crystallization of (r)-or (s)-lansoprazole

Publication numberPriority datePublication dateAssigneeTitle

WO2012004802A12009-07-072012-01-12Council Of Scientific & Industrial ResearchContinuous flow process for the preparation of sulphoxide compounds

CN107964005A *2017-11-102018-04-27扬子江药业集团江苏海慈生物药业有限公司A kind of preparation method of Lansoprazole

References

External links

• “Lansoprazole”. Drug Information Portal. U.S. National Library of Medicine.