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LAFUTIDINE, ラフチジン

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LafutidineChemSpider 2D Image | lafutidine | C22H29N3O4S

Lafutidine.pngLafutidine.svg

LAFUTIDINE

N-[4-[4-(Piperidin-1-ylmethyl)pyridin-2-yloxy]-(Z)-but-2-en-1-yl]-2-(furfurylsulfinyl)acetamide

    • FRG-8813
    • ATC:A02B
  • Use:antisecretory, gastric H2-antagonist
  • (+)-2-[(2-furanylmethyl)sulfinyl]-N-[(2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butenyl]acetamide
  • Formula:C22H29N3O4S
  • MW:431.56 g/mol
  • CAS-RN:118288-08-7
  • (±)-2-(Furfurylsulfinyl)-N-(4-(4-(piperidinomethyl)-2-pyridyl)oxy-(Z)-2-butenyl)acetamide
  • (Z)-2-((2-Furanylmethyl)sulfinyl)-N-(4-((4-(1-piperidinylmethyl)-2-pyridinyl)oxy)-2-butenyl)acetamide
  • 118288-08-7

FRG‐8813、2‐(Furfurylsulfinyl)‐N‐[(Z)‐4‐[[4‐(piperidinomethyl)‐2‐pyridinyl]oxy]‐2‐butenyl]acetamide、ロクチジン、Loctidine、ラフチジン・・・

2-[(furan-2-ylmethyl)sulfinyl]-N-[(2Z)-4-{[4-(piperidin-1-ylmethyl)pyridin-2-yl]oxy}but-2-en-1-yl]acetamide
49S4O7ADLC
7173
Acetamide, 2-[(2-furanylmethyl)sulfinyl]-N-[(2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-yl]- [ACD/Index Name]
lafutidine [INN] [Wiki]
UNII:49S4O7ADLC
(Z)-2-((Furan-2-ylmethyl)sulfinyl)-N-(4-((4-(piperidin-1-ylmethyl)pyridin-2-yl)oxy)but-2-en-1-yl)acetamide

Lafutidine , also named N-[4-[4-(piperidin-1-ylmethyl)pyridin-2-yloxy]-(Z)-but-2-en-1-yl]-2-(furfurylsulfinyl)acetamide, is a histamine H2 receptor antagonist that was first produced in Japan by Taiho and UCB Japan for the oral treatment of peptic ulcers in 2000. In 2010 it was approved for the treatment of mild gastroesophageal reflux disease, and in 2012 it was approved to help improve symptoms of gastric mucosal lesions due to gastritis

Lafutidine (INN) is a second generation histamine H2 receptor antagonist having multimodal mechanism of action and used to treat gastrointestinal disorders. It is marketed in Japan and India.

Medical use

Lafutidine is used to treat gastric ulcersduodenal ulcers, as well as wounds in the lining of the stomach associated with acute gastritis and acute exacerbation of chronic gastritis.[1][2]

Adverse effects

Adverse events observed during clinical trials included constipationdiarrhea, drug rashnauseavomiting and dizziness.[2]

Mechanism of action

Like other H2 receptor antagonists it prevents the secretion of gastric acid.[2] It also activates calcitonin gene-related peptide, resulting in the stimulation of nitric oxide (NO) and regulation of gastric mucosal blood flow, increases somatostatin levels also resulting in less gastric acid secretion, causes the stomach lining to generate more mucin, inhibits neutrophil activation thus preventing injury from inflammation, and blocks the attachment of Helicobacter pylori to gastric cells.[2]

Image result for LAFUTIDINE SYNTHESIS

Trade names

It is marketed in Japan as Stogar by UCB[1] and in India as Lafaxid by Zuventus Healthcare.[2]

N-[4-[4-(Piperidin-1-ylmethyl)pyridin-2-yloxy]-(Z)-but-2-en-1-yl]-2-(furfurylsulfinyl)acetamide 1 as a white solid (15.8 kg, 91.3%).(2,3)

1H NMR (600 MHz, CDCl3): δ 1.43 (m, 2H), 1.56–1.60 (m, 4H), 2.36 (m, 4H), 3.34 (d, 1H, J = 14.4 Hz), 3.40 (s, 2H), 3.59 (d, 1H, J = 14.4 Hz), 4.10 (t, 2H, J = 6.6 Hz), 4.17 (d, 1H, J = 13.8 Hz), 4.31 (d, 1H, J = 13.8 Hz), 4.93 (d, 2H, J = 6.6 Hz), 5.67–5.69 (m, 1H), 5.83–5.87 (m, 1H), 6.39 (dd, 1H, J = 1.8, 3.0 Hz), 6.47 (d, 1H, J = 3.0 Hz), 6.72 (s, 1H), 6.87 (d, 1H, J = 5.4 Hz), 7.19 (s, 1H), 7.43 (d, 1H, J = 1.8 Hz), 8.03 (d, 1H, J = 5.4 Hz).

13C NMR (150 MHz, CDCl3): δ 24.2, 26.0, 26.0, 37.2, 50.2, 53.4, 54.6, 54.6, 61.4, 62.4, 110.8, 111.3, 112.2, 117.7, 128.4, 128.9, 143.3, 143.9, 146.3, 151.5, 163.6, 163.6.

IR (KBr): 3325, 2935, 1638, 1613, 1041 cm–1.

ESI-MS: m/z 431.1.

Increasing the Purity of Lafutidine Using a “Suicide Substrate”

Chengjun Wu Zhen LiChunchao WangYanan Zhou, and Tiemin Sun* 

Key Laboratory of Structure-Based Drug Design and DiscoveryShenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, P. R. China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00070

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00070/suppl_file/op8b00070_si_001.pdf

CLIP

http://www.drugfuture.com/synth/syndata.aspx?ID=145925

EP 0282077; JP 1988225371; JP 1989230556; JP 1989230576; US 4912101

1) The reaction of 2-bromo-4-(piperidin-1-ylmethyl)pyridine (I) with 4-amino-2(Z)-buten-1-ol (II) by means of NaH in THF gives 4-[4-(piperidin-1-ylmethyl)pyridin-2-yloxy]-2(Z)-buten-1-amine (III), which is then condensed with 2-(2-furylmethylsulfinyl)acetic acid (IV) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCD) in dichloromethane.

EP 0582304; JP 1994192195

The condensation of 2-chloro-4-(piperidin-1-ylmethyl)pyridine (V) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (VI) by means of NaH in THF gives 4-(piperidin-1-ylmethyl)-2-[4-(tetrahydropyranyloxy)-2(Z)-butenyloxy)pyridine (VII), which is deprotected with 4-methylbenzenesulfonic acid in methanol, yielding the free butenol (VIII). The acylation of (VIII) with methanesulfonyl chloride in toluene affords the corresponding mesylate (IX), which is finally condensed with 2-(2-furylmethylsulfonyl)acetamide (X) (obtained from the corresponding 4-nitrophenyl ester (XI) with ammonia) by means of potassium tert-butoxide in toluene.

Chem Pharm Bull 1998,46(4),616

A new synthesis of lafutidine has been described: The condensation of 2-bromopyridine-4-carbaldehyde ethylene ketal (I) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (II) by means of NaOH, K2CO3 and tetrabutylammonium bisulfate in refluxing toluene gives the corresponding substitution product (III), which by treatment with pyridinium p-toluenesulfonate (PPTS) in hot ethanol yields the 2(Z)-butenol (IV). The reaction of (IV) with SOCl2 and then with potassium phthalimide (V) affords the substituted phthalimide (VI), which by treatment with hydrazine hydrate in refluxing methanol gives the 2(Z)-butenamine (VII). The condensation of (VII) with 2-(2-furylmethylsulfinyl)acetic acid 4-nitrophenyl ester (VIII) in THF yields the expected amide (IX), which is treated with p-toluenesulfonic acid in refluxing acetone/water to eliminate the ethylene ketal protecting group yilding the aldehyde (X). Finally, this compound is reductocondensed with piperidine (XI) by means of NaBH4 in ethanol.

CLIP

Synthesis Path

Lafutidine
CAS Registry Number: 118288-08-7
CAS Name: 2-[(2-Furanylmethyl)sulfinyl]-N-[(2Z)4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butenyl]-acetamide
Additional Names: 2-(furfurylsulfinyl)-N-[(Z)-4-[[4-(piperidinomethyl)-2-pyridyl]oxy]-2-butenyl]acetamide
Manufacturers’ Codes: FRG-8813
Trademarks: Protecadin (Taiho); Stogar (Fujirebio)
Molecular Formula: C22H29N3O4S
Molecular Weight: 431.55
Percent Composition: C 61.23%, H 6.77%, N 9.74%, O 14.83%, S 7.43%
Literature References: Second generation histamine H2-receptor antagonist. Prepn of racemate: N. Hirakawa et al., EP 282077eidem, US 4912101 (1988, 1990 both to Fujirebio); and pharmacology: eidem, Chem. Pharm. Bull. 46, 616 (1998). Pharmacology: S. Onodera et al., Jpn. J. Pharmacol. 68, 161 (1995). Mode of action study: M. Umeda et al., J. Gastroenterol. Hepatol. 14, 859 (1999). Gastroprotective effects in rats: H. Ajioka et al., Pharmacology 61, 83 (2000). Clinical pharmacokinetics: S. Haruki et al.,Yakuri to Chiryo 23, 3049 (1995). Toxicology study: A. Broadmeadow et al., Oyo Yakuri 50, 167 (1995).
Properties: Prepd as the (±) mixture, crystals from benzene-hexane, mp 92.7-94.9°. Slightly bitter taste. Freely sol in DMF, glacial acetic acid; sol in methanol; sparingly sol in dehydrated ethanol; very slightly sol in ether. Practically insol in water.
Melting point: mp 92.7-94.9°
Therap-Cat: Antiulcerative.
Keywords: Antiulcerative; Histamine H2-Receptor Antagonist.

References

References

  1. Jump up to:a b UCB Japan Revised: April 2005 Stogar tablets
  2. Jump up to:a b c d e Zuventus Healthcare Ltd. India Lafaxid tablets
    • a EP 582 304 (Fujirebio; 5.8.1993; J-prior. 7.8.1992).
  • preparation of 2-benzenesulfonyl-4-methylpyridine:

    • EP 931 790 (Kuraray; 26.1.1999; J-prior. 26.1.1998).
  • chlorination of 2-benzenesulfonyl-4-methylpyridine:

    • JP 10 231 288 (Kuraray; 2.9.1998; J-prior. 21.2.1997).
    • WO 9 626 188 (Sagami Res. Center; 21.2.1996; J-prior. 22.2.1995).
    • b EP 282 077 (Fujirebio; 11.3.1988; J-prior. 13.3.1987).
    •  US 4 912 101 (Fujirebio; 27.3.1990; J-prior. 13.3.1987).
  • preparation of I:

    • JP 10 231 288 (Kuraray; 2.9.1998; J-prior. 21.2.1997).
  • chlorination of 2-chloromethylpyridines forming 2-chloro-4-trichloromethylpyridine:

    • EP 557 967 (Central Glass Co.; 1.9.1993; J-prior. 24.2.1993).
  • treatment of I with (Z)-4-(tetrahydro-2H-pyran-2-yloxy)-2-buten-1-ol:

    • US 5 382 589 (Fujirebio; 17.1.1995; J-prior. 27.1.1992).
  • preparation of furfuryl acetate and derivatives:

    • JP 8 198 844 (Fujirebio; 6.8.1996; J-prior. 23.1.1995).
    • JP 8 198 843 (Fujirebio; 6.8.1996; J-prior. 23.1.1995).
    • JP 07 010 860 (Central Glass Co.; 13.1.1995; J-prior. 25.6.1993).
    • JP 07 010 864 (Central Glass Co.; 13.1.1995; J-prior. 25.6.1993).
  • 2-(furfurylsulfinyl)acetic acid nitrophenyl ester:

    • JP 07 010 862 (Central Glass Co.; 13.1.1995; J-prior. 25.6.1993).
  • 4-(tetrahydro-2-pyranyloxy)-2(Z)-buten-1-ol from 2(Z)-butene-1,4-diol:

    • Nishiguchi, T. et al.: J. Org. Chem. (JOCEAH) 63, 23, 8183 (1998).
    • Davis, K. J. et al.: Synth. Commun. (SYNCAV) 29, 10, 1679 (1999).
    • Nishiguchi, T. et al.: J. Chem. Soc., Perkin Trans. 1 (JCPRB4) 1995, 24, 2491.

/////////////////LAFUTIDINE, ラフチジン , FRG-8813, ATC:A02B

FRG‐8813
2‐(Furfurylsulfinyl)‐N‐[(Z)‐4‐[[4‐(piperidinomethyl)‐2‐pyridinyl]oxy]‐2‐butenyl]acetamide
ロクチジン
Loctidine
ラフチジン
Laftidine
2‐[[(2‐Furyl)methyl]sulfinyl]‐N‐[(Z)‐4‐[[4‐(piperidinomethyl)‐2‐pyridyl]oxy]‐2‐butenyl]acetamide
N‐[(Z)‐4‐[4‐(Piperidinomethyl)‐2‐pyridyloxy]‐2‐butenyl]‐2‐(furfurylsulfinyl)acetamide
(Z)‐2‐フルフリルスルフィニル‐N‐[4‐(4‐ピペリジノメチル‐2‐ピリジルオキシ)‐2‐ブテニル]アセトアミド
ストガー
Stogar
プロテカジン
Protecadin
(+)‐ラフチジン
(+)‐Laftidine
ラフルチジン
Laflutidine
(Z)‐2‐Furfurylsulfinyl‐N‐[4‐(4‐piperidinomethyl‐2‐pyridyloxy)‐2‐butenyl]acetamide
2‐[[(2‐フリル)メチル]スルフィニル]‐N‐[(Z)‐4‐[[4‐(ピペリジノメチル)‐2‐ピリジル]オキシ]‐2‐ブテニル]アセトアミド
N‐[(Z)‐4‐[4‐(ピペリジノメチル)‐2‐ピリジルオキシ]‐2‐ブテニル]‐2‐(フルフリルスルフィニル)アセトアミド
2‐(フルフリルスルフィニル)‐N‐[(Z)‐4‐[[4‐(ピペリジノメチル)‐2‐ピリジニル]オキシ]‐2‐ブテニル]アセトアミド

C1CCN(CC1)CC2=CC(=NC=C2)OCC=CCNC(=O)CS(=O)CC3=CC=CO3

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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