LAFUTIDINE

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

• • FRG-8813
  • ATC:A02B

• 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・・・

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 ulcers, duodenal 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 constipation, diarrhea, drug rash, nausea, vomiting 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]

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 Li, Chunchao Wang, Yanan Zhou, and Tiemin Sun* 

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 282077; eidem, 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

Clinical data
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	A02BA08 (WHO)
Identifiers
IUPAC name[show]
CAS Number	118288-08-7
PubChem CID	5282136
ChemSpider	4445337
UNII	49S4O7ADLC
KEGG	D01131
ECHA InfoCard	100.118.935
Chemical and physical data
Formula	C22H29N3O4S
Molar mass	431.54 g/mol
3D model (JSmol)	Interactive image

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

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