Pranlukast

PRANLUKAST

Antiasthmatic.

• Benzamide, N-(4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl)-4-(4-phenylbutoxy)-
•  N-(4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl)-p-(4-phenylbutoxy)benzamide
• 4-Oxo-8-(4-(4-phenylbutoxy)benzoylamino)-2-(tetrazol-5-yl)-4H-1-benzopyran
• N-(4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl)-p-(4-phenylbutoxy)benzamide

Launched – 1995 japan

hemihydrate, 103177-37-3 anhydrous, 103180-28-5 (monosodium salt)

150821-03-7, C27 H23 N5 O4 . H2O, 499.5179

Ono-1078
Ono-RS-411
RS-411
SB-205312
Ono-1070 (monosodium salt)

 Ultair; Ono-1078; HY-B0290;

• Azlaire
• CCN 00401
• ONO 1078
• ONO-1078
• ONO-RS 411
• Pranlukast
• RS 411
• SB 205312
• UNII-TB8Z891092

N-[4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-4-(4-phenylbutoxy)benzamide hemihydrate

Ono (Originator)Schering-Plough (Licensee)

This is described in…………

J Med Chem 1988, 31(1): 84,

WO 2010002075,

Synth Commun 1997, 27(6): 1065,

WO 1994012492

Leukotriene antagonist.

Prepn: M. Toda et al., EP 173516; eidem, US 4780469 (1986, 1988 both to Ono);

H. Nakai et al., J. Med. Chem. 31, 84 (1988).

Pharmacology: T. Obata et al., Adv. Prostaglandin Thromboxane Leukotriene Res. 15, 229 (1985); idem et al., ibid. 17,540 (1987).

Clinical evaluations in asthma: Y. Taniguchi et al., J. Allergy Clin. Immunol. 92, 507 (1993); H. Yamamoto et al. Am. J. Respir. Crit. Care Med. 150, 254 (1994).

AU 8546462; EP 0173516; JP 8650977; US 4780469; US 4939141

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. It antagonizes or reduces bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.

 Pranlukast

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.‘s Singulair (montelukast). It is widely used in Japan.

synthesis
http://newdrugapprovals.org/2014/10/21/pranlukast/

………………….

http://www.google.com/patents/WO2010002075A1?cl=en

Pranlukast and its hydrates come into the market as a capsule of Onon® Cap. (112.5 mg pranlukast hydrates/capsule, Dong-A Pharmaceutical).

The conventional method for preparing pranlukast was disclosed in US Pat. No. 5,587,483 and pranlukart is prepared by the following reaction formula I.

Reaction Formula I

As described in the reaction formula I, the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride. The resulting compound is reacted with the compound represented by formula 4. The compound (n = 4) represented by formula 5 is reacted with the tetrazol derivative represented by formula 6 to introduce tetrazol group and then benzopyran ring is formed, preparing pranlukast. However, the preparation method according to the reaction formula I has quite a few problems: (a) difficult manipulation due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature when the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride;

(b) hard elimination of thionyl chlorides toxic in a body after terminating the reactions; (c) requirement of base in an equivalent ratio of above 4 to collect the compound represented by formula 7; (d) unsuitability of massive production in a economical area because the compound is modified into a form of natrium salt and then purified for removal of contaminants after preparing pranlukart.

On the other hand, as described in the following reaction formula II in US Pat. No. 5,874,593, nitril compounds of formula 8 are reacted with hydrazine to prepare amidrazone compounds of formula 9a and 9b, and then pranlukart is fabricated by performing a tetrazol ring reaction using nitrous acids.

Reaction Formula II

However, the preparation method according to the reaction formula II has also the following difficulties: (a) it is difficult to perform the method due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature to obtain the acid chloride derivative in the preparation of the compounds represented by formula 8; (b) it is very difficult and toxic in body to eliminate thionyl chlorides after terminating the reactions; (c) it is not easy to massively produce the compounds of interest in an industrial-scale because much hydrazine toxic in body and nitrogen oxides harmful in environment are generated and unstable nitrous acids are used during the reactions.

Likewise, US Pat. No. 5,874,593, as described in the following reaction formula III, discloses that benzoic derivatives of formula 10′ are reacted with oxalyl chlorides to isolate acid chlorides represented by formula 11′, and the resulting acid chlorides are reacted with benzopyran amine derivatives containing tetrazol of formula 12, producing various derivatives containing pranlukart.

Reaction Formula III

( I D’ ] (H ‘ )

Oxalyl chlorides are massively used because the preparation method according to the reaction formula III is very expensive cost and has highly hygroscopic characteristics. In addition, the method has to be carried out under violent conditions that the temperature is increased up to around reflux temperature using 1,2- dichloroethanol as a solvent and further reacted for 1 hr. It is also difficult to remove harmful carbon monoxide and chlorine gases massively generated in elimination of oxalyl chloride after terminating the reactions, and it is not feasible to be applied into an industrial mass-production because the reaction is carried out under conditions of anhydrous and inactive gases

EXAMPLE 1: Preparation of Pranlukart Hemihydrates 4-(4-phenylbutoxy)benzoic acid (29.1 g; 1.1 equivalent ratio; prepared according to the method disclosed in US Pat. No. 4,780,469) was dissolved in 80 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (14.2 g, 1.2 equivalent ratio, Aldrich) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H- 1-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio; prepared according to the method disclosed in US Pat. No. 4,780,469) and triethylamine (TEA, 10.1 g, 1 equivalent ratio, Aldrich) dissolved in 80 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C.

The reaction mixture was mixed with 300 ml H2O and stirred for 1 hr at 250C. The solid material obtained by filtering the solid material produced was washed with 100 ml H2O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 47.0 g pranlukart hemihydrates (yield rate: 98%): melting point 231-233°C (decomposition); 1H-NMR (DMSO-d6, 300 MHz) δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0 (m, 2H), 8.3 (t, IH), 10.0 (bs, IH).