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

 

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

Toda synthetic complete with 3 – nitro-2 – hydroxyphenyl ko one for raw materials, ni ko with oxalic ester Claisen condensation occurs, and then heated to reflux for cyclization to construct benzo pyran ring; dehydrated by an amide synthesized ring cyano group, the cyano compound and then with sodium azide tetrazole synthesis. The nitro group on the compound in 5% Pd / C catalyzed hydrogenation of amino acid reacted with the compound Pranlukast held. This method directly using 4 – (4 – phenyl-butoxy)-benzoic acid reaction. Synthetic route is as follows:

[0006]

[0007]

[0008] ② Robert Graham and routes are routes to I-bromo-butane as a raw material, were used as a palladium catalyst, ligand compound formylation carbonylation reactions and condensation of potassium tert-butoxide, closed dehydration under acidic conditions benzopyran ring method. Synthetic route is as follows:

[0009] Robert routes:

[0010]

[0011] Graham route:

[0012]

[0013] The two synthetic routes are not disclosed in the I-Bromo butane feedstock pathway.

[0014] ③ Masayohi 2_ cyano synthetic route to a benzopyran derivative and hydrogen sulfide gas in the base-catalyzed addition reaction of 2 – thiocarbamoylbenzothiazol and pyran derivatives, and then were reacted with anhydrous hydrazine group hydrazone, with sodium nitrite under acidic conditions nitrosation reaction occurs tetrazole ring. Synthetic route is as follows:

[0015]

[0016] The materials used are not mentioned route synthesis method, it is only reflected in the improvement of the synthesis of the tetrazole ring.

[0017] ④ Giles, Hideki and Hayler are tetrazole substituent on the increase, making it easier condensation reaction, but the synthesis of substituted on the nitrogen with tetrazole difficult, and ultimately elimination reaction of lithium used tetrahydro aluminum and other hazardous reagents, is not easy to Eri industrialization. Reaction scheme is as follows:

[0018]

[0019] ⑤ Lee NK with 4_ (4_ Phenylbutoxy) benzonitrile and 2_ hydroxy _3_ iodobenzene ko 1H_4_ thiazolyl ketone and ester ko _5_ acid, concentrated sulfuric acid catalyzed cyclization iodide copper and potassium phosphate removal under the action of hydrogen iodide get Pranlukast held. Reaction scheme is as follows:

[0021] does not mention the route starting 4 – (4 – phenyl-butoxy)-benzonitrile synthesis method, while two – hydroxy – 3 – Synthesis of iodobenzene ko difficult one.

The synthesis method comprises the following steps: a. 4 – Synthesis of chlorobutanol THF was added concentrated hydrochloric acid, feeding the mass ratio of I: I. 389 ~ 5. 556,45-80 ° C was stirred for 5-18h, cooled, extracted with methylene chloride, removal of the solvent, distillation under reduced pressure to give 4 – chlorobutanol; b. 4 – phenyl butanol take benzene, aluminum chloride mixture ,0-25 ° C solution of 4 – chlorobutanol, reaction 5 -10h then poured into ice-water, a liquid, in addition to homogeneous solution U, distillation under reduced pressure, and the resulting colorless transparent liquid that is, 4 – phenyl butanol; c. I-bromo-4 – phenyl butane synthesis of 4 – phenyl butanol 40% hydrobromic acid mixture, feeding the mass ratio of I: 2. 857 ~ 11. 428, heat refluxing, cooling, liquid separation, the organic solvent divided by distillation under reduced pressure to give I-bromo-4 – phenyl butane; d. Synthesis of methyl p-hydroxybenzoate take-hydroxybenzoic acid and methanol, concentrated sulfuric acid and refluxed for 5-20h spin methanol, poured into cold water to precipitate a white solid which was filtered and dried to give the hydroxy benzoate; e. 4 – (4 – phenyl-butoxy)-benzoic acid methyl ester _ take I-bromo-4 – phenyl butane,

DMF, toluene, methyl p-hydroxybenzoate and potassium carbonate, a reflux 5 ~ 20h, cooling water, extracted with toluene, light yellow liquid rotary evaporation, recrystallization, and the resulting white solid, that is, 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester; f. 4 – (4 – phenyl-butoxy yl) – benzoic acid taken 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester, 15% NaOH solution was refluxed for I ~ 5h, cooled, acidified, filtered and dried to give 4 – (4 – phenylbutyrate oxy) – benzoic acid; g. sprinkle bromophenyl acetic acid ester molar ratio Preparation of I: I ~ I. 5: O. I ~ I of bromophenol, acetic anhydride, pyridine feeding, reflux 3 ~ 10h, distilled pyridine, acetic acid and excess acetic anhydride distilled under reduced pressure to give the acetic acid esters bromophenol; h. 5 – bromo-2 – Preparation of light taken acetophenone molar ratio of I: I ~ 5: I of acetic acid bromophenol esters, aluminum chloride, tetrachlorethylene for feeding, reflux O. 5 ~ 5. 5h, cooled, the reaction solution was poured into 5% hydrochloric acid and extracted with methylene chloride, the solvent evaporated under reduced pressure, to obtain a gray crystalline 5 – bromo-2 – Light acetophenone; i. 5 – bromo-3 – nitro-2 – Preparation of light acetophenone take 5 – bromo-2 – Light acetophenone, carbon tetrachloride, 50 ~ 90 ° C is added dropwise nitric acid, reflux I ~ 4h, cooled, filtered, and the resulting yellow solid which is 5 – bromo-3 – nitro-2 – hydroxyacetophenone; j. 3 – amino-2 – Light benzene ethanone Preparation of 5 – bromo-3 – nitro-2 – hydroxyacetophenone, 5% Pd / C, methylene chloride, methanol, concentrated hydrochloric acid, water, hydrogenation; the end of the reaction mixture was filtered, the filtrate was The solvent was removed, neutralized with sodium bicarbonate, and the resulting yellow solid ginger i.e., 3 – amino-2 – hydroxyacetophenone; k. 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 _ light base Preparation of acetophenone 4 – (4 – phenyl-butoxy)-benzoic acid, toluene, DMF, 45 ~ 105 ° C was added dropwise SOCl2, 30min the reaction liquid droplets to the 3 – amino-2 – hydroxyphenyl toluene solution of ethyl ketone, the reaction 3 ~ 10h, cooled, neutralized with dilute hydrochloric acid, extracted with toluene, rotary evaporation, and the resulting pale yellow crystals is 3 – [4 – (4_ phenylbutoxy) benzamido] 2_-hydroxyacetophenone; I. 2 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol synthetic sodium, THF, 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – hydroxyacetophenone, diethyl oxalate 4 ~ IOh After stirring the reaction was poured into dilute hydrochloric acid to precipitate the yellow solid which was filtered, and the resulting product, i.e. 2 – [4 – (4_ phenylbutoxy) benzamido] _6_ [1,3 – dioxo-3 – ethoxy propyl intended yl] phenyl discretion ·; m. 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran take 2 – [4 – (4 – phenyl-butoxy yl) benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol, THF, force mouth heat, the addition of concentrated hydrochloric acid, refluxed for 8 ~ 15h, cooled, filtered, and the resulting white solid,

that is, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran; η. 4 – oxo-8 – [ 4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran synthesis take four – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – ethoxycarbonyl-4Η-benzopyran was dissolved in DMF,

and leads to dry ammonia gas, the reaction solution changed from yellow to red, the reaction solution was poured into cold water, adjusted to acidic, and filtered to give the product 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran; P. 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4Η-benzopyran take DMF, S0C12, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoic amido] _2_ aminocarbonyl-4H-benzopyran, O ~ 15 ° C under stirring for 2 ~ IOh poured into cold water, filtered, and the resulting white solid that is, 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4H-benzopyran; q. Synthesis of pranlukast take four – oxo-8 – [4 – (4 – phenyl-butoxy) benzoyl amino]-2_ cyano-4H-benzopyran, ammonium chloride, sodium azide, DMF, heating I ~ 8h then poured into ice-water, dilute hydrochloric acid, filtered, and the resulting white solid that the final product Pranlukast.

The reaction of ethyl 8-nitro-4-oxo-1-benzopyran-2-carboxylate (I) with ammonia in methanol gives the corresponding amide (II), which is dehydrated with POCl3 yielding 2-cyano-8-nitro-1-benzopyran-4-one (III). The cyclization of (III) with sodium azide by means of pyridinium chloride in hot DMF affords 8-nitro-2-(tetrazol-5-yl)-1-benzopyran-4-one (IV), which is hydrogenated with H2 over Pd/C in methanol – HCl giving 8-amino-2-(tetrazol-5-yl)-1-benzopyran-4-one (V). Finally, this compound is condensed with 4-(4-phenylbutoxy)benzoic acid (VI) by means of oxalyl chloride in dichloromethane-pyridine\

………………………..

 

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).

EXAMPLE 2: Preparation of Pranlukart Hemihydrates – Substitution of the Chlorinating Agent

4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 0⁰C and then oxalyl chloride (15.2 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) and triethylamine (TEA, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution 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 25°C. 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 43.3 g pranlukart hemihydrates (yield rate: 92%).

EXAMPLE 3: Preparation of Pranlukart Hemihydrates – Change of Base Condition

4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 0⁰C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) 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-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and pyridine (7.9 g, 1 equivalent ratio, Aldrich) dissolved in 80 ml dimethylacetamide (DMAC) solution 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 25°C. 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 45.6 g pranlukart hemihydrates (yield rate: 95%).

EXAMPLE 4: Preparation of Pranlukart Hemihydrates – Change of Reaction Temperature Condition

4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 0⁰C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at O⁰C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 50⁰C. The reaction mixture was mixed with 300 ml H₂O and stirred for 1 hr at 50⁰C. 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 45.6 g pranlukart hemihydrates (yield rate: 95%).

EXAMPLE 5: Preparation of Pranlukart Hemihydrates – Substitution of Reaction Solvent 4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml N-methylpyrrolidine (NMP, Aldrich) at O⁰C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) 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-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml N-methylpyrrolidine (NMP) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 25⁰C. The reaction mixture was mixed with 300 ml H₂O and stirred for 1 hr at 25°C.

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 43.3 g pranlukart hemihydrates (yield rate: 90%).

EXAMPLE 6: Preparation of Pranlukart Hemihydrates – Equivalent Ratio Change of the Chlorinating Agent

4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 0⁰C and then thionyl chloride (14.2 g, 1 equivalent ratio) 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-l-benzopyran hydrochloride salt (26.7 g, 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 25°C.

The reaction mixture was mixed with 300 ml H₂O and stirred for 1 hr at 25°C. 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 44.6 g pranlukart hemihydrates (yield rate: 93%).

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