(4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE

(4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE Chemische Eigenschaften,Einsatz,Produktion Methoden

• S-Sätze Betriebsanweisung:

  S22:Staub nicht einatmen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.

• Originator

  Vapiprost,GlaxoSmithKline

• Verwenden

  Antagonist (thromboxane A2).

• Verwenden

  Vapiprost is a potent and specific thromboxane A2 receptor blocking drug on platelets, vascular and airways smooth muscle.

• Manufacturing Process

  [1R-[1α(Z),2β,3β,5α]]-7-[5-([1,1'-Biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1- piperidinyl)cyclopentyl]-4-heptenoic acid may be prepared in 9 steps: 1). [1R-(endo,anti)]-(+)-5-[[4'-Methoxy-(1,1'-biphenyl)-4-yl]methoxy]-7-(1- piperidinyl)bicyclo[2.2.1]heptan-2-one: A mixture of 1-[1R-(endo,anti)]-(+)-5-Hydroxy-7-(1- piperidinyl)bicyclo[2.2.1]heptan-2-one (30.51 g), benzyltriethylammonium chloride (6.65 g) and 4-(bromomethyl)-4'-methoxy(1,1'-biphenyl) (52.6 g) in CH2Cl2 (365 ml) and 17 N NaOH (325 ml) was vigorously stirred at ambient temperature for 18 h. The mixture was diluted with water (1 L) and extracted with CH2Cl2 (3x150 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ether-petroleum ether (boiling point 60°C) 1:1 followed by 7:3 as eluent to give the title compound (40.2 g). A portion was recrystallized from ether-petroleum ether (boiling point 60°C). MP: 109.5-110.5°C [α]D23 =+22.7° (CHCl3)
  2). [1R-(endo,anti)]-(-)-6-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy]-8-(1- piperidinyl)-2-oxabicyclo[3.2.1]octan-3-one: A solution of peracetic acid in acetic acid (5.6 M, 124 ml) was added slowly to a stirred mixture of [1R(endo,anti)]-(+)-5-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy]-7-(1- piperidinyl)bicyclo[2.2.1]heptan-2-one (42 g) in CH2Cl2 (235 ml), 2 N H2SO4 (29 ml) and water (159 ml) and the mixture stirred at ambient temperature for 24 h. The mixture was adjusted to ca. pH 7 using 5 N NaOH and pH 6.5 phosphate buffer then extracted with CH2Cl2 (3x200 ml). The combined organic extracts were added to an excess of sodium metabisulphite solution and stirred for 24 h. The mixture was extracted with ethyl acetate (1x500, 2x250 ml) and the combined organic extracts were dried and evaporated and the residue was purified by chromatography using 1:1 ethyl acetate-petroleum ether as eluent to give the title compound (24.4 g). A portion was recrystallized from ethyl acetatepetroleum ether MP: 116.5-117.5°C [α] D23 =-24.5° (CHCl3).
  3). [1R-(1α,2β,3α,5α)]-(3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)-4- yl]methoxy]-2-(1-piperidinyl)cyclopentane acetaldehyde: Diisobutylaluminum hydride in hexane (1 M, 114 ml) was added slowly to a cold (-70°C) stirred solution of the above made compound from item 3 (24 g) in CH2Cl2 (240 ml). After 0.5 h methanol (240 ml) was added, slowly at first, and the mixture was stirred at ambient temperature for 16 h. The precipitate was filtered off and the filtrate evaporated to give the title compound as a foam (24.1 g).
  4). [1R-(1α,2β,3α,5α)]-(+)-4-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy]-3-(3- methoxy-2-propenyl)-2-(1-piperidinyl)cyclopentanol, hydrochloride: A solution of [1R-(1α,2β,3α,5α)]-(3-Hyoroxy-5-[[4'-methoxy(1,1'-biphenyl)-4- yl]methoxy]-2-(1-piperidinyl)cyclopentane acetaldehyde (24.1 g) in THF (75 ml) was added to a cooled (-5° to 0°C), stirred solution of the ylid derived from methoxymethyltriphenylphosphonium chloride (78 g) and potassium tertbutoxide (25.5 g) in THF (800 ml). After 1.5 h methanol (100 ml) was added and the solvents removed in vacuo. The residue in pH 6.5 phosphate buffer (600 ml) was extracted with CH2Cl2 (3x150 ml) and the combined extracts were dried and evaporated. The residue was purified by chromatography using 4:1 ethyl acetate-methanol as eluent to give the title compound, base as an oil (24.8 g). A portion was converted into the hydrochloride salt; m.p. 150- 151°C (dec.), [α]D23 = +38.1 (CHCl3).
  5). [1 R-(1α,2β,3α,5α)-(+)-3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)-4- yl]methoxy]-2-(1-piperidinyl)cyclopentanepropanol, hydrochloride: A solution of the end product from item4 (24.3 g) in 2 N HCl (55 ml) and acetone (250 ml) was stirred at ambient temperature for 1 h. Most of the acetone was removed in vacuo and the residue in water was extracted with CH2Cl2 (3x150 ml). The combined extracts were dried and evaporated to give a solid (23.6 g). A portion was triturated with ether to give the title compound as a p

• Therapeutic Function

  Thomboxane A2-antagonist

• Biologische Aktivität

  Potent thromboxane A 2 (TP) receptor antagonist. Inhibits platelet aggregation (pA 2 ~ 8.3) and relaxes vascular and airway smooth muscle (pA 2 = 7.9-10.3).

(4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE Upstream-Materialien And Downstream Produkte

(4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(14)Suppliers