Ciprostene calcium

(5Z)-9β-Methyl-6a-carbaprostaglandin I₂, calcium salt, 9-β-methylcarbacyclin,

Restenosis Treatment of Antiplatelet Therapy

81703-55-1 (anhydrous ca salt)
81845-44-5 (free base, anhydrous)

U-61431F (anhydrous)

Pfizer (Originator)

CIPROSTENE Ca

Carbacyclin and closely related compounds are known in the art. See Japanese Kokia 63,059 and 63,060, also abstracted respectively as Derwent Farmdoc CPI Numbers 48154B/26 and 48155B/26. See also British published specifications 2,012,265 and German Offenlegungsschrift 2,900,352, abstracted as Derwent Farmdoc CPI Number 54825B/30. See also British published applications 2,017,699, 2,014,143 and 2,013,661.

The synthesis of carbacyclin and related compounds is also reported in the chemical literature, as follows: Morton, D. R., et al., J. Organic Chemistry, 44:2880 (1979); Shibasaki, M., et al. Tetrahedron Letters, 433-436 (1979); Kojima, K., et al., Tetrahedron Letters, 3743-3746 (1978); Nicolaou, K. C., et al., J. Chem. Soc., Chemical Communications, 1067-1068 (1978); Sugie A., et al., Tetrahedron Letters 2607-2610 (1979); Shibasaki, M., Chemistry Letters, 1299-1300 (1979), and Hayashi, M., Chem. Lett. 1437-40 (1979); and Li, Tsung-tee, “A Facial Synthesis of 9(0)-Methano-prostacyclin”, Abstract No. 378, (Organic Chemistry), and P. A. Aristoff, “Synthesis of 6a-Carbaprostacyclin I.sub.2 “, Abstract No. 236 (Organic Chemistry) both at Abstract of Papers (Part II) Second Congress of the North American Continent, San Francisco, Calif. (Las Vegas, Nev.), USA, 24-29 August 1980.

7-Oxo and 7-hydroxy-CBA.sub.2 compounds are apparently disclosed in U.S. Pat. No. 4,192,891. 19-Hydroxy-CBA.sub.2 compounds are disclosed in U.S. Ser. No. 054,811, filed July 5, 1979. CBA.sub.2 aromatic esters are disclosed in U.S. Pat. No. 4,180,657. 11-Deoxy-Δ.sup.10 – or Δ.sup.11 -CBA.sub.2 compounds are described in Japanese Kokai 77/24,865, published Feb. 24, 1979.

Prostaglandin E.sub.1 (3-hydroxy-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneheptanoic acid) is a naturally occurring prostaglandin and was one of the first to be isolated and characterised. It is available commercially for the treatment of peripheral vascular disease.

Prostacyclin (otherwise known as epoprostenol and PGI.sub.2) is also a natural prostaglandin occurring within the arterial wall of mammals. It has potent vasodilatory and antiplatelet properties and is available commercially as its sodium salt, sodium epoprostenol, for use in extracorporeal circuits during cardiopulmonary bypass, renal dialysis, and charcoal haemoperfusion. A number of recent publications in the literature have suggested that prostacyclin may also have fibrinolytic activity (J. Pharmac. Exp. Therap. 1982, 222(3), 544 to 549 and Thrombos, Res., 1983, 29, 655 to 660). Similar reports have also occurred for the prostacyclin analogue, iloprost (Brit. J. Pharmac., 1985, 86, 8138 and Thromb. Haemost., 1983, 50, 893). It has also been suggested that prostacyclin augments the thrombolytic activity of streptokinase (J. Cardiovasc. Pharmac., 1985, 7, 739 to 746).

A number of prostacyclin analogues have also been synthesised and evaluated as antithrombotic or antiplatelet agents (Circulation, 1985, 72(6), 1219 to 1225 and Progress in Medicinal Chemistry, 1984, 21, 237 to 279).

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Treatment of the optically pure lactone (I) with lithium dimethyl methylphosphonate in tetrahydrofuran gives hemiacetal (II), which is oxidized to the diketone (III) using Jones’ reagent in acetone. Then in the key step, compound (III) cyclizes to enone (IV) using potassium carbonate and 18-crown-6 in warm toluene. Lithium dimethyl cuprate addition to enone (IV) in ether gives ketone (V), which is converted to acid (VI) (a 1:1 mixture of E and Z olefins at C-5) using (4-carboxybutyl)triphenylphosphorane in dimethyl sulfoxide. Cleavage of the alcohol-protecting groups in (VI) with an acetic acid-water-tetrahydrofuran mixture followed by chromatography to remove the 5-E isomer affords 9-methylcarbacyclin (VII). Finally, treatment of (VII) with calcium oxide in tetrahydrofuran gives U-61431F (ciprostene calcium).

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ciprostene ca

J Org Chem 1983,v 48, 26,  pg 5341 as label 10, mp , ir given

http://pubs.acs.org/doi/pdf/10.1021/jo00174a035  pdf dowload

Ciprostene calcium Calcium salt  10

5Z -9BETA-Methyl-6alpha-carbaprostaglandin I2, Calcium Salt (10). A suspension of 350 mg (0.96 mmol) of acid 8b, 23.6 mg (0.42 mmol) of calcium oxide, 5 mL of water, and 4 mL of THF was heated for 20 min at 50 “C and filtered, and the solvents were removed under reduced pressure. The resulting foam was dissolved in 4 mL of THF and then added dropwise to 50 mL of  ether. The resulting suspension was stirred for 15 min, then filtered (rinsing with ether) to give 265 mg (82%) of calcium salt

10 as a white solid: mp 101-108 OC;

IR (mull) 3330,1670,1555, 1455, 1345, 1310, 1270, 1075, 1020, 970 cm-‘.

Anal. Calcd for C4H,,08Ca: C, 68.89; H, 9.20; Ca, 5.23. Found: C, 68.55; H, 8.94; Ca, 5.29

Ciprostene calcium FREE BASE 8b

(5Z)-9BETA-Methyl-6ALPHA-carbaprostaglandin I2 (8b) and (5E)-9BETA-Methyl-6a-carbaprostaglandin I2 (9b).

A solution of 17 mmol of sodium methylsulfinylmethide (prepared from 0.81 g of a 50% sodium hydride dispersion and 66 mL of Me2SO) was cooled to 15 “C, treated with 4.20 g (9.60 mmol) of (4-carboxybuty1)triphenylphosphonium bromide, stirred for 20 min, treated with 0.80 g (1.78 mmol) of ketone 6b in 12 mL of THF, stirred for 5 hat 45 “C, cooled to 0 “C, treated with 6 mL of water, stirred for 1 h, acidified with a solution of 5 mL of HZSO, in 100 mL of 1:1 water-brine, and extracted with ether. The ether extracts were washed several times with water and then with brine and were dried (Na2S04). The solvents were removed under reduced pressure and the residue was chromatographed on acid-washed silica gel eluted with 20% ethyl acetate in hexane to give 0.932 g (98%) of acid mixture 7b as an oil (Rf 0.38 in 65:34:1 hexane ethyl acetate-acetic acid). Without further purification, 0.75 g (1.41 mmol) of acid 7b was heated at 45 “C in a solution of 5 mL of THF, 7.5 mL of water, and 15 mL of glacial acetic acid. After 3 h the solution was cooled and partitioned between brine and 32 ethyl acetatehexme. The organic portion was dried (Na2S04) and the solvent removed under reduced pressure (using a toluene azeotrope to remove any remaining acetic acid). The crude product was chromatographed on HPLC silica gel eluted with 1000:405 chloroform-methanol-acetic acid to give 0.24 g (47%) of acid 8b as a colorless oil (Rf 0.25) and 0.23 g (45%) of acid 9b as a colorless oil (Rf 0.27). 8b:

NMR 6 0.89 (t, J = 5 Hz, 3 H), 1.02-2.8 (m including 3 H singlet at 6 1.08, 25 H), 3.5-4.35 (m, 2 H), 5.0-5.7 (m, 3 H), 6.05
(br s, 3 H);

IR (fh) 3340,2660,1710,1240,1205,1175,1130,1075, 1055,1020,970 cm-*;

mass spectrum, calcd for C30H5704Si3 [M’ – CH3 of tris(trimethylsily1) derivative],

m/e 565.3564; found, m/e 565.3552

DATA OF 9b ……….NOT DESIRED COMPD…please note

9b: NMR 6 0.90 (t, J = 5 Hz, 3 H), 1.06 (s, 3 H), 1.1-2.6 (m,22 H), 3.5-4.3 (m, 2 H), 5.0-5.7 (m, 3 H), 5.93 (br s, 3 H); IR (film) 3340, 2660, 1710, 1300, 1240, 1175, 1130, 1075, 1055, 1020, 970
cm-‘; mass spectrum, calcd for C30H5704Si3 [M+ – CH3 of tris-(trimethylsilyl) derivative], m/e 565.3564; found, m/e 565.3541

References

1. Drugs Fut 1985, 10(11): 900
2. Journal of Organic Chemistry, 1983 ,  vol. 48,  26  pg. 5341 – 5348 entry 10, mp,101 – 108 °CU-61,431F, a stable prostacyclin analogue, inhibits the proliferation of bovine vascular smooth muscle cells with little antiproliferative effect on endothelial cells.Shirotani M, Yui Y, Hattori R, Kawai C.Prostaglandins. 1991 Feb;41(2):97-110.
3. J Org Chem 1983,v 48, 26,  pg 5341 as label 10, mp , ir givenhttp://pubs.acs.org/doi/abs/10.1021/jo00174a035
4. US 4420632
5. EP257859 B1…
6. US2002/147184 A1…
7. J Org Chem 1981,46, 1954