Pocess for the preparation of high purity prostaglandins

Abstract

The subject of the invention is a process for the preparation of high purity prostaglandin acid of the general formula II wherein the bonds marked with dotted lines represent single or double bonds wherein the double bonds may be cis- or trans oriented, Y represents O or CH.sup.2, and R.sup.3 stands for a phenyl group which is optionally substituted with CF.sub.3, wherein the crude prostaglandin acid of the general formula II is purified by normal phase silicagel chromatography. ##STR00001##

Claims

1. A process for the purification of latanoprost acid of Formula IIa: ##STR00012## which consists of purifying crude latanoprost acid of Formula IIa by gravitational chromatography on a normal phase chromatography column filled with silica gel so that the purified latanoprost acid of Formula IIa has a purity of 89.9%-99.5% and isomeric impurities of trans-latanoprost acid and 15-epi-latanoprost acid obtained in the process are not individually more than 0.15%, wherein a multicomponent eluent mixture is applied as eluent, and wherein the eluent mixture contains one or more apolar solvents, one or more polar solvents and solvent of acidic character, in a ratio of (91-73%):(24-8.7%):(0.1-4.3%).

2. The process as defined in claim 1, wherein the applied silica gel is a spherical silica gel having average particle size in a range of 75-150 micrometer.

3. The process as defined in claim 1, wherein the apolar component of the eluent mixture is straight or branched open-chain or cyclic or aromatic hydrocarbon, optionally containing one or more substituents.

4. The process as defined in claim 3, wherein the substituent is halogen atom.

5. The process as defined in claim 3, wherein as apolar solvent aliphatic hydrocarbon is applied.

6. The process as defined in claim 1, wherein as polar solvent an alcohol-, ether-, ester- or ketone-type solvent is applied which contains straight or branched open-chain alkyl, alkenyl or cyclic or cycloalkyl group.

7. The process as defined in claim 6, wherein as polar solvent C.sub.1-5 alcohol is applied.

8. The process as defined in claim 7, wherein as polar solvent isopropyl alcohol is applied.

9. The process as defined in claim 1, wherein the solvent of acidic character of the solvent mixture is an organic acid optionally containing halogen substituent.

10. The process as defined in claim 9, wherein as organic acid a C.sub.1-3 organic acid is applied.

11. The process as defined in claim 1, wherein hexane:isopropanol:acetic acid mixture is applied as an eluent.

12. The process as defined in claim 5, wherein the aliphatic hydrocarbon is selected from the group consisting of pentane, hexane, heptane, octane, and cyclohexane.

13. The process as defined in claim 11, wherein the hexane:isopropanol:acetic acid mixture is in a ratio of (91-73%):(24-8.7%):(0.1-4.3%).

14. The process as defined in claim 1, wherein hexane:isopropanol:formic acid, hexane:isopropanol:trifluoro acetic acid, c-hexane:isopropanol:acetic acid, pentane:isopropanol:acetic acid, isooctane:isopropanol:acetic acid, hexane:dichloromethane:isopropanol, or diisopropyl ether:acetone:water is applied as an eluent.

15. The process as defined in claim 14, wherein the eluent is in a ratio of (91-73%):(24-8.7%):(0.1-4.3%).

16. The process as defined in claim 1, wherein the purified latanoprost acid of Formula IIa has a purity of 98.95-99.5%.

17. The process as defined in claim 1, further comprising preparing latanoprost from said latanoprost acid, wherein in the latanoprost thus obtained the isomeric impurities of trans-latanoprost and 15-epi-latanoprost are not individually more than 0.15%.

Description

EXAMPLES

Example 1a

Purification of Latanoprost Acid

(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[3(R)-3-hydroxy-5-phenylethyl]cyclopentyl]-5-heptenoic acid

(1) 165 g of crude Latanoprost acid IIa.sub.1 is dissolved in dichloromethane. The solution is purified by gravitational chromatography on a column filled with spherical silica gel having 75 micrometer average particle size and 60 angstrom pore diameter/YMC GEL SIL S-75 type/using hexane:isopropanol:acetic acid=10:1:0.11 mixture as eluent. The fractions of sufficient purity are united and evaporated. Yield: 140 g (85%).

(2) Starting Latanoprost Acid:

(3) TABLE-US-00003 Purity (HPLC area %) 96.7% trans-Latanoprost acid (HPLC area %) 2.6% 15-epi-Latanoprost acid (HPLC area %) 0.14%
Purified Latanoprost Acid:

(4) TABLE-US-00004 Purity (HPLC area %) 99.4% trans-Latanoprost acid (HPLC area %) 0.02% 15-epi-Latanoprost acid (HPLC area %) 0.15%
NMR Data:

(5) ##STR00008##

(6) TABLE-US-00005 TABLE 1 Carbon Proton chemical Proton spectrum chemical Number Function shift/ppm integrated intensity shift/ppm 1 C 174.9 2 CH.sub.2 2.19 2 33.7 3 CH.sub.2 1.54 2 25.1 4 CH.sub.2 2.03 2 26.6 5 CH 5.29 1 129.1 6 CH 5.46 1 130.4 7 CH.sub.2 2.15, 2.05 1, 1 26.4 8 CH 1.22 1 49.7 9 CH(OH) 3.88 (4.20) 1(1) 71.3 10 CH.sub.2 1.97, 1.47 1, 1 43.8 11 CH(OH) 3.62 (4.42) 1(1) 76.3 12 CH 1.50 1 50.9 13 CH.sub.2 1.39, 1.32 1, 1 28.9 14 CH.sub.2 1.41 2 35.3 15 CH(OH) 3.39 (4.38) 1(1) 69.9 16 CH.sub.2 1.62, 1.56 1, 1 39.6 17 CH.sub.2 2.69, 2.56 1, 1 32.0 18 C 143.1 19, 23 CH 7.18 2 128.7 20, 22 CH 7.25 2 128.7 21 CH 7.14 1 125.9

Example 1b

Purification of Latanoprost Acid

(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[3(R)-3-hydroxy-5-phenylethyl]cyclopentyl]-5-heptenoic acid

(7) 0.85 g of crude Latanoprost acid IIa.sub.1 is dissolved in dichloromethane. The solution is purified by gravitational chromatography on a column filled with spherical silica gel having 150 micrometer average particle size and 60 angstrom pore diameter/YMC GEL SIL S-150 type/using hexane:isopropanol:acetic acid=10:1:0.11 mixture as eluent. The fractions of sufficient purity are united and evaporated. Yield: 0.697 g (82%).

(8) Starting Latanoprost Acid:

(9) TABLE-US-00006 Purity (HPLC area %) 96.7% trans-Latanoprost acid (HPLC area %) 2.6% 15-epi-Latanoprost acid (HPLC area %) 0.14%
Purified Latanoprost Acid:

(10) TABLE-US-00007 Purity (HPLC area %) 98.2% trans-Latanoprost acid (HPLC area %) 0.04% 15-epi-Latanoprost acid (HPLC area %) 0.14%

Example 1c

Purification of Latanoprost Acid

(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[3(R)-3-hydroxy-5-phenylethyl]cyclopentyl]-5-heptenoic acid

(11) 0.85 g of crude Latanoprost acid IIa.sub.1 is dissolved in dichloromethane. The solution is purified by gravity chromatography on a column filled with spherical silica gel having average particle size 40-75 micrometer and 70 angstrom pore diameter/Fuji Chromatorex MB70-40/75 type/using hexane:isopropanol:acetic acid=10:1:0.11 mixture as eluent. The fractions of sufficient purity are united and evaporated. Yield: 0.688 g (81%).

(12) Starting Latanoprost Acid:

(13) TABLE-US-00008 Purity (HPLC area %) 96.7% trans-Latanoprost acid (HPLC area %) 2.6% 15-epi-Latanoprost acid (HPLC area %) 0.14%
Purified Latanoprost Acid:

(14) TABLE-US-00009 Purity (HPLC area %) 99.4% trans-Latanoprost acid (HPLC area %) 0.16% 15-epi-Latanoprost acid (HPLC area %) 0.14%

Example 1d

Purification of Latanoprost Acid

(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[3(R)-3-hydroxy-5-phenylethyl]cyclopentyl]-5-heptenoic acid

(15) 1 gram of crude latanoprost acid IIa.sub.1 is dissolved in dichloro-methane. The solution is purified by gravitational chromatography on a column filled with spherical silica gel having 75 micrometer average particle size and 60 angstrom pore diameter/YMC GEL SIL S-75 type/using different solvent mixtures as eluent listed in the below table. The fractions of sufficient purity are united and evaporated. The yields and the quality of the purified Latanoprost acid are listed in the Table 2:

(16) TABLE-US-00010 TABLE 2 trans- 15-epi- Silica: Latanoprost Latanoprost YMC Purity acid acid GEL SIL Quantity HPLC area HPLC area HPLC area Yield S-75 [g] [%] [%] [%] [%] Starting 165 96.7 2.6 0.14 Latanoprost acid Purified Latanoprost acid 1 Eluent: Hexane:isopropanol:acetic acid 10:1:0.11 140 99.4 0.02 0.15 85 2 Hexane:isopropanol:formic acid 10:1:0.11 1.00 99.1 0.04 0.14 83 3 Hexane:isopropanol:trifluoro acetic acid 10:1:0.10 1.00 89.9 0.05 0.15 82 4 Hexane:isopropanol:acetic acid 9.5:1:0.11 1.00 99.3 0.03 0.14 76 5 Hexane:isopropanol:acetic acid 10.5:1:0.11 1.00 99.5 0.04 0.14 79 6 Heptane:isopropanol:acetic acid 10:1:0.11 1.00 99.2 0.06 0.15 79 7 c-Hexane:isopropanol:acetic acid 9:1:0.11 1.00 99.3 0.06 0.13 68 8 c-Hexane:isopropanol:acetic acid 10:1:0.11 1.00 99.0 0.03 0.14 76 9 c-Hexane:isopropanol:acetic acid 15:1:0.11 1.00 99.3 0.02 0.13 80 10 Pentane:isopropanol:acetic acid 10:1:0.11 1.00 99.1 0.04 0.14 67 11 Pentane:isopropanol:acetic acid 15:1:0.11 1.00 99.2 0.03 0.13 80 12 isooctane:isopropanol:acetic acid 10:1:0.11 1.00 99.1 0.05 0.15 78

Example 2

Preparation of Latanoprost (Ia)

5-Heptenoic acid, 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-,1-methylethyl ester, (5Z)

(17) 140 g of Latanoprost acid (IIa) is dissolved in dimethylformamide. To the solution 128.8 g of potassium carbonate and 80 ml of isopropyl iodide are added and the mixture is stirred at 50 C. After reaching the desired conversion, the reaction mixture is cooled and under agitation sodium hydrogen sulphate solution, hexane and ethyl acetate are poured to it. The phases are separated, the aqueous layer is extracted with hexane:ethyl acetate mixture. The organic phase is washed consecutively with sodium hydrogen carbonate solution and water and then evaporated. The solid residue (crude Latanoprost) is dissolved in hexane:dichloromethane:isopropanol=20:10:1 mixture and purified by chromatography on irregular silica gel/average particle size: 63-200 micrometer, pore diameter: 60 angstrom/column using hexane:dichloromethane:isopropanol=20:10:1, hexane:dichloromethane:isopropanol=20:10:2 and finally hexane:dichloromethane:isopropanol=20:10:3 mixtures as eluents. For the dissolution and the chromatography distilled solvents are used.

(18) The fractions of suitable purity are united and evaporated. The residue is dissolved in distilled isopropanol and filtered on membrane filter. The filtrate solution is evaporated and dried.

(19) Yield: 105 g (68%) colourless oil.

(20) TABLE-US-00011 Assay (HPLC) 99.8% trans-Latanoprost (HPLC m %) 0.04% 15-epi-Latanoprost (HPLC m %) 0.14%
NMR Data:

(21) ##STR00009##

(22) TABLE-US-00012 TABLE 3 Carbon Proton chemical Proton spectrum chemical Number Function shift/ppm integrated intensity shift/ppm 1 C 172.2 2 CH.sub.2 2.22 2 33.3 3 CH.sub.2 1.55 2 24.6 4 CH.sub.2 2.03 2 26.0 5 CH 5.29 1 128.4 6 CH 5.46 1 130.1 7 CH.sub.2 2.15; 2.04 1; 1 25.9 8 CH 1.21 1 49.2 19 CH(OH) 3.88 (4.19) 1 (1) 70.8 10 CH.sub.2 1.97; 1.47 1; 1 43.3 11 CH(OH) 3.62 (4.41) 1 (1) 75.9 12 CH 1.50 1 50.5 13 CH.sub.2 1.38, 1.32 1; 1 28.4 14 CH.sub.2 1.44; 1.40 1; 1 34.9 15 CH(OH) 3.38 (4.36) 1 (1) 69.5 16 CH.sub.2 1.63; 1.56 1; 1 39.1 17 CH.sub.2 2.69; 2.56 1; 1 31.5 18 C 142.6 19, 23 CH 7.18 2 128.2 20, 22 CH 7.26 2 128.2 21 CH 7.15 1 125.4 24 CH 4.86 1 66.8 25, 26 CH.sub.3 1.15 6 21.6

Example 3

Purification of Travoprost Acid

5-Heptenoic acid, 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]cyclopentyl]-, (5Z)

(23) 500 mg of Travoprost acid IIb is dissolved in dichloromethane. The solution is purified by gravity chromatography on a column filled with spherical silica gel having 75 micrometer average particle size and 60 angstrom pore diameter/YMC GEL SIL S-75 type/using hexane:isopropanol:acetic acid=10:1:0.11 mixture as eluent. The fractions of sufficient purity are united and evaporated. Yield: 420 mg (84%).

(24) Starting Travoprost Acid:

(25) TABLE-US-00013 Purity (HPLC area %) 97.34% trans-Travoprost acid (HPLC area %) 2.4% 15-epi-Travoprost acid (HPLC area %) 0.12%
Purified Travoprost Acid:

(26) TABLE-US-00014 Purity (HPLC area %) 98.26% trans-Travoprost acid (HPLC area %) 1.45% 15-epi-Travoprost acid (HPLC area %) 0.15%
NMR Data:

(27) ##STR00010##

(28) TABLE-US-00015 TABLE 4 Coupling .sup.13C/.sup.19F constant (Hz) Number (ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/0.2 Hz) 1 174.37 1-COOH 11.95 1 broad (s) 2 33.09 2.13* 2 t J.sub.2,3 = 7.4 3 24.46 1.49** 2 m (tt) J.sub.3,4 = 7.4 4 26.06 1.96*** 2 m 5 128.56 5.23 1 dt J.sub.5,6 = 10.7; J.sub.4,5 = 7.2 6 129.73 5.43 1 dt J.sub.6,7 = 7.4 7 24.78 b:2.10* 1 m a: 1.96*** 1 m 8 48.78 1.32 1 m (dddd/tt) 11.1; 10.0; 5.0; 5.0 9 69.58 3.90.sup.+ 1 m 9-OH 4.36.sup.++,$ 1 broad (s) 10 43.96 b: 2.20* 1 ddd J.sub.gem = 14.1; a: 1.44** 1 ddd J.sub.10b,11 = 8.4; J.sub.9,10b = 5.8; J.sub.10a,11 = 5.6; J.sub.9,10a = 2.3; 11 75.64 3.69 1 m 11-OH 4.53 1 broad (s) 12 54.30 2.18* 1 m (td) 13 133.97 5.57 1 dd J.sub.13,14 = 15.5; J.sub.12,13 = 8.0 14 131.01 5.51 1 dd J.sub.14,15 = 5.7 15 69.51 4.32.sup.++ 1 q (ddd) 5.6 15-OH 5.125.sup.$ 1 broad (s) 16 72.55 b: 3.96.sup.+ 1 dd J.sub.gem = 9.9; a: 3.93.sup.+ 1 dd J.sub.15,16b = 4.9 J.sub.15,16a = 6.6 17 158.97 18 111.13 (q) 7.20.sup.+ 1 m (t/dd) .sup.3J.sub.C-18,F = 3.7 J.sub.18,20 = 1.5; J.sub.18,22 = 2.5 19 130.29 (q) .sup.2J.sub.C-19,F = 31.7 20 117.01 (q) 7.26.sup.+++ 1 m (ddd) .sup.3J.sub.C-20,F = 3.8; J.sub.20,21 = 7.8; J.sub.20,22 = 0.7 21 130.68 7.50 1 t (dd) J.sub.21,22 = 8.2 22 118.75 7.24.sup.+++ 1 m (ddd) 23 124.01 (q) .sup.1J.sub.C-23,F = 272.4 23-F 61.19 (s, 3) *,**,***,.sup.+,.sup.++,.sup.+++Overlapping .sup.1H NMR signals .sup.$these coupling constants and chemical shifts are determined on the basis of the literature data of Travoprost

Example 4

Purification of Bimatoprost Acid

5-Heptenoic acid, 7-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]cyclopentyl]-, (5Z)

(29) 500 mg of Bimatoprost acid lie is dissolved in dichloromethane. The solution is purified by gravity chromatography on a column filled with irregular silica gel having 50 micrometer average particle size and 65 angstrom pore diameter/Sepra Silica 50 type/using diisopropyl ether:acetone:water=40:25:1 mixture as eluent. The fractions of appropriate purity are united and evaporated. Yield: 210 mg (42%).

(30) Starting Bimatoprost Acid:

(31) TABLE-US-00016 Purity (HPLC area %) 95.09% trans-Bimatoprost acid (HPLC area %) 1.51% 15-epi-Bimatoprost acid (HPLC area %) 0.08%
Purified Bimatoprost Acid:

(32) TABLE-US-00017 Purity (HPLC area %) 98.95% trans-Bimatoprost acid (HPLC area %) 0.75% 15-epi-Bimatoprost acid (HPLC area %) 0.3%
NMR Data:

(33) ##STR00011##

(34) TABLE-US-00018 TABLE 5 Coupling constant (Hz) Number .sup.13 C (ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/0.2 Hz) 1 174.34 1-COOH 11.96 1 broad 2 33.15 2.12* 2 m (t) J.sub.2,3 = 7.4 3 24.51 1.49** 2 m (tt) J.sub.3,4 = 7.2 4 26.14 1.975*** 2 m (q) J.sub.4,5 = 7.2 5 128.58 5.26 1 dt J.sub.5,6 = 10.7 6 129.69 5.455.sup.+ 1 m (dt) J.sub.6,7 = 7.7 7 24.79 2.11* 1 m 1.995*** 1 m 8 48.86 1.30 1 m (dddd) 10.5; 10.5; 5.2; 5.2 9 69.51 3.91.sup.++ 1 m 9-OH 4.35 1 broad 10 43.95 : 2.19* 1 m(ddd) J.sub.gem = 14.1; : 1.44** 1 m (ddd) 8.3; 6.0 5.6; 2.2 11 75.74 3.67 1 m (td/dddd) 7.5; 7.5; 6.4 11-OH 4.50 1 broad 12 54.26 2.15* 1 m 13 132.08 5.365 1 dd J.sub.13,14 = 15.4; J.sub.12,13 = 8.2 14 135.15 5.43.sup.+ 1 m (dd) J.sub.14,15 = 6.3 15 70.57 3.90.sup.++ 1 m 15-OH 4.66 1 broad 16 39.52.sup.$ 1.71.sup.+++ 1 m 1.65.sup.+++ 1 m 17 31.34 2.58.sup.# 1 m 2.615.sup.# 1 m 18 142.29 19, 23 128.20 7.17.sup.## 2 d J.sub.19,20 = 7.4 20, 22 128.24 7.26 2 t J.sub.20,21 = 7.4 21 125.55 7.15.sup.## 1 t .sup.$.sup.13 C NMR signals are overlapping with the signals of DMSO. *,**.***,.sup.+,.sup.++,.sup.+++,.sup.#,.sup.##Overlapping .sup.1H NMR signals.