NEW PROCESS 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 0 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. Process for the preparation of high purity prostaglandin acid of the general formula II ##STR00012## where in the formula the bonds marked with dotted lines represent single- or double bond where the double bond may be cis or trans oriented, Y represents oxygen atom or CH.sub.2 group and R.sup.3 stands for phenyl group optionally substituted with CF.sub.3 group wherein the crude prostaglandin acid of the general formula II, where in the formula the bonds marked with dotted lines represent single- or double bond where the double bond may be cis or trans oriented, and the meanings of Y and R.sup.3 are as defined above is purified on normal phase silica gel chromatography.

2. The process as defined in claim 1, wherein chromatography is carried out by normal phase gravitational, medium- or high pressure silica gel chromatography.

3. 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 10-150 micrometer.

4. The process as defined in claim 1, wherein a multicomponent eluent mixture is applied as eluent.

5. The process as defined in claim 4, 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%).

6. The process as defined in claim 5, 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.

7. The process as defined in claim 6, wherein the substituent is halogen atom.

8. The process as defined in claim 6, wherein as apolar solvent aliphatic hydrocarbon is applied.

9. The process as defined in claim 5, 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.

10. The process as defined in claim 9, wherein as polar solvent C.sub.1-5 alcohol is applied.

11. The process as defined in claim 10, wherein as polar solvent isopropyl alcohol is applied.

12. The process as defined in claim 5, wherein the solvent of acidic character of the solvent mixture is an organic acid optionally containing halogen substituent.

13. The process as defined in claim 12, wherein as organic acid a C.sub.1-3 organic acid is applied.

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

15. Process as defined in claim 1, wherein the amount of the isomeric impurities of the high purity Latanoprost acid of formula IIa, ##STR00013## obtained in the process is individually not more than 0.15%.

16. High purity Latanoprost acid of formula IIa, ##STR00014## in which the amount of the isomeric impurities is individually not more than 0.15%.

17. Process for the preparation of high purity prostagladin derivative of the general formula I, ##STR00015## where in the formula the bonds marked with dotted lines represent single- or double bond where the double bond may be cis or trans oriented, R.sup.1 represents OR.sup.2 or NR.sup.2 group, where R.sup.2 stands for straight or branched C.sub.1-5 alkyl group or hydrogen, Y represents oxygen atom or CH.sub.2 group and R.sup.3 stands for phenyl group optionally substituted with CF.sub.3 group, wherein the crude prostaglandin derivative obtained from the high purity prostaglandin acid of the general formula II prepared according to claim 1, is purified by chromatography.

18. Process according to claim 17, wherein chromatography is carried out by normal phase gravitational, medium- or high pressure silica gel chromatography.

19. Process according to claim 18, wherein as silica gel a spherical silica gel having average particle size 75 or 150 micrometer is applied.

20. Process according to claim 18, wherein as eluent, a multicomponent eluent mixture is applied.

21. Process according to claim 20, wherein the eluent mixture contains one or more apolar solvents and one or more polar solvents in a ratio of (65-31%)-(9.1-2.4%).

22. Process according to claim 21, wherein the apolar solvent component of the eluent mixture is a straight or branched open-chain, or cyclic or aromatic hydrocarbon, optionally bearing one or more substituents.

23. Process according to claim 22, wherein the substituent is halogen atom.

24. Process according to claim 22, wherein as apolar solvent dichloromethane is applied.

25. Process according to claim 22, wherein as apolar solvent aliphatic hydrocarbon is applied.

26. Process according to claim 21, wherein as polar solvent an alcohol-, ether-, ester- or ketone-type solvent is applied which contain straight or branched open-chain alkyl, alkenyl, or cyclic or cycloalkyl group.

27. Process according to claim 26, wherein as polar solvent a C.sub.1-5 alcohol is applied.

28. Process according to claim 27, wherein as polar solvent isopropyl alcohol is applied.

29. Process according to claim 20, wherein the eluent is a gradient mixture containing hexane, dichloromethane and isopropanol, where the composition of the mixture is periodically changed with the time.

30. Process as defined in claim 17, wherein the purity of the high purity Latanoprost of formula Ia, ##STR00016## obtained in the process is higher than 99.5% and the amount of its isomeric impurities is individually not more than 0.15%.

31. The process as defined in claim 8, wherein the aliphatic hydrocarbon is selected from the group consisting of pentane, hexane, heptane, octane, and cyclohexane.

32. Process according to claim 25, wherein the aliphatic hydrocarbon is selected from the group consisting of pentane, hexane, heptane, octane and cyclohexane.

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

[0080] 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%).

Starting Latanoprost Acid:

[0081]

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:

[0082]

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:

[0083] ##STR00008##

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

[0084] 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%).

Starting Latanoprost Acid:

[0085]

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:

[0086]

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

[0087] 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%).

Starting Latanoprost Acid:

[0088]

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:

[0089]

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

[0090] 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:

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)

[0091] 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.

[0092] 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.

[0093] Yield: 105 g (68%) colourless oil.

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

NMR Data:

[0094] ##STR00009##

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)

[0095] 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%).

Starting Travoprost Acid:

[0096]

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:

[0097]

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:

[0098] ##STR00010##

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)

[0099] 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%).

Starting Bimatoprost Acid:

[0100]

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:

[0101]

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:

[0102] ##STR00011##

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.