US20130253218A1 - Process for preparing prostaglandin derivatives - Google Patents
Process for preparing prostaglandin derivatives Download PDFInfo
- Publication number
- US20130253218A1 US20130253218A1 US13/901,170 US201313901170A US2013253218A1 US 20130253218 A1 US20130253218 A1 US 20130253218A1 US 201313901170 A US201313901170 A US 201313901170A US 2013253218 A1 US2013253218 A1 US 2013253218A1
- Authority
- US
- United States
- Prior art keywords
- compound
- prostaglandin
- derivative
- followed
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000003180 prostaglandins Chemical class 0.000 title abstract description 8
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 36
- 229960002368 travoprost Drugs 0.000 claims description 8
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 8
- 229960002470 bimatoprost Drugs 0.000 claims description 7
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 7
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 abstract description 21
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 abstract description 20
- BGTOWKSIORTVQH-HOSYLAQJSA-N cyclopentanone Chemical group O=[13C]1CCCC1 BGTOWKSIORTVQH-HOSYLAQJSA-N 0.000 abstract description 7
- 125000000468 ketone group Chemical group 0.000 abstract description 7
- 125000006239 protecting group Chemical group 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 29
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- 239000000203 mixture Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 12
- -1 borane compound Chemical class 0.000 description 11
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
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- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000007012 clinical effect Effects 0.000 description 2
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- ZEFWRWWINDLIIV-UHFFFAOYSA-N tetrafluorosilane;dihydrofluoride Chemical compound F.F.F[Si](F)(F)F ZEFWRWWINDLIIV-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
- C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a process for efficiently preparing a prostaglandin derivative with high purity and an intermediate therefor.
- Prostaglandin derivatives particularly travoprost, bimatoprost and latanoprost of the following formula (2) have been extensively used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
- the prostaglandin derivatives have been conventionally prepared through many synthetic steps in poor yields.
- the most common commercial processes use Corey lactone as a starting material to produce the prostaglandin derivatives, as shown in the following Reaction Scheme 1 (see E. J. Corey et al., J. Amer. Chem. Soc., 91, 5675-5677, 1969).
- Corey lactone is expensive and the processes require a chromatographic separation for removing ⁇ -OH which is produced as a by-product on the reduction of 15-ketone group into ⁇ -OH after the introduction of ⁇ -chain. Therefore, the processes are unsuitable for large-scale production of the prostaglandin derivatives in terms of poor yields and high costs.
- the ⁇ -OH produced as a by-product may be reduced by using a chiral borane compound as a stereoselective reducing agent, but the chiral borane compound is also very expensive.
- PGF prostaglandin F
- PGE prostaglandin E
- the present inventors have endeavored to overcome the above problems and found that a highly pure PGF derivative having little or no ⁇ -OH can be efficiently prepared by removing the protecting group of the prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring.
- PGE prostaglandin E
- An object of the present invention is, therefore, to provide a process for efficiently preparing a PGF derivative with high purity.
- Another object of the present invention is to provide a novel intermediate used in said process.
- One aspect of the present invention relates to a process for preparing a prostaglandin F (PGF) derivative of the following formula (1), which comprises the steps of:
- X is O or NH
- Y is ⁇ -OH or difluoro, preferably ⁇ -OH;
- Y′ is ⁇ -OPG or difluoro, preferably ⁇ -OPG;
- Z is CH 2 , O or S, preferably CH 2 or O;
- R is H or C 10 -C 5 alkyl, preferably C 10 -C 5 alkyl
- R′ is C 10 -C 5 alkyl, C 3 -C 7 cycloalkyl or aryl, preferably phenyl optionally substituted by C 10 -C 5 haloalkyl or halogen, more preferably CF 3 , Cl or F, most preferably CF 3 ;
- PG is a hydroxy protecting group, preferably tetrahydropyranyl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, more preferably triethylsilyl.
- C 1 -C 5 alkyl as used herein means a straight or branched hydrocarbon having 1 to 5 carbon atoms, which includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, etc., but is not limited thereto.
- C 3 -C 7 cycloalkyl as used herein means a cyclic hydrocarbon having 3 to 7 carbon atoms, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but is not limited thereto.
- aryl as used herein includes all of aromatic group, heteroaromatic group and partially reduced derivatives thereof.
- the aromatic group means a 5 to 15-membered simple or fused ring.
- the heteroaromatic group means an aromatic group containing at least one atom selected from oxygen, sulfur and nitrogen. Examples of the aryl include phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl, thiazolyl, tetrahydronaphthyl, etc., but are not limited thereto.
- the C 10 -C 5 alkyl, C 3 -C 7 cycloalkyl and aryl may have one or more hydrogens substituted by C 10 -C 5 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 10 -C 5 haloalkyl, C 10 -C 5 alkoxy, C 10 -C 5 thioalkoxy, aryl, acyl, hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxyl, carbamoyl, cyano, nitro, etc.
- the prostaglandin E (PGE) derivative of formula (6) is prepared by removing the hydroxy protecting group of the protected PGE derivative of formula (5).
- the deprotection may be carried out under an acidic condition.
- silyl protecting groups may be deprotected by using various fluoride compounds.
- the acidic condition for silyl protecting groups may be provided by the use of d-HCl, an aqueous NaHSO 4 solution, pyridinium p-toluensulfonate (PPTS), etc.
- PPTS pyridinium p-toluensulfonate
- fluoride compounds include tetrabutylammonium fluoride (Bu 4 N + F ⁇ ), hydrogen fluoride-pyridine (HF-pyridine), fluorosilicic acid (H 2 SiF 6 ), etc., but are not limited thereto.
- the compound of formula (5) having a carbon-carbon double bond at 13 and 14 position may be prepared by converting an alkenyl tin compound of the following formula (3) to its cuprate, followed by conjugate addition to a cyclopentenone compound of the following formula (4), according to a known method (see J. Am. Chem. Soc. 1988, 110, 2641-2643).
- the alkenyl tin compound of formula (3) is added to a solution of Me 2 Cu(CN)Li 2 and converted to a higher order mixed cuprate of the following formula (7), which is subjected to conjugate addition to the cyclopentenone compound of formula (4).
- the above reaction is preferably carried out in a mixture of tetrahydrofuran (THF) and hexane or a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
- THF tetrahydrofuran
- ether a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
- the conjugate addition is preferably carried out in a low temperature of ⁇ 60° C. or less.
- the alkenyl tin compound of formula (3) may be prepared by reacting a w-chain precursor containing a terminal acetylene group with Bu 3 SnH, according to a known method (see J. Am. Chem. Soc. 1988, 110, 2641-2643).
- the compound of formula (5) having a carbon-carbon single bond at 13 and 14 position may be prepared by the method disclosed in WO 02/090324.
- the prostaglandin F (PGF) derivative of formula (1) is prepared by stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of formula (6).
- a reducing agent used in the present invention includes sodium borohydride (NaBH 4 ), L-selectride, N-selectride, K-selectride, LS-selectride, 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc., but is not limited thereto.
- NaBH 4 sodium borohydride
- L-selectride L-selectride
- N-selectride N-selectride
- K-selectride K-selectride
- LS-selectride 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc.
- DIBAL diisobutyl aluminium hydride
- 2,6-di-tert-butyl-4-methyl phenol and DIBAL leads to stereoselective preparation of ⁇ -OH compound having no ⁇ -OH.
- the reduction is carried out by reacting 2,6-di-tert-butyl-4-methyl phenol in an amount of 2 to 10 equivalents, preferably 5 equivalents with DIBAL in an amount of 2 to 5 equivalents, preferably 4 equivalents in toluene as a solvent at ⁇ 10 to 10° C., preferably 0° C.
- the prostaglandin F (PGF) derivative of formula (1) wherein X is NH may be prepared by reacting the PGF derivative of formula (1) wherein X is O and R is methyl, with RNH 2 .
- the above reaction is preferably carried out at room temperature.
- Examples of the prostaglandin F (PGF) derivative of formula (1) prepared by the present process include travoprost, bimatoprost and latanoprost, which are widely used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
- travoprost, bimatoprost and latanoprost can be prepared with high purity of 99.5% or more by further comprising the step of purifying them by HPLC using a mixture of hydrocarbon and alcohol, preferably a mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane and anhydrous ethanol, or a mixture of dichloromethane and alcohol, preferably a mixture of dichloromethane and isopropanol.
- Another aspect of the present invention relates to a compound of the following formula (8), which is an intermediate of travoprost, and a compound of formula (9), which is an intermediate of bimatoprost.
- the prostaglandin F (PGF) derivative can be efficiently prepared with high purity by removing the protecting group of the protected prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring of the PGE derivative.
- PGE protected prostaglandin E
- the ⁇ -OH compound having no ⁇ -OH can be stereoselectively prepared using 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminum hydride (DIBAL) as a reducing agent.
- DIBAL diisobutyl aluminum hydride
- 2,6-Di-tert-butyl-4-methyl phenol (560 g) was dissolved in toluene (6.5 L), followed by cooling to 0° C., and DIBAL (1.0 M toluene, 2.05 L) was added dropwise thereto for 1 hour.
- the resulting reaction solution was cooled to ⁇ 70° C., and compound (6-II) (205 g) dissolved in toluene (1.6 L) was added dropwise thereto.
- the resulting reaction solution was stirred for about 2 hours, and its temperature was slowly raised to ⁇ 40 to ⁇ 20° C., followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (2.5 L) was added.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for preparing a prostaglandin derivative and an intermediate therefor. In accordance with the present invention, the prostaglandin F (PGF) derivative can be efficiently prepared with high purity by removing the protecting group of a protected prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring of the PGE derivative.
Description
- This application is a divisional of U.S. application Ser. No. 13/255,417 filed Dec. 20, 2011, which is a National Stage of International Application No. PCT/KR2010/001529 filed Mar. 11, 2010, claiming priority based on Korean Patent Application No. 10-2009-0020920, filed Mar. 11, 2009, the contents of all of which are incorporated herein by reference in their entirety.
- The present invention relates to a process for efficiently preparing a prostaglandin derivative with high purity and an intermediate therefor.
- Prostaglandin derivatives, particularly travoprost, bimatoprost and latanoprost of the following formula (2) have been extensively used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
- The prostaglandin derivatives have been conventionally prepared through many synthetic steps in poor yields. The most common commercial processes use Corey lactone as a starting material to produce the prostaglandin derivatives, as shown in the following Reaction Scheme 1 (see E. J. Corey et al., J. Amer. Chem. Soc., 91, 5675-5677, 1969). However, Corey lactone is expensive and the processes require a chromatographic separation for removing β-OH which is produced as a by-product on the reduction of 15-ketone group into α-OH after the introduction of ω-chain. Therefore, the processes are unsuitable for large-scale production of the prostaglandin derivatives in terms of poor yields and high costs. The β-OH produced as a by-product may be reduced by using a chiral borane compound as a stereoselective reducing agent, but the chiral borane compound is also very expensive.
- To overcome the above disadvantages, it was suggested to prepare the prostaglandin derivatives by conjugate addition of ω-chain including α-OH to cyclopentenone derivatives having α-side chain, as shown in the following Reaction Scheme 2. In particular, a process developed by Lipshuts et al. can stereoselectively introduce ω-chain by using higher order mixed organocuprate (see U.S. Pat. Nos. 4,785,124, 4,904,820, 4,952,710 and 5,055,604, and WO 02/090324).
- Such process requires that, in order to synthesize prostaglandin F (PGF) derivatives, the ketone group on the cyclopentanone ring of the prostaglandin E (PGE) derivatives obtained from the conjugate addition should be stereoselectively reduced to α-OH. The use of sodium borohydride (NaBH4) as a reducing agent gives the PGF derivatives in the form of a 6:4 mixture of α-OH and β-OH, and the use of a bulky hydride such as L-selectride, N-selectride, K-selectride and LS-selectride gives the PGF derivatives in increased selectivity of 9:1 (α:β ratio). However, a significant amount of β-OH should be still removed by using a difficult method causing large yield loss.
- Therefore, there has been a need to develop a process for more stereoselectively reducing the ketone group on the cyclopentanone ring of the prostaglandin E derivatives.
- The present inventors have endeavored to overcome the above problems and found that a highly pure PGF derivative having little or no β-OH can be efficiently prepared by removing the protecting group of the prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring.
- An object of the present invention is, therefore, to provide a process for efficiently preparing a PGF derivative with high purity.
- Another object of the present invention is to provide a novel intermediate used in said process.
- One aspect of the present invention relates to a process for preparing a prostaglandin F (PGF) derivative of the following formula (1), which comprises the steps of:
- (i) removing the hydroxy protecting group of a protected prostaglandin E (PGE) derivative of the following formula (5) to give a prostaglandin E (PGE) derivative of the following formula (6); and
- (ii) stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of the following formula (6):
- wherein,
-
- X is O or NH;
- Y is α-OH or difluoro, preferably α-OH;
- Y′ is α-OPG or difluoro, preferably α-OPG;
- Z is CH2, O or S, preferably CH2 or O;
- R is H or C10-C5 alkyl, preferably C10-C5 alkyl;
- R′ is C10-C5 alkyl, C3-C7 cycloalkyl or aryl, preferably phenyl optionally substituted by C10-C5 haloalkyl or halogen, more preferably CF3, Cl or F, most preferably CF3; and
- PG is a hydroxy protecting group, preferably tetrahydropyranyl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, more preferably triethylsilyl.
- The term “C1-C5 alkyl” as used herein means a straight or branched hydrocarbon having 1 to 5 carbon atoms, which includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, etc., but is not limited thereto.
- The term “C3-C7 cycloalkyl” as used herein means a cyclic hydrocarbon having 3 to 7 carbon atoms, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but is not limited thereto.
- The term “aryl” as used herein includes all of aromatic group, heteroaromatic group and partially reduced derivatives thereof. The aromatic group means a 5 to 15-membered simple or fused ring. The heteroaromatic group means an aromatic group containing at least one atom selected from oxygen, sulfur and nitrogen. Examples of the aryl include phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl, thiazolyl, tetrahydronaphthyl, etc., but are not limited thereto.
- The C10-C5 alkyl, C3-C7 cycloalkyl and aryl may have one or more hydrogens substituted by C10-C5 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C10-C5 haloalkyl, C10-C5 alkoxy, C10-C5 thioalkoxy, aryl, acyl, hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxyl, carbamoyl, cyano, nitro, etc.
- The process of the present invention is, hereinafter, described in more detail referring to the following Reaction Scheme 3.
- The prostaglandin E (PGE) derivative of formula (6) is prepared by removing the hydroxy protecting group of the protected PGE derivative of formula (5).
- The deprotection may be carried out under an acidic condition. Particularly, silyl protecting groups may be deprotected by using various fluoride compounds.
- The acidic condition for silyl protecting groups may be provided by the use of d-HCl, an aqueous NaHSO4 solution, pyridinium p-toluensulfonate (PPTS), etc. Preferably, PPTS is used in a catalytic amount in a mixture of acetone and water. Examples of the fluoride compounds include tetrabutylammonium fluoride (Bu4N+F−), hydrogen fluoride-pyridine (HF-pyridine), fluorosilicic acid (H2SiF6), etc., but are not limited thereto.
- The compound of formula (5) having a carbon-carbon double bond at 13 and 14 position may be prepared by converting an alkenyl tin compound of the following formula (3) to its cuprate, followed by conjugate addition to a cyclopentenone compound of the following formula (4), according to a known method (see J. Am. Chem. Soc. 1988, 110, 2641-2643).
- Preferably, the alkenyl tin compound of formula (3) is added to a solution of Me2Cu(CN)Li2 and converted to a higher order mixed cuprate of the following formula (7), which is subjected to conjugate addition to the cyclopentenone compound of formula (4).
- The above reaction is preferably carried out in a mixture of tetrahydrofuran (THF) and hexane or a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
- The conjugate addition is preferably carried out in a low temperature of −60° C. or less.
- The alkenyl tin compound of formula (3) may be prepared by reacting a w-chain precursor containing a terminal acetylene group with Bu3SnH, according to a known method (see J. Am. Chem. Soc. 1988, 110, 2641-2643).
- Meanwhile, the compound of formula (5) having a carbon-carbon single bond at 13 and 14 position may be prepared by the method disclosed in WO 02/090324.
- The prostaglandin F (PGF) derivative of formula (1) is prepared by stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of formula (6).
- A reducing agent used in the present invention includes sodium borohydride (NaBH4), L-selectride, N-selectride, K-selectride, LS-selectride, 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc., but is not limited thereto. Preferably, 2,6-di-tert-butyl-4-methyl phenol and DIBAL are used.
- The use of 2,6-di-tert-butyl-4-methyl phenol and DIBAL leads to stereoselective preparation of α-OH compound having no β-OH. Generally, the reduction is carried out by reacting 2,6-di-tert-butyl-4-methyl phenol in an amount of 2 to 10 equivalents, preferably 5 equivalents with DIBAL in an amount of 2 to 5 equivalents, preferably 4 equivalents in toluene as a solvent at −10 to 10° C., preferably 0° C. for 1 to 2 hours, preferably 1 hour; lowering the temperature of the reaction solution to −70° C.; adding the compound of formula (6) thereto, followed by stirring for 1 to 3 hours, preferably 2 hours; raising the temperature of the reaction solution to −40 to −20° C., preferably −30° C.; and stirring the reaction solution for 3 to 6 hours, preferably 4 hours.
- Alternatively, the prostaglandin F (PGF) derivative of formula (1) wherein X is NH may be prepared by reacting the PGF derivative of formula (1) wherein X is O and R is methyl, with RNH2.
- The above reaction is preferably carried out at room temperature.
- Examples of the prostaglandin F (PGF) derivative of formula (1) prepared by the present process include travoprost, bimatoprost and latanoprost, which are widely used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth. According to the present invention, travoprost, bimatoprost and latanoprost can be prepared with high purity of 99.5% or more by further comprising the step of purifying them by HPLC using a mixture of hydrocarbon and alcohol, preferably a mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane and anhydrous ethanol, or a mixture of dichloromethane and alcohol, preferably a mixture of dichloromethane and isopropanol.
- Another aspect of the present invention relates to a compound of the following formula (8), which is an intermediate of travoprost, and a compound of formula (9), which is an intermediate of bimatoprost.
- In accordance with the present invention, the prostaglandin F (PGF) derivative can be efficiently prepared with high purity by removing the protecting group of the protected prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring of the PGE derivative. Particularly, the α-OH compound having no β-OH can be stereoselectively prepared using 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminum hydride (DIBAL) as a reducing agent.
- The present invention is further illustrated by the following examples, which are not to be construed to limit the scope of the invention.
-
- Copper cyanide (30 g) was dissolved in THF (680 ml), followed by cooling to 0° C., and methyllithium (1.6 M diethyl ether, 445 ml) was added dropwise thereto. The resulting reaction solution was stirred for 10 to 20 minutes, and compound (3-I) (215 g) dissolved in THF (200 ml) was added thereto. The resulting reaction solution was stirred for 1.5 to 2 hours, followed by cooling to −70° C., and compound (4-I) (90 g) dissolved in THF (680 ml) was rapidly added thereto, and then the temperature of the reaction solution was slowly raised to −45° C. After the reaction was completed, the resulting reaction solution was added to a mixture of aqueous ammonium chloride solution/ammonia water (9:1, 1.8 L) and diethyl ether (2 L), followed by stirring at room temperature for 1 to 2 hours. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=10:1) to give the target compound (127 g, Yield: 75%).
-
- Pyridinium p-toluensulfonate (PPTS, 2.3 g) was added to compound (8) (127 g) dissolved in a mixture of acetone (1.2 L) and water (0.25 L), followed by stirring at room temperature for 12 hours. After the reaction was completed, the resulting reaction solution was concentrated under vacuum, and ethyl acetate (1.5 L) and water (1 L) were added thereto, followed by stirring. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=1:3) to give the target compound (78 g, Yield: 89%).
-
- 2,6-Di-tert-butyl-4-methyl phenol (172 g) was dissolved in toluene (2 L), followed by cooling to 0° C., and DIBAL (1.0 M toluene, 625 ml) was added dropwise thereto for 1 hour. The resulting reaction solution was cooled to −70° C., and compound (6-I) (78 g) dissolved in toluene (0.5 L) was added dropwise thereto. The resulting reaction solution was stirred for about 2 hours, and its temperature was slowly raised to −40 to −20° C., followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (1 L) was added. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=1:5) to give travoprost (Purity: 96% or more). The obtained compound was subjected to preparative HPLC (eluent: dichloromethane:isopropanol=90:10) to give highly pure travoprost (50 g, Purity: 99.5% or more, Yield: 63%).
-
- Copper cyanide (98 g) was dissolved in THF (2.2 L), followed by cooling to 0° C., and methyllithium (1.6 M diethyl ether, 1.44 L) was added dropwise thereto. The resulting reaction solution was stirred for 10 to 20 minutes, and compound (3-II) (598 g) dissolved in THF (1.4 L) was added thereto. The resulting reaction solution was stirred for 1.5 to 2 hours, followed by cooling to −70° C., and compound (4-II) (270 g) dissolved in THF (2.2 L) was added thereto for 15 minutes, and then the temperature of the reaction solution was slowly raised to −45° C. After the reaction was completed, the resulting reaction solution was added to a mixture of aqueous ammonium chloride solution/ammonia water (9:1, 7.0 L) and diethyl ether (3.5 L), followed by stirring at room temperature for 1 to 2 hours. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=10:1) to give the target compound (420 g, Yield: 88%).
-
- Pyridinium p-toluensulfonate (PPTS, 8.8 g) was added to compound (9) (420 g) dissolved in a mixture of acetone (4.3 L) and water (0.83 L), followed by stirring at room temperature for 12 hours. After the reaction was completed, the resulting reaction solution was concentrated under vacuum, and ethyl acetate (5.0 L) and water (2.0 L) were added thereto, followed by stirring. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=1:3) to give the target compound (205 g, Yield: 76%).
-
- 2,6-Di-tert-butyl-4-methyl phenol (560 g) was dissolved in toluene (6.5 L), followed by cooling to 0° C., and DIBAL (1.0 M toluene, 2.05 L) was added dropwise thereto for 1 hour. The resulting reaction solution was cooled to −70° C., and compound (6-II) (205 g) dissolved in toluene (1.6 L) was added dropwise thereto. The resulting reaction solution was stirred for about 2 hours, and its temperature was slowly raised to −40 to −20° C., followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (2.5 L) was added. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=1:5) to give the target compound (155 g, Yield: 76%).
-
- Compound (1-I) (155 g) was added to a 70% aqueous solution of ethylamine (3.0 L), followed by stirring at room temperature for 60 hours. After the reaction was completed, the resulting reaction solution was concentrated to be its half level under reduced pressure, neutralized with a 2M aqueous solution of sodium hydrogensulfate (3.0 L, pH=4˜5) and extracted with ethyl acetate (3.0 L). The organic layer was dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to preparative HPLC (eluent: n-hexane:anhydrous ethanol=90:10), concentrated, and crystallized with diethyl ether (1.5 L). The resulting solid was filtered and dried under vacuum to give highly pure bimatoprost (100 g, Purity: 99.5% or more, Yield: 62%).
-
- Pyridinium p-toluensulfonate (PPTS, 4.3 g) was added to compound (5-I) (217 g) dissolved in a mixture of acetone (1.2 L) and water (0.2 L), followed by stirring at room temperature for 12 hours. After the reaction was completed, the resulting reaction solution was concentrated under vacuum, and ethyl acetate (1.5 L) and water (1.0 L) were added thereto, followed by stirring. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=1:3) to give the target compound (128 g, Yield: 90%).
-
- 2,6-Di-tert-butyl-4-methyl phenol (408 g) was dissolved in toluene (3.7 L), followed by cooling to 0° C., and DIBAL (1.0 M toluene, 1484 ml) was added dropwise thereto for 1 hour. The resulting reaction solution was stirred at the same temperature for 1 hour, cooled to −70° C., and compound (6-III) (128 g) dissolved in toluene (128 ml) was added dropwise thereto. The resulting reaction solution was stirred at the same temperature for about 2 hours, and its temperature was slowly raised to −40 to −20° C., followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (1.8 L) was added. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate=1:3) to give latanoprost (Purity: 96% or more). The obtained compound was subjected to preparative HPLC (eluent: heptane:anhydrous ethanol=94:6) to give highly pure latanoprost (96 g, Purity: 99.8% or more, Yield: 75%).
Claims (4)
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US13/901,170 US20130253218A1 (en) | 2009-03-11 | 2013-05-23 | Process for preparing prostaglandin derivatives |
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KR1020090020920A KR101045935B1 (en) | 2009-03-11 | 2009-03-11 | Method for preparing prostaglandin derivative |
KR10-2009-0020920 | 2009-03-11 | ||
PCT/KR2010/001529 WO2010104344A2 (en) | 2009-03-11 | 2010-03-11 | Process for preparing prostaglandin derivatives |
US201113255417A | 2011-12-20 | 2011-12-20 | |
US13/901,170 US20130253218A1 (en) | 2009-03-11 | 2013-05-23 | Process for preparing prostaglandin derivatives |
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US201113255417A Division | 2009-03-11 | 2011-12-20 |
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WO2013164729A1 (en) | 2012-05-03 | 2013-11-07 | Lupin Limited | An improved and scalable process for preparation of prostaglandin derivatives and intermediates thereof |
TWI435752B (en) * | 2012-08-15 | 2014-05-01 | Everlight Chem Ind Corp | Method of purification of prostaglandins including fluorine atoms by preparative hplc |
CN104297352B (en) * | 2013-07-16 | 2017-11-07 | 天津金耀集团有限公司 | A kind of travoprost content and the analysis method about material |
US9115109B2 (en) * | 2013-08-15 | 2015-08-25 | Chirogate International Inc. | Processes and intermediates for the preparations of isomer free prostaglandins |
US10100028B2 (en) | 2013-09-30 | 2018-10-16 | Patheon Api Services Inc. | Synthesis routes for prostaglandins and prostaglandin intermediates using metathesis |
HU231214B1 (en) | 2014-03-13 | 2021-11-29 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | New process for preparing high purity prostaglandins |
CN105254657B (en) * | 2014-07-10 | 2018-06-15 | 台湾神隆股份有限公司 | Metal catalytic asymmetry 1,4- conjugate addition reactions generate prostaglandin and prostaglandin analogue |
KR20160015100A (en) | 2014-07-30 | 2016-02-12 | 미래파인켐 주식회사 | Preparation method of Prostaglandin Intermediate |
KR20170025682A (en) | 2015-08-31 | 2017-03-08 | 미래파인켐 주식회사 | Novel method for preparing Prostaglandin derivatives |
US11458041B2 (en) | 2015-10-08 | 2022-10-04 | Ocular Therapeutix, Inc. | Punctal plug and bioadhesives |
HU231175B1 (en) * | 2015-12-04 | 2021-06-28 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Production of latanoprostene bunod by gravity column chromatography, in optional, previously definied quality |
US11407772B2 (en) | 2018-09-18 | 2022-08-09 | Tohoku University | Optically-active cyclopentenone derivatives |
AU2021215929A1 (en) | 2020-02-06 | 2022-08-04 | Ocular Therapeutix, Inc. | Compositions and methods for treating ocular diseases |
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ZA772255B (en) * | 1976-05-04 | 1978-11-29 | Upjohn Co | Prostaglandin analogs |
US5329035A (en) * | 1984-10-08 | 1994-07-12 | Teijin Limited | Process for producing 2,3-disubstituted-4-substituted cyclopentanones, enantiomorphs, or mixtures thereof |
JPH064557B2 (en) * | 1985-10-04 | 1994-01-19 | 帝人株式会社 | Process for producing 2,3-disubstituted-4-substituted cyclopentanones |
US4785124A (en) | 1987-06-08 | 1988-11-15 | G. D. Searle & Co. | Process for preparing higher order cuprate complexes |
US4904820A (en) | 1987-06-09 | 1990-02-27 | G. D. Searle & Co. | Process for substituting a hydrocarbon group |
US4952710A (en) | 1988-10-07 | 1990-08-28 | G. D. Searle & Co. | Cyclopenteneheptenoic acid derivatives and method of preparation thereof |
US5055604A (en) | 1990-04-17 | 1991-10-08 | G. D. Searle & Co. | Process for preparing prostaglandin analogs using organozirconium compounds |
US5075478A (en) * | 1991-01-17 | 1991-12-24 | G. D. Searle & Co. | Process for preparing prostaglandins |
JPH0649021A (en) * | 1992-07-29 | 1994-02-22 | Lion Corp | Production of prostaglandin f2alpha |
WO1996026891A1 (en) * | 1995-03-02 | 1996-09-06 | Nissan Chemical Industries, Ltd. | Substituted cyclopentene derivatives and process for the preparation thereof |
KR100437873B1 (en) | 2001-05-08 | 2004-06-26 | 연성정밀화학(주) | Process for preparing prostaglandin derivatives and stereospecific starting material thereof |
US6531504B2 (en) * | 2001-05-17 | 2003-03-11 | Allergan, Inc. | Prostanoic acid derivatives as agents for lowering intraocular pressure |
AR071312A1 (en) * | 2008-04-09 | 2010-06-09 | Scinopharm Taiwan Ltd | PROCESS FOR THE PREPARATION OF PROSTAGLANDINE ANALOGS AND THEIR INTERMEDIARIES |
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