US20030004368A1 - Novel intermediate for the synthesis of prostaglandins - Google Patents
Novel intermediate for the synthesis of prostaglandins Download PDFInfo
- Publication number
- US20030004368A1 US20030004368A1 US10/224,250 US22425002A US2003004368A1 US 20030004368 A1 US20030004368 A1 US 20030004368A1 US 22425002 A US22425002 A US 22425002A US 2003004368 A1 US2003004368 A1 US 2003004368A1
- Authority
- US
- United States
- Prior art keywords
- prostaglandin
- solution
- lactone
- synthesis
- conversion
- 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 claims description 11
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 229940094443 oxytocics prostaglandins Drugs 0.000 title description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 150000004820 halides Chemical class 0.000 claims abstract description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 2
- 150000002596 lactones Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- -1 lactone compound Chemical class 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000007239 Wittig reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 4
- GHXZPUGJZVBLGC-UHFFFAOYSA-N iodoethene Chemical compound IC=C GHXZPUGJZVBLGC-UHFFFAOYSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LNLLHUHPGPKRBM-UHFFFAOYSA-N bicyclo[3.2.0]hept-3-en-7-one Chemical compound C1=CCC2C(=O)CC21 LNLLHUHPGPKRBM-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- LAGQPAQLJHAWKJ-DNEYBRDTSA-N [2H]B(C)S.[2H]B(C)S.[3H]OC1CC2OC(=O)CC1C2/C=C/[C@H](CO[Ar])O[3H] Chemical compound [2H]B(C)S.[2H]B(C)S.[3H]OC1CC2OC(=O)CC1C2/C=C/[C@H](CO[Ar])O[3H] LAGQPAQLJHAWKJ-DNEYBRDTSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 description 1
- KZROEDQNIJGVQP-GNKBTFGDSA-N CCC1C(O[Ac])CC2OC(=O)CC21.[2H]B(C)S.[H][C@]12C=CC[C@@]1([H])C(=O)C2.[H][C@]12CC(O[3H])C3CC(C1=O)[C@@]32[H] Chemical compound CCC1C(O[Ac])CC2OC(=O)CC21.[2H]B(C)S.[H][C@]12C=CC[C@@]1([H])C(=O)C2.[H][C@]12CC(O[3H])C3CC(C1=O)[C@@]32[H] KZROEDQNIJGVQP-GNKBTFGDSA-N 0.000 description 1
- DQPNLKUTSMLWGC-IKKNCSPWSA-N CCCC/C=C\CC1C(O)CC(O)[C@@H]1/C=C/C(O)COC1=CC=CC(C(F)(F)F)=C1 Chemical compound CCCC/C=C\CC1C(O)CC(O)[C@@H]1/C=C/C(O)COC1=CC=CC(C(F)(F)F)=C1 DQPNLKUTSMLWGC-IKKNCSPWSA-N 0.000 description 1
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- YQVLYPKUSHUTJJ-KNQWGNCESA-N O=C(CCC/C=C\CC1C(O)CC(O)[C@@H]1/C=C/C(O)COC1=CC=CC(C(F)(F)F)=C1)O[IH][Pr].[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B([3H])CSOC1CC(O)[C@H](/C=C/C(COC2=CC=CC(C(F)(F)F)=C2)O[3H])C1C/C=C\CCCC(=O)O.[2H]B([3H])CSOC1CC(O)[C@H](/C=C/C(COC2=CC=CC(C(F)(F)F)=C2)O[3H])C1C/C=C\CCCC(=O)O[IH][Pr].[3H]OC1CC2OC(=O)CC1C2/C=C/[C@H](COC1=CC(C(F)(F)F)=CC=C1)O[3H].[3H]OC1CC2OC(O)CC1C2/C=C/[C@H](COC1=CC(C(F)(F)F)=CC=C1)O[3H] Chemical compound O=C(CCC/C=C\CC1C(O)CC(O)[C@@H]1/C=C/C(O)COC1=CC=CC(C(F)(F)F)=C1)O[IH][Pr].[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B(C)S.[2H]B([3H])CSOC1CC(O)[C@H](/C=C/C(COC2=CC=CC(C(F)(F)F)=C2)O[3H])C1C/C=C\CCCC(=O)O.[2H]B([3H])CSOC1CC(O)[C@H](/C=C/C(COC2=CC=CC(C(F)(F)F)=C2)O[3H])C1C/C=C\CCCC(=O)O[IH][Pr].[3H]OC1CC2OC(=O)CC1C2/C=C/[C@H](COC1=CC(C(F)(F)F)=CC=C1)O[3H].[3H]OC1CC2OC(O)CC1C2/C=C/[C@H](COC1=CC(C(F)(F)F)=CC=C1)O[3H] YQVLYPKUSHUTJJ-KNQWGNCESA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- YFVBZGPAZQLBLJ-DRJIAWMKSA-N [2H]B(C)S.[2H]B(C)S.[3H]OC1CC2OC(=O)CC1C2/C=C/[C@H](COC1=CC(C(F)(F)F)=CC=C1)O[3H] Chemical compound [2H]B(C)S.[2H]B(C)S.[3H]OC1CC2OC(=O)CC1C2/C=C/[C@H](COC1=CC(C(F)(F)F)=CC=C1)O[3H] YFVBZGPAZQLBLJ-DRJIAWMKSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 1
- PSEHHVRCDVOTID-VMAIWCPRSA-N chloro-bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@H]([C@@H]1C)B(Cl)[C@H]2[C@H](C)[C@]3(C[C@@](C2)(C3(C)C)[H])[H])[C@@]2([H])C(C)(C)[C@]1([H])C2 PSEHHVRCDVOTID-VMAIWCPRSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 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
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- PGOLTJPQCISRTO-UHFFFAOYSA-N vinyllithium Chemical compound [Li]C=C PGOLTJPQCISRTO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- This invention relates to the preparation of a novel crystalline lactone and its use in prostaglandin synthesis.
- the synthetic prostaglandin 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF 2a. and its ester derivatives, in particular the isopropyl ester (2), are potent drugs for the treatment of glaucoma and ocular hypertension.
- Optimum therapeutic benefit is achieved when compound (2) is used in the form of the dextrorotatory single enantiomer (+)-2, as depicted below.
- an economically viable route is required for the synthesis of (+)-2 in quantities of at least 1 kg.
- EP-A-0639563 describes biological studies of compound 2 and analogues, and synthetic methods which are applicable to its preparation.
- EP-A-0074856 describes resolution of racermic bicyclo[3.2.0]hept-2-en-6-one (5) by forming diastereomeric salts of its ⁇ -hydroxysulfonic acid derivative with a chiral amine, and separation by crystallisation.
- This invention is based on the unexpected discovery of a crystalline lactone 1
- This compound can be used in the stereoselective synthesis of 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF 2a and its ester derivatives, for example (+)-2.
- the crystalline lactone can be obtained in highly pure form. The crystallinity of the lactone is crucial in enabling impurities to be removed at this stage without resort to column chromatography. This provides the basis for an industrially viable synthesis of the prostaglandin 2 for pharmaceutical use.
- this discovery may also be applied to other substituted 16-phenoxy prostaglandins, where the substituent is haloalkyl, alkyl or halide.
- the alkyl group may have up to 6 C atoms.
- Halide is preferably 3-CI.
- Step (i) is the preparation of the tricyclic ketone 4. This is achieved by treatment of the bromohydrin 6 with base in an appropriate solvent, preferably potassium tert-butoxide in toluene.
- the unstable tricycle 4 is used without purification in step (iii). It is not necessary to evaporate the tricycle solution to dryness.
- Step (ii) is the formation of an alkenylcuprate reagent from the vinyl iodide 7, precursor to the ⁇ -side chain.
- the preparation of vinyl iodide 7 in enantiomerically enriched form is disclosed in the copending patent application, filed on the same date, entitled Process for the Preparation of Prostaglandin Precursors, and claiming priority from British Patent Application No. 9908327.1.
- the vinyl iodide is metallated with an alkyllithium reagent, preferably tert-butyllithium, and then treated with a cuprate of the form RCu(CN)Li where R is a non-transferable group which may be 2-thienyl.
- Step (iii) is reaction of the alkenylcuprate with the tricycle to form the bicyclic ketone 8.
- Step (iv) is the Baeyer-Villiger reaction producing the lactone 1.
- a peracid preferably peracetic acid
- a 3:1 mixture of regioisomers isolated as an oil.
- Further processing is then required to render this material as usable in subsequent steps.
- the minor and unwanted regioisomer can be selectively hydrolysed by treatment with aqueous alkali, for example, aqueous sodium hydroxide in acetonitrile.
- Potassium tert-butoxide (114.2 g, 1.02 mol) is suspended in toluene (2 L) and cooled to ⁇ 15° C. The suspension is stirred under a nitrogen atmosphere and a solution of the bromoketone (250 g, 0.783 mol) in dry toluene (400 ml) is added over 1 hour. The internal temperature is maintained at ⁇ 10 to ⁇ 20° C. The mixture is stirred for 1 hour. The mixture is warmed to room temperature, activated carbon (75 g) is added, and the mixture is stirred for 5 minutes. The mixture is filtered through Celite and the cake is washed with toluene (2.5 L) The filtrates are concentrated under reduced pressure, at 20° C., to approximately 700 ml volume. This solution is used directly in the next step.
- a dry 10 L flange flask fitted with an overhead stirrer, temperature probe, nitrogen inlet and pressure equalised dropping funnel, is purged with nitrogen and cooled to ⁇ 70° C.
- a solution of tert-butyllithium (1.7 M in pentane, 1013 ml, 1.72 mol) is added.
- the solution is re-cooled to ⁇ 70° C. and a solution of the vinyl iodide (436 g, 0.923 mol) in diethyl ether (1.3 L) is added over 90 minutes, maintaining the internal temperature below ⁇ 60° C.
- thiophene (75.2 ml, 0.94 mol) is placed in a dry 2L 3-necked flask, under a nitrogen atmosphere.
- THF 600 ml
- n-Butyllithium 2.5 M in hexanes, 376 ml, 0.94 mol
- the solution is stirred for 20 minutes at ⁇ 20° C., then the resulting yellow solution is added to a suspension of copper(I) cyanide (84.15 g, 0.94 mol) in THF (800 ml) at ⁇ 20° C. over 15 minutes.
- the resulting dark brown solution is re-cooled to ⁇ 10° C., and stirred for 20 minutes.
- the mixture is stirred for 20 minutes, the aqueous layer becomes deep blue in colour and a yellow/green precipitate forms.
- the mixture is filtered through a No 3 filter paper and the filter cake is washed with methyl tert-butyl ether (1 L).
- the organic layer is separated, and the aqueous layer is extracted with methyl tert-butyl ether (1 L).
- the combined organic layers are washed with brine (2 L), dried (MgSO 4 ) and decolourised with activated carbon.
- the solution is filtered, the cake is washed with methyl tert-butyl ether (2.5 L), and the filtrate is evaporated under reduced pressure.
- the ketone (362.6 g, 0.62 mol) and sodium acetate(170 g, 2.07 mol) are dissolved in glacial acetic acid (1.7 L).
- the reaction vessel is placed in a water bath at 20° C. and peracetic acid (40% in dilute acetic acid, 176.7 ml, 0.93 mol) is added over a period of 20 minutes.
- the solution is stirred at room temperature for 3 h. More peracetic acid (30 ml) is added, and the solution is stirred for a further 2 h.
- the reaction mixture is poured onto water (2.5 L), and the products are extracted into MTBE (2 ⁇ 750 ml, then 500 ml).
- the combined organic phases are washed with water (2 L).
- the aqueous phase is back extracted with MTBE (500 ml).
- the combined organic extracts are neutralised with saturated sodium carbonate solution (500 ml) and water (2 L) is added to aid phase separation.
- the organic phase is washed with water (1 L), brine (I L), dried (MgSO 4 ) and evaporated under reduced pressure, to give a yellow oil (363.8 g).
- the crude product (consisting of a mixture of regiolsomers) is dissolved in acetonitrile (1 L) at room temperature.
- Sodium hydroxide solution (1 M, 300 ml) is added and the solution stirred at room temperature for 2 h.
- Water (1 L) is added and the product is extracted into MTBE (3 ⁇ 500 ml).
- the combined organic phases are washed with brine (500 ml), dried (MgSO 4 ), filtered and evaporated under reduced pressure.
- the residue is recrystallised from heptane (1 L) at ⁇ 70° C. (cold bath temperature), filtered and washed with cold ( ⁇ 70° C., cold bath) heptane (2 ⁇ 200 ml).
- the solid is dried, to give the lactone as a white solid (141.2 g,38%).
- the mother liquors are filtered through silica gel (1 Kg) eluting with 20% DCM/Heptane, to remove baseline.
- lactone of example 7 can be converted to (+)-16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF 2a isopropyl ester using conventional processes; see Scheme II and associated publications.
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Abstract
wherein Ar is phenyl optionally substituted with one or more groups selected from haloalkyl, alkyl and halide. This compound can be isolated in crystalline form, and used in the preparation of (+)-16-[3-trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2α isopropyl ester.
Description
- This invention relates to the preparation of a novel crystalline lactone and its use in prostaglandin synthesis.
-
-
- An alternative and more convergent approach to prostaglandins involves addition of a cuprate reagent, incorporating the entire ω-side chain, to the tricyclo[3.2.0.02.7]heptanone 4 (Lee et al, J. Chem. Soc., Perkin Trans 1, 1978,1176). Tricyclic ketone 4 is prepared from a TBDMS-protected bromohydrin which is in turn derived from bicyclo[3.2.0]hept-2-en-6-one (5). In comparison to routes proceeding by a Corey lactone of type 3, significantly fewer steps are required. For example, preparation of prostaglandin F2a, from compound 5 requires only 8 steps (10 steps from cyclopentadiene). Avoidance of awkward late-stage reduction to establish the required configuration of the C-15-OH functionality provides another advantage.
- EP-A-0074856 describes resolution of racermic bicyclo[3.2.0]hept-2-en-6-one (5) by forming diastereomeric salts of its α-hydroxysulfonic acid derivative with a chiral amine, and separation by crystallisation.
- Certain lactones are described in Newton et al, Tetrahedron, 1980, 2163. None is crystalline.
-
- This compound can be used in the stereoselective synthesis of 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2aand its ester derivatives, for example (+)-2. The crystalline lactone can be obtained in highly pure form. The crystallinity of the lactone is crucial in enabling impurities to be removed at this stage without resort to column chromatography. This provides the basis for an industrially viable synthesis of the prostaglandin 2 for pharmaceutical use.
- According to the invention, this discovery may also be applied to other substituted 16-phenoxy prostaglandins, where the substituent is haloalkyl, alkyl or halide. The alkyl group may have up to 6 C atoms. Halide is preferably 3-CI.
- By way of illustration, the synthesis of the lactone 1 is depicted in Scheme I. All reactants depicted are used in enantiomerically enriched form, typically in >95% ee or higher.
- Step (i) is the preparation of the tricyclic ketone 4. This is achieved by treatment of the bromohydrin 6 with base in an appropriate solvent, preferably potassium tert-butoxide in toluene. The unstable tricycle 4 is used without purification in step (iii). It is not necessary to evaporate the tricycle solution to dryness.
- Step (ii) is the formation of an alkenylcuprate reagent from the vinyl iodide 7, precursor to the ω-side chain. The preparation of vinyl iodide 7 in enantiomerically enriched form is disclosed in the copending patent application, filed on the same date, entitled Process for the Preparation of Prostaglandin Precursors, and claiming priority from British Patent Application No. 9908327.1. The vinyl iodide is metallated with an alkyllithium reagent, preferably tert-butyllithium, and then treated with a cuprate of the form RCu(CN)Li where R is a non-transferable group which may be 2-thienyl. Step (iii) is reaction of the alkenylcuprate with the tricycle to form the bicyclic ketone 8.
- Step (iv) is the Baeyer-Villiger reaction producing the lactone 1. A peracid, preferably peracetic acid, is used, resulting in a 3:1 mixture of regioisomers, isolated as an oil. Further processing is then required to render this material as usable in subsequent steps. Conveniently, the minor and unwanted regioisomer can be selectively hydrolysed by treatment with aqueous alkali, for example, aqueous sodium hydroxide in acetonitrile. Extraction of the unreacted lactone 1 into an organic solvent, followed by evaporation of solvent, yields a solid residue which can be recrystallised at low temperature to give highly pure crystalline material with convenient handling and storage characteristics. These processing operations are pivotal to the success of the overall synthetic route.
-
- The following Examples illustrate the invention.
- Potassium tert-butoxide (114.2 g, 1.02 mol) is suspended in toluene (2 L) and cooled to −15° C. The suspension is stirred under a nitrogen atmosphere and a solution of the bromoketone (250 g, 0.783 mol) in dry toluene (400 ml) is added over 1 hour. The internal temperature is maintained at −10 to −20° C. The mixture is stirred for 1 hour. The mixture is warmed to room temperature, activated carbon (75 g) is added, and the mixture is stirred for 5 minutes. The mixture is filtered through Celite and the cake is washed with toluene (2.5 L) The filtrates are concentrated under reduced pressure, at 20° C., to approximately 700 ml volume. This solution is used directly in the next step.
- A dry 10 L flange flask, fitted with an overhead stirrer, temperature probe, nitrogen inlet and pressure equalised dropping funnel, is purged with nitrogen and cooled to −70° C. A solution of tert-butyllithium (1.7 M in pentane, 1013 ml, 1.72 mol) is added. The solution is re-cooled to −70° C. and a solution of the vinyl iodide (436 g, 0.923 mol) in diethyl ether (1.3 L) is added over 90 minutes, maintaining the internal temperature below −60° C.
- In the mean time, thiophene (75.2 ml, 0.94 mol) is placed in a dry 2L 3-necked flask, under a nitrogen atmosphere. THF (600 ml) is added, and the solution is cooled to −30° C. n-Butyllithium (2.5 M in hexanes, 376 ml, 0.94 mol) is added over 20 minutes. The solution is stirred for 20 minutes at −20° C., then the resulting yellow solution is added to a suspension of copper(I) cyanide (84.15 g, 0.94 mol) in THF (800 ml) at −20° C. over 15 minutes. The resulting dark brown solution is re-cooled to −10° C., and stirred for 20 minutes.
- The freshly prepared lithium 2-thienylcyanocuprate solution, at −10° C., is added to the vinyllithium solution at −70° C. over 20-30 minutes. The resulting solution is stirred for 30 minutes at −70° C. The tricycle solution (approximately 187 g in 600 ml toluene, +100 ml THF added) is cooled to −70° C., and added to the cuprate solution, at −70° C over 20 minutes. The mixture is stirred at −70° C. for one hour, then the cooling bath is removed from the reaction vessel and saturated ammonium chloride (3 L) is added. The mixture is stirred for 20 minutes, the aqueous layer becomes deep blue in colour and a yellow/green precipitate forms. The mixture is filtered through a No 3 filter paper and the filter cake is washed with methyl tert-butyl ether (1 L). The organic layer is separated, and the aqueous layer is extracted with methyl tert-butyl ether (1 L). The combined organic layers are washed with brine (2 L), dried (MgSO4) and decolourised with activated carbon. After 20 minutes the solution is filtered, the cake is washed with methyl tert-butyl ether (2.5 L), and the filtrate is evaporated under reduced pressure.
- The residue is taken up in heptane and passed through a plug of silica (1.5 Kg). eluting with 2% EtOAc/heptane to 10% EtOAc/heptane to provide the pure ketone as a yellow solid (293g, 64%), m.p. 64-72° C.; [α]D 20+35.9° (c=1.05, DCM); δH(400 MHz, CDCl3) 7.38 (1 H, t, J 8), 7.25 (1 H, d, J 8), 7.13 (1 H, s), 7.07 (1 H, d, J 8), 5.86 (1 H, dd, J 16,8), 5.73 (1 H, dd, J 16,6), 4.55 (2H, m), 3.90 (2H, d, J 7). 2.80 (1 H, m)2.77 (1 H, d, J 18), 2.57 (2 H, m), 2.45 (1 H, m), 2.05 (1 H, dd, J 18, 4). 1.35 (1 H, m), 0.95 (9 H,s), 0.90 (9 H, s), 0.15 (3 H, s), 0.14 (3 H, s) and 0.05 (6 H, s); δc (100 MHz, CDCl3) 216.0, 158.8, 132.02, 131.54 (q, J 32), 129.98, 127.77, 123.90 (q, J 270), 118.04, 117.55, 111.13, 72.32, 71.34, 69.92, 54.37, 50.23, 46.24, 38.80, 33.39, 25.76, 18.30, 17.97, −4.67, −4.74, −4.86 and −4.92.
- The ketone (362.6 g, 0.62 mol) and sodium acetate(170 g, 2.07 mol) are dissolved in glacial acetic acid (1.7 L). The reaction vessel is placed in a water bath at 20° C. and peracetic acid (40% in dilute acetic acid, 176.7 ml, 0.93 mol) is added over a period of 20 minutes. The solution is stirred at room temperature for 3 h. More peracetic acid (30 ml) is added, and the solution is stirred for a further 2 h. The reaction mixture is poured onto water (2.5 L), and the products are extracted into MTBE (2×750 ml, then 500 ml). The combined organic phases are washed with water (2 L). The aqueous phase is back extracted with MTBE (500 ml). The combined organic extracts are neutralised with saturated sodium carbonate solution (500 ml) and water (2 L) is added to aid phase separation. The organic phase is washed with water (1 L), brine (I L), dried (MgSO4) and evaporated under reduced pressure, to give a yellow oil (363.8 g). The crude product (consisting of a mixture of regiolsomers) is dissolved in acetonitrile (1 L) at room temperature. Sodium hydroxide solution (1 M, 300 ml) is added and the solution stirred at room temperature for 2 h. Water (1 L) is added and the product is extracted into MTBE (3×500 ml). The combined organic phases are washed with brine (500 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue is recrystallised from heptane (1 L) at −70° C. (cold bath temperature), filtered and washed with cold (−70° C., cold bath) heptane (2−200 ml). The solid is dried, to give the lactone as a white solid (141.2 g,38%). The mother liquors are filtered through silica gel (1 Kg) eluting with 20% DCM/Heptane, to remove baseline. Recrystallisation from cold (−70° C., cold bath) heptane (400 ml) gave a second batch of lactone (34 g, 9%). m.p. 77-78° C.; [α]D 20 −10.9° (c=1.05, DCM); δH (400 MHz, CDCl3) 7.40 (1 H, t, J 8), 7.22 (1 H, d, J 8), 7.10(1 H, s), 7.05(1 H, d, J 8), 5.70(2 H, m), 4.52(3 H, m), 3.87 (2 H, d, J 6), 3.16 (1 H, d, J 18), 3.00 (1H, d, J 6), 2.56 (1 H, dd ,J 18, 6), 2.46 (1 H, m), 2.39 (1 H, m), 1.88 (1 H, dt, J 16,3), 0.95 (9 H, s), 0.89 (9 H, s), 0.10 (6 H, s) and 0.04 (6 H, s); ωc (100 MHz, CDCl3) 170.39, 158.75, 132.43, 131.92 (q, J 32), 130.05, 127.87, 123.91 (q, J 270), 118.06, 117.68, 111.11, 82.20, 72.26, 71.64, 71.10, 48.94, 42.48, 40.40, 33.05, 25.75, 18.30, 18.04, −4.64, −4.76, −4.88 and −5.10.
- The lactone of example 7 can be converted to (+)-16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2a isopropyl ester using conventional processes; see Scheme II and associated publications.
Claims (3)
1. A process for preparing a prostaglandin, or an ester derivative thereof, wherein said process comprises the conversion of a lactone compound of formula 1
wherein Ar is phenyl optionally substituted with one or more groups selected from haloalkyl, alkyl and halide; and wherein said conversion to said prostaglandin comprises the following steps:
(i) reduction of the lactone to the corresponding lactol,
(ii) introduction of a prostaglandin α-chain by a Wittig reaction, and
(iii) conversion of the OTBDMS groups to OH groups.
2. The process according to claim 1 , wherein the prostaglandin is (+)-16-[3-trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2a isopropyl ester.
3. The process, according to claim 1 , wherein said process further comprises an acid-ester conversion either before or after step (Iii).
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US10/224,250 US20030004368A1 (en) | 1999-04-12 | 2002-08-19 | Novel intermediate for the synthesis of prostaglandins |
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GBGB9908326.3A GB9908326D0 (en) | 1999-04-12 | 1999-04-12 | Novel process intermediate for the synthesis of prostaglandins |
GB9908326.3 | 1999-04-12 | ||
US13646499P | 1999-05-28 | 1999-05-28 | |
US09/547,205 US6294679B1 (en) | 1999-04-12 | 2000-04-12 | Intermediate for the synthesis of prostaglandins |
US09/898,241 US6437152B1 (en) | 1999-04-12 | 2001-07-03 | Intermediate for the synthesis of prostaglandins |
US10/224,250 US20030004368A1 (en) | 1999-04-12 | 2002-08-19 | Novel intermediate for the synthesis of prostaglandins |
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US10/224,250 Abandoned US20030004368A1 (en) | 1999-04-12 | 2002-08-19 | Novel intermediate for the synthesis of prostaglandins |
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EP1810967B1 (en) | 2006-01-18 | 2014-07-30 | Chirogate International Inc. | Processes and intermediates for the preparations of prostaglandins |
US8524939B2 (en) | 2011-08-24 | 2013-09-03 | Chirogate International Inc. | Intermediates for the synthesis of benzindene prostaglandins and preparations thereof |
US11458041B2 (en) | 2015-10-08 | 2022-10-04 | Ocular Therapeutix, Inc. | Punctal plug and bioadhesives |
EP3861985B1 (en) | 2020-02-06 | 2023-06-14 | Ocular Therapeutix, Inc. | Compositions and methods for treating ocular diseases |
US11884613B2 (en) | 2022-05-05 | 2024-01-30 | Chirogate International Inc. | Processes and intermediates for the preparation of carbaprostacyclin analogues |
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EP0074856A3 (en) | 1981-09-16 | 1984-02-01 | Glaxo Group Limited | Resolution of racemic bicycloheptenones |
US4824993A (en) * | 1984-04-23 | 1989-04-25 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
US5510383A (en) * | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
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US6294679B1 (en) | 2001-09-25 |
US20020111499A1 (en) | 2002-08-15 |
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