CN107226790A - A kind of preparation method and midbody compound of high-purity tafluprost and its similar compound - Google Patents
A kind of preparation method and midbody compound of high-purity tafluprost and its similar compound Download PDFInfo
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- CN107226790A CN107226790A CN201610200791.1A CN201610200791A CN107226790A CN 107226790 A CN107226790 A CN 107226790A CN 201610200791 A CN201610200791 A CN 201610200791A CN 107226790 A CN107226790 A CN 107226790A
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- tafluprost
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost 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(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 title claims abstract description 26
- 229960004458 tafluprost Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- -1 ester group butyltriphenylphosphonium bromide phosphines Chemical class 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000001449 isopropyl group Chemical class [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 230000004224 protection Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
- 150000003613 toluenes Chemical class 0.000 description 5
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- ZOIRKXLFEHOVER-UHFFFAOYSA-N Isopropyl 3-methylbutanoate Chemical compound CC(C)CC(=O)OC(C)C ZOIRKXLFEHOVER-UHFFFAOYSA-N 0.000 description 4
- 230000001384 anti-glaucoma Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 2
- 0 OC(C1)*C(C[C@]2O)[C@@]1[C@]2C=CC(COc1ccccc1)(F)F Chemical compound OC(C1)*C(C[C@]2O)[C@@]1[C@]2C=CC(COc1ccccc1)(F)F 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- 229940005605 valeric acid Drugs 0.000 description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101100045312 Caenorhabditis elegans taf-4 gene Proteins 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 235000007466 Corylus avellana Nutrition 0.000 description 1
- 240000003211 Corylus maxima Species 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229960002470 bimatoprost Drugs 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000000720 eyelash Anatomy 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical class CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 1
- 229960001160 latanoprost Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- ZGKIYLYSHXFWES-UHFFFAOYSA-N pentanoic acid;hydrobromide Chemical class Br.CCCCC(O)=O ZGKIYLYSHXFWES-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, it is related to the preparation method and related intermediate of a kind of tafluprost and its similar compound, including using structure 4 ester group butyltriphenylphosphonium bromide phosphines as follows as witting reaction reagents：
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to the preparation method and related midbody compound of a kind of high-purity tafluprost and its similar compound.
Background technology
Glaucoma is a kind of common eye illness, it has also become second largest common ophthalmological disorder.The topical drug for the treatment of glaucoma has：Beta-adrenergic antagonist, principal item has betaxolol, timolol etc.；Alpha-2 adrenoceptor agonists, principal item has clonidine, Apraclonldine；Derivatives of prostaglandins, including tafluprost, Latanoprost, Bimatoprost etc..Derivatives of prostaglandins mainly reduces intraocular pressure by increasing uveal scleral approach ah outflow, and the drop intraocular pressure effect of alone such medicine is better than other class medicines.In addition, because the mechanism of action of derivatives of prostaglandins class anti-glaucoma medicine is different from other class anti-glaucoma medicines, synergy can be produced with other class anti-glaucoma medicines.Less plus this kind of side effects of pharmaceutical drugs, common adverse effect has conjunctival congestion, eyelashes growth and iris pigment to increase, and is more common in filbert iris.Such medicine has become the first-line drug of open angle glaucoma.
Tafluprost (Tafluprost) is developed jointly by the towering pharmacy of Japan and MSD Corp., and trade name " Saflutan " included two chain structures of α, ω, structure is shown below in Germany's listing, its structure first in 2008：
The preparation method of published tafluprost, its synthetic route is as follows：
In this route, when synthesizing VI by compound V, in presently disclosed preparation technology, such as document CN97126331.0, CN201310166937, witting reactions are carried out using 4- Carboxy-butyls triphenylphosphinebromide as reaction reagent to introduce ω chains, but the signified VI of the technique, the suitable inverse proportion of double bond is about 9: 1.Purified because trans-VI is difficult to simple remove, it is necessary to prepare HPLC, this allows for the technique and is not suitable for industrialized production.
The content of the invention
Present invention aims at the preparation method for providing a kind of high-purity tafluprost and its similar compound, this method is simple and feasible, facilitates industrialized production, is made and is substantially free of tafluprost of ω chain transisomers and the like.
Heretofore described tafluprost for being substantially free of ω chain transisomers and the like, refer to the cis-trans-isomer ratio ＞ 95: 5 of tafluprost and the like ω chain double bonds, it is preferred that ＞ 97: 3, further preferred ＞ 99: 1.
To achieve these goals, it is an aspect of the invention to provide firstly a class 4- ester groups-butyltriphenylphosphonium bromide phosphine, structure is as follows：
Wherein R is alkyl or aryl.
As a class preferably, the R is C2~C12 alkyl, including ethyl ester, isopropyl ester, the tert-butyl ester etc..Further preferably described R is isopropyl or the tert-butyl group, the most preferably tert-butyl group.
As it is another kind of preferably, the R is aryl, preferably optionally substituted phenyl, optionally substituted benzyl etc.；More preferably phenyl or benzyl, most preferably benzyl.
Another aspect of the present invention is there is provided a kind of method of new witting reactions, including using above-mentioned 4- ester groups-butyltriphenylphosphonium bromide phosphine as reaction reagent.
Another aspect of the present invention is there is provided the new tafluprost similar compound of a class, and its structure is as shown in following formula 6：
Wherein R is as defined above, and does not include isopropyl；Preferably described R is aryl, preferably optionally substituted phenyl, optionally substituted benzyl etc.；More preferably phenyl or benzyl.
When wherein R is isopropyl, the compound of formula 6 is tafluprost.When R defines substituent for other, the compound of formula 6 is tafluprost analog, and it can be used as the intermediate for preparing tafluprost.
In another aspect of this invention there is provided a kind of preparation method of the tafluprost similar compound compound, including obtained through witting reactions by Formula V compound and described 4- ester groups-butyltriphenylphosphonium bromide phosphine.
Wherein R is as defined above, and does not include isopropyl.
Another aspect of the present invention is obtained there is provided a kind of preparation method of tafluprost, including by Formula V compound with 4- isopropyl esters-butyltriphenylphosphonium bromide phosphine through witting reactions.
Another aspect of the invention is there is provided a kind of preparation method of tafluprost, including by the preparation of compounds of formula VI compounds of formula 6, then obtains tafluprost with the reaction such as 2- iodopropanes.The preparation method can be method commonly used in the art, such as bibliography CN97126331.0, CN201310166937.
Heretofore described witting reactions, reaction temperature is preferably -60 DEG C~40 DEG C, more preferably -20 DEG C~20 DEG C, most preferably -10 DEG C~0 DEG C.
The present invention provides the preparation method of tafluprost and its similar compound, simple and feasible, facilitates industrialized production, and is made and is substantially free of tafluprost of ω chain transisomers and the like.
Embodiment
In order that the present invention may be better understood in those skilled in the art, technical solution of the present invention is further described below by way of specific embodiment.It is to be appreciated that following embodiments only provide for the present invention is better described, it is not the limitation to present invention.
Embodiment 1：5- (triphenylphosphine) ethyl n-valerate bromide
5- bromines ethyl n-valerate (4.16g) and triphenylphosphine (5.24g, 1eq) are dissolved in 100mL dry toluenes, flowed back 2 days under N2 protections.Cooling down filters the white solid separated out to room temperature, is eluted with cold n-hexane.Gained solid is dried in vacuo to obtain title compound 8.46g (yield 90%)
Embodiment 2：The positive isopropyl isovalerate bromides of 5- (triphenylphosphine)
The positive isopropyl isovalerate of 5- bromines (4.44g) and triphenylphosphine (5.24g, 1eq) are dissolved in 100mL dry toluenes, flowed back 2 days under N2 protections.Cooling down filters the white solid separated out to room temperature, is eluted with cold n-hexane.Gained solid is dried in vacuo to obtain title compound 9.0g (yield 93%)
HNMR：7.23~7.56 (15H), 3.89 (1H), 2.32~2.87 (4H), 1.45~1.75 (4H), 1.32 (6H)
Embodiment 3：The positive pentanoate bromides of 5- (triphenylphosphine)
The positive pentanoate of 5- bromines (4.72g) and triphenylphosphine (5.24g, 1eq) are dissolved in 100mL dry toluenes, flowed back 2 days under N2 protections.Cooling down filters the white solid separated out to room temperature, is eluted with cold n-hexane.Gained solid is dried in vacuo to obtain title compound 7.1g (yield 71%)
HNMR：7.23~7.56 (15H), 2.32~2.87 (4H), 1.45~1.75 (4H), 1.25 (9H)
Embodiment 4：The positive valeric acid phenyl ester bromides of 5- (triphenylphosphine)
The tertiary phenyl ester of the positive valeric acid of 5- bromines (5.12g) and triphenylphosphine (5.24g, 1eq) are dissolved in 100mL dry toluenes, flowed back 2 days under N2 protections.Cooling down filters the white solid separated out to room temperature, is eluted with cold n-hexane.Gained solid is dried in vacuo to obtain title compound 8.3g (yield 80%)
HNMR：7.23~7.78 (20H), 2.32~2.87 (4H), 1.45~1.75 (4H)
Embodiment 5：The positive benzyl valerianate bromides of 5- (triphenylphosphine)
The tertiary benzyl ester of the positive valeric acid of 5- bromines (5.4g) and triphenylphosphine (5.24g, 1eq) are dissolved in 100mL dry toluenes, flowed back 2 days under N2 protections.Cooling down filters the white solid separated out to room temperature, is eluted with cold n-hexane.Gained solid is dried in vacuo to obtain title compound 7.5g (yield 71%)
HNMR：7.23~7.78 (20H), 4.87 (2H), 2.32~2.87 (4H), 1.45~1.75 (4H)
Embodiment 6：1- (5Z) -7- { (1R, 2R, 3R, 5S) -2- [the fluoro- 4- phenylaminos -1- cyclobutenyls of (1E) -3,3- bis-] -3,5- dihydroxies cyclopentyl } -5- heptenoates
Under nitrogen protection; compound A1 (2g, 4.26mmol) and tetrahydrofuran (20mL) are added in 10L reaction bulbs to drying, -10 DEG C are cooled to; NaHMDS (4.26mmol) tetrahydrofuran solution is added dropwise, room temperature reaction is raised to after adding 1~2 hour.- 10 DEG C are cooled to, compound V (1.3g, 4mmol) tetrahydrofuran (10mL) solution is added dropwise, control temperature is stirred 1~3 hour between -10~0 DEG C.Reaction solution is poured into frozen water (50mL), is extracted with ethyl acetate three times.Merge organic phase, be washed with water, saturated common salt washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title compound.HPLC shows, double bond Z/E=95/5.
HNMR：7.28 (2H), 6.99~6.91 (3H), 6.10 (1H), 5.80 (1H), 5.40~5.38 (2H), 4.99 (1H), 4.19 (3H), 4.00 (1H), 3.2~2.47 (5H), 2.31~2.25 (3H), 2.12~2.05 (4H), 1.82 (1H), 1.65~1.58 (3H), 1.18 (3H)
Embodiment 7：1- (5Z) -7- { (1R, 2R, 3R, 5S) -2- [the fluoro- 4- phenylaminos -1- cyclobutenyls of (1E) -3,3- bis-] -3,5- dihydroxies cyclopentyl } -5- heptene isopropyl propionates
Under nitrogen protection; compound A2 (2.1g, 4.26mmol) and tetrahydrofuran (20mL) are added in 10L reaction bulbs to drying, -10 DEG C are cooled to; NaHMDS (4.26mmol) tetrahydrofuran solution is added dropwise, room temperature reaction is raised to after adding 1~2 hour.- 10 DEG C are cooled to, compound V (1.3g, 4mmol) tetrahydrofuran (10mL) solution is added dropwise, control temperature is stirred 1~3 hour between -10~0 DEG C.Reaction solution is poured into frozen water (50mL), is extracted with ethyl acetate three times.Merge organic phase, be washed with water, saturated common salt washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title compound.HPLC shows, double bond Z/E=97/3.
HNMR：7.28 (2H), 6.99~6.91 (3H), 6.10 (1H), 5.80 (1H), 5.40~5.38 (2H), 4.99 (1H), 4.19 (3H), 4.00 (1H), 3.2~2.47 (3H), 2.31~2.25 (3H), 2.12~2.05 (4H), 1.82 (1H), 1.65~1.58 (3H), 1.22 (6H)
Embodiment 8：1- (5Z) -7- { (1R, 2R, 3R, 5S) -2- [the fluoro- 4- phenylaminos -1- cyclobutenyls of (1E) -3,3- bis-] -3,5- dihydroxies cyclopentyl } -5- heptene tert-butyl acrylates
Under nitrogen protection; compound A-13 (2.1g, 4.26mmol) and tetrahydrofuran (20mL) are added in 10L reaction bulbs to drying, -10 DEG C are cooled to; NaHMDS (4.26mmol) tetrahydrofuran solution is added dropwise, room temperature reaction is raised to after adding 1~2 hour.- 10 DEG C are cooled to, compound V (1.3g, 4mmol) tetrahydrofuran (10mL) solution is added dropwise, control temperature is stirred 1~3 hour between -10~0 DEG C.Reaction solution is poured into frozen water (50mL), is extracted with ethyl acetate three times.Merge organic phase, be washed with water, saturated common salt washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title compound.HPLC shows, double bond Z/E=98/2.
HNMR：7.28 (2H), 6.99~6.91 (3H), 6.10 (1H), 5.80 (1H), 5.40~5.38 (2H), 4.99 (1H), 4.19 (3H), 4.00 (1H), 3.2~2.47 (2H), 2.31~2.25 (3H), 2.12~2.05 (4H), 1.82 (1H), 1.65~1.58 (3H), 0.94 (9H)
Embodiment 9：1- (5Z) -7- { (1R, 2R, 3R, 5S) -2- [the fluoro- 4- phenylaminos -1- cyclobutenyls of (1E) -3,3- bis-] -3,5- dihydroxies cyclopentyl } -5- heptene acid phenenyl esters
Under nitrogen protection; compound A4 (2.2g, 4.26mmol) and tetrahydrofuran (20mL) are added in 10L reaction bulbs to drying, -10 DEG C are cooled to; NaHMDS (4.26mmol) tetrahydrofuran solution is added dropwise, room temperature reaction is raised to after adding 1~2 hour.- 10 DEG C are cooled to, compound V (1.3g, 4mmol) tetrahydrofuran (10mL) solution is added dropwise, control temperature is stirred 1~3 hour between -10~0 DEG C.Reaction solution is poured into frozen water (50mL), is extracted with ethyl acetate three times.Merge organic phase, be washed with water, saturated common salt washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title compound.HPLC shows, double bond Z/E=97/3.
HNMR：7.64~7.28 (7H), 6.99~6.91 (3H), 6.10 (1H), 5.80 (1H), 5.40~5.38 (2H), 4.99 (1H), 4.19 (3H), 4.00 (1H), 3.2~2.47 (2H), 2.31~2.25 (3H), 2.12~2.05 (4H), 1.82 (1H), 1.65~1.58 (3H)
Embodiment 10：1- (5Z) -7- { (1R, 2R, 3R, 5S) -2- [the fluoro- 4- phenylaminos -1- cyclobutenyls of (1E) -3,3- bis-] -3,5- dihydroxies cyclopentyl } -5- heptene acid benzyl esters
Under nitrogen protection; compound A-45 (2.3g, 4.26mmol) and tetrahydrofuran (20mL) are added in 10L reaction bulbs to drying, -10 DEG C are cooled to; NaHMDS (4.26mmol) tetrahydrofuran solution is added dropwise, room temperature reaction is raised to after adding 1~2 hour.- 10 DEG C are cooled to, compound V (1.3g, 4mmol) tetrahydrofuran (10mL) solution is added dropwise, control temperature is stirred 1~3 hour between -10~0 DEG C.Reaction solution is poured into frozen water (50mL), is extracted with ethyl acetate three times.Merge organic phase, be washed with water, saturated common salt washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title compound.HPLC shows, double bond Z/E=99/1.
HNMR：7.64~7.28 (7H), 6.99~6.91 (3H), 6.10 (1H), 5.80 (1H), 5.40~5.38 (2H), 4.99 (1H), 4.56 (2H), 4.19 (3H), 4.00 (1H), 3.2~2.47 (2H), 2.31~2.25 (3H), 2.12~2.05 (4H), 1.82 (1H), 1.65~1.58 (3H)
Comparative example：1- (5Z) -7- { (1R, 2R, 3R, 5S) 2- [the fluoro- 4- phenylaminos -1- cyclobutenyls of (1E) -3,3- bis-] -3,5- dihydroxies cyclopentyl } -5- heptene isopropyl propionates
Title compound is prepared according to the method for CN201310166937 preparation examples 1 by Taf4, and HPLC is shown, double bond Z/E=89/11.
Claims (10)
1. the preparation method of a kind of tafluprost and its similar compound, including obtained by Formula V compound with 4- isopropyl esters-butyltriphenylphosphonium bromide phosphine through witting reactions,
Wherein R is alkyl or aryl.
2. preparation method as claimed in claim 1, it is characterised in that the R is C2~C12 alkyl, including ethyl ester, isopropyl ester, the tert-butyl ester etc.；Preferably described R is isopropyl or the tert-butyl group, the most preferably tert-butyl group.
3. preparation method as claimed in claim 1, it is characterised in that the R is aryl, preferably optionally substituted phenyl, optionally substituted benzyl etc.；More preferably phenyl or benzyl, most preferably benzyl.
4. preparation method as claimed in claim 1, it is characterised in that the cis-trans-isomer ratio ＞ 95: 5 of the ω chain double bonds of the tafluprost and its similar compound, preferably ＞ 97: 3, further preferred ＞ 99: 1.
5. preparation method as claimed in claim 1, it is characterised in that the reaction temperature of described witting reactions is preferably -60 DEG C~40 DEG C, more preferably -20 DEG C~20 DEG C, most preferably -10 DEG C~0 DEG C.
6.4- ester groups-butyltriphenylphosphonium bromide phosphine compound, structure is as follows：
Wherein R is alkyl or aryl.
7. compound as claimed in claim 6, it is characterised in that R is C2~C12 alkyl, including ethyl ester, isopropyl ester, the tert-butyl ester, and further preferably described R is isopropyl or the tert-butyl group, the most preferably tert-butyl group.
8. compound as claimed in claim 6, it is characterised in that R is aryl, preferably optionally substituted phenyl, most preferably optionally substituted benzyl, more preferably phenyl or benzyl, benzyl.
9. the purposes as described in claim any one of 6-8, it is characterised in that the reaction reagent that the compound is reacted as witting.
10. purposes as claimed in claim 9, it is characterised in that the reaction temperature of described witting reactions is preferably -60 DEG C~40 DEG C, more preferably -20 DEG C~20 DEG C, most preferably -10 DEG C~0 DEG C.
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