A kind of preparation method and midbody compound of high-purity tafluprost and its similar compoundTechnical 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.