CN102643178A - Preparation methods of lasofoxifene tartrate and intermediate thereof - Google Patents
Preparation methods of lasofoxifene tartrate and intermediate thereof Download PDFInfo
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Abstract
The invention provides preparation methods of lasofoxifene tartrate and an intermediate thereof. The preparation methods are available in raw material, low in cost, high in reaction yield, safe and reliable in production, high in product purity, and suitable for industrial production.
Description
Technical field
The present invention relates to tartrate Lasofoxifene and intermediates preparation thereof.
Background technology
Tartrate Lasofoxifene (lasofoxifene tartrate), structural formula are suc as formula shown in (I), and chemistry is called (5R; 6S)-5,6,7; 8-tetrahydrochysene-6-phenyl-5-[4-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-beta naphthal (2S, 3S)-tartrate, be the selective estrogen receptor modulators of Pfizer Inc.'s research and development; In April, 2009 is the approval listing in Europe, and its commercial tablets is called Fablyn.These article present selectivity excitement or antagonistic action in different oestrogenic hormon target tissues, ERs ER α and ER β are had the affinity of height, clinically are used to treat postmenopausal women's osteoporosis.
The method of the synthetic Lasofoxifene of bibliographical information mainly contains following several kinds at present:
WO96021656 and WO97016434 have reported the synthetic of Lasofoxifene tartrate, and synthetic route is as follows:
6-methoxyl group-1-tetralone and compound I I generate 1-[2-[4-(6-methoxyl group-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl] tetramethyleneimine (III) under the effect of n-Butyl Lithium; Compound (III) generates 1-[2-[4-(2-bromine 6-methoxyl group-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl] tetramethyleneimine (IV) with the pyridinium reactant salt of crossing bromination; (IV) at Pd (Ph
3P)
4, PhB (OH)
2The Suzuki reaction takes place down and obtains compound (VI) in effect; Compound (VI) is by Pd/C or Pd (OH)
2/ C reaction obtains the compound VI I of cis through catalytic hydrogenation; VII is at HBr or BBr
3Existing down, demethyl obtains VIII; This route is a starting raw material with 6-methoxyl group-1-tetralone, and reaction obtains intermediate III in the presence of butyllithium, and there is potential safety hazard in severe reaction conditions.
WO97016434 has reported that also the ethanol/water that used 95: 5 splits VIII as resolution solvent; Splitting the back content of isomer is 5%; With 95: 5 ethanol/waters Lasofoxifene tartrate is carried out recrystallization and obtain optical purity greater than 99: 1 Lasofoxifene tartrate, the content of isomer that the product that this fractionation obtains is difficult to reach medicinal requirements is less than 0.15% requirement.
EP1055658A (2000-11-29 is open), the novel synthesis of report midbody (VII), route is as follows:
This route passes through diketone compound (IX) through TiCl
3The McMurry linked reaction takes place and obtains 4-(4-benzyloxy-phenyl)-7-methoxyl group-3-phenyl-1 in/Zn-Cu catalysis, 2-dihydronaphthalene (Xa), and compound (Xa) is through Pd (OH)
2The catalytic hydrogenation reduction is also sloughed hydroxyl protecting group, under the Mitsunobu condition, obtains cis-compound (VII) with N-(2-hydroxyethyl) tetramethyleneimine condensation then.The used intermediate compound I X synthetic reaction condition of this route is harsh, has potential safety hazard, and follow-up used reagent cost an arm and a leg (like DEAD).
Bioorganic & Medicinal Chemistry Letters, 15 (2005), the 5124-5128 page or leaf has been reported a kind of method of synthetic Lasofoxifene newly, route is as follows:
This route obtains intermediate X IIa to be initial passing through to the bromobenzene benzyl oxide through grignard reaction, bromo, coupling and catalytic hydrogenation, splits through chirality HPLC again, obtains Lasofoxifene alkali at last.This route agents useful for same is cheap and easy to get, realizes but the industriallization of HPLC chiral separation is difficult.
Summary of the invention
First aspect of the present invention has provided a kind of method for preparing Lasofoxifene midbody tetralin compounds (XII), and the technical scheme of employing is following:
A kind of method for preparing tetralin compounds (XII), synthetic route is as follows:
Above-mentioned various in, R
1Be selected from phenyl, C
1～C
4Substituted phenyl is preferably phenyl; R
2Be C
1～C
4Alkyl is preferably methyl; X is Cl, Br, I, further is preferably Br;
May further comprise the steps:
(a) compounds X I in solvent under alkali, triphenyl phosphorus and palladium catalyst effect with phenylo boric acid under 10～150 ℃, react and obtained compounds X in 1～48 hour;
(b) under 10～100 ℃, catalytic hydrogenation obtained compounds X II in 1～48 hour to compounds X in solvent;
Below be the preferred scheme of the present invention:
The described palladium catalyst of step (a) is selected from palladium carbon, palladium hydroxide carbon, palladium, further is preferably palladium; Catalyst system therefor is 0.0001%～10% with the compound quality ratio of formula XI, further is preferably 0.1%～5%;
The said alkali of step (a) is selected from basic metal hydrogen-oxygen hydrogenate or alkaline carbonate; Further be preferably sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood;
The said solvent of step (a) is selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, THF, N, dinethylformamide, toluene; Further be preferably methyl alcohol, ethanol, THF, toluene.
The temperature of reaction of step (a) is 10～150 ℃, further is preferably 40～110 ℃;
The reaction times of step (a) is 1～48 hour, further is preferably 4～10 hours;
Step (b) is to be that raw material realizes that with hydrogen reducing one step deprotection of reduction and phenolic hydroxyl group gets in the presence of catalyzer with polysubstituted dialin shown in the formula (X);
The catalyzer that step (b) catalytic reduction uses is selected from one or more mixing in palladium carbon, palladium hydroxide/carbon, the Raney Ni; The compound quality ratio of catalyst system therefor and formula (X) is 0.1%～30%, further is preferably 5%～15%;
Step (b) hydrogen pressure is preferably 0.1～1.5MPa;
The said solvent of step (b) is selected from polar solvent; Be preferably water, methyl alcohol, ethanol, Virahol, acetonitrile;
Step (b) is reduced under acidic conditions, and described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid; Preferably, the amount that acidic substance add is 0.1～10% with the compound quality ratio of formula X, further is preferably 1%～5%.
Step (b) temperature of reaction is under 10～100 ℃, further is preferably 40～60 ℃;
Step (b) reaction times is 1～48 hour, further is preferably 4～20 hours.
First aspect of the present invention, typical synthetic route is as follows:
The technical scheme that first aspect present invention adopts compared with prior art, raw material is easy to get, cost is low, reaction yield is high, production safety is reliable, the three wastes are few.
XIIa obtains compound VI I without splitting directly to react with chloroethyl pyrroles or its hydrochloride, with reference to Bioorganic & Medicinal Chemistry Letters, 15 (2005), the method for 5124-5128 page or leaf; Make VII demethyl in the presence of HBr or BBr3 obtain VIII with reference to WO96021656 then, synthetic route is as follows:
Second aspect of the present invention provides a kind of and split the method that compound VIII obtains D-tartrate Lasofoxifene with D-(-)-tartrate, and it is characterized in that: resolution solvent is anhydrous C
1～C
4Alcoholic solvent.Synthetic route is as follows:
Compound VIII is the racemic modification of cis, and chemistry is by name: (5R, 6S/5S, 6R)-5,6,7,8-tetrahydrochysene-6-phenyl-5-[4-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-beta naphthal.
As preferred scheme, resolution solvent is selected from absolute ethyl alcohol, anhydrous methanol, and anhydrous isopropyl alcohol further is preferably ethanol.
The present invention also provides a kind of method that content of isomer is less than 0.15% tartrate Lasofoxifene for preparing, said isomer be (5S, 6R)-5,6,7,8-tetrahydrochysene-6-phenyl-5-[4-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-beta naphthal may further comprise the steps:
(a) compound (VIII) is dissolved in anhydrous C
1～C
4In the alcoholic solvent, add D-(-)-tartrate; Crystal is separated out in cooling, filters;
(b) filter cake is used organic solvent extraction again with the aqueous solution neutralization of mineral alkali; Concentrated organic layer obtains solid;
(c) repeating step (a) obtains title product.
Said anhydrous C
1～C
4Alcoholic solvent is preferably absolute ethyl alcohol, anhydrous methanol, anhydrous isopropyl alcohol; Extract used organic solvent and be preferably C
1～C
4The mixture of alcoholic solvent and methylene dichloride.
The 3rd aspect of the present invention provides a kind of new tartrate Lasofoxifene crystal formation I, and PXRD (powder x-ray diffraction spectrogram) is as shown in Figure 1, diffraction peak 2 θ (unit: degree) be positioned at: 5.63,11.25,11.41,11.55,14.73; 15.822,16.03,16.77,17.89,18.66,19.51,21.03; 21.13,21.64,21.72,22.22,22.41,22.57,23.82; 23.97,25.02,25.17,25.35,26.42,27.54.
The DSC (differential scanning calorimetric) of above-mentioned tartrate Lasofoxifene crystal formation I is as shown in Figure 2, and the DSC fusing point is positioned at 185.7～193.7 ℃.
Description of drawings
The PXRD figure of Fig. 1 tartrate Lasofoxifene crystal formation I
The DSC figure of Fig. 2 tartrate Lasofoxifene crystal formation I.
Embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
1, the compound method of polysubstituted dialin compound
Embodiment 1.1
4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1,2-dialin synthetic
Accurately add 21.0g 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-bromo-1,2-dialin in the reaction flask), 6.9g phenylo boric acid, 5.7g KOH, 420mg Pd (OAc)
2, 980mg PPh
3, add 120mL ethanol, be warming up to 60 ℃ of stirring reaction 4h, TLC detection reaction terminal point.Filter, concentrated filtrate reclaims, recrystallization, and 40 ℃ of vacuum-drying 3h of filter cake get white solid 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1, the 2-dialin), yield 92%.
Embodiment 1.2
4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1,2-dialin synthetic
Accurately add 21.0g 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-bromo-1,2-dialin in the reaction flask), 6.9g phenylo boric acid, 5.0g salt of wormwood, 100mg Pd (OAc)
2, 100mg PPh
3, add 120mL methyl alcohol, be warming up to refluxing and stirring reaction 4h, TLC detection reaction terminal point.Filter, concentrated filtrate reclaims, recrystallization, and 40 ℃ of vacuum-drying 3h of filter cake get white solid 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1, the 2-dialin), yield 85%.
Embodiment 1.3
4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1,2-dialin synthetic
Accurately add 21.0g 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-bromo-1,2-dialin in the reaction flask), the 6.9g phenylo boric acid; 5.0gKOH, 100mg palladium carbon, 100mg PPh3; Add 120mL DMF, be warming up to 120 ℃ of stirring reaction 8h, TLC detection reaction terminal point.Filter, concentrated filtrate reclaims, recrystallization, and 40 ℃ of vacuum-drying 3h of filter cake get white solid 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1, the 2-dialin), yield 89%.
Embodiment 1.4
4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1,2-dialin synthetic
Accurately add 20.5g 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-chloro-1,2-dialin in the reaction flask), 6.9g phenylo boric acid, 5.0gNaOH, 10mg palladium carbon, 100mg PPh
3, add the 120mL THF, be warming up to 40 ℃ of stirring reaction 8h, TLC detection reaction terminal point.Filter, concentrated filtrate reclaims, recrystallization, and 40 ℃ of vacuum-drying 3h of filter cake get white solid 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1, the 2-dialin), yield 75%.
Embodiment 1.5
4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1,2-dialin synthetic
Accurately add 20.5g 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-iodo-1,2-dialin in the reaction flask), 6.9g phenylo boric acid, 5.0g salt of wormwood, 200mg palladium carbon, 100mg PPh
3, add the 120mL acetonitrile, be warming up to 60 ℃ of stirring reaction 8h, TLC detection reaction terminal point.Filter, concentrated filtrate reclaims, recrystallization, and 40 ℃ of vacuum-drying 3h of filter cake get white solid 4-(4-(phenoxy) phenyl)-7-methoxyl group-3-phenyl-1, the 2-dialin), yield 92%.
Embodiment 1.6
4-(4-(phenoxy) phenyl)-7-oxyethyl group-3-phenyl-1,2-dialin synthetic
Accurately add 21.0g 4-(4-(phenoxy) phenyl)-7-oxyethyl group-3-iodo-1,2-dialin in the reaction flask), 6.9g phenylo boric acid, 5.0g salt of wormwood, 100mg palladium hydroxide/carbon, 100mg PPh
3, add 120mL toluene, be warming up to 110 ℃ of stirring reaction 10h, TLC detection reaction terminal point.Filter, concentrated filtrate reclaims, recrystallization, and 40 ℃ of vacuum-drying 3h of filter cake get white solid 4-(4-(phenoxy) phenyl)-7-oxyethyl group-3-phenyl-1, the 2-dialin), yield 76%.
2, the compound method of polysubstituted tetralin compounds
Embodiment 2.1
Synthesizing of 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol
Accurately take by weighing 1-(4-(benzyloxy) phenyl)-6-methoxyl group-2-phenyl-3,4-dialin 71.5g, 7.2g Pd/C (5%) add 1000mL ethanol, the dense HCl of 0.1mL.Sealed reactor with nitrogen replacement 3 times, is used H again
2Replace 3 times.Pressure 0.8MPa pressurize 10min is set.After the no gas leakage, H is set
2Pressure is that 0.1MPa, stir speed (S.S.) are 650r/min, slowly is warming up to 60 ℃.Isothermal reaction 4h.Reaction solution is taken out in release, and filtered while hot concentrates recovery ethanol and obtains white solid 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol, in 45 ℃ of vacuum-dryings, gets 48.7g, yield 86.9%.
Embodiment 2.2
Synthesizing of 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol
Accurately take by weighing 1-(4-(benzyloxy) phenyl)-6-methoxyl group-2-phenyl-3,4-dialin 71.5g, 7.2g Pd/C (5%) add the 1000mL acetonitrile, the dense HCl of 0.1mL.Sealed reactor with nitrogen replacement 3 times, is used H again
2Replace 3 times.Pressure 0.5MPa pressurize 10min is set.After the no gas leakage, H is set
2Pressure is that 0.3MPa, stir speed (S.S.) are 650r/min, slowly is warming up to 60 ℃.Isothermal reaction 8h.Reaction solution is taken out in release, and filtered while hot concentrates recovery ethanol and obtains white solid 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol, in 45 ℃ of vacuum-dryings, gets 50.0g, yield 89.3%.
Embodiment 2.3
Synthesizing of 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol
Accurately take by weighing 1-(4-(benzyloxy) phenyl)-6-methoxyl group-2-phenyl-3,4-dialin 71.5g, 7.2g Pd/C (5%) add 500mL methyl alcohol, the 1mL vitriol oil.Sealed reactor with nitrogen replacement 3 times, is used H again
2Replace 3 times.Pressure 0.5MPa pressurize 10min is set.After the no gas leakage, H is set
2Pressure is that 0.5MPa, stir speed (S.S.) are 650r/min, slowly is warming up to 60 ℃.Isothermal reaction 8h.Reaction solution is taken out in release, and filtered while hot concentrates recovery ethanol and obtains white solid 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol, in 45 ℃ of vacuum-dryings, gets 41.0g, yield 73.2%.
Embodiment 2.4
Synthesizing of 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol
Accurately take by weighing 1-(4-(phenoxy) phenyl)-6-methoxyl group-2-phenyl-3,4-dialin 71.5g, 7.2g Pd (OH)
2, add 500mL ethanol, 10mL acetic acid.Sealed reactor with nitrogen replacement 3 times, is used H again
2Replace 3 times.Pressure 1.5MPa pressurize 10min is set.After the no gas leakage, H is set
2Pressure is that 1.5MPa, stir speed (S.S.) are 650r/min, slowly is warming up to 60 ℃.Isothermal reaction 18h.Reaction solution is taken out in release, and filtered while hot concentrates recovery ethanol and obtains white solid 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol, in 45 ℃ of vacuum-dryings, gets 41.2g, yield 74.8%.
Embodiment 2.5
Synthesizing of 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol
Accurately take by weighing 1-(4-(phenoxy) phenyl)-6-methoxyl group-2-phenyl-3,4-dialin 71.5g, 4.0g Pd (OH)
2, add the 500mL Virahol.Sealed reactor with nitrogen replacement 3 times, is used H again
2Replace 3 times.Pressure 1.0MPa pressurize 10min is set.After the no gas leakage, H is set
2Pressure is that 1.0MPa, stir speed (S.S.) are 650r/min, slowly is warming up to 60 ℃.Isothermal reaction 20h.Reaction solution is taken out in release, and filtered while hot concentrates recovery ethanol and obtains white solid 4-(6-methoxyl group-2-phenyl-1,2,3,4-tetralin) phenol, in 45 ℃ of vacuum-dryings, gets 40.0g, yield 72.4%.
3, the preparation of tartrate Lasofoxifene
Embodiment 3.1
The preparation of tartrate Lasofoxifene form I
Accurately take by weighing the 2.07g compound IV, add the 150mL absolute ethyl alcohol, reflux 20min.Add 1.50g D-(-)-tartrate, behind the 20～30min that refluxes, slowly cooling.There is solid to separate out, continues to stir 2 hours.Filter, with 5mL * 2 absolute ethanol washings, solid adds 20mL 1%NaOH stirring 1～2h (can dry and weigh; Calculate the product rate, be about 44%), use the 40mL absolute ethyl alcohol: the mixed extractant solvent of methylene dichloride=1: 3; Get organic layer, with the water washing of 5mL saturated common salt, anhydrous MgSO
4Dry.Filter, organic layer concentrates (solid foam shape).Solid adds the 50mL absolute ethyl alcohol, and reflux 20min adds 0.75g D-(-)-tartrate, backflow 30min.Slowly cool to 50 ℃, crystallization (process is with splitting for the first time).Filter, filter cake is with 5mL * 2 absolute ethanol washings.The solid oven dry obtains 0.89g, and yield is 31.6%.
Embodiment 3.2
The preparation of tartrate Lasofoxifene form I
Accurately take by weighing the 2.07g compound IV, add the 150mL Virahol, reflux 20min.Add 1.50g D-(-)-tartrate, behind the 20～30min that refluxes, slowly cooling.There is solid to separate out, continues to stir 2 hours.Filter, with 5mL * 2 washed with isopropyl alcohol, solid adds 20mL 1%NaOH stirring 1～2h (can dry and weigh; Calculate the product rate, be about 44%), use the 40mL Virahol: the mixed extractant solvent of methylene dichloride=1: 3; Get organic layer, with the water washing of 5mL saturated common salt, anhydrous MgSO
4Dry.Filter, organic layer concentrates (solid foam shape).Solid adds the 50mL Virahol, and reflux 20min adds 0.75g D-(-)-tartrate, backflow 30min.Slowly cool to 50 ℃, crystallization (process is with splitting for the first time).Filter, filter cake is with 5mL * 2 washed with isopropyl alcohol.The solid oven dry obtains 0.70g, and yield is 25.0%.
Embodiment 3.3
The preparation of tartrate Lasofoxifene form I
Accurately take by weighing the 2.07g compound IV, add 150mL methyl alcohol, reflux 20min.Add 1.50g D-(-)-tartrate, behind the 20～30min that refluxes, slowly cooling.There is solid to separate out, continues to stir 2 hours.Filter, with 5mL * 2 methanol wash, solid adds 20mL1%NaOH stirring 1～2h (can dry and weigh; Calculate the product rate, be about 44%), use 40mL methyl alcohol: the mixed extractant solvent of methylene dichloride=1: 3; Get organic layer, with the water washing of 5mL saturated common salt, anhydrous MgSO
4Dry.Filter, organic layer concentrates (solid foam shape).Solid adds 50mL methyl alcohol, and reflux 20min adds 0.75g D-(-)-tartrate, backflow 30min.Slowly cool to 50 ℃, crystallization (process is with splitting for the first time).Filter, filter cake is with 5mL * 2 methanol wash.The solid oven dry obtains 0.79g, and yield is 28.0%.
Claims (13)
1. method for preparing tetralin compounds (XII), synthetic route is as follows:
Above-mentioned various in, R
1Be selected from phenyl, C
1～C
4Substituted phenyl is preferably phenyl; R
2Be C
1～C
4Alkyl is preferably methyl; X is Cl, Br, I, is preferably Br;
May further comprise the steps:
(a) compounds X I is in solvent, under alkali, triphenyl phosphorus and palladium catalyst effect with phenylo boric acid under 10～150 ℃, react and obtained compounds X in 1～48 hour.
(b) under 10～100 ℃, catalytic hydrogenation obtained compounds X II in 1～48 hour to compounds X under catalyst action in solvent.
2. method according to claim 1, the described palladium catalyst of step (a) is selected from palladium carbon, palladium hydroxide carbon, palladium; Further be preferably palladium; The mass ratio of catalyzer and compounds X I is 0.0001%～10%, further is preferably 0.1%～5%.
3. method according to claim 1, the said alkali of step (a) is selected from basic metal hydrogen-oxygen hydrogenate or alkaline carbonate; Further be preferably sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood.
4. method according to claim 1, the said solvent of step (a) is selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, THF, N, dinethylformamide, toluene.
5. method according to claim 1, step (b) catalyzer is selected from one or more mixing in palladium carbon, palladium hydroxide/carbon, the Raney Ni; The compound quality ratio of catalyst system therefor and formula (X) is 0.1%～30%, further is preferably 5%～15%.
6. method according to claim 1, step (b) hydrogen pressure is preferably 0.1～1.5Mpa.
7. method according to claim 1, the said solvent of step (b) is selected from polar solvent; Be preferably water, methyl alcohol, ethanol, Virahol, acetonitrile.
8. method according to claim 1, step (b) is carried out catalytic hydrogenation under acidic conditions, and described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid; The amount that acidic substance add is 0.1～10% with the compound quality ratio of formula X, further is preferably 1%～5%.
9. method for preparing the tartrate Lasofoxifene; Comprise with D-(-)-tartrate split (5R, 6S/5S, 6R)-5; 6; 7,8-tetrahydrochysene-6-phenyl-5-[4-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-beta naphthal (VIII) obtains the method for D-tartrate Lasofoxifene (I), and it is characterized in that: resolution solvent is anhydrous C
1～C
4Alcoholic solvent, synthetic route is as follows:
10. method according to claim 9 is characterized in that resolution solvent is selected from absolute ethyl alcohol, anhydrous methanol, anhydrous isopropyl alcohol.
11. a method for preparing the tartrate Lasofoxifene may further comprise the steps:
(a) with (6R)-5,6,7,8-tetrahydrochysene-6-phenyl-5-[4-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-beta naphthal (VIII) is dissolved in anhydrous C for 5R, 6S/5S
1～C
4In the alcoholic solvent, add D-(-)-tartrate; Crystal is separated out in cooling, filters;
(b) filter cake is used organic solvent extraction again with the aqueous solution neutralization of mineral alkali; Concentrated organic layer obtains solid;
(c) with step (b) gained solid, the operation of repeating step (a) obtains title product.
12. method according to claim 11, the wherein anhydrous C of step (a)
1～C
4Alcoholic solvent is an absolute ethyl alcohol, anhydrous methanol, anhydrous isopropyl alcohol; Extracting used organic solvent is C
1～C
4The mixture of alcoholic solvent and methylene dichloride.
13. a tartrate Lasofoxifene crystal formation I, the diffraction peak 2 θ values of its powder x-ray diffraction spectrogram (unit: degree) be positioned at: 5.63,11.25,11.41,11.55,14.73,15.822; 16.03,16.77,17.89,18.66,19.51,21.03,21.13; 21.64,21.72,22.22,22.41,22.57,23.82; 23.97,25.02,25.17,25.35,26.42,27.54.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109317203A (en) * | 2018-12-03 | 2019-02-12 | 毕云丽 | A kind of preparation method for treating postmenopausal osteoporosis pharmaceutical intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109317203A (en) * | 2018-12-03 | 2019-02-12 | 毕云丽 | A kind of preparation method for treating postmenopausal osteoporosis pharmaceutical intermediate |
| CN109317203B (en) * | 2018-12-03 | 2019-09-03 | 毕云丽 | A kind of preparation method for treating postmenopausal osteoporosis pharmaceutical intermediate |
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