CN105085365B - The preparation method of bazedoxifene acetate and its intermediate - Google Patents
The preparation method of bazedoxifene acetate and its intermediate Download PDFInfo
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Abstract
The invention discloses the preparation methods of bazedoxifene acetate intermediate and bazedoxifene acetate intermediate.The invention also discloses the methods that bazedoxifene acetate is prepared with bazedoxifene acetate intermediate.The present invention provides preparing shown in bazedoxifene acetate key new intermediate such as formula (II), the intermediate is with C1‑6Alkanoyl is protecting group, and preparing bazedoxifene acetate using the intermediate has the following advantages：1st, the high-pressure hydrogenation hydrogenation that conventional method (protecting phenolic group by blocking group of benzyl) sloughs high risk required during protecting group is avoided, greatly reduces experimental risk；2nd, the reaction time has been saved, has reduced industrial energy consumption；3rd, reaction of the invention does not need to the palladium carbon of larger proportion amount, and reaction condition is mild, easy to operate, environmentally friendly, is suitble to industrialized production.
Description
Technical field
The present invention relates to the preparation methods of a kind of drug and its intermediate, are dredged more particularly to sclerotin after treatment postmenopausal women
The preparation method of loose drug bazedoxifene acetate and its intermediate.
Background technology
Entitled 1- { 4- [2- (cycloheximide base -1-) ethoxies of bazedoxifene acetate (bazedoxifene acetate) chemistry
Base] benzyl } -2- (4- hydroxy phenyls) -3- Methyl-1H-indole -5- phenol acetate is by European Ligand companies affiliate
Wyeth is in the selective estrogen receptor modulators (SERM) of research and development in 1997, in 2010 in Spain's (trade name
Conbriza) and Japanese (trade name Viviant) listing, indication are prevention and treatment women's osteosporosis after menopause.
Osteoporosis can betide different sexes and age, but be more common in postmenopausal women and elderly men.Post menopausal
Osteoporosis (Postmenopausal Osteoporosis, POP) is a kind of common disease related with aging, main to occur
In postmenopausal women, since estrogen deficiency leads to bone amount reduction and bone structure variation, increase bone brittleness and be easy to fracture,
And the pain as caused by fracture, textured bone, occur complication so that it is dead the problems such as, belong to primary osteoporosis.
Primary national extensive epidemiological survey in 2003 to 2006 shows that 50 years old or more crowd is close with centrum and femoral neck bone
Osteoporosis total prevalence rate women based on angle value is 20.7%.The epidemiological survey of the area based on iconography such as Beijing
It has been shown that, the illness rate of 50 years old or more women's spinal fracture is 15%, is equivalent in every 7 50 years old or more women with regard to there are one occur
Cross spinal fracture.The danger (40%) of osteoporotic fracture occurs all over the body for women, higher than breast cancer, carcinoma of endometrium and ovum
The summation of nest cancer.
Treatment postmenopausal osteoporosis drug mainly has：1st, bisphosphonates (Bisphosphonates)；2nd, estrogens
(Estrogen)；3rd, parathyroid hormone (PTH)；4th, selective estrogen receptor modulators class (SERMs)；5th, active vitamin
D and the like.
Different medicines has Diphosphonate, strontium ranelate and nearest new drug denomsumab, there is certain change
The effect of kind postmenopausal osteoporosis, but and not all women be suitable for.It is hidden due to the use of the health caused by these drugs
Suffer from, such as the cancer of the esophagus, lower jaw osteonecrosis；Use fracture subtrochanteric after Diphosphonate；It may lead to vein using Strontium Ranelate
Embolism；The discovery of Bazedoxifene can increase the selection of osteoporosis therapy scheme, and this new selective estrogen by
Body conditioning agent may have stronger anti-osteoporosis potentiality.
In recent years, people are continuing to optimize and are improving always the synthesis technology of bazedoxifene acetate, the patent reported for work recently
US2012253038A1, WO2009012734A etc. using bromo- (4- benzyloxy-phenyls) acetone of 2- and to benzyloxy aniline hydrochloride as
Starting material passes throughSynthesis of indole ring is reacted, seven yuan of azacyclo-s on parental materials, then hydrogenated reaction
Debenzylation protecting group obtains Bazedoxifene.The main route of synthesis bazedoxifene acetate is as follows at present：
This method protects phenolic group by blocking group of benzyl, during hydrogenation debenzylation blocking group, needs to be more than 3MPa
High-pressure hydrogenation kettle, in experiment exist very big danger.The reaction time generally needs 4-7 days, and the reaction time is longer, raw
It consumes energy in production larger, and the palladium carbon of larger proportion amount is needed in reacting, expensive to increase cost, post processing trouble is to environment
It is seriously polluted.
Invention content
First of the present invention is designed to provide new bazedoxifene acetate intermediate.
Second object of the present invention is to provide the method for preparing above-mentioned bazedoxifene acetate intermediate.The intermediate
Preparation is to be passed through with formula (II-a) and formula (II-b) for starting materialReact synthesis of indole ring.
Third object of the present invention is to provide prepares bazedoxifene acetate with above-mentioned bazedoxifene acetate intermediate
Method.
As the first aspect of the invention, shown in the structure such as formula (II) of the bazedoxifene acetate intermediate,
Wherein R1And R3It is C1-6Alkanoyl, and R1And R3It is identical or different.
Preferably, shown in the structure such as formula (II) of the bazedoxifene acetate intermediate, wherein R1For acetyl group or fourth
Acyl group, R3For acetyl group or propiono.
It is that the bazedoxifene acetate intermediate is 3- methyl -5- bytyries -2- as present invention further optimization
(4- propionyloxies phenyl) -1H- indoles, wherein R1For bytyry, R3For propiono.
It is that the bazedoxifene acetate intermediate is 3- methyl -5- acetyl group -2- as present invention further optimization
(4- propionyloxies phenyl) -1H- indoles, wherein R1For acetyl group, R3For propiono.
It is that bazedoxifene acetate intermediate is 3- methyl -5- acetyl group -2- (4- second as present invention further optimization
Phenyl) -1H- indoles (formula (II -1)), wherein R1And R3It is acetyl group.
As the second aspect of the invention, the method for preparing above-mentioned bazedoxifene acetate intermediate includes the following steps：
Wherein, R2For C1-6Alkanoyl, R2Preferably acetyl group, propiono or bytyry.
In the preparation method, formula (II-a) and formula (II-b) carry out instead in the presence of polar non-solute and organic base
It should.
As present invention further optimization, the reaction reacts 8-12h at 90-130 DEG C；Further preferably, it is described
Reaction reacts 10h at 110 DEG C.
As present invention further optimization, the polar non-solute is n,N-Dimethylformamide, N- methyl pyrroles
The one or more of pyrrolidone, 1,4- dioxane or dimethyl sulfoxide (DMSO).The polar non-solute is preferably N, N- diformazans
Base formamide.
As present invention further optimization, the organic base is triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA) or three fourths
The one or more of amine；Preferably triethylamine.
As present invention further optimization, the molar feed ratio of the formula (II-a) and formula (II-b) is 1:1-2.5；It is excellent
It is selected as 1:1.5-2.5；Further preferably 1:2.2.
As present invention further optimization, the volume ratio of the polar non-solute and organic base is 3-8:1, preferably
For 4-6:1, further preferably 5:1.
The synthetic method of the bazedoxifene acetate intermediate is with C1-6Alkanoyl protects phenolic group for blocking group, passes throughReact synthesis of indole ring.
As present invention further optimization, the formula (II-a) is 4 '-acetyl group -2- brom-acetophenones (II-a1), wherein
R1For acetyl group；The formula (II-b) is N- (to acetoxyl group) phenyl-acetamides (II-b1), wherein R2、R3It is acetyl group.
As present invention further optimization, the formula (II-a) be 4 '-bytyry -2- brom-acetophenones, wherein R1For fourth
Acyl group；The formula (II-b) be N- (to propionyloxy) Phenylpropionamide, wherein R2、R3It is propiono.
As present invention further optimization, the formula (II-a) be 4 '-acetyl group -2- brom-acetophenones, wherein R1For second
Acyl group；The formula (II-b) be N- (to propionyloxy) phenylbutanamides, wherein R2For bytyry, R3For propiono.
As the third aspect of the invention, the side of bazedoxifene acetate is prepared with above-mentioned bazedoxifene acetate intermediate
Method includes the following steps：
(1) formula (II) and formula (II-c) are alkylated reaction, reaction knot in the presence of NaH and polar non-solute
Shu Hou adds in aqueous slkali and obtained formula (III) is hydrolyzed；
(2) formula (III) forms formula (I) in the presence of ascorbic acid and organic solvent with acetic acid reaction.
As present invention further optimization, it is in the step (1) Chinese style (II) and the molar feed ratio of formula (II-c)
1:0.8-1.5, preferably 1:1-1.3 further preferably 1:1.2.
As present invention further optimization, step (1) Chinese style (II) reacts 10- with formula (II-c) at 20-30 DEG C
15h, preferably 25 DEG C reaction 15h.
As present invention further optimization, the polar non-solute is selected from n,N-Dimethylformamide, Isosorbide-5-Nitrae-two
Six ring of oxygen, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO) one or more；The polar non-solute used is preferably N, N- bis-
Methylformamide.
As present invention further optimization, the inorganic base described in the step (1) is selected from sodium hydroxide, hydroxide
Potassium, potassium carbonate, cesium carbonate one or more；The inorganic base used is preferably sodium hydroxide or potassium hydroxide.
As present invention further optimization, the organic solvent described in the step (2) is selected from ethyl acetate, isopropyl acetate
Ester, isopropanol, acetonitrile, methyl tertiary butyl ether(MTBE) one or more；The organic solvent used is preferably isopropanol.
As present invention further optimization, the step (2) reacts 2-5h at 50-60 DEG C；Preferably 60 DEG C reaction 3h.
Bazedoxifene is synthesized by C1-6Seven yuan on the bazedoxifene acetate intermediate parental materials of alkanoyl protecting group
Azacyclo-, then alkaline water frees C again1-6Alkanoyl protecting group, avoids high-pressure hydrogenation, reduces the danger of experiment.
The C of the present invention1-6Alkanoyl includes acetyl group, propiono, bytyry, valeryl and acyl group.
Compared with prior art, the present invention has the advantages that：
The present invention provides the method for preparing bazedoxifene acetate new intermediate (as shown in formula (II)), preparations of the invention
Method substrate is with C1-6Alkanoyl protects phenolic group for blocking group, passes throughSynthesis of indole ring is reacted, this is anti-
Should have many advantages, such as that reaction condition is mild, yield is high.
Bazedoxifene acetate intermediate formula (II) using the present invention prepares bazedoxifene acetate and has the following advantages：1st, it keeps away
The high-pressure hydrogenation hydrogen that conventional method (protecting phenolic group by blocking group of benzyl) sloughs high risk required during protecting group is exempted from
Change reaction, greatly reduce experimental risk；2nd, the reaction time has been saved, has reduced industrial energy consumption；3rd, reaction of the invention is not required to
The palladium carbon of larger proportion amount is wanted, reaction condition is mild, easy to operate, environmentally friendly, is suitble to industrialized production.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail, but is not defined to protection domain
The embodiment.
The preparation of the intermediate (formula II) of bazedoxifene acetate
Embodiment 1：The preparation of 3- methyl -5- acetyl group -2- (4- acetoxyl groups phenyl) -1H- indoles (formula (II-1))
Method A
By the 4 ' of 270g-acetyl group -2- brom-acetophenones (II-a1), N- (to acetoxyl group) phenyl-acetamides of 425g
(II-b1), the n,N-Dimethylformamide of 1350ml and 270ml triethylamines input reaction kettle in, be heated with stirring to 110 DEG C of reactions
10h.TLC detections are cooled to room temperature, reaction solution are poured into 540ml ice water after the reaction was complete, stir 1h, filter, and solid is with 50
DEG C methanol mashing washing, 40 DEG C of forced air dryings of obtained solid for 24 hours, obtain 271g brown solids, yield：84%.
MS：M/z=324 [M+1]+。
1HNMR(DMSO-d6):2.04-2.16ppm(s,6H),2.30ppm(s,3H),7.0ppm(dd,2H),7.13ppm
(dd,2H),7.20ppm(d,1H),7.45ppm(dd,2H),9.58ppm(s,1H)。
Method B
By the 4 ' of 270g-acetyl group -2- brom-acetophenones (II-a1), N- (to acetoxyl group) phenyl-acetamides of 193g
(II-b1), Isosorbide-5-Nitrae-dioxane of 1080ml and 270ml triethylamines input reaction kettle in, be heated with stirring to 90 DEG C reaction 12h.
TLC detections are cooled to room temperature, reaction solution are poured into 540ml ice water after the reaction was complete, stir 1h, filter, solid is with 50 DEG C
Methanol mashing washing, 40 DEG C of forced air dryings of obtained solid for 24 hours, obtain 242g brown solids, yield：75%.
Method C
By the 4 ' of 270g-acetyl group -2- brom-acetophenones (II-a1), N- (to acetoxyl group) phenyl-acetamides of 290g
(II-b1), the dimethyl sulfoxide (DMSO) of 1620ml and 270ml triethylamines input reaction kettle in, be heated with stirring to 130 DEG C reaction 8h.TLC
Detection is cooled to room temperature, reaction solution is poured into 540ml ice water after the reaction was complete, stirs 1h, filters, 50 DEG C of first of solid
Alcohol mashing washing, 40 DEG C of forced air dryings of obtained solid for 24 hours, obtain 234g brown solids, yield：80%.
Method D
By the 4 ' of 270g-acetyl group -2- brom-acetophenones (II-a1), N- (to acetoxyl group) phenyl-acetamides of 482g
(II-b1), the N-Methyl pyrrolidone of 2160ml and 270ml diisopropyl ethyl amines input reaction kettle in, be heated with stirring to 120
DEG C reaction 10h.TLC detections are cooled to room temperature, reaction solution are poured into 540ml ice water after the reaction was complete, stir 1h, filter, Gu
Body is beaten washing with 50 DEG C of methanol, and 40 DEG C of forced air dryings of obtained solid for 24 hours, obtain 226g brown solids, yield：70%.
Embodiment 2：The preparation of 3- methyl -5- bytyries -2- (4- propionyloxies phenyl) -1H- indoles
By the 4 ' of 300g-bytyry -2- brom-acetophenones, N- (to propionyloxy) Phenylpropionamide of 440g, 2100ml
In Isosorbide-5-Nitrae-dioxane and 420ml triethylamines input reaction kettle, it is heated with stirring to 110 DEG C of reaction 10h.The reaction was complete for TLC detections
Afterwards, room temperature is cooled to, reaction solution is poured into 600ml ice water, stirs 1h, is filtered, solid is beaten washing, institute with 50 DEG C of methanol
It obtains 40 DEG C of forced air dryings of solid for 24 hours, obtains 275g brown solids, yield 75%.
MS：M/z=366 [M+1]+。
1HNMR(DMSO-d6):1.03-1.12ppm(t,6H),1.60ppm(s,2H),2.23-2.29ppm(m,4H),
2.32ppm(s,3H),7.06ppm(dd,2H),7.18ppm(dd,2H),7.24ppm(d,1H),7.47ppm(dd,2H),
9.86ppm(s,1H)。
Embodiment 3:The preparation of 3- methyl -5- acetyl group -2- (4- propionyloxies phenyl) -1H- indoles
By the 4 ' of 270g-acetyl group -2- brom-acetophenones, N- (to propionyloxy) phenylbutanamides of 423g, 2100ml
In n,N-Dimethylformamide and 420ml triethylamines input reaction kettle, it is heated with stirring to 110 DEG C of reaction 10h.TLC detection reactions
After completely, room temperature is cooled to, reaction solution is poured into 600ml ice water, stir 1h, filtered, solid is washed with 50 DEG C of methanol mashing
It washs, 40 DEG C of forced air dryings of obtained solid for 24 hours, obtain 257g brown solids, yield：70%.
MS：M/z=338 [M+1]+。
1HNMR(DMSO-d6):1.13ppm(t,3H),2.09ppm(s,3H),2.25ppm(m,2H),2.33ppm(s,
3H),7.0ppm(dd,2H),7.13ppm(dd,2H),7.20ppm(d,1H),7.45ppm(dd,2H),10.01ppm(s,1H)。
The preparation of Bazedoxifene (formula III)
Embodiment 4：1- { 4- [2- (hexamethylene ammonia) ethyoxyl] benzyl } -2- (4- hydroxy phenyls) -3- methyl -5- hydroxyls
The preparation of base-indoles
Method I
In the n,N-Dimethylformamide input reaction kettle that the 60%NaH of 72g and 1500ml is dried, -5 DEG C are cooled to,
Nitrogen is protected.3- methyl -5- acetyl group -2- (4- acetoxyl groups the phenyl) -1H- indoles (formula (II -1)) of 300g is dissolved in
It in the n,N-Dimethylformamide of 800ml, instills in above-mentioned reaction solution, dropping temperature control continues in 0-5 DEG C, completion of dropwise addition
Stir 2h.1- [2- (4- chloromethyls) Phenoxyethyl] azepan hydrochloride (formula (II-c)) of 405g is dissolved in 1600ml
N,N-Dimethylformamide in, instill above-mentioned reaction solution, 0-5 DEG C of dropping temperature, drop controlled to rise to 25 DEG C after finishing, stirs 15h.
After TLC detection raw materials disappear, stop reaction, 300ml 48 grams of sodium hydroxides of water, 25 DEG C of stirrings 15h, TLC are added in into reaction solution
Detection the reaction was complete, above-mentioned solution is slowly poured into the ice water of 5000ml, stir 2h, filtering, obtained solid with water rinse to
Washing lotion is neutral, and drying obtains 291 grams of solids, yield：89%.
Method II
In the Isosorbide-5-Nitrae that the 60%NaH of 72g and 1500ml is dried-dioxane input reaction kettle, -5 DEG C are cooled to, nitrogen
Protection.3- methyl -5- acetyl group -2- (4- acetoxyl groups the phenyl) -1H- indoles (formula (II -1)) of 300g is dissolved in 800ml's
It in Isosorbide-5-Nitrae-dioxane, instills in above-mentioned reaction solution, dropping temperature control continues to stir 2h in 0-5 DEG C, completion of dropwise addition.It will
1- [2- (4- chloromethyls) Phenoxyethyl] azepan hydrochloride (formula (II-c)) of 337g is dissolved in the 1,4- bis- of 1600ml
In six ring of oxygen, above-mentioned reaction solution is instilled, 0-5 DEG C of dropping temperature, drop is controlled to rise to 30 DEG C after finishing, stirs 10h, TLC detection raw materials
After disappearance, stop reaction, 300ml 67 grams of potassium hydroxide of water are added in into reaction solution, 25 DEG C of stirring 15h, TLC detections have been reacted
Entirely, above-mentioned solution is slowly poured into the ice water of 5000ml, stirs 2h, filtering, obtained solid is rinsed to washing lotion neutrality with water, dried
It is dry to obtain 271.7 grams of solids, yield：83%.
Method III
In the N-Methyl pyrrolidone input reaction kettle that the 60%NaH of 72g and 1500ml is dried, -5 DEG C are cooled to, nitrogen
Gas shielded.3- methyl -5- bytyries -2- (4- propionyloxies phenyl) -1H- indoles of 300g is dissolved in the N- methyl pyrroles of 800ml
It in pyrrolidone, instills in above-mentioned reaction solution, dropping temperature control continues to stir 2h in 0-5 DEG C, completion of dropwise addition.By the 1- of 447g
[2- (4- chloromethyls) Phenoxyethyl] azepan hydrochloride (formula (II-c)) is dissolved in the N-Methyl pyrrolidone of 1600ml
In, above-mentioned reaction solution is instilled, 0-5 DEG C of dropping temperature, drop is controlled to rise to 20 DEG C after finishing, stirs 15h.After TLC detection raw materials disappear,
Stop reaction, 300ml 118 grams of potassium carbonate of water are added in into reaction solution, the reaction was complete for 25 DEG C of stirring 15h, TLC detections, will be above-mentioned
Solution is slowly poured into the ice water of 5000ml, stirs 2h, filtering, and obtained solid is rinsed with water to washing lotion neutrality, and drying obtains 256
Gram solid, yield：78%.
Method IV
In the dimethyl sulfoxide (DMSO) input reaction kettle that the 60%NaH of 72g and 1500ml is dried, -5 DEG C are cooled to, nitrogen is protected
Shield.3- methyl -5- acetyl group -2- (4- propionyloxies phenyl) -1H- indoles of 300g is dissolved in the dimethyl sulfoxide (DMSO) of 800ml,
It instills in above-mentioned reaction solution, dropping temperature control continues to stir 2h in 0-5 DEG C, completion of dropwise addition.By 1- [2- (the 4- chloromethanes of 388g
Base) Phenoxyethyl] azepan hydrochloride (formula (II-c)) is dissolved in the dimethyl sulfoxide (DMSO) of 1600ml, instill above-mentioned reaction
Liquid controls 0-5 DEG C of dropping temperature, drop to rise to 25 DEG C after finishing, stirs 12h.After TLC detection raw materials disappear, stop reaction, to reaction
300ml 160 grams of cesium carbonates of water are added in liquid, the reaction was complete for 25 DEG C of stirring 15h, TLC detections, and above-mentioned solution is slowly poured into
In the ice water of 5000ml, 2h, filtering are stirred, obtained solid is rinsed with water to washing lotion neutrality, and drying obtains 263.4 grams of solids, receives
Rate：80%.
The preparation of bazedoxifene acetate (formula I)
Embodiment 5：1- { 4- [2- (hexamethylene ammonia) ethyoxyl] benzyl } -2- (4- hydroxy phenyls) -3- methyl -5- hydroxyls
The preparation of base-indoleacetic acid salt
Method I
By 150 grams of 1- { 4- [2- (hexamethylene ammonia) ethyoxyl] benzyl } -2- (4- hydroxy phenyls) -3- methyl -5- hydroxyls
In the ascorbic acid input reaction kettle of base-indoles (formula (III)), 3000ml isopropanols and 1.5g, nitrogen protection is heated to reflux molten
Solution filters off insoluble matter, and 29g glacial acetic acid is instilled in filtrate, and drop keeps 60 DEG C of stirring 3h after finishing.20 DEG C are cooled to, is filtered, filter cake is used
A small amount of isopropanol washing, 45 DEG C of vacuum drying 12h, obtains white solid, and a small amount of methanol of solid is beaten washing 12h, is filtered, Gu
Body is dried in vacuo 12h at 45 DEG C, obtains white solid 153g, yield：90%.
1HNMR(DMSO-d6):1.50ppm(m,8H),1.50ppm(m,8H),1.91-2.12ppm(s,6H),2.66-
2.81ppm(t,6H),3.94ppm(t,2H),5.09ppm(s,2H),6.61ppm(dd,1H),6.75ppm(m,4H),6.84-
7.16ppm(d,6H),9.69ppm(s,3H)。
Method II
By 150 grams of 1- { 4- [2- (hexamethylene ammonia) ethyoxyl] benzyl } -2- (4- hydroxy phenyls) -3- methyl -5- hydroxyls
In the ascorbic acid input reaction kettle of base-indoles (formula (III)), 3000ml methyl tertiary butyl ether(MTBE)s and 1.5g, nitrogen protection, heating
Reflux dissolving filters off insoluble matter, and 29g glacial acetic acid is instilled in filtrate, and drop keeps 60 DEG C of stirring 3h after finishing.20 DEG C are cooled to, is filtered,
Filter cake is washed with a small amount of methyl tertiary butyl ether(MTBE), and 45 DEG C of vacuum drying 12h obtain white solid, solid with a small amount of methanol is beaten and is washed
12h is washed, is filtered, solid is dried in vacuo 12h at 45 DEG C, obtains white solid 135g, yield：80%.
Method III
By 150 grams of 1- { 4- [2- (hexamethylene ammonia) ethyoxyl] benzyl } -2- (4- hydroxy phenyls) -3- methyl -5- hydroxyls
In the ascorbic acid input reaction kettle of base-indoles (formula (III)), 3000ml ethyl acetate and 1.5g, nitrogen protection is heated to reflux
Dissolving filters off insoluble matter, and 29g glacial acetic acid is instilled in filtrate, and drop keeps 60 DEG C of stirring 3h after finishing.20 DEG C are cooled to, is filtered, filter cake
It is washed with a small amount of ethyl acetate, 45 DEG C of vacuum drying 12h obtain white solid, and a small amount of methanol of solid is beaten washing 12h, is taken out
Filter, solid are dried in vacuo 12h at 45 DEG C, obtain white solid 147g, yield：87%.
Method IV
By 150 grams of 1- { 4- [2- (hexamethylene ammonia) ethyoxyl] benzyl } -2- (4- hydroxy phenyls) -3- methyl -5- hydroxyls
In the ascorbic acid input reaction kettle of base-indoles (formula (III)), 3000ml acetonitriles and 1.5g, nitrogen protection is heated to reflux dissolving,
Insoluble matter is filtered off, 29g glacial acetic acid is instilled in filtrate, drop keeps 60 DEG C of stirring 3h after finishing.20 DEG C are cooled to, is filtered, filter cake is with less
Acetonitrile washing is measured, 45 DEG C of vacuum drying 12h obtain white solid, and a small amount of methanol of solid is beaten washing 12h, is filtered, solid exists
45 DEG C of vacuum drying 12h, obtain white solid 140g, yield：83%.
Claims (8)
- A kind of 1. method for preparing bazedoxifene acetate intermediate, it is characterised in that：II-a of formula and II-b of formula are in aprotic, polar Production II under the conditions of solvent and organic base are existing, reaction equation is as follows：Wherein, R2Preferably acetyl group, propiono or bytyry；R1、R3It is acetyl group；Or R1For bytyry, R3For propiono；Or R1For acetyl group, R3For propiono.
- 2. the method according to claim 1 for preparing bazedoxifene acetate intermediate, it is characterised in that：The non-matter of polarity Sub- solvent is selected from one kind or several of N,N-dimethylformamide, N-Methyl pyrrolidone, 1,4- dioxane, dimethyl sulfoxide (DMSO) Kind.
- 3. the method according to claim 1 or 2 for preparing bazedoxifene acetate intermediate, it is characterised in that：It is described organic Alkali is selected from the one or more of triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA) or tri-n-butylamine.
- 4. the method according to claim 1 or 2 for preparing bazedoxifene acetate intermediate, it is characterised in that：Formula II-a with The molar feed ratio of Formula II-b is 1:1-2.5.
- 5. the method according to claim 1 or 2 for preparing bazedoxifene acetate intermediate, it is characterised in that：Formula II-a with The molar feed ratio of Formula II-b is 1:1.5-2.5.
- 6. the method according to claim 1 or 2 for preparing bazedoxifene acetate intermediate, it is characterised in that：Formula II-a with The molar feed ratio of Formula II-b is 1:2.2.
- 7. the method according to claim 1 or 2 for preparing bazedoxifene acetate intermediate, it is characterised in that：The reaction 8-12h is reacted at 90-130 DEG C.
- 8. the method according to claim 1 or 2 for preparing bazedoxifene acetate intermediate, it is characterised in that：The reaction 10h is reacted at 110 DEG C.
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