CN111138409B - Preparation method of raloxifene hydrochloride and intermediate thereof - Google Patents
Preparation method of raloxifene hydrochloride and intermediate thereof Download PDFInfo
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- CN111138409B CN111138409B CN202010004638.8A CN202010004638A CN111138409B CN 111138409 B CN111138409 B CN 111138409B CN 202010004638 A CN202010004638 A CN 202010004638A CN 111138409 B CN111138409 B CN 111138409B
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention discloses a preparation method of raloxifene hydrochloride and an intermediate thereof, which comprises the steps of preparing a raloxifene hydrochloride precursor (intermediate 2) from 1- {4- [2- (piperidine-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (intermediate 1) and 4-methoxybenzoyl halide, demethylating and protecting, and preparing raloxifene hydrochloride from hydrochloric acid; intermediate 1 is formed from intermediate 3 (1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylsulfanyl-4-methoxyphenyl) ethanone) debenzylated in trifluoroacetic acid to oxidize (3-methoxyphenyl) benzyl sulfide to the sulfoxide compound, which is then reacted with 1- [2- (4-ethynylphenoxy) ethyl ] piperidine to form intermediate 3; the method has the advantages of mild reaction conditions, less side reactions, high yield, cheap and easily-recycled reagent raw materials, and suitability for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of raloxifene hydrochloride and an intermediate thereof.
Background
Raloxifene hydrochloride (Raloxifene hydrochloride) is the first selective estrogen receptor modulator developed by Lilly in the United states, was approved by the United states FDA in 1997 for 12 months and marketed in the United states in 1998 for use in post-menopausal women to prevent osteoporosis. Raloxifene hydrochloride is chemically named as [ 6-hydroxy-2- (4-hydroxyphenyl) benzo [ b ] thiophen-3-yl ] {4- [2- (piperidin-1-yl) ethoxy ] phenyl } methanone hydrochloride, and has the chemical structural formula:
at present, a plurality of different process methods reported in documents and patents are available for preparing raloxifene hydrochloride, and the raloxifene hydrochloride has characteristics, advantages and disadvantages.
The first method (Journal of Medicinal Chemistry 1984, vol.27(8), pp.1057-1066, WO2011132194A1, US4380635) uses 3-methoxy thiophenol and 4-methoxy-alpha-bromoacetophenone as raw materials, and the 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] is obtained by substitution, cyclization and rearrangement]Thiophene, further with 4- [2- (piperidin-1-yl) ethoxy]Performing Friedel-crafts acylation reaction on benzoyl chloride, finally removing methyl protection and salifying under the action of mercaptoethanol to obtain raloxifene hydrochloride, wherein cyclization rearrangement reaction is used for preparing a key intermediate 6-methoxy-2- (4-methyl)Oxyphenyl) benzo [ b]In the step of thiophene, polyphosphoric acid is used as an acid catalyst and a solvent, so that a large amount of waste acid is generated in the production process, and the industrial production and the environmental protection requirements are not facilitated; the Friedel-crafts acylation reaction uses AlCl3As an acid catalyst, the post-treatment not only produces a large amount of waste acid, but also brings metallic aluminum residue to the substrate, thereby affecting the quality of the final product, and meanwhile, the catalyst cannot be recycled, so that the production cost is increased. The general synthetic route is as follows:
method two (literature Tetrahedron Letters 1999, vol.40(4), pp.675-678, [ Tetrahedron Letters 1999, vol.40(28), pp.5155-5159, patent US5420349), with 6 major intermediate fragments: 2-dimethylamino-6-methoxybenzo [ b ] thiophene, 4-fluorobenzoyl chloride, 1- (2-hydroxyethyl) piperidine, Grignard reagent 4-methoxyphenyl magnesium bromide, and key fragments related to the method I, 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] thiophene and 4- [2- (piperidin-1-yl) ethoxy ] benzoyl chloride, are subjected to butt joint in different sequences, so that 4 different butt joint modes are mainly obtained, and the synthetic route is as follows:
the method relates to a plurality of docking modes, has potential disadvantages similar to those described in the method I, increases the complexity and the danger of industrial production due to the preparation of Grignard reagent, and the preparation of 2-dimethylamino-6-methoxybenzo [ b ] thiophene involves multi-step synthesis, requires the reaction of hypertoxic sodium cyanide and hydrogen sulfide gas, and is not suitable for industrial production.
Method III (Letters in Organic Chemistry 2009, vol.6(1), pp.8-10), the key fragment 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] thiophene is constructed by Suzuki coupling reaction, then the next steps of reaction are carried out in a butt joint mode similar to method II, and finally the target molecule raloxifene hydrochloride is obtained, and the synthetic route is as follows:
the preparation method disclosed in patent CN105753836A also applies Suzuki coupling reaction to construct key fragments, but they all require the use of noble metal catalysts, so that the cost is high, and the coupling reaction has many side reactions, which is not favorable for large-scale production and popularization.
Method IV (Synthetic Communications 2014, vol.44(22), pp.3271-3276), which also uses 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] thiophene as the starting material, and then performs Friedel-crafts acylation reaction with 4- (2-chloroethoxy) benzoyl chloride, and then performs butt joint with piperidine to obtain raloxifene precursor, and finally obtains raloxifene hydrochloride after methyl protection and salt formation, wherein the Synthetic route is as follows:
method five (patents WO9848792A1, WO2011047878A2) prepares raloxifene hydrochloride by butt-jointing 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] thiophene, hydroxyl-protected 4-hydroxybenzoyl chloride fragment and 1- (2-chloroethyl) piperidine, and the synthetic route is as follows:
method six (patent EP0675121a1), also first docking 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] thiophene with another hydroxy-protected 4-hydroxybenzoyl chloride fragment, and then docking 1, 2-dibromoethane, piperidine in sequence, or directly docking 1- (2-hydroxyethyl) piperidine, to obtain raloxifene precursor, and finally demethylation and salification to obtain raloxifene hydrochloride, the synthetic route is as follows:
the reaction types and key intermediate raw materials related to the fourth method, the fifth method and the sixth method are the same as those described in the first method, so that various inevitable process defects exist, and the industrial production and application are not facilitated.
Method seven (literature Tetrahedron 2018, vol.74(20), pp.2493-2499, U.S. Pat. No. 4,9751852,9790199), coupling of 1- [ (2-bromo-5-methoxyphenylsulfinyl) methyl ] -4-methoxybenzene with bis-silyl-protected 4-ethynylphenol to give 4- {2- [2- (4-methoxybenzylsulfinyl) -4-methoxyphenyl ] ethynyl } phenol, which is then cyclized by oxidation of DDQ under catalysis of mercuric chloride to give (4-hydroxyphenyl) [ 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] thiophen-3-yl ] methanone, which is subjected to docking reaction with 1- (2-chloroethyl) piperidine to give raloxifene precursor, similarly to the above demethyl protection and salt formation, finally obtaining raloxifene hydrochloride, wherein the synthetic route is as follows:
eight (patent CN109320494A), coupling and cyclizing 1-methoxy-3-methylthio-4- [2- (4-methoxyphenyl) ethynyl ] benzene and 2- (4-methoxyphenyl) -2-oxoacetic acid under the action of Ag catalyst and oxidant to obtain (4-methoxyphenyl) [ 6-methoxy-2- (4-methoxyphenyl) benzo [ b ] thiophen-3-yl ] methanone, then removing methyl protection, and butting with 1- (2-chloroethyl) piperidine to obtain raloxifene precursor, wherein the synthetic route is as follows:
the reactions related to the seventh method and the eighth method both need to adopt heavy metal catalysts, so that the cost is high, the environmental impact is great, and meanwhile, the initial raw materials are not easy to prepare and are not beneficial to industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art, and provide an improved method for preparing the raloxifene hydrochloride precursor shown in the formula 1, which can obtain ideal yield and purity under mild reaction conditions, reduces the occurrence of side reactions, is cheap in reagent raw materials, easy to recover and prepare, and is suitable for industrial large-scale production.
The invention also provides a preparation method of raloxifene hydrochloride.
The invention also provides an intermediate for preparing raloxifene hydrochloride.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a preparation method of raloxifene hydrochloride precursor shown as formula 1 comprises the following steps: the compound is prepared by carrying out sulfydryl esterification and cyclization reaction on 1- {4- [2- (piperidine-1-yl) ethoxy ] phenyl } -2- (2-sulfydryl-4-methoxyphenyl) ethanone shown in a formula 2 and 4-methoxybenzoyl halide in an organic solvent in the presence of an acid binding agent;
wherein X is fluorine, chlorine or bromine.
According to a particular aspect of the invention, the 4-methoxybenzoyl halide is 4-methoxybenzoyl chloride, which is commercially available or may be prepared by conventional methods in the art (e.g. from 4-methoxybenzoic acid (CAS 100-09-4) by acid chlorination).
According to some preferred aspects of the present invention, the mercaptoesterification and the ring closure reactions are each carried out at a temperature of 40-80 ℃.
According to some preferred aspects of the present invention, the 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone represented by the formula 2, the 4-methoxybenzoyl halide and the acid-binding agent are fed in a molar ratio of 1.0: 1.2 to 1.5: 3.5 to 5.5.
According to some preferred and specific aspects of the present invention, the acid scavenger is a combination of one or more selected from triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, diisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate and cesium carbonate.
According to some preferred and specific aspects of the present invention, the organic solvent is a combination of one or more selected from the group consisting of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, 1, 4-dioxane and acetonitrile.
In some embodiments of the invention, during the preparation of the raloxifene hydrochloride precursor of formula 1 from 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone of formula 2 with 4-methoxybenzoyl halide, the 4-methoxybenzoyl halide is dissolved in an organic solvent and added dropwise to a solution of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone of formula 2.
According to some preferred aspects of the invention, the preparation method further comprises: subjecting 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylsulfanyl-4-methoxyphenyl) ethanone represented by formula 3 to debenzylation protection reaction in trifluoroacetic acid to produce 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone represented by formula 2;
according to some preferred aspects of the invention, the debenzylation protection reaction is carried out at a temperature of 60 to 80 ℃.
According to some preferred aspects of the present invention, the molar ratio of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone represented by the formula 3 to the trifluoroacetic acid is 1.0: 2.0-10.0.
According to some preferred aspects of the invention, the preparation method further comprises: oxidizing the (3-methoxyphenyl) benzyl sulfide represented by formula 5 to generate a sulfoxide compound represented by formula 4, and then reacting the sulfoxide compound represented by formula 4 with 1- [2- (4-ethynylphenoxy) ethyl ] piperidine in trifluoromethanesulfonic acid to generate 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone represented by formula 3;
according to the present invention, the (3-methoxyphenyl) benzylsulfide (CAS 695160-62-4) can be obtained commercially or prepared by methods conventional in the art (e.g., from the reaction of 3-methoxythiophenol (CAS15570-12-4) and benzyl bromide (CAS 100-39-0), see the document Journal of Organic Chemistry 2012, vol.77(7), pp.3288-3296).
According to the invention, said 1- [2- (4-ethynylphenoxy) ethyl ] piperidine (CAS 2222763-20-2) is commercially available or can be prepared by methods conventional in the art (for example, it can be prepared from 1- (2-chloroethyl) piperidine hydrochloride (CAS 2008-75-5) docked with 4-iodophenol (CAS 540-38-5), then Sonogashira coupled with trimethylethynylsilicon (CAS 1066-54-2) and deprotected, see literature Tetrahedron 2018, vol.74(20), pp.2493-2499 for the preparation of the same compounds).
According to some preferred aspects of the invention, the oxidizing agent used for the oxidation is periodic acid (formula H)5IO6)。
According to some preferred aspects of the present invention, the (3-methoxyphenyl) benzylsulfide represented by formula 5, the oxidizing agent, the 1- [2- (4-ethynylphenoxy) ethyl ] piperidine, and the trifluoromethanesulfonic acid are fed in a molar ratio of 1.0-1.5: 1.5-4.0: 1.0: 5.0-15.0.
The invention provides another technical scheme that: a preparation method of raloxifene hydrochloride comprises the steps of preparing a raloxifene hydrochloride precursor shown as a formula 1 by the method, performing demethylation protection on the raloxifene hydrochloride precursor shown as the formula 1, and forming hydrochloride with hydrochloric acid to obtain the raloxifene hydrochloride;
the invention provides another technical scheme that: an intermediate for preparing the raloxifene hydrochloride precursor shown in the formula 1, wherein the structure of the intermediate is shown in a formula 2 or a formula 3:
due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention innovatively adopts 1- {4- [2- (piperidine-1-yl) ethoxy ] phenyl } -2- (2-sulfydryl-4-methoxyphenyl) ethanone shown in formula 2 as a starting material, and then the starting material and 4-methoxybenzoyl halide are subjected to sulfydryl esterification and ring closure reaction to prepare the parent nucleus structure of raloxifene, the reaction condition is mild, the used reagents are cheap and easy to obtain, the side reaction is less, the impurity control is facilitated, and meanwhile, compared with the conventional method that the parent nucleus structure is brought into the reaction process at the initial reaction stage, the loss of the parent nucleus structure in the reaction process is reduced, the atom utilization rate is improved, and the method has the advantages of simple process, low cost and high yield
The preparation method provided by the invention has the advantages that the adopted acid reagents such as trifluoroacetic acid, trifluoromethanesulfonic acid and the like can be recycled and reused after the reaction is finished, so that the problem that in the prior art, a large amount of waste acid is generated by the reagents adopted for Friedel-crafts acylation and cannot be recycled, or the production cost is greatly increased due to the adoption of noble metal in the reactions such as coupling and the like, or the safety and environmental friendliness are influenced due to the adoption of toxic reagents is avoided.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified.
The following examples 1-3 provide the following route for raloxifene hydrochloride:
example 1
A) Preparation of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylsulfanyl-4-methoxyphenyl) ethanone (formula 3):
(3-methoxyphenyl) benzyl sulfide (50.0g, formula 5) was dissolved in acetonitrile (700mL), cooled in an ice bath, periodic acid (75.0g) and ferric chloride (1.1g,6.8mmol) were slowly added, reacted at 25 ℃ for 6 hours, reduced pressure rotary evaporated to dryness, extracted with dichloromethane, washed successively with brine and a 5% sodium thiosulfate solution, dried over anhydrous sodium sulfate, reduced pressure rotary evaporated to dryness, and the obtained crude sulfoxide compound (formula 4) was mixed with 1- [2- (4-ethynylphenoxy) ethyl ] piperidine (50.0g), trifluoromethanesulfonic acid (163g,1.09mol), reacted at 70 ℃ for 6 hours, after the reaction was completed, the reaction mixture was worked up, and recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone (formula 3), off-white to pale yellow solid (89.0g), yield 86%, purity 97.8%.
B) Preparation of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (formula 2):
1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone (89.0g, formula 3) was dissolved in trifluoroacetic acid (43.0g,0.38mol), reacted at 60 ℃ for 12 hours, after completion of the reaction, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (formula 2) as an off-white to pale yellow solid (67.0g), in 93% yield and 98.2% purity.
C) Preparing a raloxifene hydrochloride precursor (formula 1):
1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (67.0g, formula 2) was dissolved in dichloromethane (750mL), N-diethylaniline (92.0g,0.62mol) was added, stirring was performed, a solution of 4-methoxybenzoyl chloride (36.0g,0.21mol) in dichloromethane (40mL) was added dropwise, reaction was performed at 40 ℃ for 12h, reduced pressure rotary evaporation was performed to dryness, dichloromethane extraction was performed, brine washing was performed, anhydrous sodium sulfate was dried, reduced pressure rotary evaporation was performed to dryness, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give raloxifene hydrochloride precursor (formula 1), white solid (70.0g), yield 80%, and purity was 98.4%.
D) Preparing raloxifene hydrochloride:
raloxifene hydrochloride precursor (formula 1) (70.0g) is dissolved in dichloromethane (800mL), ethanethiol (22.0g,0.35mol) is added, reaction is carried out at 32-34 ℃ for 2h, tetrahydrofuran (550mL), 20% hydrochloric acid (150mL) and water (150mL) are added, stirring is carried out at 30 ℃ for 2h, suction filtration and water washing are carried out, and the crude product is recrystallized to obtain the raloxifene hydrochloride, light yellow solid (65.5g), yield is 92%, and purity is 99.3%.
Example 2
A) Preparation of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylsulfanyl-4-methoxyphenyl) ethanone (formula 3):
(3-methoxyphenyl) benzyl sulfide (65.0g, formula 5) was dissolved in toluene (850mL), cooled in an ice bath, periodic acid (170.0g) and ferric chloride (0.9g,5.5mmol) were slowly added, reacted at 27 ℃ for 4 hours, vacuum-evaporated to dryness, extracted with dichloromethane, washed successively with brine and 5% sodium thiosulfate solution, dried over anhydrous sodium sulfate, vacuum-evaporated to dryness, and the obtained crude sulfoxide compound (formula 4) was mixed with 1- [2- (4-ethynylphenoxy) ethyl ] piperidine (43.0g), trifluoromethanesulfonic acid (422g,2.8mol), reacted at 80 ℃ for 4 hours, after the reaction was completed, the reaction mixture was worked up, and recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone (formula 3), off-white to pale yellow solid (77.5g) in 87% yield with 98.0% purity.
B) Preparation of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (formula 2):
1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone (77.0g, formula 3) was dissolved in trifluoroacetic acid (166g,1.46mol), reacted at 70 ℃ for 8 hours, after the reaction was completed, rotary evaporated under reduced pressure to dryness, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, rotary evaporated under reduced pressure to dryness, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (formula 2) as an off-white to pale yellow solid (56.0g), in 90% yield, and with a purity of 98.3%.
C) Preparing a raloxifene hydrochloride precursor (formula 1):
1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (56.0g, formula 2) was dissolved in chloroform (700mL), pyridine (50.0g,0.63mol) was added, stirring was performed, a chloroform (40mL) solution of 4-methoxybenzoyl chloride (32.0g,0.19mol) was added dropwise, reaction was performed at 60 ℃ for 8h, reduced pressure rotary evaporation was performed to dryness, dichloromethane extraction was performed, brine washing was performed, anhydrous sodium sulfate was dried, reduced pressure rotary evaporation was performed to dryness, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to obtain raloxifene hydrochloride precursor (formula 1), a white solid (58.0g), yield 80%, and purity 98.5%.
D) Preparing raloxifene hydrochloride:
dissolving a raloxifene hydrochloride precursor (formula 1) (58.0g) in chloroform (700mL), adding ethanethiol (20.0g,0.32mol), reacting at 32-34 ℃ for 2h, adding tetrahydrofuran (450mL), 20% hydrochloric acid (100mL) and water (100mL), stirring at 30 ℃ for 2h, performing suction filtration, washing with water, and recrystallizing a crude product to obtain raloxifene hydrochloride which is a light yellow solid (53.5g), wherein the yield is 91% and the purity is 99.2%.
Example 3
A) Preparation of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylsulfanyl-4-methoxyphenyl) ethanone (formula 3):
(3-methoxyphenyl) benzyl sulfide (300.0g, formula 5) is dissolved in methyl tert-butyl ether (4000mL), cooled in an ice bath, periodic acid (700.0g,3.07mol) and ferric trichloride (5.0g,0.03mol) are slowly added, the reaction is carried out for 2h at 30 ℃, reduced pressure rotary evaporation is carried out until the reaction is finished, dichloromethane is extracted, saline solution and 5% sodium thiosulfate solution are sequentially used for washing, anhydrous sodium sulfate is dried, reduced pressure rotary evaporation is carried out until the reaction is finished, the obtained crude sulfoxide compound (formula 4) is mixed with 1- [2- (4-ethynylphenoxy) ethyl ] piperidine (230.0g) and trifluoromethanesulfonic acid (1500.0g,10mol) and the reaction is carried out for 2h at 100 ℃, the reaction mixture is subjected to post-treatment and recrystallization is carried out through an ethyl acetate-petroleum ether mixed solvent to obtain 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone (formula 3) Off-white to pale yellow solid (405.0g), 85% yield, 97.9% purity.
B) Preparation of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (formula 2):
1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone (400.0g, formula 3) was dissolved in trifluoroacetic acid (480.0g,4.2mol), reacted at 80 ℃ for 6 hours, after the reaction was completed, rotary evaporated under reduced pressure to dryness, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, rotary evaporated under reduced pressure to dryness, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (formula 2) as an off-white to pale yellow solid (308.0g), in 95% yield, and with a purity of 98.5%.
C) Preparing a raloxifene hydrochloride precursor (formula 1):
1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone (308.0g, formula 2) was dissolved in 1, 2-dichloroethane (4000mL), sodium carbonate (460.0g,4.34mol) was added, stirring was performed, a solution of 4-methoxybenzoyl chloride (202.0g) in 1, 2-dichloroethane (250mL) was added dropwise, the reaction was carried out at 70 ℃ for 3 hours, the mixture was rotary evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, rotary evaporated to dryness under reduced pressure, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give raloxifene hydrochloride precursor (formula 1) as a white solid (312.0g) in 78% yield with a purity of 98.6%.
D) Preparing raloxifene hydrochloride:
raloxifene hydrochloride precursor (formula 1) (310.0g) is dissolved in 1, 2-dichloroethane (3500mL), ethanethiol (100.0g,1.61mo) is added, reaction is carried out at 32-34 ℃ for 2h, tetrahydrofuran (2500mL), 20% hydrochloric acid (700mL) and water (700mL) are added, stirring is carried out at 30 ℃ for 2h, suction filtration, water washing and crude product recrystallization are carried out, thus obtaining raloxifene hydrochloride which is light yellow solid (280.0g), yield is 89% and purity is 99.3%.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (10)
1. A preparation method of raloxifene hydrochloride precursor shown as formula 1 is characterized by comprising the following steps: the compound is prepared by carrying out sulfydryl esterification and cyclization reaction on 1- {4- [2- (piperidine-1-yl) ethoxy ] phenyl } -2- (2-sulfydryl-4-methoxyphenyl) ethanone shown in a formula 2 and 4-methoxybenzoyl halide in an organic solvent in the presence of an acid binding agent;
wherein X is fluorine, chlorine or bromine.
2. The method for preparing a raloxifene hydrochloride precursor represented by formula 1 according to claim 1, wherein the thiol esterification and cyclization reactions are carried out at a temperature of 40-80 ℃.
3. The method for preparing the raloxifene hydrochloride precursor shown in the formula 1 according to claim 1, wherein the feeding molar ratio of the 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone shown in the formula 2 to the 4-methoxybenzoyl halide to the acid-binding agent is 1.0: 1.2-1.5: 3.5-5.5; and/or the acid-binding agent is one or more of triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, diisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate and cesium carbonate; and/or the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, 1, 4-dioxane and acetonitrile.
4. A method for preparing a raloxifene hydrochloride precursor of formula 1 according to any of claims 1-3, further comprising: subjecting 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylsulfanyl-4-methoxyphenyl) ethanone represented by formula 3 to debenzylation protection reaction in trifluoroacetic acid to produce 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-mercapto-4-methoxyphenyl) ethanone represented by formula 2;
5. the method for preparing a raloxifene hydrochloride precursor represented by formula 1 according to claim 4, wherein the debenzylation protection reaction is performed at a temperature of 60-80 ℃.
6. The method for preparing the raloxifene hydrochloride precursor represented by formula 1 according to claim 4, wherein the charging molar ratio of 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone represented by formula 3 to trifluoroacetic acid is 1.0: 2.0-10.0.
7. The method of preparing a raloxifene hydrochloride precursor of formula 1 according to claim 4, further comprising: oxidizing the (3-methoxyphenyl) benzyl sulfide represented by formula 5 to generate a sulfoxide compound represented by formula 4, and then reacting the sulfoxide compound represented by formula 4 with 1- [2- (4-ethynylphenoxy) ethyl ] piperidine in trifluoromethanesulfonic acid to generate 1- {4- [2- (piperidin-1-yl) ethoxy ] phenyl } -2- (2-benzylthio-4-methoxyphenyl) ethanone represented by formula 3;
8. the method for preparing the raloxifene hydrochloride precursor represented by the formula 1 according to claim 7, wherein an oxidizing agent used for the oxidation is periodic acid, and the molar ratio of the (3-methoxyphenyl) benzyl sulfide represented by the formula 5 to the oxidizing agent to the 1- [2- (4-ethynylphenoxy) ethyl ] piperidine to the trifluoromethanesulfonic acid is 1.0-1.5: 1.5-4.0: 1.0: 5.0-15.0.
9. A preparation method of raloxifene hydrochloride, which is characterized by comprising the steps of preparing a raloxifene hydrochloride precursor shown as a formula 1 by the method of any one of claims 1-8, performing demethylation protection on the raloxifene hydrochloride precursor shown as the formula 1, and reacting the raloxifene hydrochloride precursor with hydrochloric acid to form hydrochloride to obtain the raloxifene hydrochloride;
10. an intermediate for preparing raloxifene hydrochloride precursor of formula 1 according to any of claims 1-8, wherein the intermediate has the structure of formula 2 or formula 3:
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