CN104230723A - Synthesis method of toremifene - Google Patents
Synthesis method of toremifene Download PDFInfo
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- CN104230723A CN104230723A CN201410415900.2A CN201410415900A CN104230723A CN 104230723 A CN104230723 A CN 104230723A CN 201410415900 A CN201410415900 A CN 201410415900A CN 104230723 A CN104230723 A CN 104230723A
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- JRAPAWFDOQVLLC-DQRAZIAOSA-N OCC/C(/c1ccccc1)=C(\c1ccccc1)/c(cc1)ccc1O Chemical compound OCC/C(/c1ccccc1)=C(\c1ccccc1)/c(cc1)ccc1O JRAPAWFDOQVLLC-DQRAZIAOSA-N 0.000 description 1
Abstract
The invention provides a synthesis method of toremifene. The synthesis method comprises the following steps: S1. performing McMurry reaction to a compound B as shown in a structural formula II and a compound C as shown in a structural formula III, to obtain a compound D as shown in a structural formula IV; S2. performing selective alkylation reaction of phenolic hydroxyl to the compound D and a compound E as shown in a structural formula V or hydrochloride of the compound E, to obtain a compound F as shown in a structural formula VI; and S3. reacting the compound F with thionyl chloride, to obtain the toremifene, wherein the structural formula II, the structural formula III, the structural formula IV, the structural formula V and the structural formula VI are respectively shown in the specification. The obtained compound D has higher stereoselectivity, therefore, the reaction yield of the toremifene with a Z configuration can be increased when the compound D serves as an intermediate to synthesize the toremifene, and the purity of the toremifene with the Z configuration can be improved; and the synthesis method is stable in technology, mild in reaction conditions, the intermediate is easily separated, and the synthesis method can be used for mass production.
Description
Technical field
The present invention relates to medical synthesis technical field, in particular to a kind of synthetic method of toremifene.
Background technology
Toremifene (Toremifene), chemistry chloro-1, the 2-phenylbenzene-1-of (Z)-4-[4-(2-(N, N dimethylamine base) oxyethyl group) phenyl]-1-butylene by name, has structure I.Toremifene is the analogue of tamoxifen (Tamoxifen), there is antiestrogenic, can be used for treating hormone-dependent breast cancer, and its E-isomer has estrogen activity, the existence of E-isomer may offset the antiestrogenic of toremifene, and therefore the enantiomeric purity of toremifene is most important.Toremifene is developed in nineteen eighty-three by Famos company of Finland, and within 1996, gone on the market in European Union by Orion company, commodity are called Fareston, and within 2002, enter China, commodity are called fareston.
R.J.Toivola etc. are in European patent EP 95875; the synthetic route of toremifene is disclosed in US Patent No. 4696949A; namely following synthetic route one; this synthetic route one take phenol as raw material; 1 is obtained through acidylate, rearrangement, alkylation and addition reaction; 2-phenylbenzene-1-[4-[2-(N; N dimethylamine base) phenelyl]]-1; 4-glycol (compound 5) is key intermediate; further at ethanol solution hydrochloride or hydrochloric acid generation eliminative reaction, be then obtained by reacting toremifene with thionyl chloride.The subject matter that the method exists is that above-claimed cpd 5 is when eliminative reaction occurring in acidic alcohol or concentrated hydrochloric acid, the triaryl butenol (compound 6) generated has Z/E configuration, both ratios are 1:2 ~ 2:1, stereoselectivity is not high, and also has the cyclization by product of 5% to produce; Fractional crystallization is carried out to Z/E configuration triaryl butenol, the triaryl butenol of pure Z-type can be obtained, but yield is only 41%; Then, there is chlorination in Z-type triaryl butenol under sulfur oxychloride effect, purifiedly obtains toremifene product.
US Patent No. 5491173A reports again the another kind of synthetic route of toremifene and following synthetic route two.This route, with the addition reaction of aryl ketones (compound 7) with phenyl grignard reagent generation ketone carbonyl, obtains triaryl butyleneglycol (compound 5), and elimination occurs the latter again and chlorination obtains toremifene product.
Publication number is a kind of method that the Chinese patent application of CN1125716A reports efficient synthesis Z-type triaryl butenol (compound 6), compared with US Patent No. 4696949A, the method mild condition, reduce acid concentration and temperature of reaction, extend the reaction times, triaryl butyleneglycol (compound 5) is under concentrated hydrochloric acid or concentrated hydrochloric acid Virahol or the effect of concentrated hydrochloric acid ethanol, Z-type triaryl butenol can be obtained with 95% selectivity and 60-78% yield, but repeat after experiment through the contriver that publication number is the patent application of CN102126969A, prove that technical scheme disclosed in this patent application can not realize its technique effect claimed.
Publication number is that the Chinese patent application of CN102126969A is by configuration conversion occurs under concentrated hydrochloric acid catalysis intermediate triaryl butenol, utilize the difference of solubleness simultaneously, E-type triaryl butenol is made constantly to be converted into Z-type triaryl butenol (compound 6) and to separate out, thus destruction of balance, make E type triaryl butenol wherein constantly be converted into Z-type triaryl butenol (compound 6), obtain Z-type triaryl butenol (compound 6) and after sulfur oxychloride chlorination, obtain toremifene again.Although improve yield to a certain extent, add operation steps, be unfavorable for industrialized production.
At present; key intermediate is by patent protection; and the stereoselectivity of Z-type triaryl butenol (compound 6) intermediate and isolated yield low; for solving this difficult problem; capture the technology barriers of external drugmaker; suddenly wait to find a technique simple, with low cost, be easy to be separated and the practicable synthetic route of applicable large-scale production.
Summary of the invention
The present invention aims to provide a kind of synthetic method of toremifene, causes with the stereoselectivity difference solving Z-type triaryl butenol intermediate in prior art the problem that Product formation rate is low.
To achieve these goals, according to an aspect of the present invention, provide a kind of synthetic method of toremifene, synthetic method comprises: step S1, the compd B making to have structural formula II and the Compound C with structural formula III occur Mike not in react, obtain the Compound D with structural formula IV; Step S2, makes Compound D and the selective alkylation reaction had on the compd E of structural formula V or the hydrochloride generation phenolic hydroxyl group of compd E, obtains the compound F 17-hydroxy-corticosterone with structural formula VI; Step S3, makes compound F 17-hydroxy-corticosterone and thionyl chloride react, obtains toremifene, wherein,
Structural formula II is:
structural formula III is:
structural formula IV is
structural formula V is ClCH
2cH
2n (CH
3)
2; Structural formula VI is
Further, the mol ratio of above-claimed cpd B and Compound C is 0.8:1 ~ 1.2:1, preferred 1:1; Mike not in reaction temperature of reaction be 60 ~ 120 DEG C, preferably 60 ~ 65 DEG C, the reaction times is 1 ~ 5h, preferred 5h.
Further, above-mentioned steps S1 comprises: under the effect of titanium chloride and reductive agent, make compd B and Compound C occur in non-protonic solvent Mike not in react, obtain the first product system containing compound; Purification process is carried out to the first product system, obtains Compound D.
Further, the mol ratio of above-mentioned titanium chloride and Compound C is 1:1 ~ 5:1, preferred 3:1, and preferred titanium chloride is the complex compound of titanous chloride, titanium tetrachloride, titanous chloride and glycol dimethyl ether or the complex compound of titanium tetrachloride and glycol dimethyl ether.
Further, the mol ratio of above-mentioned reductive agent and Compound C is 2:1 ~ 10:1, preferred 6:1; Preferred reductive agent is lithium aluminum hydride, zinc copper couple, zinc powder, magnesium amalgam, magnesium or basic metal.
Further, the amount ratio of above-mentioned non-protonic solvent and Compound C is 5 ~ 30ml/g, preferred 15ml/g; Preferred non-protonic solvent be selected from Isosorbide-5-Nitrae-dioxane, toluene, glycol dimethyl ether, tetrahydrofuran (THF) and DMF composition group in one or more.
Further, the process of above-mentioned purification process comprises: adopt the first alkaline matter to neutralize the first product system, obtain in first and system; Filter in first with system, obtain the first filter residue and the first filtrate; Adopt the first organic solvent to carry out extraction treatment to the first filtrate, be extracted solution; Extraction solution is filtered, obtains the second filter residue and the second filtrate; Second filtrate is concentrated, obtains the first crude product of Compound D; Recrystallization is carried out to the first crude product, obtains Compound D.
Further, above-mentioned first alkaline matter is selected from one or more in the group of sodium carbonate, salt of wormwood, sodium hydroxide and potassium hydroxide composition; First organic solvent be selected from ethyl acetate, toluene and methylene dichloride composition group in one or more; Adopt the first mixed solvent to carry out recrystallization to the first crude product, the first mixed solvent is mass ratio is the methyl tertiary butyl ether of 1:1 ~ 5:1 and the mixed solvent of acetone, the methyl tertiary butyl ether of preferred 2.5:1 and the mixed solvent of acetone.
Further, in above-mentioned steps S2, compd E and Compound D with the mol ratio of 1:1 ~ 3:1 50 ~ 110 DEG C, react 1 ~ 5h in the second organic solvent of alkalescence, obtain compound F 17-hydroxy-corticosterone.
Further, above-mentioned second organic solvent is selected from one or more in the group of acetone, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and toluene composition; The alkalescence of the second organic solvent is formed by the second alkaline matter, second alkaline matter is selected from any one or a few material in the group of sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate and potassium methylate composition, and the mol ratio of the second alkaline matter and Compound D is 1:1 ~ 10:1.
Further, above-mentioned steps S3 comprises: in toluene, and compound F 17-hydroxy-corticosterone and thionyl chloride react 1 ~ 6h at 50 ~ 110 DEG C, obtains the third product system containing toremifene; Purification process is carried out to third product system, obtains toremifene.
Further, the amount ratio of above-mentioned toluene and compound F 17-hydroxy-corticosterone is 5 ~ 30ml/g, and the mol ratio of compound F 17-hydroxy-corticosterone and thionyl chloride is 1:1 ~ 1:3.
Further, the process of above-mentioned purification process comprises: adopt the 3rd alkaline matter to neutralize third product system, obtain in second and system; Carry out separatory by second with system, obtain aqueous phase and organic phase; Adopt the second organic solvent to carry out extraction treatment to aqueous phase, obtain the second extraction solution; Concentrate after organic phase and the second extraction solution are merged, obtain the second crude product of toremifene; Recrystallization is carried out to the second crude product, obtains toremifene.
Further, above-mentioned second organic solvent is selected from one or more in the group of ethyl acetate, toluene, methylene dichloride and methyl tertiary butyl ether composition; 3rd alkaline matter be selected from sodium carbonate salt of wormwood, sodium hydroxide and potassium hydroxide composition group in one or more; Adopt the second mixed solvent to carry out recrystallization to the second crude product, the second mixed solvent be selected from acetone, methyl ethyl ketone, methyl alcohol and ethyl acetate composition group in one or more.
Apply technical scheme of the present invention, the stereoselectivity of the Compound D obtained is higher, wherein the molar ratio of Z configuration and E is greater than 5:1, therefore when synthesizing toremifene using it further as intermediate, the reaction yield of the toremifene of Z configuration can be increased, and then the purity of the toremifene of raising Z configuration; And above-mentioned synthetic method craft is stablized, reaction conditions is gentle, and post-processing operation is simple, and intermediate is easy to be separated, and can be applied to large-scale production toremifene.
Accompanying drawing explanation
The Figure of description forming a application's part is used to provide a further understanding of the present invention, and schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 shows the hydrogen nuclear magnetic resonance spectrogram of the Compound D that the embodiment of the present invention 1 obtains;
Fig. 2 shows the hydrogen nuclear magnetic resonance spectrogram of the compound F 17-hydroxy-corticosterone that the embodiment of the present invention 1 obtains;
Fig. 3 shows the hydrogen nuclear magnetic resonance spectrogram of the toremifene that the embodiment of the present invention 1 obtains.
Embodiment
It should be noted that, when not conflicting, the embodiment in the application and the feature in embodiment can combine mutually.Below with reference to the accompanying drawings and describe the present invention in detail in conjunction with the embodiments.
In a kind of typical embodiment of the present invention, provide a kind of synthetic method of toremifene, this synthetic method comprises: step S1, the compd B making to have structural formula II and the Compound C with structural formula III occur Mike not in react, obtain the Compound D with structural formula IV; Step S2, makes Compound D and the selection sexual type alkylated reaction had on the compd E of structural formula V or the hydrochloride generation phenolic hydroxyl group of compd E, obtains the compound F 17-hydroxy-corticosterone with structural formula VI; Step S3, makes compound F 17-hydroxy-corticosterone and thionyl chloride react, obtains toremifene, and wherein, structural formula II is:
structural formula III is:
structural formula IV is
structural formula V is ClCH
2cH
2n (CH
3)
2; Structural formula VI is
The synthetic route of above-mentioned synthetic method is as follows:
The said synthesis route that the present invention adopts, the stereoselectivity of the Compound D obtained is higher, wherein the molar ratio of Z configuration and E is greater than 5:1, therefore when synthesizing toremifene using it further as intermediate, the reaction yield of the toremifene of Z configuration can be increased, and then the purity of the toremifene of raising Z configuration; And above-mentioned synthetic method craft is stablized, reaction conditions is gentle, and post-processing operation is simple, and intermediate is easy to be separated, and can be applied to large-scale production toremifene.
In above-mentioned synthetic method, the theory reaction mol ratio of compd B and Compound C is 1:1, and therefore the present invention controls the mol ratio of above-claimed cpd B and above-claimed cpd C is 0.8:1 ~ 1.2:1, preferred 1:1; Mike not in reaction temperature of reaction be 60 ~ 120 DEG C, preferably 60 ~ 65 DEG C, reaction times is 1 ~ 5h, preferred 5h, utilize compd B and the proportioning of Compound C about theoretical mol ratio, react under said temperature and time conditions, can make fully to react as the compd B of raw material and Compound C, improve the productive rate of Compound D further.
The present invention is in order to improve the productive rate of compound F 17-hydroxy-corticosterone and reduce the purifying difficulty of toremifene, preferred above-mentioned steps S1 comprises: under the effect of titanium chloride and reductive agent, make compd B and Compound C occur in non-protonic solvent Mike not in react, obtain the first product system containing compound; Purification process is carried out to the first product system, obtains Compound D.Compound D in first product system is extracted participation subsequent reactions, productive rate and the purity of compound F 17-hydroxy-corticosterone can be improved.
Carry out above-mentioned Mike not in react time, above-mentioned titanium chloride, reductive agent and non-protonic solvent all can select the reagent of prior art routine, the application is from raising products collection efficiency and angle simple to operate, the mol ratio of preferred above-mentioned titanium chloride and Compound C is 1:1 ~ 5:1, further preferred 3:1; Above-mentioned titanium chloride is the complex compound of titanous chloride, titanium tetrachloride, titanous chloride and glycol dimethyl ether or the complex compound of titanium tetrachloride and glycol dimethyl ether; The mol ratio of preferred above-mentioned reductive agent and Compound C is 2:1 ~ 10:1, further preferred 6:1; Preferred above-mentioned reductive agent is lithium aluminum hydride, zinc copper couple, zinc powder, magnesium amalgam, magnesium or basic metal; The amount ratio of preferred non-protonic solvent and Compound C is 5 ~ 30ml/g, preferred 15ml/g, preferred above-mentioned non-protonic solvent be selected from Isosorbide-5-Nitrae-dioxane, toluene, glycol dimethyl ether, tetrahydrofuran (THF) and DMF composition group in one or more.
In order to be separated the Compound D of the Z configuration in the first product system as far as possible, the process of preferred above-mentioned purification process comprises: adopt the first alkaline matter to neutralize the first product system, obtain in first and system; Filter in first with system, obtain the first filter residue and the first filtrate; Adopt the first organic solvent to carry out extraction treatment to the first filtrate, be extracted solution; Extraction solution is filtered, obtains the second filter residue and the second filtrate; Second filtrate is concentrated, obtains the first crude product of Compound D; Recrystallization is carried out to the first crude product, obtains Compound D.
When carrying out above-mentioned purge process, preferably above-mentioned first alkaline matter is selected from one or more in the group of sodium carbonate, salt of wormwood, sodium hydroxide and potassium hydroxide composition; First organic solvent be selected from ethyl acetate, toluene and methylene dichloride composition group in one or more; Adopt the first mixed solvent to carry out recrystallization to the first crude product, the first mixed solvent is mass ratio is the methyl tertiary butyl ether of 1:1 ~ 5:1 and the mixed solvent of acetone.
Equally, in order to increase the productive rate of compound F 17-hydroxy-corticosterone in above-mentioned synthetic method, in preferred above-mentioned steps S2, compd E and Compound D with the mol ratio of 1:1 ~ 3:1 50 ~ 110 DEG C, react 1 ~ 5h in the second organic solvent of alkalescence, obtain compound F 17-hydroxy-corticosterone.Above-mentioned steps S2 utilizes the organic solvent of alkalescence to increase Compound D and compd E solubleness wherein, and then the reactive behavior both improving, and increases the productive rate of product Compound F; Simultaneously in order to make Compound D fully react, the mol ratio controlling compd E and Compound D is more than or equal to both mol ratios, and then alleviates the low problem of sterically hindered both reaction efficiencies caused of Compound D from another aspect.
Second alkaline matter of the second organic solvent required for above-mentioned steps S2 and formation the second organic solvent thereof all can be selected from the conventional reagent of prior art, the application is in order to ensure that Compound D and compd E have enough solvabilities, preferably above-mentioned second organic solvent is selected from one or more in the group of acetone, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and toluene composition; The alkalescence of the second organic solvent is formed by the second alkaline matter, second alkaline matter is selected from any one or a few material in the group of sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate and potassium methylate composition, and the mol ratio of the second alkaline matter and Compound D is 1:1 ~ 10:1.
The present invention is utilizing after step S1 improves the Compound D of Z configuration, after the Compound D obtained after utilizing purifying carries out the reaction of step S2, yield and the higher compound F 17-hydroxy-corticosterone of purity can be obtained, can with reference to prior art when carrying out step S3, the preferred above-mentioned steps S3 of the application comprises: in toluene, compound F 17-hydroxy-corticosterone and dihalo-sulfoxide react 1 ~ 6h at 50 ~ 110 DEG C, obtain the third product system containing toremifene; Purification process is carried out to third product system, obtains toremifene.
Utilize above-mentioned toluene as solvent, when making compound F 17-hydroxy-corticosterone and dihalo-sulfoxide react wherein, in order to ensure that compound F 17-hydroxy-corticosterone fully dissolves wherein, the amount ratio of preferred above-mentioned toluene and compound F 17-hydroxy-corticosterone is 5 ~ 30ml/g.
The process of the purification process of above-mentioned steps S3 preferably includes: adopt the 3rd alkaline matter to neutralize third product system, obtain in second and system; Carry out separatory by second with system, obtain aqueous phase and organic phase; Adopt the second organic solvent to carry out extraction treatment to aqueous phase, obtain the second extraction solution; Concentrate after organic phase and the second extraction solution are merged, obtain the second crude product of toremifene; Recrystallization is carried out to the second crude product, obtains toremifene.Utilize the purge process of above-mentioned neutralization, separatory, extraction, concentrated and recrystallization, can as far as possible fully toremifene be separated.
The all ingredients that above-mentioned purification process process adopts all can be selected from existing conventional reagent, in order to reduce the complicacy of reagent, preferably this purification process process is selected from same reality with identical reagent used in the purification process process in step S1, and preferably above-mentioned second organic solvent is selected from one or more in the group of ethyl acetate, toluene, methylene dichloride and methyl tertiary butyl ether composition; 3rd alkaline matter be selected from sodium carbonate salt of wormwood, sodium hydroxide and potassium hydroxide composition group in one or more; Adopt the second mixed solvent to carry out recrystallization to the second crude product, the second mixed solvent be selected from acetone, methyl ethyl ketone, methyl alcohol and ethyl acetate composition group in one or more.
In order to absolutely prove essence of the present invention, preparation thinking and design; verify preparation method of the present invention in the following embodiments; these embodiments only to represent with special case for illustrating; should do not explained or be interpreted as the restriction to the present invention's protection; in addition, the present invention's all tests material is commercially available purchase product if no special instructions.
Embodiment 1
The synthesis of Z configuration of compound D:
130.8g (2mol) zinc powder and 1.5L tetrahydrofuran (THF) is added in 5L reaction flask, stir formation first mixed system, control the first mixed system temperature lower than-15 DEG C, slowly in the first mixed system, drip 189.7g (1mol) titanium tetrachloride, dropwise, continue stirring and form the second mixed system after 2 hours; Controlling the second mixed system temperature is 20 ~ 25 DEG C, and form the 3rd mixed system to the 1.5L tetrahydrofuran solution that the second mixed system slowly drips containing 156.2g (0.8mol) compd B and 150g (1mol) Compound C, after dropwising, the 3rd mixed system is warming up to 60 ~ 65 DEG C, insulated and stirred is after 5 hours, be cooled to 25 DEG C, obtain the first product system; First product system is slowly poured in 2L water, adds sodium carbonate and be neutralized to the first product system pH value and obtain in first between 9 ~ 10 and system, by first and system filter, the first filtrate obtained is extracted solution with 2L extraction into ethyl acetate; Extraction solution is filtered, the second filtrate obtained is concentrated to be obtained containing Z configuration of compound D crude product, this crude product is the methyl tertiary butyl ether of 1/1 and the admixture solvent recrystallization of acetone through mass ratio, and obtain 158.1g Z configuration of compound D, the productive rate of Z configuration of compound D is 50% as calculated.
The synthesis of Z configuration of compound F:
1L acetone is added in 2L reaction flask, Z configuration of compound D and 265.3g (1.92mol) salt of wormwood obtained in 100g (0.32mol) above-mentioned steps forms the 4th mixed system, control the 4th mixed system temperature lower than 25 DEG C, 67.2g (0.48mol) 2-(N, N dimethylamine base) monochloroethane hydrochloride (ClCH is slowly added in the 4th mixed system
2cH
2n (CH
3)
2hCl), add complete formation the 5th mixed system, 5th mixed system is heated to 50 DEG C, react after 5 hours, stopped reaction obtains the second product system, filter after second product system is cooled to 15 ~ 25 DEG C, the filtrate obtained carries out concentrated obtaining enriched product, in enriched product, add 1L ethyl acetate form mixed organic solvents, utilize 2L moisture to wash above-mentioned mixed organic solvents for twice and form oil-water mixture, separatory is carried out to oil-water mixture, the organic phase obtained is concentrated the compound F 17-hydroxy-corticosterone obtaining 120g Z configuration, the productive rate 98% of the compound F 17-hydroxy-corticosterone of Z configuration as calculated, the purity 95.4% of the compound F 17-hydroxy-corticosterone of Z configuration after testing.
The synthesis of toremifene:
1.1L toluene is added in 2L reaction flask, the compound F 17-hydroxy-corticosterone of the Z configuration obtained in 110g (0.28mol) above-mentioned steps, obtain the 6th mixed system, 6th mixed system is cooled to 0 ~ 5 DEG C, slow dropping 99.93g (0.84mol) thionyl chloride, dropwise formation the 7th mixed system, 7th mixed system is slowly warming up to 110 DEG C, react and obtain third product system after 1 hour, stop heating third product system and be cooled to 15 ~ 25 DEG C, slowly third product system is poured in 1L water, adding NaOH solution, to be neutralized to pH value be 9 ~ 10 obtain in second and system, to in second and system carry out separatory, the aqueous phase 1L toluene extraction obtained obtains the second extraction solution, it is concentrated after the organic phase second extraction solution and separatory obtained merges, obtain toremifene crude product, this crude product is ethyl acetate and the acetone mixed solvent crystallization of 1:1 through mass ratio, obtain 103.7g toremifene product.
Embodiment 2
The synthesis of Z configuration of compound D:
294.2g (4.5mol) zinc powder and 2.25L glycol dimethyl ether is added in 5L reaction flask, stir formation first mixed system, control the first mixed system temperature lower than-15 DEG C, slowly in the first mixed system, drip 462.6g (3mol) titanous chloride, dropwise, continue stirring and form the second mixed system after 2 hours; Controlling the second mixed system temperature is 20 ~ 25 DEG C, and form the 3rd mixed system to the 2.25L ethylene glycol dimethyl ether solution that the second mixed system slowly drips containing 237.8g (1.2mol) compd B and 150g (1mol) Compound C, after dropwising, the 3rd mixed system is warming up to 60 ~ 65 DEG C, insulated and stirred is after 5 hours, be cooled to 25 DEG C, obtain the first product system; First product system is slowly poured in 2L water, adds sodium carbonate and be neutralized to the first product system pH value and obtain in first between 9 ~ 10 and system, by first and system filter, the first filtrate obtained is extracted solution with 2L extraction into ethyl acetate; Extraction solution is filtered, the second filtrate obtained is concentrated to be obtained containing Z configuration of compound D crude product, this crude product is the methyl tertiary butyl ether of 5/1 and the admixture solvent recrystallization of acetone through mass ratio, and obtain 237g Z configuration of compound D, the productive rate of Z configuration of compound D is 75% as calculated.
The synthesis of Z configuration of compound F:
3L toluene is added in 5L reaction flask, Z configuration of compound D and 339.22g (3.2mol) sodium carbonate obtained in 100g (0.32mol) above-mentioned steps forms the 4th mixed system, control the 4th mixed system temperature lower than 25 DEG C, 134.4g (0.96mol) 2-(N, N dimethylamine base) monochloroethane hydrochloride (ClCH is slowly added in the 4th mixed system
2cH
2n (CH
3)
2hCl), add complete formation the 5th mixed system, 5th mixed system is heated to 110 DEG C, react after 3 hours, stopped reaction obtains the second product system, filter after second product system is cooled to 15 ~ 25 DEG C, the filtrate obtained carries out concentrated obtaining enriched product, in enriched product, add 1L ethyl acetate form mixed organic solvents, utilize 2L moisture to wash above-mentioned mixed organic solvents for twice and form oil-water mixture, separatory is carried out to oil-water mixture, the organic phase obtained is concentrated the compound F 17-hydroxy-corticosterone obtaining 117.6g Z configuration, the productive rate 96% of the compound F 17-hydroxy-corticosterone of Z configuration as calculated, the purity 90.5% of the compound F 17-hydroxy-corticosterone of Z configuration after testing.
The synthesis of toremifene:
3.3L toluene is added in 5L reaction flask, the compound F 17-hydroxy-corticosterone of the Z configuration obtained in 110g (0.28mol) above-mentioned steps, obtain the 6th mixed system, 6th mixed system is cooled to 0 ~ 5 DEG C, slow dropping 33.31g (0.28mol) thionyl chloride, dropwise formation the 7th mixed system, 7th mixed system is slowly warming up to 110 DEG C, react and obtain third product system after 6 hours, stop heating third product system and be cooled to 15 ~ 25 DEG C, slowly third product system is poured in 1L water, adding solution of potassium carbonate, to be neutralized to pH value be 9 ~ 10 obtain in second and system, to in second and system carry out separatory, the aqueous phase 1L extraction into ethyl acetate obtained obtains the second extraction solution, it is concentrated after the organic phase second extraction solution and separatory obtained merges, obtain toremifene crude product, this crude product is acetone crystallization through mass ratio, obtain 92.2g toremifene product.
Embodiment 3
The synthesis of Z configuration of compound D:
392.3g (6mol) zinc powder and 2.25L glycol dimethyl ether is added in 5L reaction flask, stir formation first mixed system, control the first mixed system temperature lower than-15 DEG C, slowly in the first mixed system, drip 569.0g (3mol) titanium tetrachloride, dropwise, continue stirring and form the second mixed system after 2 hours; Controlling the second mixed system temperature is 20 ~ 25 DEG C, and form the 3rd mixed system to the 2.25L ethylene glycol dimethyl ether solution that the second mixed system slowly drips containing 198.2g (1mol) compd B and 150g (1mol) Compound C, after dropwising, the 3rd mixed system is warming up to 60 ~ 65 DEG C, insulated and stirred is after 5 hours, be cooled to 25 DEG C, obtain the first product system; First product system is slowly poured in 2L water, adds sodium carbonate and be neutralized to the first product system pH value and obtain in first between 9 ~ 10 and system, by first and system filter, the first filtrate obtained is extracted solution with 2L extraction into ethyl acetate; Extraction solution is filtered, the second filtrate obtained is concentrated to be obtained containing Z configuration of compound D crude product, this crude product is the methyl tertiary butyl ether of 2.5/1 and the admixture solvent recrystallization of acetone through mass ratio, obtain 284.4g Z configuration of compound D, the productive rate of Z configuration of compound D is 90% as calculated.
The synthesis of Z configuration of compound F:
3L acetonitrile is added in 5L reaction flask, Z configuration of compound D and 339.22g (3.2mol) sodium carbonate obtained in 100g (0.32mol) above-mentioned steps forms the 4th mixed system, control the 4th mixed system temperature lower than 25 DEG C, 134.4g (0.96mol) 2-(N, N dimethylamine base) monochloroethane hydrochloride (ClCH is slowly added in the 4th mixed system
2cH
2n (CH
3)
2hCl), add complete formation the 5th mixed system, 5th mixed system is heated to 80 DEG C, react after 1 hour, stopped reaction obtains the second product system, filter after second product system is cooled to 15 ~ 25 DEG C, the filtrate obtained carries out concentrated obtaining enriched product, in enriched product, add 1L ethyl acetate form mixed organic solvents, utilize 2L moisture to wash above-mentioned mixed organic solvents for twice and form oil-water mixture, separatory is carried out to oil-water mixture, the organic phase obtained is concentrated the compound F 17-hydroxy-corticosterone obtaining 113.9g Z configuration, the productive rate 93% of the compound F 17-hydroxy-corticosterone of Z configuration as calculated, the purity 96.8% of the compound F 17-hydroxy-corticosterone of Z configuration after testing.
The synthesis of toremifene:
2.2L toluene is added in 5L reaction flask, the compound F 17-hydroxy-corticosterone of the Z configuration obtained in 110g (0.28mol) above-mentioned steps, obtain the 6th mixed system, 6th mixed system is cooled to 0 ~ 5 DEG C, slow dropping 66.62g (0.56mol) thionyl chloride, dropwise formation the 7th mixed system, 7th mixed system is slowly warming up to 110 DEG C, react and obtain third product system after 3 hours, stop heating third product system and be cooled to 15 ~ 25 DEG C, slowly third product system is poured in 1L water, adding NaOH solution, to be neutralized to pH value be 9 ~ 10 obtain in second and system, to in second and system carry out separatory, the aqueous phase 2L methyl tertiary butyl ether extraction obtained obtains the second extraction solution, it is concentrated after the organic phase second extraction solution and separatory obtained merges, obtain toremifene crude product, this crude product is acetone and the methanol mixed solvent crystallization of 1:1 through mass ratio, obtain 106g toremifene product.
Embodiment 4
The synthesis of Z configuration of compound D:
392.3g (6mol) zinc powder and 2.25L glycol dimethyl ether is added in 5L reaction flask, stir formation first mixed system, control the first mixed system temperature lower than-15 DEG C, slowly in the first mixed system, drip 569.0g (3mol) titanium tetrachloride, dropwise, continue stirring and form the second mixed system after 2 hours; Controlling the second mixed system temperature is 20 ~ 25 DEG C, and slowly drip the 2.25L1 containing 297.3g (1.5mol) compd B and 150g (1mol) Compound C to the second mixed system, 4-dioxane solution forms the 3rd mixed system, after dropwising, the 3rd mixed system is warming up to 80 ~ 85 DEG C, insulated and stirred is after 3 hours, be cooled to 25 DEG C, obtain the first product system; First product system is slowly poured in 2L water, adds sodium carbonate and be neutralized to the first product system pH value and obtain in first between 9 ~ 10 and system, by first and system filter, the first filtrate obtained is extracted solution with 2L extraction into ethyl acetate; Extraction solution is filtered, the second filtrate obtained is concentrated to be obtained containing Z configuration of compound D crude product, this crude product is the methyl tertiary butyl ether of 2.5/1 and the admixture solvent recrystallization of acetone through mass ratio, obtain 268.6g Z configuration of compound D, the productive rate of Z configuration of compound D is 85% as calculated.
The synthesis of Z configuration of compound F:
3L acetonitrile is added in 5L reaction flask, Z configuration of compound D and 339.22g (3.2mol) sodium carbonate obtained in 100g (0.32mol) above-mentioned steps forms the 4th mixed system, control the 4th mixed system temperature lower than 25 DEG C, 44.8g (0.32mol) 2-(N, N dimethylamine base) monochloroethane hydrochloride (ClCH is slowly added in the 4th mixed system
2cH
2n (CH
3)
2hCl), add complete formation the 5th mixed system, 5th mixed system is heated to 80 DEG C, react after 3 hours, stopped reaction obtains the second product system, filter after second product system is cooled to 15 ~ 25 DEG C, the filtrate obtained carries out concentrated obtaining enriched product, in enriched product, add 1L ethyl acetate form mixed organic solvents, utilize 2L moisture to wash above-mentioned mixed organic solvents for twice and form oil-water mixture, separatory is carried out to oil-water mixture, the organic phase obtained is concentrated the compound F 17-hydroxy-corticosterone obtaining 112.7g Z configuration, the productive rate 92% of the compound F 17-hydroxy-corticosterone of Z configuration as calculated, the purity 94.3% of the compound F 17-hydroxy-corticosterone of Z configuration after testing.
The synthesis of toremifene:
2.2L toluene is added in 5L reaction flask, the compound F 17-hydroxy-corticosterone of the Z configuration obtained in 110g (0.28mol) above-mentioned steps, obtain the 6th mixed system, 6th mixed system is cooled to 0 ~ 5 DEG C, slow dropping 33.31g (0.28mol) thionyl chloride, dropwise formation the 7th mixed system, 7th mixed system is slowly warming up to 50 ~ 60 DEG C, react and obtain third product system after 6 hours, stop heating third product system and be cooled to 15 ~ 25 DEG C, slowly third product system is poured in 1L water, adding NaOH solution, to be neutralized to pH value be 9 ~ 10 obtain in second and system, to in second and system carry out separatory, the aqueous phase 2L methyl tertiary butyl ether extraction obtained obtains the second extraction solution, it is concentrated after the organic phase second extraction solution and separatory obtained merges, obtain toremifene crude product, this crude product is acetone and the methanol mixed solvent crystallization of 1:1 through mass ratio, obtain 94.3g toremifene product.
Embodiment 5
The synthesis of Z configuration of compound D:
653.9g (10mol) zinc powder and 2.25L glycol dimethyl ether is added in 5L reaction flask, stir formation first mixed system, control the first mixed system temperature lower than-15 DEG C, slowly in the first mixed system, drip 189.7g (1mol) titanium tetrachloride, dropwise, continue stirring and form the second mixed system after 2 hours; Controlling the second mixed system temperature is 20 ~ 25 DEG C, and slowly drip the 2.25LN containing 198.2g (1.0mol) compd B and 150g (1mol) Compound C to the second mixed system, dinethylformamide solution forms the 3rd mixed system, after dropwising, the 3rd mixed system is warming up to 115 ~ 120 DEG C, insulated and stirred is after 1 hour, be cooled to 25 DEG C, obtain the first product system; First product system is slowly poured in 2L water, adds sodium carbonate and be neutralized to the first product system pH value and obtain in first between 9 ~ 10 and system, by first and system filter, the first filtrate obtained is extracted solution with 2L extraction into ethyl acetate; Extraction solution is filtered, the second filtrate obtained is concentrated to be obtained containing Z configuration of compound D crude product, this crude product is the methyl tertiary butyl ether of 2.5/1 and the admixture solvent recrystallization of acetone through mass ratio, obtain 278.1g Z configuration of compound D, the productive rate of Z configuration of compound D is 90% as calculated.
The synthesis of Z configuration of compound F:
3L acetonitrile is added in 5L reaction flask, Z configuration of compound D and 339.22g (3.2mol) sodium carbonate obtained in 100g (0.32mol) above-mentioned steps forms the 4th mixed system, control the 4th mixed system temperature lower than 25 DEG C, 89.6g (0.64mol) 2-(N, N dimethylamine base) monochloroethane hydrochloride (ClCH is slowly added in the 4th mixed system
2cH
2n (CH
3)
2hCl), add complete formation the 5th mixed system, 5th mixed system is heated to 80 DEG C, react after 3 hours, stopped reaction obtains the second product system, filter after second product system is cooled to 15 ~ 25 DEG C, the filtrate obtained carries out concentrated obtaining enriched product, in enriched product, add 1L ethyl acetate form mixed organic solvents, utilize 2L moisture to wash above-mentioned mixed organic solvents for twice and form oil-water mixture, separatory is carried out to oil-water mixture, the organic phase obtained is concentrated the compound F 17-hydroxy-corticosterone obtaining 115.1g Z configuration, the productive rate 94% of the compound F 17-hydroxy-corticosterone of Z configuration as calculated, the purity 95.2% of the compound F 17-hydroxy-corticosterone of Z configuration after testing.
The synthesis of toremifene:
0.5L toluene is added in 1L reaction flask, the compound F 17-hydroxy-corticosterone of the Z configuration obtained in 100g (0.26mol) above-mentioned steps, obtain the 6th mixed system, 6th mixed system is cooled to 0 ~ 5 DEG C, slow dropping 92.8g (0.78mol) thionyl chloride, dropwise formation the 7th mixed system, 7th mixed system is slowly warming up to 80 DEG C, react and obtain third product system after 3 hours, stop heating third product system and be cooled to 15 ~ 25 DEG C, slowly third product system is poured in 1L water, adding NaOH solution, to be neutralized to pH value be 9 ~ 10 obtain in second and system, to in second and system carry out separatory, the aqueous phase 2L methyl tertiary butyl ether extraction obtained obtains the second extraction solution, it is concentrated after the organic phase second extraction solution and separatory obtained merges, obtain toremifene crude product, this crude product is acetone and the methanol mixed solvent crystallization of 1:1 through mass ratio, obtain 92.3g toremifene product.
Embodiment 6
The synthesis of Z configuration of compound D:
392.3g (6mol) zinc powder and 0.75L glycol dimethyl ether is added in 5L reaction flask, stir formation first mixed system, control the first mixed system temperature lower than-15 DEG C, slowly in the first mixed system, drip 950.0g (5mol) titanium tetrachloride, dropwise, continue stirring and form the second mixed system after 2 hours; Controlling the second mixed system temperature is 20 ~ 25 DEG C, and form the 3rd mixed system to the 2.25L ethylene glycol dimethyl ether solution that the second mixed system slowly drips containing 198.2g (1.0mol) compd B and 150g (1mol) Compound C, after dropwising, the 3rd mixed system is warming up to 50 ~ 60 DEG C, insulated and stirred is after 6 hours, be cooled to 25 DEG C, obtain the first product system; First product system is slowly poured in 2L water, adds sodium carbonate and be neutralized to the first product system pH value and obtain in first between 9 ~ 10 and system, by first and system filter, the first filtrate obtained is extracted solution with 2L extraction into ethyl acetate; Extraction solution is filtered, the second filtrate obtained is concentrated to be obtained containing Z configuration of compound D crude product, this crude product is the methyl tertiary butyl ether of 2.5/1 and the admixture solvent recrystallization of acetone through mass ratio, obtain 189.6g Z configuration of compound D, the productive rate of Z configuration of compound D is 60% as calculated.
The synthesis of Z configuration of compound F:
3L acetonitrile is added in 5L reaction flask, Z configuration of compound D and 339.22g (3.2mol) sodium carbonate obtained in 100g (0.32mol) above-mentioned steps forms the 4th mixed system, control the 4th mixed system temperature lower than 25 DEG C, 134.4g (0.96mol) 2-(N, N dimethylamine base) monochloroethane hydrochloride (ClCH is slowly added in the 4th mixed system
2cH
2n (CH
3)
2hCl), add complete formation the 5th mixed system, 5th mixed system is heated to 80 DEG C, react after 3 hours, stopped reaction obtains the second product system, filter after second product system is cooled to 15 ~ 25 DEG C, the filtrate obtained carries out concentrated obtaining enriched product, in enriched product, add 1L ethyl acetate form mixed organic solvents, utilize 2L moisture to wash above-mentioned mixed organic solvents for twice and form oil-water mixture, separatory is carried out to oil-water mixture, the organic phase obtained is concentrated the compound F 17-hydroxy-corticosterone obtaining 110.2g Z configuration, the productive rate 90% of the compound F 17-hydroxy-corticosterone of Z configuration as calculated, the purity 90.8% of the compound F 17-hydroxy-corticosterone of Z configuration after testing.
The synthesis of toremifene:
2.2L toluene is added in 5L reaction flask, the compound F 17-hydroxy-corticosterone of the Z configuration obtained in 110g (0.28mol) above-mentioned steps, obtain the 6th mixed system, 6th mixed system is cooled to 0 ~ 5 DEG C, slow dropping 33.31g (0.28mol) thionyl chloride, dropwise formation the 7th mixed system, 7th mixed system is slowly warming up to 80 DEG C, react and obtain third product system after 3 hours, stop heating third product system and be cooled to 15 ~ 25 DEG C, slowly third product system is poured in 1L water, adding NaOH solution, to be neutralized to pH value be 9 ~ 10 obtain in second and system, to in second and system carry out separatory, the aqueous phase 2L methyl tertiary butyl ether extraction obtained obtains the second extraction solution, it is concentrated after the organic phase second extraction solution and separatory obtained merges, obtain toremifene crude product, this crude product is acetone and the methanol mixed solvent crystallization of 1:1 through mass ratio, obtain 98.0g toremifene product.
Comparative example 1
Repeat the embodiment 10 in US Patent No. 4696949, the productive rate calculating toremifene is 30.4%, and purity is 87.6%.
Comparative example 2
Repeat the embodiment 5 in US Patent No. 5491173, the productive rate calculating toremifene is 22.1%, and purity is 89.3%.
In the various embodiments described above, the calculation of yield formula of Z configuration of compound D is as follows:
Productive rate=(molecular weight of Z configuration of compound D quality/Z configuration of compound D)/(molecular weight of the quality/Compound C of Compound C) × 100% of Z configuration of compound D
In the various embodiments described above, the calculation of yield formula of Z configuration of compound F is as follows:
Productive rate=(molecular weight of Z configuration of compound F quality/Z configuration of compound F)/(molecular weight of the quality/Z configuration of compound D of Z configuration of compound D) × 100% of Z configuration of compound F
In the various embodiments described above, the calculation of yield formula of toremifene is as follows:
Productive rate=(molecular weight of the quality/toremifene of toremifene)/(molecular weight of the quality/Compound C of Compound C) × 100% of type toremifene
The intermediate product that the present invention obtains each embodiment and comparative example and the auspicious sweet smell of final Tommy have carried out magnetic resonance detection, the hydrogen nuclear magnetic resonance spectrogram obtained all confirms the structure of obtained intermediate and the structure of the auspicious sweet smell of Tommy, wherein, the hydrogen nuclear magnetic resonance spectrogram of Compound D in embodiment 1 invests in accompanying drawing 1, figure and shows spectrogram result and be by the present invention
1h NMR (400MHz, DMSO) δ=9.20 (s, 1H), 7.37 (t, J=7.4Hz, 2H), 7.30 – 7.23 (m, 3H), 7.22 – 7.15 (m, 2H), 7.15 – 7.06 (m, 3H), 6.61 (dd, J=9.0,2.2Hz, 2H), 6.49 – 6.32 (m, 2H), 4.48 (s, 1H), 3.30 (m, 2H), 2.55 (t, J=7.5Hz, 2H); The hydrogen nuclear magnetic resonance spectrogram of compound F 17-hydroxy-corticosterone invests in accompanying drawing 2, figure and shows spectrogram result and be
1h NMR (400MHz, DMSO) δ=7.36 (d, J=7.3Hz, 2H), 7.31 – 7.25 (m, 3H), 7.21 – 7.10 (m, 5H), 6.75 – 6.69 (m, 2H), 6.59 (d, J=8.8Hz, 2H), 4.49 (s, 1H), 3.88 (t, J=5.8Hz, 2H), 3.31 (d, J=4.3Hz, 2H), 2.57 (t, J=7.5Hz, 2H), 2.52 (t, J=4.6Hz, 2H), 2.15 (s, 6H); The hydrogen nuclear magnetic resonance spectrogram of the auspicious sweet smell of Tommy invests in accompanying drawing 3, figure and shows spectrogram result and be
1h NMR (400MHz, CDCl
3) δ=7.41 – 7.33 (m, 2H), 7.29 (dt, J=7.1,2.9Hz, 3H), 7.20 (dd, J=10.0,4.3Hz, 2H), 7.13 (dd, J=7.1,4.3Hz, 3H), 6.87 – 6.72 (m, 2H), 6.57 (dd, J=6.8,4.8Hz, 2H), 3.92 (t, J=5.8Hz, 2H), 3.41 (t, J=7.5Hz, 2H), 2.92 (t, J=7.5Hz, 2H), 2.63 (t, J=5.8Hz, 2H), 2.28 (s, 6H).
Purity and the Z/E ratio detection method of above-claimed cpd D are as follows:
Get product, add moving phase dissolve and dilute the solution made containing 1.0mg in 1ml, according to high performance liquid chromatography, be weighting agent with octadecylsilane chemically bonded silica, with 0.1% phosphate aqueous solution (A) and acetonitrile (B) for moving phase, gradient elution (T=0min 10%B; T=10min 95%B; T=12min 100%B; T=15min 10%B), determined wavelength is 210nm; Area normalization method calculates purity and the Z/E ratio of Z configuration of compound D, and wherein Z configuration of compound D retention time is 6.21min, and E Compound D retention time is 6.59min.
The method for detecting purity of above-claimed cpd F is as follows:
Get product, add moving phase dissolve and dilute the solution made containing 1.0mg in 1ml, according to high performance liquid chromatography, be weighting agent with octadecylsilane chemically bonded silica, with 0.1% aqueous citric acid solution (A) and acetonitrile (B) for moving phase, gradient elution (T=0min 10%B; T=10min 90%B; T=12min 100%B; T=15min 10%B), determined wavelength is 210nm; Area normalization method calculates the purity of Z configuration of compound F, and wherein Z configuration of compound F retention time is 5.0min.
The method for detecting purity of toremifene is as follows:
Get product, add moving phase dissolve and dilute the solution made containing 1.0mg in 1ml, according to high performance liquid chromatography, be weighting agent with octadecylsilane chemically bonded silica, with 0.1% trifluoroacetic acid aqueous solution (A) and acetonitrile (B) for moving phase, gradient elution (T=0min 10%B; T=10min 95%B; T=12min 100%B; T=15min 10%B), determined wavelength is 210nm; Area normalization method calculates the purity of Z configuration of compound F, and wherein Z configuration of compound F retention time is 6.76min.The purity of Z configuration of compound D above-mentioned calculating or detection obtained, the Z configuration of Compound D and the weight ratio of E, the productive rate of toremifene and purity record are in Table 1.
Table 1
The productive rate of the toremifene that process contrast various embodiments of the present invention and each comparative example obtain and purity, can obviously draw, the yield of the toremifene of the application and purity are all higher; And the Z configuration of midbody compound D of the present invention and the large percentage of E, illustrate that there is higher stereoselectivity.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (14)
1. a synthetic method for toremifene, is characterized in that, described synthetic method comprises:
Step S1, the compd B making to have structural formula II and the Compound C with structural formula III occur Mike not in react, obtain the Compound D with structural formula IV;
Step S2, makes described Compound D and the selective alkylation reaction had on the compd E of structural formula V or the hydrochloride generation phenolic hydroxyl group of described compd E, obtains the compound F 17-hydroxy-corticosterone with structural formula VI;
Step S3, makes described compound F 17-hydroxy-corticosterone and thionyl chloride react, obtains described toremifene,
Wherein,
Described structural formula II is:
Described structural formula III is:
Described structural formula IV is
Described structural formula V is ClCH
2cH
2n (CH
3)
2;
Described structural formula VI is
2. synthetic method according to claim 1, is characterized in that, the mol ratio of described compd B and described Compound C is 0.8:1 ~ 1.2:1, preferred 1:1; Described Mike not in reaction temperature of reaction be 60 ~ 120 DEG C, preferably 60 ~ 65 DEG C, the reaction times is 1 ~ 5h, preferred 5h.
3. synthetic method according to claim 1, is characterized in that, described step S1 comprises:
Under the effect of titanium chloride and reductive agent, make described compd B and described Compound C occur in non-protonic solvent Mike not in react, obtain the first product system containing described compound;
Purification process is carried out to described first product system, obtains described Compound D.
4. synthetic method according to claim 3, it is characterized in that, the mol ratio of described titanium chloride and described Compound C is 1:1 ~ 5:1, preferred 3:1, preferred described titanium chloride is the complex compound of titanous chloride, titanium tetrachloride, titanous chloride and glycol dimethyl ether or the complex compound of titanium tetrachloride and glycol dimethyl ether.
5. synthetic method according to claim 3, is characterized in that, the mol ratio of described reductive agent and described Compound C is 2:1 ~ 10:1, preferred 6:1; Preferred described reductive agent is lithium aluminum hydride, zinc copper couple, zinc powder, magnesium amalgam, magnesium or basic metal.
6. synthetic method according to claim 3, is characterized in that, the amount ratio of described non-protonic solvent and described Compound C is 5 ~ 30ml/g, preferred 15ml/g; Preferred described non-protonic solvent be selected from Isosorbide-5-Nitrae-dioxane, toluene, glycol dimethyl ether, tetrahydrofuran (THF) and DMF composition group in one or more.
7. synthetic method according to claim 3, is characterized in that, the process of described purification process comprises:
Adopt the first alkaline matter to neutralize described first product system, obtain in first and system;
Filter in described first with system, obtain the first filter residue and the first filtrate;
Adopt the first organic solvent to carry out extraction treatment to described first filtrate, be extracted solution;
Described extraction solution is filtered, obtains the second filter residue and the second filtrate;
Described second filtrate is concentrated, obtains the first crude product of described Compound D;
Recrystallization is carried out to described first crude product, obtains described Compound D.
8. synthetic method according to claim 7, is characterized in that, described first alkaline matter be selected from sodium carbonate, salt of wormwood, sodium hydroxide and potassium hydroxide composition group in one or more; Described first organic solvent be selected from ethyl acetate, toluene and methylene dichloride composition group in one or more; Adopt the first mixed solvent to carry out recrystallization to described first crude product, described first mixed solvent is mass ratio is the methyl tertiary butyl ether of 1:1 ~ 5:1 and the mixed solvent of acetone, the methyl tertiary butyl ether of preferred 2.5:1 and the mixed solvent of acetone.
9. synthetic method according to claim 1, is characterized in that, in described step S2, described compd E and described Compound D with the mol ratio of 1:1 ~ 3:1 50 ~ 110 DEG C, react 1 ~ 5h in the second organic solvent of alkalescence, obtain described compound F 17-hydroxy-corticosterone.
10. synthetic method according to claim 9, is characterized in that, described second organic solvent be selected from acetone, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and toluene composition group in one or more; The alkalescence of described second organic solvent is formed by the second alkaline matter, described second alkaline matter is selected from any one or a few material in the group of sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate and potassium methylate composition, and the mol ratio of described second alkaline matter and described Compound D is 1:1 ~ 10:1.
11. synthetic methods according to claim 1, is characterized in that, described step S3 comprises:
In toluene, described compound F 17-hydroxy-corticosterone and thionyl chloride react 1 ~ 6h at 50 ~ 110 DEG C, obtain the third product system containing described toremifene;
Purification process is carried out to described third product system, obtains described toremifene.
12. synthetic methods according to claim 11, is characterized in that, the amount ratio of described toluene and described compound F 17-hydroxy-corticosterone is 5 ~ 30ml/g, and the mol ratio of compound F 17-hydroxy-corticosterone and thionyl chloride is 1:1 ~ 1:3.
13. synthetic methods according to claim 11, is characterized in that, the process of described purification process comprises:
Adopt the 3rd alkaline matter to neutralize described third product system, obtain in second and system;
Carry out separatory by described second with system, obtain aqueous phase and organic phase;
Adopt the second organic solvent to carry out extraction treatment to described aqueous phase, obtain the second extraction solution;
Concentrate after described organic phase and described second extraction solution are merged, obtain the second crude product of described toremifene;
Recrystallization is carried out to described second crude product, obtains described toremifene.
14. synthetic methods according to claim 13, is characterized in that, described second organic solvent be selected from ethyl acetate, toluene, methylene dichloride and methyl tertiary butyl ether composition group in one or more; Described 3rd alkaline matter be selected from sodium carbonate salt of wormwood, sodium hydroxide and potassium hydroxide composition group in one or more; Adopt the second mixed solvent to carry out recrystallization to described second crude product, described second mixed solvent be selected from acetone, methyl ethyl ketone, methyl alcohol and ethyl acetate composition group in one or more.
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| WO2023112055A1 (en) * | 2021-12-15 | 2023-06-22 | Director, National Institute Of Pharmaceutical Education And Research, Guwahati (Niper-G) | New synthetic process design for the synthesis of carboxy tormifene and purity analysis to strengthen antidoping testing |
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| CN101636372A (en) * | 2007-02-14 | 2010-01-27 | 霍尔莫斯医疗有限公司 | The preparation method that the triphenylbut ene derivative of therapeutic value is arranged |
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| CN101636372A (en) * | 2007-02-14 | 2010-01-27 | 霍尔莫斯医疗有限公司 | The preparation method that the triphenylbut ene derivative of therapeutic value is arranged |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11261151B2 (en) | 2017-09-11 | 2022-03-01 | Atossa Therapeutics, Inc. | Methods for making and using endoxifen |
| US11572334B2 (en) | 2017-09-11 | 2023-02-07 | Atossa Therapeutics, Inc. | Methods for making and using endoxifen |
| US11680036B1 (en) | 2017-09-11 | 2023-06-20 | Atossa Therapeutics, Inc. | Methods for making and using endoxifen |
| WO2023112055A1 (en) * | 2021-12-15 | 2023-06-22 | Director, National Institute Of Pharmaceutical Education And Research, Guwahati (Niper-G) | New synthetic process design for the synthesis of carboxy tormifene and purity analysis to strengthen antidoping testing |
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