CN109305932B - Preparation method of silodosin intermediate - Google Patents
Preparation method of silodosin intermediate Download PDFInfo
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- CN109305932B CN109305932B CN201710633519.7A CN201710633519A CN109305932B CN 109305932 B CN109305932 B CN 109305932B CN 201710633519 A CN201710633519 A CN 201710633519A CN 109305932 B CN109305932 B CN 109305932B
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Abstract
The invention discloses a preparation method of a silodosin intermediate, relates to the technical field of medicine synthesis, and aims to solve the problem of low yield of the silodosin intermediate in the existing preparation method. The preparation method of the silodosin intermediate comprises the following steps: carrying out chiral induced reductive amination on the alpha-substituted acetone compound to obtain an initial intermediate; performing amino protection on the initial intermediate to obtain an amino-protected intermediate; the amino protection intermediate is hydroformylated to obtain a hydroformylation intermediate; oximating the hydroformylation intermediate to obtain an oximated intermediate; cyaniding the oximation intermediate to obtain a cyanidation intermediate; carrying out amino deprotection on the cyanidation intermediate to obtain free alkali of the silodosin intermediate; and salifying the free alkali of the silodosin intermediate to obtain the silodosin intermediate. The preparation method of the silodosin intermediate provided by the invention is used for preparing silodosin.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a silodosin intermediate.
Background
Silodosin is an alpha 1 adrenoreceptor antagonist developed by Kissei pharmaceutical company for the treatment of prostatic hyperplasia, and is used to treat dysuria caused by benign hyperplasia of the prostate.
Structural formula is shown as
As shown in fig. 1, in the existing synthesis process of the key intermediate of silodosin, compound X is usually reduced to prepare compound XI, and then compound XI is used for hydroformylation to obtain compound XII, but in the hydroformylation process of compound XI, because there are many reaction sites capable of hydroformylation on the benzene ring, the reaction selectivity of the hydroformylation reaction is low, the yield of compound XII is affected, and further the yield of compound IX is correspondingly reduced.
Disclosure of Invention
The invention aims to provide a preparation method of a silodosin intermediate, which is used for improving the yield of the prepared silodosin intermediate.
In order to achieve the above purpose, the invention provides the following technical scheme:
a method for preparing silodosin intermediate, comprising:
carrying out reductive amination on the alpha-substituted acetonide to obtain an initial intermediate; wherein the content of the first and second substances,
the structural formula of the alpha-substituted acetonide is as follows:
the structural formula of the initial intermediate is:
performing amino protection on the initial intermediate to obtain an amino-protected intermediate; wherein the content of the first and second substances,
the structural formula of the amino-protected intermediate is as follows:
the amino protection intermediate is hydroformylated to obtain a hydroformylation intermediate; wherein the content of the first and second substances,
the hydroformylation intermediate has the structural formula:
oximating the hydroformylation intermediate to obtain an oximated intermediate; wherein the content of the first and second substances,
the structural formula of the oximation intermediate is as follows:
cyaniding the oximation intermediate to obtain a cyanidation intermediate; wherein the content of the first and second substances,
the structural formula of the cyanated intermediate is:
carrying out amino deprotection on the cyanidation intermediate to obtain free alkali of the silodosin intermediate; wherein the content of the first and second substances,
the structural formula of the free base of the silodosin intermediate is:
salifying free alkali of the silodosin intermediate to obtain a silodosin intermediate; wherein the structural formula of the silodosin intermediate is as follows:
compared with the prior art, in the preparation method of the silodosin intermediate, alpha-substituted acetone compound is subjected to chiral induced reductive amination firstly to improve atom economy in a synthesis process to obtain an initial intermediate, then the initial intermediate is subjected to amino protection, and benzyloxycarbonyl is introduced to propyl of a benzene ring in the initial intermediate to obtain an amino-protected intermediate, at the moment, the steric hindrance of hydrogen atoms on the carbon at the ortho position of the propyl of the benzene ring in the amino-protected intermediate is larger, and the cyanide intermediate is obtained through hydroformylation, oximation and cyanidation of the amino-protected intermediate, so that the steric hindrance of hydrogen atoms on the carbon at the ortho position of the propyl of the benzene ring in the amino-protected intermediate is larger, and when the amino-protected intermediate is subjected to hydroformylation, aldehyde groups are easier to substitute hydrogen at positions alternate with the propyl substitution position in the benzene ring, and the problem of reverse hydroformylation in the prior art caused by the existence of a plurality of reactive sites capable of hydroformylation on the benzene ring is improved The selectivity is not high, thereby improving the yield of silodosin intermediate.
The invention also provides a preparation method of silodosin, which comprises the following steps:
preparing a silodosin intermediate by adopting the preparation method of the silodosin intermediate provided by the technical scheme;
silodosin is prepared using silodosin intermediates.
Compared with the prior art, the beneficial effects of the preparation method of silodosin provided by the invention are the same as those of the preparation method of silodosin intermediate provided by the technical scheme, and are not repeated herein.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 is a schematic representation of the prior art compound conversion for the preparation of silodosin intermediates;
FIG. 2 is a first flow chart of a process for preparing a silodosin intermediate according to an embodiment of the present invention;
FIG. 3 is a second flow chart of the process for preparing silodosin intermediate provided in the examples of the present invention;
FIG. 4 is a flow chart III of the preparation method of silodosin intermediate provided by the embodiment of the invention;
FIG. 5 is a fourth flow chart of the preparation method of silodosin intermediate provided in the example of the present invention;
fig. 6 is a flow chart of a fifth process for preparing silodosin intermediate provided in the examples of the present invention;
FIG. 7 is a sixth flow chart of a process for preparing silodosin intermediates provided in an embodiment of the present invention;
fig. 8 is a seventh flowchart of a method for preparing a silodosin intermediate provided by an embodiment of the present invention;
fig. 9 is a flow chart eight of a method for preparing a silodosin intermediate provided in an embodiment of the present invention;
FIG. 10 is a nine flow chart of a process for preparing silodosin intermediates provided in an embodiment of the present invention;
fig. 11 is a flow chart ten of a method for preparing a silodosin intermediate provided by an embodiment of the present invention;
fig. 12 is an eleventh flow chart of a method for preparing a silodosin intermediate provided by an embodiment of the present invention;
fig. 13 is a flow chart twelve of a method for preparing a silodosin intermediate provided by an embodiment of the present invention;
FIG. 14a is a liquid phase diagram of a reductive amination reaction solution in one embodiment of the present invention;
FIG. 14b is a mass spectrum of the substance corresponding to the absorption peak at 10.183min in FIG. 14 a;
FIG. 14c is a mass spectrum of the substance corresponding to the absorption peak at 11.150min in FIG. 14 a;
FIG. 15 is a mass spectrum of an amino intermediate in one example of the present invention;
FIG. 16 is a mass spectrum of an oximation intermediate in accordance with the first embodiment of the present invention;
FIG. 17 is a mass spectrum of a cyanated intermediate in accordance with example one of the present invention;
FIG. 18 is a mass spectrum of silodosin intermediate in the first embodiment of the present invention.
Detailed Description
In order to further illustrate the silodosin intermediate and the preparation method of silodosin provided by the embodiment of the invention, the following detailed description is made in conjunction with the accompanying drawings.
Referring to fig. 2, a method for preparing silodosin intermediate provided by the embodiment of the present invention includes:
s1: carrying out chiral induced reductive amination on the alpha-substituted acetone compound to obtain an initial intermediate; wherein the content of the first and second substances,
the structural formula of the alpha-substituted acetonide is:
the structural formula of the initial intermediate is:
s2: performing amino protection on the initial intermediate to obtain an amino-protected intermediate; wherein the content of the first and second substances,
the structural formula of the amino-protected intermediate is as follows:
s3: the amino protection intermediate is hydroformylated to obtain a hydroformylation intermediate; wherein the content of the first and second substances,
the hydroformylation intermediate has the structural formula:
s4: oximating the hydroformylation intermediate to obtain an oximated intermediate; wherein the content of the first and second substances,
the structural formula of the oximation intermediate is as follows:
s5: cyaniding the oximation intermediate to obtain a cyanidation intermediate; wherein the content of the first and second substances,
the structural formula of the cyanated intermediate is:
s6: carrying out amino deprotection on the cyanidation intermediate to obtain free alkali of the silodosin intermediate; wherein the content of the first and second substances,
the structural formula of the free base of the silodosin intermediate is:
s7: salifying free alkali of the silodosin intermediate to obtain a silodosin intermediate; wherein the content of the first and second substances,
the structural formula of the silodosin intermediate is:
in the preparation method of silodosin intermediate provided by this embodiment, first, a-substituted acetonide is subjected to chiral induced reductive amination to obtain an initial intermediate, then, the initial intermediate is subjected to amino protection, and benzyloxycarbonyl group is introduced to propyl group of benzene ring in the initial intermediate to obtain an amino-protected intermediate, at this time, the steric hindrance of hydrogen atom on carbon at the ortho position to propyl group of benzene ring in the amino-protected intermediate is relatively large, and the cyanide intermediate is obtained by hydroformylation, oximation, and cyanidation of the amino-protected intermediate, so that the steric hindrance of hydrogen atom on carbon at the ortho position to propyl group of benzene ring in the amino-protected intermediate is relatively large, and when hydroformylation is performed by the amino-protected intermediate, hydrogen at a position alternating with propyl group in benzene ring is more easily substituted by aldehyde group, which improves the problem of low reaction selectivity caused by the presence of a plurality of reactive sites capable of hydroformylation on benzene ring in the prior art, thereby improving the yield of silodosin intermediate.
Illustratively, the chirally induced reductive amination of α -substituted acetonides by S1 as described above to give the initial intermediates involves two approaches:
the first mode is as follows: as shown in fig. 3, the chiral-induced reductive amination of α -substituted acetonides by S1 described above to give the initial intermediates comprises:
s11: under the condition of hydrogen, alpha-substituted acetonide, reductive amination catalyst and chiral amine are mixed to carry out chiral induced reductive amination reaction, and the progress of the reductive amination reaction is monitored by thin-layer chromatography in the process of the reductive amination reaction; illustratively, the reductive amination catalyst can be any one of platinum oxide, Raney nickel and Pd/C, and the chiral amine can be any one of R-phenylglycinol, R-naphthylethylamine and R-phenylethylamine; during operation, dissolving an alpha-substituted acetonide in tetrahydrofuran to prepare an initial solution, sequentially adding platinum oxide and R-phenylethylamine into the initial solution to form a reductive amination reaction system, replacing the ambient atmosphere of the reductive amination reaction system with hydrogen, stirring the reductive amination reaction system at room temperature for 8-10 h, and monitoring the progress of the reductive amination reaction through thin-layer chromatography; wherein the mass ratio of the alpha-substituted acetonide to the reductive amination catalyst is 1 (0.1-1%); the mol ratio of the alpha-substituted acetonide to the chiral amine is 1 (1.0-1.2), and optionally, promoters such as acetic acid and hydrochloric acid can be added into the reaction system to promote the reaction;
s12: when the reductive amination reaction reaches the reaction end point, extracting an organic phase in the obtained reductive amination reaction system by using an extraction liquid; for example, the extract may be ethyl acetate;
s13: carrying out post-treatment on the extracted organic phase to obtain an initial intermediate; illustratively, after combining the organic phases extracted by ethyl acetate, washing the combined organic phases with a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying the combined organic phases with anhydrous sodium sulfate, and concentrating the combined organic phases to obtain a white to pale yellow oily substance, namely an initial intermediate, wherein the de value of the initial intermediate is 66.7%, and the yield of the initial intermediate is 91% calculated by alpha-substituted acetonide.
The second mode is as follows: as shown in fig. 4, the chiral-induced reductive amination of α -substituted acetonides by S1 described above to give the initial intermediates included:
s11: mixing an alpha-substituted acetonide, chiral amine and a reducing agent to carry out chiral induced reductive amination, and monitoring the progress of the reductive amination reaction by thin-layer chromatography in the reductive amination reaction process; illustratively, the chiral amine can be any one of R-phenylglycinol, R-naphthylethylamine and R-phenylethylamine, and the reducing agent can be any one of sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride; during operation, dissolving an alpha-substituted acetonide in an organic solvent to prepare an initial solution, then adding R-phenylethylamine and sodium triacetoxyborohydride into the initial solution, stirring a reaction system at room temperature for 8-10 h, and then monitoring the progress of reductive amination reaction by thin-layer chromatography; wherein the mol ratio of the alpha-substituted acetonide to the reducing agent is 1 (1.20-2.00); the mol ratio of the alpha-substituted acetone compound to the chiral amine is 1 (1.0-1.2), and the organic solvent can be toluene as an example;
s12: when the reductive amination reaction reaches the reaction end point, extracting an organic phase in the obtained reductive amination reaction system by using an extraction liquid; illustratively, when the reductive amination reaction reaches the reaction end point, adding a saturated sodium carbonate solution into the obtained reductive amination reaction system for 2 times for washing, then adding hydrochloric acid with the concentration of 1M into the reductive amination reaction system for 3 times for extraction to obtain an organic phase, washing the separated water phase with toluene for 2 times, then adjusting the pH value of the water phase to 9, and continuing to extract the organic phase with ethyl acetate for 3 times;
s13: carrying out post-treatment on the extracted organic phase to obtain an initial intermediate; illustratively, the extracted organic phase is washed with saturated sodium carbonate solution and saturated sodium chloride solution in sequence, then dried over anhydrous sodium sulfate and concentrated to obtain white to pale yellow oil, namely the initial intermediate, wherein the de value of the initial intermediate is 57.5%, and the yield of the initial intermediate is 92% calculated by alpha-substituted acetonide.
Illustratively, as shown in fig. 5, amino protection of the initial intermediate by S2 above to give an amino protected intermediate comprises:
s21: mixing the initial intermediate with benzyl chloroformate to carry out amino protection reaction, and monitoring the progress of the amino protection reaction by thin-layer chromatography in the process of the amino protection reaction; illustratively, dissolving an initial intermediate in an organic solvent to prepare an initial intermediate solution, stirring the prepared initial intermediate solution at room temperature, and dropwise adding benzyl chloroformate into the initial intermediate solution to form an amino protection reaction system, wherein the temperature of the amino protection reaction system is not higher than 30 ℃ during dropwise adding, so that the benzyl chloroformate and the initial intermediate undergo an amino protection reaction; wherein the molar ratio of the initial intermediate to the benzyl chloroformate is 1 (1.00-1.30); illustratively, the organic solvent may be benzene, toluene or xylene;
s22: when the amino protection reaction reaches the reaction end point, extracting an organic phase in the obtained amino protection reaction system by using an extraction liquid; illustratively, the extract can be benzene, toluene or xylene;
s23: carrying out post-treatment on the extracted organic phase to obtain an amino protection intermediate; illustratively, the extracted organic phase is washed with a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, then dried over anhydrous sodium sulfate and concentrated to obtain colorless to pale yellow oil, namely the amino-protected intermediate, wherein the yield of the amino-protected intermediate is 100% based on the initial intermediate.
As shown in fig. 6, the hydroformylation of the amino-protected intermediate by S3 above to give the hydroformylation compound comprises:
s31: mixing phosphorus oxychloride and dimethylformamide to prepare a formylation reagent; illustratively, phosphorus oxychloride is dropwise added into dimethylformamide at the temperature of 0 ℃, the temperature of the system is controlled to be 5-10 ℃ in the dropwise adding process, and after the phosphorus oxychloride is dropwise added, the reaction system is transferred to room temperature and stirred uniformly to obtain a formylation reagent;
s32: mixing a formylation reagent and an amino protection intermediate to carry out hydroformylation reaction, and monitoring the progress of the hydroformylation reaction by thin-layer chromatography in the hydroformylation reaction process; specifically, the formylation reagent obtained by S31 is cooled to 8-10 ℃, the amino protection intermediate is added into the formylation reagent, the formylation reagent is stirred for 1-1.5 h at room temperature, the temperature is raised to 40-50 ℃ and kept for 4-5 h, the amino protection intermediate is subjected to hydroformylation reaction, and the progress of the hydroformylation reaction is monitored by thin-layer chromatography in the process; illustratively, the mass ratio of the dimethylformamide to the amino-protected intermediate is 1 (0.3-0.4); the mol ratio of the dimethylformamide to the phosphorus oxychloride is 1 (1.95-2.15);
s33: when the hydroformylation reaction reaches the reaction end point, extracting an organic phase in the obtained hydroformylation reaction system by using an extraction liquid; illustratively, when the hydroformylation reaction reaches the reaction end point, adjusting the pH of the hydroformylation reaction system to 10, and adding a mixed solution of ethyl acetate and water into the hydroformylation reaction system to separate the hydroformylation reaction system, wherein the volume ratio of ethanol to water is 2: 1; then, ethyl acetate is selected as extraction liquid to extract the organic phase twice;
s34: carrying out post-treatment on the extracted organic phase to obtain a hydroformylation intermediate; illustratively, washing the organic phase obtained by extraction with a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance, namely a hydroformylation intermediate, wherein the yield of the hydroformylation intermediate is 100% calculated by taking the amino-protected intermediate;
as shown in fig. 7, oximation of the hydroformylation intermediate at S4 above to obtain an oximated intermediate includes:
s41: mixing the hydroformylation intermediate, hydroxylamine hydrochloride and pyridine to carry out oximation reaction, and monitoring the progress of the oximation reaction by thin-layer chromatography in the oximation reaction process; illustratively, after dissolving the hydroformylation intermediate in an organic solvent to prepare a solution, adding hydroxylamine hydrochloride and pyridine to the solution to form an oximation reaction system, heating the oximation reaction system to 40-50 ℃ for 1-2 h, and monitoring the progress of the oximation reaction by thin-layer chromatography; wherein the molar ratio of the hydroformylation intermediate, the hydroxylamine hydrochloride and the pyridine is 1 (1.50-2.70) to 5.45-7.55; as an illustrative example, tetrahydrofuran is used as the organic solvent;
s42: when the oximation reaction reaches the reaction end point, obtaining an oximation intermediate;
as shown in fig. 8, cyanation of the above-described S5 intermediate via oximation to give a cyanated intermediate includes:
s51: mixing the oximation intermediate with acetic anhydride to carry out a cyanidation reaction, and monitoring the progress of the cyanidation reaction by thin-layer chromatography in the process of the cyanidation reaction; illustratively, acetic anhydride is added to the oximation intermediate, stirred at the temperature of 40-50 ℃ for 25-35 min, then heated to reflux and kept for about 6-7 h, and the progress of the cyanidation reaction is monitored by thin-layer chromatography in the process; wherein the molar ratio of the oximation intermediate to the acetic anhydride is 1 (3.0-5.0);
s52: when the cyanidation reaction reaches the reaction end point, extracting an organic phase in the obtained cyanidation reaction system by using an extraction liquid; illustratively, when the cyanidation reaction reaches the reaction end point, after the organic solvent is recovered by rotary evaporation to obtain a residue, ethyl acetate is added into the residue for extraction to obtain an organic matter;
s53: carrying out post-treatment on the extracted organic phase to obtain a cyaniding intermediate; for example, the extracted organic phase may be washed with water, hydrochloric acid, a saturated sodium carbonate solution, and a saturated sodium chloride solution in sequence, and the washed organic phase is dried with anhydrous sodium sulfate, and then concentrated to obtain an oily substance, i.e., a cyanation intermediate; wherein the yield of the cyanated intermediate is 82% based on the hydroformylation intermediate.
As shown in fig. 9, amino deprotection of the cyanated intermediate at S6 above to give the free base of silodosin intermediate comprises:
s61: under the condition of hydrogen, mixing the cyanidation intermediate with palladium-carbon to carry out amino deprotection reaction, and monitoring the progress of the amino deprotection reaction by thin-layer chromatography in the process of the amino deprotection reaction; illustratively, dissolving a cyanide intermediate in an organic solvent to form a cyanide intermediate solution, adding palladium and carbon into the cyanide intermediate solution, uniformly mixing to form an amino deprotection reaction system, replacing air in the amino deprotection reaction system with hydrogen, heating the amino deprotection reaction system to 40-50 ℃ to perform amino deprotection reaction, and monitoring the progress of the amino deprotection reaction through thin-layer chromatography in the amino deprotection reaction process; wherein, the mass ratio of the cyanidation intermediate to the palladium-carbon is 1 (0.05-0.15), and in the reaction process, the organic solvent can be methanol as an example;
s62: when the amino deprotection reaction reaches the reaction end point, filtering the obtained amino deprotection reaction system to obtain a filtrate;
s63: concentrating the filtrate to obtain free alkali of silodosin intermediate; illustratively, the free base of the silodosin intermediate is 98% pure and 95% yield, calculated as the cyanated intermediate.
As shown in fig. 10, the step of S7 salifying the free base of the silodosin intermediate to obtain the silodosin intermediate is a chiral separation process, which specifically includes:
s71: under the anaerobic condition, dripping L-tartaric acid into free alkali of silodosin intermediate to carry out salt forming reaction; illustratively, the free alkali of the silodosin intermediate is dissolved in an organic solvent to prepare a free alkali solution of the silodosin intermediate, L-tartaric acid is dissolved in water to prepare an L-tartaric acid aqueous solution, the free alkali solution of the silodosin intermediate is heated to reflux, and the L-tartaric acid aqueous solution is dropwise added into the free alkali solution of the silodosin intermediate, wherein the molar ratio of the free alkali of the silodosin intermediate to the L-tartaric acid is 1 (0.90-1.10), and the protective gas can be nitrogen or argon; the organic solvent can be acetone;
s72: after the dropwise addition of the L-tartaric acid is finished, filtering the obtained salt formation reaction system to obtain a filter cake; specifically, after the L-tartaric acid is dripped, the temperature of the system is reduced to room temperature, the system is stirred for 1 to 1.5 hours, and the obtained salt forming reaction system is filtered to obtain a filter cake.
S73: carrying out post-treatment on the filter cake to obtain a silodosin intermediate; illustratively, recrystallizing the filter cake, wherein a solvent for recrystallization can be a mixed solution of acetone and water, the volume ratio of acetone to water is 1:1, and after recrystallizing the filter cake with the mixed solution of acetone and water to obtain a product, continuously recrystallizing the product with water to obtain a silodosin intermediate; illustratively, the yield of silodosin intermediate is 65-98% calculated as the free base of silodosin intermediate.
In order to improve the chiral purity of the prepared silodosin intermediate, as shown in fig. 11, the above S2 performs amino protection on the initial intermediate to obtain an amino-protected intermediate comprising:
s21': carrying out chiral resolution and purification on the initial intermediate to obtain a chiral qualified intermediate; wherein the content of the first and second substances,
the structural formula of the chiral qualified intermediate is as follows:
s22': and carrying out amino protection on the chiral qualified intermediate to obtain an amino protected intermediate.
Illustratively, as shown in fig. 12, the above S21' chiral resolution purification of the initial intermediate to obtain a chiral qualified intermediate includes:
s211': dropwise adding hydrogen chloride into the initial intermediate to form a salt, and performing chiral resolution and purification reaction; illustratively, dissolving an initial intermediate in an organic solvent to prepare an initial intermediate solution, then dropwise adding a hydrogen chloride solution of ethanol into the initial intermediate solution, and monitoring the pH of the solution in real time in the process; as an example, the organic solvent may be ethyl acetate;
s212': when the pH value of the reaction system reaches 6-7, filtering the obtained initial intermediate hydrochloride under the anhydrous condition to obtain a filter cake; illustratively, when the pH reaches 6, a small amount of seed crystals of the initial intermediate may be added to the solution to promote the formation of the chiral separation intermediate, and then the solution is filtered to obtain a filter cake, it is noted that, in order to avoid the chiral separation intermediate absorbing moisture, the chiral separation purification reaction system is prevented from contacting moisture in the air during the filtering process;
s213': carrying out post-treatment on the filter cake to obtain a chiral qualified intermediate; illustratively, ethyl acetate and ethanol can be prepared into a recrystallization solution according to the volume ratio of 4:1, and a filter cake is recrystallized by using the recrystallization solution to obtain a chiral qualified intermediate, wherein the de value of the chiral qualified intermediate is not less than 99%, and the yield of the chiral qualified intermediate is 48% calculated by the initial intermediate.
Illustratively, as shown in fig. 13, amino-protecting the chiral qualified intermediate in S22' above to yield an amino-protected intermediate comprises:
s221': mixing the chiral qualified intermediate with benzyl chloroformate to carry out amino protection reaction, and monitoring the progress of the amino protection reaction by thin-layer chromatography in the amino protection reaction process; illustratively, dissolving a chiral qualified intermediate into an organic solvent to prepare a solution, adding a sodium carbonate solution into the solution to neutralize the solution, dropwise adding benzyl chloroformate into the solution to form an amino protection reaction system after stirring at room temperature, wherein the temperature of the amino protection reaction system is not higher than 30 ℃ in the dropwise adding process, and the benzyl chloroformate and the chiral qualified intermediate are subjected to amino protection reaction; wherein, the mol ratio of the chiral qualified intermediate to the benzyl chloroformate is 1 (1.20-1.30); the molar ratio of the qualified chiral intermediate to the sodium carbonate is 1 (2.4-2.6);
s222': when the amino protection reaction reaches the reaction end point, extracting an organic phase in the obtained amino protection reaction system by using an extraction liquid; illustratively, the extract can be benzene, toluene or xylene;
s223': carrying out post-treatment on the extracted organic phase to obtain an amino protection intermediate; illustratively, the extracted organic phase is washed by saturated sodium carbonate solution and saturated sodium chloride solution in sequence, then dried by anhydrous sodium sulfate and concentrated to obtain colorless to pale yellow oily matter, namely the amino-protected intermediate, wherein the yield of the amino-protected intermediate is 100% calculated by chiral qualified intermediate.
Illustratively, the above-mentioned α -substituted acetonide compound may be prepared by a nitro compound; wherein the structural formula of the nitro compound is as follows:
it is understood that the developing agent for monitoring the reaction by the thin layer chromatography is petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 1 (3-5).
The embodiment also provides a preparation method of silodosin, which comprises the following steps:
preparing a silodosin intermediate by adopting the preparation method of the silodosin intermediate provided by the technical scheme;
silodosin is prepared using silodosin intermediates.
Compared with the prior art, the beneficial effects of the preparation method of silodosin provided by the embodiment are the same as those of the preparation method of silodosin intermediate provided by the above technical scheme, and are not repeated herein.
The silodosin intermediate and the preparation method of the silodosin intermediate provided by the present invention are specifically described below with reference to the following examples, which are merely illustrative and not limitative of the present invention. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.
Example one
This example provides a method for preparing a silodosin intermediate, comprising:
firstly, dissolving an alpha-substituted acetonide in tetrahydrofuran to prepare an initial solution under the condition of hydrogen, then adding platinum oxide and R-phenylethylamine into the initial solution, stirring the substances at room temperature to perform chiral induced reductive amination, and monitoring the progress of the reductive amination through thin-layer chromatography after 8 hours; wherein the mass ratio of the alpha-substituted acetone compound to the platinum oxide is 1: 0.1%, and the molar ratio of the alpha-substituted acetone compound to the R-phenylethylamine is 1: 1.2;
when the reductive amination reaction reaches the reaction end point, filtering and recovering platinum black obtained by platinum oxide reaction, carrying out rotary evaporation to recover solvent tetrahydrofuran, and then sequentially adding ethyl acetate and hydrochloric acid into the residue to extract an organic phase in the reductive amination reaction system; wherein the concentration of the hydrochloric acid is 1M;
adjusting the pH value of the extracted organic phase to 9 by using sodium carbonate, then washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate after washing, and then concentrating the dried organic phase to obtain white to light yellow oily matter which is an initial intermediate, wherein the de value of the initial intermediate is 66.7 percent, and the yield of the initial intermediate is 91 percent based on alpha-substituted acetonide.
In this step, a liquid phase mass spectrometry measurement is performed on the reductive amination reaction solution, and a liquid phase map is as shown in fig. 14a, and it is found from the liquid phase map shown in fig. 14a that two relatively strong absorption peaks appear at 10.183min and 11.150min respectively and are located close to each other, but an absorption peak at 10.183min is stronger than that at 11.150min, and it is seen that a substance corresponding to the absorption peak at 10.183min in the reductive amination reaction solution is a main product.
In addition, mass spectrometry of the substance corresponding to the absorption peak at 10.183min was performed, the measurement result is shown in fig. 14b, and mass spectrometry of the substance corresponding to the absorption peak at 11.150min was performed, the measurement result is shown in fig. 14c, and it can be seen from comparison of fig. 14b and 14c that the two substances have the same molecular weight, i.e., 443, and therefore, it can be determined that the substances corresponding to the absorption peak at 10.183min and the absorption peak at 11.150min should be two isomers of the starting intermediate. Further, by analyzing the physicochemical properties of the initial intermediate to be prepared, it was confirmed that the absorption peak at 10.183min was the initial intermediate to be prepared in this step.
Secondly, dissolving the initial intermediate in ethyl acetate at 10 ℃ to form an initial intermediate solution, slowly dropwise adding a hydrogen chloride solution of ethanol into the initial intermediate solution to form a chiral separation and purification reaction system, and adding seed crystals of the initial intermediate into the chiral separation and purification reaction system when the pH of the chiral separation and purification reaction system is 6 to separate out a solid; then filtering the obtained initial intermediate hydrochloride under the anhydrous condition to obtain a filter cake; wherein the molar ratio of the initial intermediate to the hydrogen chloride is 1:1.80, and the mass fraction of the seed crystal of the initial intermediate is 3%;
and (3) recrystallizing the filter cake for 3 times by using a mixed solution of ethyl acetate and ethanol with the volume ratio of 4:1 to obtain a chiral qualified intermediate, wherein the purity of the chiral qualified intermediate is 99%, the de value is 99%, and the yield of the chiral qualified intermediate is 48% calculated by using the initial intermediate.
Thirdly, dissolving the chiral qualified intermediate in toluene to form a chiral split intermediate solution, dropwise adding benzyl chloroformate to form an amino protection reaction system, keeping the temperature of the amino protection reaction system at 30 ℃ in the dropwise adding process, reacting for 1h, and monitoring the amino protection reaction progress through thin-layer chromatography, wherein the molar ratio of the chiral qualified intermediate to the benzyl chloroformate is 1: 1.20;
when the amino protection reaction reaches the reaction end point, extracting an organic phase in the obtained amino protection reaction system by using toluene;
and (3) washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate, and concentrating the dried organic phase to obtain colorless to pale yellow oily substances, namely amino-protected intermediates, wherein the yield of the amino-protected intermediates is 100 percent according to the calculation of chiral separation and purification of the intermediates.
Fourthly, mixing phosphorus oxychloride and dimethylformamide to prepare a formylation reagent;
mixing a formylation reagent and an amino protection intermediate to carry out hydroformylation reaction, and monitoring the progress of the hydroformylation reaction by thin-layer chromatography in the hydroformylation reaction process; wherein the molar ratio of the dimethylformamide to the phosphorus oxychloride is 1: 1.95; the mass ratio of the dimethylformamide to the amino protection intermediate is 1: 0.3;
when the hydroformylation reaction reaches the reaction end point, extracting an organic phase in the obtained hydroformylation reaction system by using ethyl acetate;
and (3) washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance, namely a hydroformylation intermediate, wherein the yield of the hydroformylation intermediate is 100% based on the amino protection intermediate.
From the mass spectrum of the hydroformylation reaction intermediate shown in fig. 15, it can be confirmed that this step produced a hydroformylation reaction intermediate having a molecular weight of 605.
Fifthly, mixing the hydroformylation intermediate, hydroxylamine hydrochloride and pyridine for oximation reaction, and monitoring the progress of the oximation reaction by thin-layer chromatography in the oximation reaction process; wherein the molar ratio of the hydroformylation intermediate to the hydroxylamine hydrochloride to the pyridine is 1:2.60: 7.45;
when the oximation reaction reaches the reaction end point, the preparation of the oximation intermediate is finished; then mixing the oximation intermediate with acetic anhydride to carry out a cyanidation reaction, and monitoring the progress of the cyanidation reaction by thin-layer chromatography in the process of the cyanidation reaction; wherein the molar ratio of the oximation intermediate to the acetic anhydride is 1: 4.0;
when the cyanidation reaction reaches the reaction end point, extracting an organic phase in the obtained cyanidation reaction system by using ethyl acetate; and then, washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate after washing is finished, and concentrating to obtain an oily substance, namely a cyanidation intermediate, wherein the yield of the cyanidation intermediate is 82% based on the oximation intermediate.
From the mass spectrum of the oximated intermediate shown in fig. 16, it was confirmed that this procedure produced an oximated intermediate having a molecular weight of 620.
From the mass spectrum of the cyanated intermediate shown in fig. 17, it can be confirmed that this step produced a cyanated intermediate having a molecular weight of 602.
Sixthly, under the condition of hydrogen, a cyanide compound and palladium-carbon are mixed to carry out amino deprotection reaction, and the progress of the amino deprotection reaction is monitored by thin-layer chromatography in the process of the amino deprotection reaction; wherein the mass ratio of the cyanidation intermediate to the palladium-carbon is 1: 0.05;
when the amino deprotection reaction reaches the reaction end point, filtering the amino deprotection reaction system to obtain a filtrate; concentrating the filtrate to obtain free alkali of silodosin intermediate; wherein the purity of the free base of the silodosin intermediate is 98%, and the yield of the free base of the silodosin intermediate is 95% based on the cyanide intermediate.
Then, under the condition of nitrogen, dripping L-tartaric acid into free alkali of the silodosin intermediate to carry out salt formation; after the dropwise addition of the L-tartaric acid is finished, filtering the obtained salt formation reaction system to obtain a filter cake; wherein the molar ratio of free alkali of the silodosin intermediate to L-tartaric acid is 1: 0.90;
and recrystallizing the filter cake by using a mixed solution of acetone and water with the volume ratio of 1:1 to obtain a silodosin intermediate, wherein the yield is 98 percent based on the free base of the silodosin intermediate.
From the mass spectrum of the silodosin intermediate shown in fig. 18, it can be confirmed that the product prepared in this example is a silodosin intermediate having a molecular weight of 364.
Among them, this example provides a preparation method of silodosin intermediate, which can prepare silodosin intermediate with a total yield of 33.3%.
Example two
This example provides a method for preparing a silodosin intermediate, comprising:
firstly, dissolving an alpha-substituted acetonide in tetrahydrofuran to prepare an initial solution, then adding R-naphthylethylamine and sodium borohydride into the initial solution, stirring the substances at room temperature to carry out reductive amination reaction, and monitoring the progress of the reductive amination reaction by thin-layer chromatography after 8 hours; wherein the mol ratio of the alpha-substituted acetone compound to the sodium borohydride is 1:1.80, and the mol ratio of the alpha-substituted acetone compound to the R-naphthylethylamine is 1: 1.12;
when the reductive amination reaction reaches the reaction end point, filtering and recovering platinum black obtained by platinum oxide reaction, carrying out rotary evaporation to recover solvent tetrahydrofuran, and then sequentially adding ethyl acetate and hydrochloric acid into the residue to extract an organic phase in the reductive amination reaction system; wherein the concentration of the hydrochloric acid is 1M;
adjusting the pH value of the extracted organic phase to 9 by using sodium carbonate, then washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate after washing, and then concentrating the dried organic phase to obtain a white to pale yellow oily substance which is an initial intermediate, wherein the de value of the initial intermediate is 57.5 percent, and the yield of the initial intermediate is 92 percent based on alpha-substituted acetonide;
secondly, dissolving the initial intermediate in ethyl acetate at the temperature of 8 ℃ to form an initial intermediate solution, slowly dropwise adding a hydrogen chloride solution of ethanol into the initial intermediate solution to form a chiral separation and purification reaction system, and adding seed crystals of the initial intermediate into the reaction system when the pH of the reaction system is 6 to separate out solids; then filtering the obtained initial intermediate hydrochloride under the anhydrous condition to obtain a filter cake; wherein the molar ratio of the chiral induction intermediate to the hydrogen chloride is 1:1.85, and the mass fraction of the seed crystal of the initial intermediate is 5%;
and (3) recrystallizing the filter cake for 3 times by using a mixed solution of ethyl acetate and ethanol with the volume ratio of 4:1 to obtain a chiral qualified intermediate, wherein the purity of the chiral qualified intermediate is 99%, the de value is 99%, and the yield of the chiral qualified intermediate is 44% calculated by using the initial intermediate.
Thirdly, dissolving the chiral qualified intermediate in toluene to form a chiral split intermediate solution, dropwise adding benzyl chloroformate to form an amino protection reaction system, keeping the temperature of the amino protection reaction system at 30 ℃ in the dropwise adding process, reacting for 1h, and monitoring the amino protection reaction progress through thin-layer chromatography, wherein the molar ratio of the chiral qualified intermediate to the benzyl chloroformate is 1: 1.25;
when the amino protection reaction reaches the reaction end point, extracting an organic phase in the obtained amino protection reaction system by using toluene;
and (3) washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate, and concentrating the dried organic phase to obtain colorless to pale yellow oily substances, namely amino-protected intermediates, wherein the yield of the amino-protected intermediates is 100 percent according to the calculation of chiral separation and purification of the intermediates.
Fourthly, mixing phosphorus oxychloride and dimethylformamide to prepare a formylation reagent;
mixing a formylation reagent and an amino protection intermediate to carry out hydroformylation reaction, and monitoring the progress of the hydroformylation reaction by thin-layer chromatography in the hydroformylation reaction process; wherein the molar ratio of the dimethylformamide to the phosphorus oxychloride is 1: 2.00; the mass ratio of the dimethylformamide to the amino protection intermediate is 1: 0.4;
when the hydroformylation reaction reaches the reaction end point, extracting an organic phase in the obtained hydroformylation reaction system by using ethyl acetate;
and (3) washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance, namely a hydroformylation intermediate, wherein the yield of the hydroformylation intermediate is 100% based on the amino protection intermediate.
Fifthly, mixing the hydroformylation intermediate, hydroxylamine hydrochloride and pyridine for oximation reaction, and monitoring the progress of the oximation reaction by thin-layer chromatography in the oximation reaction process; wherein the molar ratio of the hydroformylation intermediate to the hydroxylamine hydrochloride to the pyridine is 1:2.70: 7.55;
when the oximation reaction reaches the reaction end point, the preparation of the oximation intermediate is finished; then mixing the oximation intermediate with acetic anhydride to carry out a cyanidation reaction, and monitoring the progress of the cyanidation reaction by thin-layer chromatography in the process of the cyanidation reaction; wherein the molar ratio of the oximation intermediate to the acetic anhydride is 1: 4.5;
when the cyanidation reaction reaches the reaction end point, extracting an organic phase in the obtained cyanidation reaction system by using ethyl acetate; and then, washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate after washing is finished, and concentrating to obtain an oily substance, namely a cyanidation intermediate, wherein the yield of the cyanidation intermediate is 82% based on the oximation intermediate.
Sixthly, under the condition of hydrogen, a cyanide compound and palladium-carbon are mixed to carry out amino deprotection reaction, and the progress of the amino deprotection reaction is monitored by thin-layer chromatography in the process of the amino deprotection reaction; wherein the mass ratio of the cyanidation intermediate to the palladium-carbon is 1: 0.10;
when the amino deprotection reaction reaches the reaction end point, filtering the amino deprotection reaction system to obtain a filtrate; concentrating the filtrate to obtain free alkali of silodosin intermediate; wherein the purity of the free base of the silodosin intermediate is 98%, and the yield of the free base of the silodosin intermediate is 95% based on the cyanide intermediate.
Then, under the condition of nitrogen, dripping L-tartaric acid into free alkali of the silodosin intermediate to carry out salt formation; after the dropwise addition of the L-tartaric acid is finished, filtering the obtained salt formation reaction system to obtain a filter cake; wherein the molar ratio of free alkali of the silodosin intermediate to L-tartaric acid is 1: 0.95;
and recrystallizing the filter cake by using a mixed solution of acetone and water in a volume ratio of 1:1 to obtain a silodosin intermediate. The yield was 98% based on the free base of the silodosin intermediate.
Among them, this example provides a preparation method of silodosin intermediate, which can prepare silodosin intermediate with a total yield of 30.9%.
EXAMPLE III
This example provides a method for preparing a silodosin intermediate, comprising:
firstly, dissolving an alpha-substituted acetonide in tetrahydrofuran to prepare an initial solution under the condition of hydrogen, then adding raney nickel and R-phenylglycinol into the initial solution, stirring the substances at room temperature to carry out reductive amination reaction, and monitoring the progress of the reductive amination reaction by thin-layer chromatography after 8 hours; wherein the mass ratio of the alpha-substituted acetonide to the Raney nickel is 1: 0.1%, and the molar ratio of the alpha-substituted acetonide to the R-phenylglycinol is 1: 1.0;
when the reductive amination reaction reaches the reaction end point, recovering tetrahydrofuran as a solvent by rotary evaporation, and then sequentially adding ethyl acetate and hydrochloric acid into the remainder to extract an organic phase in the reductive amination reaction system; wherein the concentration of the hydrochloric acid is 1M;
adjusting the pH value of the extracted organic phase to 9 by using sodium carbonate, then washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate after washing, and then concentrating the dried organic phase to obtain a white to pale yellow oily substance which is an initial intermediate, wherein the de value of the initial intermediate is 66.7 percent, and the yield of the initial intermediate is 92 percent based on alpha-substituted acetonide;
secondly, dissolving the initial intermediate in toluene to form an initial intermediate solution, dropwise adding benzyl chloroformate to form an amino protection reaction system, keeping the temperature of the amino protection reaction system at 30 ℃ in the dropwise adding process, reacting for 1h, and monitoring the amino protection reaction progress through thin-layer chromatography, wherein the molar ratio of the initial intermediate to the benzyl chloroformate is 1: 1.30;
when the amino protection reaction reaches the reaction end point, extracting an organic phase in the obtained amino protection reaction system by using toluene;
and (3) washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying the organic phase by using anhydrous sodium sulfate, and concentrating the dried organic phase to obtain colorless to pale yellow oily substances, namely amino-protected intermediates, wherein the yield of the amino-protected intermediates is 100 percent according to the calculation of chiral separation and purification of the intermediates.
Thirdly, mixing phosphorus oxychloride and dimethylformamide to prepare a formylation reagent;
mixing a formylation reagent and an amino protection intermediate to carry out hydroformylation reaction, and monitoring the progress of the hydroformylation reaction by thin-layer chromatography in the hydroformylation reaction process; wherein the molar ratio of the dimethylformamide to the phosphorus oxychloride is 1: 2.15; the mass ratio of the dimethylformamide to the amino protection intermediate is 1: 0.35;
when the hydroformylation reaction reaches the reaction end point, extracting an organic phase in the obtained hydroformylation reaction system by using ethyl acetate;
and (3) washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance, namely a hydroformylation intermediate, wherein the yield of the hydroformylation intermediate is 100% based on the amino protection intermediate.
Fourthly, mixing the hydroformylation intermediate, hydroxylamine hydrochloride and pyridine to carry out oximation reaction, and monitoring the progress of the oximation reaction by thin-layer chromatography in the oximation reaction process; wherein the molar ratio of the hydroformylation intermediate to the hydroxylamine hydrochloride to the pyridine is 1:1.50: 5.45;
when the oximation reaction reaches the reaction end point, the preparation of the oximation intermediate is finished; then mixing the oximation intermediate with acetic anhydride to carry out a cyanidation reaction, and monitoring the progress of the cyanidation reaction by thin-layer chromatography in the process of the cyanidation reaction; wherein the molar ratio of the oximation intermediate to the acetic anhydride is 1: 3.0;
when the cyanidation reaction reaches the reaction end point, extracting an organic phase in the obtained cyanidation reaction system by using ethyl acetate; and then, washing the extracted organic phase by using a saturated sodium carbonate solution and a saturated sodium chloride solution in sequence, drying by using anhydrous sodium sulfate after washing is finished, and concentrating to obtain an oily substance, namely a cyanidation intermediate, wherein the yield of the cyanidation intermediate is 82% based on the oximation intermediate.
Fifthly, under the condition of hydrogen, a cyanide compound and palladium-carbon are mixed to carry out amino deprotection reaction, and the progress of the amino deprotection reaction is monitored by thin-layer chromatography in the process of the amino deprotection reaction; wherein the mass ratio of the cyanidation intermediate to the palladium-carbon is 1: 0.15;
when the amino deprotection reaction reaches the reaction end point, filtering the amino deprotection reaction system to obtain a filtrate; concentrating the filtrate to obtain free alkali of silodosin intermediate; wherein the purity of the free base of the silodosin intermediate is 98%, and the yield of the free base of the silodosin intermediate is 95% based on the cyanide intermediate.
Then, under the condition of nitrogen, dripping L-tartaric acid into free alkali of the silodosin intermediate to carry out salt formation; after the dropwise addition of the L-tartaric acid is finished, filtering the obtained salt formation reaction system to obtain a filter cake; wherein the molar ratio of free alkali of the silodosin intermediate to L-tartaric acid is 1: 1.10; and recrystallizing the filter cake by using a mixed solution of acetone and water in a volume ratio of 1:1 to obtain a silodosin intermediate. The yield was 65% based on the free base of the silodosin intermediate.
Among them, this example provides a method for preparing silodosin intermediate with a total yield of silodosin intermediate of 46.5%.
Table 1 total yield results for silodosin intermediates
As can be seen from table 1, the yields of silodosin intermediates (calculated as α -substituted acetone intermediates) obtained in the examples of the present invention were in the range of 30.9% to 46.5%, which is much greater than the yields of silodosin intermediates obtained using the prior art.
In addition, the comparison of the first to third examples shows that the yield of the last step of the first and second examples reaches 98%, while the yield of the last step of the third example is only 65%, that is, the yield of the last step of the third example is the lowest yield of the three examples, but the total yield of the third example is the highest yield of the three examples, and the reason can be found as follows: examples one and two, although the initial intermediate is subjected to chiral resolution, this also results in a greater loss of the chiral qualified intermediate from the initial intermediate, resulting in a lower overall yield of silodosin intermediate. And in the third embodiment, when preparing the silodosin intermediate, chiral purification of the initial intermediate is skipped, the initial intermediate is directly subjected to an amino protection reaction, an hydroformylation reaction, an oximation reaction, a cyanation reaction and an amino deprotection reaction, and then the free base of the silodosin intermediate obtained by the amino deprotection reaction is subjected to chiral purification in the last step, so that the total yield of the silodosin intermediate is improved.
Table 2 purity results for silodosin intermediates
From the point of view of the preparation of the silodosin intermediates, the silodosin intermediates prepared in examples one and two were subjected to two chiral purifications (the first is a chiral resolution process of the initial intermediate, and the second is a salt formation process using the free base of the silodosin intermediate of L-tartaric acid), while the silodosin intermediate prepared in example three was subjected to one chiral purifications (a salt formation process using the free base of the silodosin intermediate of L-tartaric acid), which makes the chiral purities of the silodosin intermediates prepared in examples one and two higher than that of the silodosin intermediate prepared in example three, but it can be seen from the data presented in table 2 that although the chiral purities of the silodosin intermediates prepared in example three are relatively low, there is only a 2% difference, so small differences in the preparation of silodosin, does not have great influence on the preparation of silodosin. In addition, as can be seen from table 2, although the processes for preparing the silodosin intermediate in examples one and two are different from those in example three, the chemical purity of the prepared silodosin intermediate is 99.5%.
In the foregoing description of embodiments, the particular features, structures, materials, or characteristics may be combined in any suitable manner in any one or more embodiments or examples.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (10)
1. A preparation method of silodosin intermediate is characterized by comprising the following steps:
carrying out chiral induced reductive amination on the alpha-substituted acetone compound to obtain an initial intermediate; wherein the content of the first and second substances,
the structural formula of the alpha-substituted acetonide is as follows:
the structural formula of the initial intermediate is as follows:
performing amino protection on the initial intermediate to obtain an amino-protected intermediate; wherein the content of the first and second substances,
the structural formula of the amino-protected intermediate is as follows:
the amino protection intermediate is hydroformylated to obtain a hydroformylation intermediate; wherein the content of the first and second substances,
the hydroformylation intermediate has a structural formula as follows:
oximating the hydroformylation intermediate to obtain an oximated intermediate; wherein the content of the first and second substances,
the structural formula of the oximation intermediate is as follows:
cyaniding the oximation intermediate to obtain a cyanidation intermediate; wherein the content of the first and second substances,
the structural formula of the cyanidation intermediate is:
carrying out amino deprotection on the cyanidation intermediate to obtain free alkali of the silodosin intermediate; wherein the content of the first and second substances,
the structural formula of the free alkali of the silodosin intermediate is as follows:
salifying free alkali of the silodosin intermediate to obtain a silodosin intermediate; wherein the structural formula of the silodosin intermediate is as follows:
2. the process for preparing silodosin intermediate as claimed in claim 1, wherein said subjecting an α -substituted acetonide to chirally induced reductive amination to obtain an initial intermediate comprises:
under the condition of hydrogen, alpha-substituted acetonide, reductive amination catalyst and chiral amine are mixed to carry out chiral induced reductive amination reaction, and the progress of the reductive amination reaction is monitored by thin-layer chromatography in the process of the reductive amination reaction; the mass ratio of the alpha-substituted acetonide to the reductive amination catalyst is 1 (0.1-1%); the mol ratio of the alpha-substituted acetone compound to the chiral amine is 1 (1.0-1.2);
when the reductive amination reaction reaches the reaction end point, extracting an organic phase in the obtained reductive amination reaction system by using an extraction liquid;
and carrying out post-treatment on the extracted organic phase to obtain an initial intermediate.
3. The method of claim 1, wherein the subjecting the alpha-substituted acetonide to the chirally induced reductive amination reaction to obtain an initial intermediate comprises:
mixing an alpha-substituted acetonide, chiral amine and a reducing agent to carry out chiral induced reductive amination reaction, and monitoring the progress of the reductive amination reaction by thin-layer chromatography in the reductive amination reaction process; the mol ratio of the alpha-substituted acetonide to the reducing agent is 1 (1.20-2.00); the mol ratio of the alpha-substituted acetone compound to the chiral amine is 1 (1.0-1.2);
when the reductive amination reaction reaches the reaction end point, extracting an organic phase in the obtained reductive amination reaction system by using an extraction liquid;
and carrying out post-treatment on the extracted organic phase to obtain an initial intermediate.
4. The method of claim 1, wherein the amino-protecting the initial intermediate to obtain an amino-protected intermediate comprises:
mixing the initial intermediate with benzyl chloroformate to carry out amino protection reaction, and monitoring the progress of the amino protection reaction by thin-layer chromatography in the process of the amino protection reaction; the molar ratio of the initial intermediate to benzyl chloroformate is 1 (1.00-1.30);
when the amino protection reaction reaches the reaction end point, extracting an organic phase in the obtained amino protection reaction system by using an extraction liquid;
and carrying out post-treatment on the extracted organic phase to obtain an amino-protected intermediate.
5. The method of claim 1, wherein the hydroformylation of the amino-protected intermediate to provide a hydroformylation intermediate comprises:
mixing phosphorus oxychloride and dimethylformamide to prepare a formylation reagent; the molar ratio of the dimethyl formamide to the phosphorus oxychloride is 1 (1.95-2.15);
mixing a formylation reagent and an amino protection intermediate to carry out hydroformylation reaction, and monitoring the progress of the hydroformylation reaction by thin-layer chromatography in the hydroformylation reaction process; the mass ratio of the dimethylformamide to the amino protection intermediate is 1 (0.3-0.4);
when the hydroformylation reaction reaches the reaction end point, extracting an organic phase in the obtained hydroformylation reaction system by using an extraction liquid;
and carrying out post-treatment on the extracted organic phase to obtain a hydroformylation intermediate.
6. The method of preparing a silodosin intermediate of claim 1 wherein oximating the hydroformylation intermediate to obtain an oximated intermediate comprises:
mixing the hydroformylation intermediate, hydroxylamine hydrochloride and pyridine to carry out oximation reaction, and monitoring the progress of the oximation reaction by thin-layer chromatography in the oximation reaction process; the molar ratio of the hydroformylation intermediate, the hydroxylamine hydrochloride and the pyridine is 1 (1.50-2.70) to 5.45-7.55;
when the oximation reaction reaches the reaction end point, an oximation intermediate is obtained.
7. The process for preparing a silodosin intermediate as claimed in claim 1, wherein said cyanating the oximatozed intermediate to obtain a cyanated intermediate comprises:
mixing the oximation intermediate with acetic anhydride to carry out a cyanidation reaction, and monitoring the progress of the cyanidation reaction by thin-layer chromatography in the process of the cyanidation reaction; the mol ratio of the oximation intermediate to the acetic anhydride is 1 (3.0-5.0);
when the cyanidation reaction reaches the reaction end point, extracting an organic phase in the obtained cyanidation reaction system by using an extraction liquid;
and carrying out post-treatment on the extracted organic phase to obtain a cyaniding intermediate.
8. A process according to claim 1, wherein the amino deprotection of the cyanated intermediate to give the free base of silodosin intermediate comprises:
under the condition of hydrogen, mixing the cyanidation intermediate with palladium-carbon to carry out amino deprotection reaction, and monitoring the progress of the amino deprotection reaction by thin-layer chromatography in the process of the amino deprotection reaction; the mass ratio of the cyanidation intermediate to the palladium-carbon is 1 (0.05-0.15);
when the amino deprotection reaction reaches the reaction end point, filtering the obtained amino deprotection reaction system to obtain a filtrate; the filtrate was concentrated to give the free base of the silodosin intermediate.
9. The method for preparing a silodosin intermediate according to claim 1, wherein the salifying the free base of the silodosin intermediate to obtain the silodosin intermediate comprises:
under the anaerobic condition, dripping L-tartaric acid into free alkali of a silodosin intermediate to carry out salt formation; the molar ratio of the free alkali of the silodosin intermediate to the L-tartaric acid is 1 (0.90-1.10);
after the L-tartaric acid is dripped, filtering the obtained salt formation reaction system to obtain a filter cake;
and carrying out post-treatment on the filter cake to obtain a silodosin intermediate.
10. The method of claim 1, wherein the amino-protecting the initial intermediate to obtain an amino-protected intermediate comprises:
dropwise adding hydrochloric acid into the initial intermediate to carry out salifying treatment, and carrying out chiral resolution and purification reaction; the molar ratio of the initial intermediate to the hydrogen chloride in the hydrochloric acid is 1 (1.00-1.90);
when the pH value of the reaction system reaches 6-7, filtering the obtained initial intermediate hydrochloride under the anhydrous condition to obtain a filter cake; carrying out post-treatment on the filter cake to obtain a chiral qualified intermediate; the structural formula of the chiral qualified intermediate is as follows:
mixing the chiral qualified intermediate with benzyl chloroformate to carry out amino protection reaction, and monitoring the progress of the amino protection reaction by thin-layer chromatography in the amino protection reaction process;
when the amino protection reaction reaches the reaction end point, extracting an organic phase in the obtained amino protection reaction system by using an extraction liquid;
and carrying out post-treatment on the extracted organic phase to obtain an amino-protected intermediate.
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| JP2001199956A (en) * | 2000-01-14 | 2001-07-24 | Kissei Pharmaceut Co Ltd | Method for producing optically active indoline derivative and intermediate for producing the derivative |
| CN105254553A (en) * | 2015-11-09 | 2016-01-20 | 黄欢 | Method for preparing silodosin midbody |
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| JP2001199956A (en) * | 2000-01-14 | 2001-07-24 | Kissei Pharmaceut Co Ltd | Method for producing optically active indoline derivative and intermediate for producing the derivative |
| CN105254553A (en) * | 2015-11-09 | 2016-01-20 | 黄欢 | Method for preparing silodosin midbody |
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| Synthesis of Silodosin by Copper‐Catalysed C–C Arylation;Francesco Calogero et al.;《European Journal of Organic Chemistry》;20150807;第2015卷(第27期);第6011-6016页 * |
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