CN113214251A - Preparation method of tadalafil intermediate impurity - Google Patents
Preparation method of tadalafil intermediate impurity Download PDFInfo
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- CN113214251A CN113214251A CN202110477971.5A CN202110477971A CN113214251A CN 113214251 A CN113214251 A CN 113214251A CN 202110477971 A CN202110477971 A CN 202110477971A CN 113214251 A CN113214251 A CN 113214251A
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- 239000012535 impurity Substances 0.000 title claims abstract description 64
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract description 32
- 229960000835 tadalafil Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000002904 solvent Substances 0.000 claims abstract description 54
- 239000002994 raw material Substances 0.000 claims abstract description 34
- 238000003756 stirring Methods 0.000 claims abstract description 33
- 238000002425 crystallisation Methods 0.000 claims abstract description 30
- 230000008025 crystallization Effects 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000000706 filtrate Substances 0.000 claims abstract description 23
- 238000010438 heat treatment Methods 0.000 claims abstract description 23
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 23
- 238000010992 reflux Methods 0.000 claims abstract description 23
- 239000006227 byproduct Substances 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 22
- 239000012065 filter cake Substances 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 22
- 239000012670 alkaline solution Substances 0.000 claims abstract description 18
- 238000000605 extraction Methods 0.000 claims abstract description 13
- 238000001704 evaporation Methods 0.000 claims abstract description 12
- 230000008020 evaporation Effects 0.000 claims abstract description 11
- 239000012074 organic phase Substances 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960005235 piperonyl butoxide Drugs 0.000 description 8
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 240000005819 Magnolia denudata Species 0.000 description 1
- 235000003415 Michelia alba Nutrition 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- ROYJOKDTCKPQHK-KQKCUOLZSA-N methyl (1r,3r)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate;hydrochloride Chemical compound Cl.C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=C1 ROYJOKDTCKPQHK-KQKCUOLZSA-N 0.000 description 1
- LIPVUDSNGRJSQE-QAPCUYQASA-N methyl (1s,3r)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCOC2=CC([C@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=C1 LIPVUDSNGRJSQE-QAPCUYQASA-N 0.000 description 1
- KCUNTYMNJVXYKZ-SNVBAGLBSA-N methyl (2r)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-SNVBAGLBSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparation method of tadalafil intermediate impurities comprises the steps of fully dissolving raw materials in an isomerization solvent, sequentially carrying out heating reflux reaction and reduced pressure concentration to obtain a residue I, then adding an alkaline solution and an extraction solvent into the residue I, sequentially stirring at room temperature, standing, then taking an organic phase, carrying out reduced pressure evaporation to obtain a residue II, then adding a resolution solvent into the residue II, sequentially carrying out heating reflux reaction, naturally stirring for crystallization, filtering to obtain a filtrate and a filter cake, and finally drying the filter cake to obtain the intermediate impurities, wherein the temperature for natural stirring crystallization is 30-60 ℃. The design utilizes the principle that the intermediate impurities and the reaction byproducts have different solubilities in the resolution solvents at different temperatures to split the intermediate impurities and the reaction byproducts, so that the preparation efficiency is high, the cost is low, and the purity of the prepared intermediate impurities is high.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of tadalafil intermediate impurities, which is suitable for improving preparation efficiency and reducing preparation cost.
Background
Tadalafil is a selective and reversible phosphodiesterase 5 inhibitor developed and developed by the american etiquette company, methyl (1R, 3R) -1, 2, 3, 4-tetrahydro-1- (3, 4-methylenedioxyphenyl) -9H-pyrido [3, 4-b ] indole-3-carboxylate hydrochloride obtained by performing the Pictet-Spengler reaction on D-tryptophan methyl ester and piperonal is a key intermediate for synthesizing tadalafil, the step reaction is the most effective means for constructing a beta-tetrahydrocarboline ring which is an important structure of the tadalafil parent, the stereoselectivity problem existing in the construction of a chiral ring is an important part of process research, and the process can generate the isomerization reaction shown in fig. 1. The intermediate impurity (1S, 3R) -1, 2, 3, 4-tetrahydro-1- (3, 4-methylenedioxyphenyl) -9H-pyrido [3, 4-b ] indole-3-carboxylic acid methyl ester generated by isomerization can continuously participate in subsequent reactions along with the synthesis process of tadalafil, and the quality of the tadalafil product is seriously influenced, so that the control on the intermediate impurity is one of the key factors for preparing high-quality tadalafil products. The intermediate impurities are typically isolated by column chromatography, such as Shi, Xiao-Xin; liu, Shi-Ling; xu, Wei; xu, Yu-Lan; tetrahedron Asymmetry; vol.19; nb.4; (2008) (ii) a p.435-442 reports that the yield is only 7%, and the preparation process is time-consuming, labor-consuming, inefficient, and costly, and is not suitable for mass production.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide a preparation method of tadalafil intermediate impurities with high efficiency and low cost.
In order to achieve the above purpose, the invention provides the following technical scheme:
a preparation method of tadalafil intermediate impurities, wherein the intermediate impurities have a structural formula:
the preparation method sequentially comprises the following steps:
firstly, fully dissolving raw materials in an isomerization solvent, and then sequentially carrying out heating reflux reaction and reduced pressure concentration to obtain a remainder I;
wherein the structural formula of the raw material is as follows:
step two, adding an alkaline solution and an extraction solvent into the residue I, then sequentially stirring at room temperature, standing, and taking an organic phase to perform reduced pressure evaporation to dryness to obtain a residue II;
adding a resolution solvent into the residue II, and then sequentially carrying out heating reflux reaction, natural stirring crystallization and filtration to obtain a filtrate and a filter cake, wherein the natural stirring crystallization temperature is 30-60 ℃;
and step four, drying the filter cake obtained in the step three to obtain intermediate impurities.
In the third step, the natural stirring crystallization time is 0.5-1 h, and the filtering temperature is 30-60 ℃.
The preparation method also comprises the following step five:
crystallizing and filtering the filtrate obtained in the third step in sequence to obtain a filter cake, and drying the filter cake to obtain a byproduct;
wherein the crystallization temperature is room temperature or below, and the byproduct is free alkali of the raw material.
In the first step, the isomerization solvent is methanol, dimethyl sulfoxide or dimethylformamide, and the mass volume ratio of the raw material to the isomerization solvent is 1: 10-30.
in the second step, the alkaline solution is a saturated sodium bicarbonate aqueous solution, and the mass volume ratio of the raw material to the alkaline solution is 1: 5-15.
in the third step, the resolution solvent is methanol water solution, and the volume ratio of methanol to water in the resolution solvent is 50-90%: 1, the mass volume ratio of the raw material to the resolution solvent is 1: 1-15.
in the second step, the extraction solvent is dichloromethane.
In the first step and the third step, the heating reflux reaction time is 6-18 h and 1-2 h respectively.
In the fourth and fifth steps, the drying temperature is 55-65 ℃.
And in the second step, before the reduced pressure evaporation to dryness, sequentially carrying out water washing, saturated saline water washing, anhydrous sodium sulfate drying and filtering on the organic phase to obtain a filtrate, and then carrying out reduced pressure evaporation to dryness on the filtrate to obtain a residue II.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention relates to a preparation method of tadalafil intermediate impurities, which comprises the steps of fully dissolving raw materials in an isomerization solvent, sequentially carrying out heating reflux reaction and reduced pressure concentration to obtain a residue I, then adding an alkaline solution and an extraction solvent into the residue I, sequentially stirring at room temperature, standing, then carrying out reduced pressure evaporation on an organic phase to obtain a residue II, then adding a resolution solvent into the residue II, sequentially carrying out heating reflux reaction, naturally stirring for crystallization, filtering to obtain a filtrate and a filter cake, and finally drying the filter cake to obtain intermediate impurities, wherein the natural stirring crystallization temperature is 30-60 ℃, the design utilizes the different solubilities of the intermediate impurities and the reaction byproducts in the resolution solvents at different temperatures, when the temperature is 30-60 ℃, a large amount of the intermediate impurities are separated out, the reaction byproducts are not separated out, and the intermediate impurities with the purity of more than 99 percent can be prepared only through one-time crystallization operation, the preparation method has high preparation efficiency and low cost, can be used for qualitative and quantitative analysis of the impurities, and can provide a stable and cheap compound source for preparing related derivative impurities from the impurities, so that the quality of tadalafil is improved, the medication risk is reduced, and an important guarantee is provided for safe medication of people. Therefore, the method has the advantages of high preparation efficiency and low cost, and the prepared intermediate has high impurity purity.
2. According to the preparation method of the tadalafil intermediate impurity, the filtrate is crystallized and filtered sequentially to obtain the filter cake, then the filter cake is dried to obtain the byproduct, wherein the crystallization temperature is room temperature or below, the byproduct is the free alkali of the raw material, the byproduct obtained by the design and the hydrochloric acid can be recycled after salifying, the preparation process is repeated, and the recycling rate is high. Therefore, the invention has high recycling rate.
Drawings
FIG. 1 is a schematic diagram of isomerization reaction in the synthesis of tadalafil intermediate in the prior art.
FIG. 2 is a reaction scheme of the present invention.
Figure 3 is an HPLC profile of the intermediate impurity prepared from example 1.
FIG. 4 is a LC-MS spectrum of the intermediate impurity prepared from example 1.
FIG. 5 is a NMR spectrum of an intermediate impurity prepared in example 1.
FIG. 6 is a NMR carbon spectrum of an intermediate impurity prepared in example 1.
Detailed Description
The present invention will be further described with reference to the following embodiments.
A preparation method of tadalafil intermediate impurities, wherein the intermediate impurities have a structural formula:
the preparation method sequentially comprises the following steps:
firstly, fully dissolving raw materials in an isomerization solvent, and then sequentially carrying out heating reflux reaction and reduced pressure concentration to obtain a remainder I;
wherein the structural formula of the raw material is as follows:
step two, adding an alkaline solution and an extraction solvent into the residue I, then sequentially stirring at room temperature, standing, and taking an organic phase to perform reduced pressure evaporation to dryness to obtain a residue II;
adding a resolution solvent into the residue II, and then sequentially carrying out heating reflux reaction, natural stirring crystallization and filtration to obtain a filtrate and a filter cake, wherein the natural stirring crystallization temperature is 30-60 ℃;
and step four, drying the filter cake obtained in the step three to obtain intermediate impurities.
In the third step, the natural stirring crystallization time is 0.5-1 h, and the filtering temperature is 30-60 ℃.
The preparation method also comprises the following step five:
crystallizing and filtering the filtrate obtained in the third step in sequence to obtain a filter cake, and drying the filter cake to obtain a byproduct;
wherein the crystallization temperature is room temperature or below, and the byproduct is free alkali of the raw material.
In the first step, the isomerization solvent is methanol, dimethyl sulfoxide or dimethylformamide, and the mass volume ratio of the raw material to the isomerization solvent is 1: 10-30.
in the second step, the alkaline solution is a saturated sodium bicarbonate aqueous solution, and the mass volume ratio of the raw material to the alkaline solution is 1: 5-15.
in the third step, the resolution solvent is methanol water solution, and the volume ratio of methanol to water in the resolution solvent is 50-90%: 1, the mass volume ratio of the raw material to the resolution solvent is 1: 1-15.
in the second step, the extraction solvent is dichloromethane.
In the first step and the third step, the heating reflux reaction time is 6-18 h and 1-2 h respectively.
In the fourth and fifth steps, the drying temperature is 55-65 ℃.
And in the second step, before the reduced pressure evaporation to dryness, sequentially carrying out water washing, saturated saline water washing, anhydrous sodium sulfate drying and filtering on the organic phase to obtain a filtrate, and then carrying out reduced pressure evaporation to dryness on the filtrate to obtain a residue II.
The principle of the invention is illustrated as follows:
the reaction principle of the preparation method of the tadalafil intermediate impurity is shown in figure 2, the preparation route is short, the efficiency is high, the raw material is the intermediate for preparing tadalafil, a large amount of tadalafil is supplied on the market or the production line, the tadalafil intermediate impurity is simple and easy to obtain and low in price, the reaction condition is mild, high-temperature and high-pressure or special catalyst raw materials are not needed, the operation is simple, the resolution yield is high, the quality is stable, and the preparation method is suitable for mass production. In addition, the reaction by-product is free alkali of the raw material, the reaction by-product and hydrochloric acid can be continuously recycled after salifying, and the preparation process is repeated, so that the recycling rate is high.
The invention discloses a method for preparing a hydrochloride intermediate, which comprises the steps of dissolving a raw material into an isomerization solvent, isomerizing the raw material under an acidic condition, and converting the raw material into a target isomer to the maximum extent, wherein the isomerization degree of intermediate impurities in methanol is highest, adding an alkaline solution into a residue I after isomerization is finished, wherein the alkaline solution is used for neutralizing hydrochloric acid, so that the residue I is separated from an acidic environment, the isomerization proportion is kept unchanged, finally adding a resolution solvent into a residue II, performing resolution by using the principle that the solubility of the intermediate impurities and reaction byproducts in the resolution solvents at different temperatures is different, and finally performing natural stirring crystallization once to ensure that the purity of the prepared intermediate impurities reaches over 99 percent, while the high-purity isomer is difficult to obtain through one-time crystallization resolution in a reaction system for preparing the isomer, it needs to be refined again or even for a plurality of times.
Solid can be separated out when the temperature is reduced little in the natural stirring crystallization process, the solid can be filtered after stirring for 0.5-1 h, if the filtering is carried out in advance, the stirring time is short, the separation of intermediate impurities is not complete enough when the filtrate obtained in the third step is naturally stirred and crystallized, so that the residual intermediate impurities are separated out together with byproducts when the filtrate obtained in the third step is crystallized subsequently, and the obtained byproducts are impure.
Because the filtrate obtained in the third step is supersaturated solution of the by-product, the crystallization of the filtrate obtained in the third step can be standing crystallization or stirring crystallization, and the by-product has a structural formula as follows:
example 1:
a preparation method of tadalafil intermediate impurities, wherein the intermediate impurities have a structural formula:
the preparation method sequentially comprises the following steps:
firstly, fully dissolving a raw material in an isomerization solvent, and then sequentially carrying out heating reflux reaction and reduced pressure concentration to obtain a remainder I, wherein the structural formula of the raw material is as follows:
wherein the raw material is 5g, the isomerization solvent is 100mL of methanol, and the heating reflux reaction time is 10 h;
adding an alkaline solution and an extraction solvent into the residue I, then sequentially stirring at room temperature, standing for liquid separation, washing an organic phase with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering to obtain a filtrate, and then evaporating the filtrate under reduced pressure to dryness to obtain a residue II, wherein the alkaline solution is 50mL of saturated sodium bicarbonate solution, the extraction solvent is 60mL of dichloromethane, and the stirring time at room temperature is 30 min;
adding a resolution solvent into the residue II, and then sequentially carrying out heating reflux reaction, natural stirring crystallization and filtration to obtain a filtrate and a filter cake, wherein the resolution solvent is 50mL of methanol aqueous solution, and the volume ratio of methanol to water in the resolution solvent is 90%: 1, the heating reflux reaction time is 1h, the natural stirring crystallization time is 0.5h, the temperature is 47 ℃, and the filtration temperature is 35 ℃;
step four, drying the filter cake obtained in the step three to obtain 2.23g of intermediate impurities, wherein the drying temperature is 60 ℃;
referring to fig. 3, the intermediate impurity was detected to have an HPLC purity of 99.78% and a resolution yield of 98.5%.
Example 2:
the difference from example 1 is that:
in the first step, the raw material is 10g, the isomerization solvent is 250mL of dimethyl sulfoxide, and the heating reflux reaction time is 6 h;
in the second step, the alkaline solution is 50mL of saturated sodium bicarbonate solution, the extraction solvent is 120mL of dichloromethane, and the stirring time at room temperature is 50 min;
in the third step, the volume ratio of the methanol to the water in the resolving solvent is 70%: 1, the heating reflux reaction time is 1.5h, the natural stirring crystallization time is 0.8h, the temperature is 50 ℃, and the filtering temperature is 45 ℃;
in the fourth step, the drying temperature is 55 ℃, and 4.47g of intermediate impurity is obtained;
the HPLC purity of the intermediate impurity is 99.56% and the resolution yield is 98.8% through detection.
Example 3:
the difference from example 1 is that:
in the first step, the raw material is 20g, the isomerization solvent is 200mL of dimethylformamide, and the heating reflux reaction time is 12 h;
in the second step, the alkaline solution is 200mL of saturated sodium bicarbonate solution, the extraction solvent is 240mL of dichloromethane, and the stirring time at room temperature is 45 min;
in the third step, the volume ratio of the methanol to the water in the resolving solvent is 90%: 1, the heating reflux reaction time is 2 hours, the natural stirring crystallization time is 0.6 hour, the temperature is 60 ℃, and the filtration temperature is 60 ℃;
in the fourth step, the drying temperature is 65 ℃, and 8.97g of the obtained intermediate impurity is obtained;
the HPLC purity of the intermediate impurity is 99.24% and the resolution yield is 99.1% through detection.
Example 4:
the difference from example 1 is that:
in the first step, the raw material is 50g, the isomerization solvent is 1500mL, and the heating reflux reaction time is 18 h;
in the second step, the alkaline solution is 750mL of saturated sodium bicarbonate solution, the extraction solvent is 600mL of dichloromethane, and the stirring time at room temperature is 50 min;
in the third step, the volume ratio of the methanol to the water in the resolving solvent is 50%: 1, the heating reflux reaction time is 1.5h, the natural stirring crystallization time is 1h, the temperature is 30 ℃, and the filtration temperature is 30 ℃;
in the fourth step, the drying temperature is 60 ℃, and 22.5g of intermediate impurities are obtained;
the preparation method also comprises the following step five:
and D, crystallizing and filtering the filtrate obtained in the third step in sequence to obtain a filter cake, and drying the filter cake to obtain a byproduct 20.3g, wherein the crystallization temperature is 26 ℃, the drying temperature is 60 ℃, and the byproduct is free alkali of the raw material.
The HPLC purity of the intermediate impurity is 99.07% and the resolution yield is 99.4%.
Detection assay
1. See alsoFIG. 4 shows the detection of the intermediate impurities obtained in example 1 by LC-MS (m/z): 351.4[ M + H]+；
2. Referring to FIG. 5, the hydrogen atoms in the intermediate impurities obtained in example 1 were detected by NMR1H-NMR (600MHz, DMSO). delta.: 9.71(s, 1H, five-membered heterocycle NH), 7.50, (d, 1H, J ═ 7.8Hz, piperonyl ArH), 7.30, (d, 1H, J ═ 7.8Hz, piperonyl ArH), 7.09-6.77, (m, 5H, ArH + piperonyl ArH), 5.98(s, 2H, piperonyl CH), 7.50, (d, 1H, J ═ 7.8Hz, piperonyl ArH), 7.09-6.77, (m, 5H, ArH + piperonyl ArH), 5.98(s, 2H, piperonyl CH)2) 5.38(s, 1H, piperonyl CH), 3.94(m, 1H, CH), 3.68(s, 3H, CH)3)，3.19–3.01(m，2H，CH2)；
3. Referring to FIG. 6, the intermediate impurity obtained in example 1 was detected for carbon atoms using NMR13C-NMR(600MHz，DMSO)δ：205.3，173.8，147.8，147.1，137.3，136.7，134.4，127.2，121.6，121.2，118.7，117.7，111.0，108.6，107.6，107.3，101.1，54.4，52.4，51.1，24.6。
Claims (10)
1. A preparation method of tadalafil intermediate impurities is characterized by comprising the following steps:
the structural formula of the intermediate impurity is as follows:
the preparation method sequentially comprises the following steps:
firstly, fully dissolving raw materials in an isomerization solvent, and then sequentially carrying out heating reflux reaction and reduced pressure concentration to obtain a remainder I;
wherein the structural formula of the raw material is as follows:
step two, adding an alkaline solution and an extraction solvent into the residue I, then sequentially stirring at room temperature, standing, and taking an organic phase to perform reduced pressure evaporation to dryness to obtain a residue II;
adding a resolution solvent into the residue II, and then sequentially carrying out heating reflux reaction, natural stirring crystallization and filtration to obtain a filtrate and a filter cake, wherein the natural stirring crystallization temperature is 30-60 ℃;
and step four, drying the filter cake obtained in the step three to obtain intermediate impurities.
2. The method for preparing tadalafil intermediate impurities according to claim 1, wherein: in the third step, the natural stirring crystallization time is 0.5-1 h, and the filtering temperature is 30-60 ℃.
3. The method for preparing tadalafil intermediate impurity according to claim 1 or 2, characterized in that:
the preparation method also comprises the following step five:
and D, crystallizing and filtering the filtrate obtained in the step three in sequence to obtain a filter cake, and drying the filter cake to obtain a byproduct, wherein the crystallization temperature is room temperature or below, and the byproduct is free alkali of the raw material.
4. The method for preparing tadalafil intermediate impurity according to claim 1 or 2, characterized in that: in the first step, the isomerization solvent is methanol, dimethyl sulfoxide or dimethylformamide, and the mass volume ratio of the raw material to the isomerization solvent is 1: 10-30.
5. the method for preparing tadalafil intermediate impurity according to claim 1 or 2, characterized in that: in the second step, the alkaline solution is a saturated sodium bicarbonate solution, and the mass volume ratio of the raw material to the alkaline solution is 1: 5-15.
6. the method for preparing tadalafil intermediate impurity according to claim 1 or 2, characterized in that: in the third step, the resolution solvent is methanol water solution, and the volume ratio of methanol to water in the resolution solvent is 50-90%: 1, the mass volume ratio of the raw material to the resolution solvent is 1: 1-15.
7. the method for preparing tadalafil intermediate impurity according to claim 1 or 2, characterized in that: in the second step, the extraction solvent is dichloromethane.
8. The method for preparing tadalafil intermediate impurity according to claim 1 or 2, characterized in that: in the first step and the third step, the heating reflux reaction time is 6-18 h and 1-2 h respectively.
9. The method for preparing tadalafil intermediate impurities according to claim 3, wherein: in the fourth and fifth steps, the drying temperature is 55-65 ℃.
10. The method for preparing tadalafil intermediate impurity according to claim 1 or 2, characterized in that: and in the second step, before the reduced pressure evaporation to dryness, sequentially carrying out water washing, saturated saline water washing, anhydrous sodium sulfate drying and filtering on the organic phase to obtain a filtrate, and then carrying out reduced pressure evaporation to dryness on the filtrate to obtain a residue II.
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