CN102993205B - High-yield purification method for preparation of high-purity sildenafil freebases - Google Patents
High-yield purification method for preparation of high-purity sildenafil freebases Download PDFInfo
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- CN102993205B CN102993205B CN201210581758.XA CN201210581758A CN102993205B CN 102993205 B CN102993205 B CN 102993205B CN 201210581758 A CN201210581758 A CN 201210581758A CN 102993205 B CN102993205 B CN 102993205B
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- Prior art keywords
- toluene
- free base
- methanol
- sildenafil
- sildenafil free
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- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title claims abstract description 106
- 229960003310 sildenafil Drugs 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 51
- 238000000746 purification Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title description 7
- 239000012535 impurity Substances 0.000 claims abstract description 47
- 239000012458 free base Substances 0.000 claims abstract description 39
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 239000000047 product Substances 0.000 claims abstract description 19
- 239000012043 crude product Substances 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 98
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 17
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 15
- 239000008096 xylene Substances 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- UNXNGGMLCSMSLH-UHFFFAOYSA-N dihydrogen phosphate;triethylazanium Chemical compound OP(O)(O)=O.CCN(CC)CC UNXNGGMLCSMSLH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 241000599985 Beijerinckia mobilis Species 0.000 claims description 2
- 241000206601 Carnobacterium mobile Species 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- 239000003643 water by type Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 abstract 1
- 238000010792 warming Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- -1 sildenafil citrate compound Chemical class 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- DSGKWFGEUBCEIE-UHFFFAOYSA-N (2-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1C(Cl)=O DSGKWFGEUBCEIE-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 6
- 229960002639 sildenafil citrate Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- XDZMPRGFOOFSBL-UHFFFAOYSA-N 2-ethoxybenzoic acid Chemical compound CCOC1=CC=CC=C1C(O)=O XDZMPRGFOOFSBL-UHFFFAOYSA-N 0.000 description 2
- MDKAAWDKKBFSTK-UHFFFAOYSA-N 2-ethoxybenzoyl chloride Chemical compound CCOC1=CC=CC=C1C(Cl)=O MDKAAWDKKBFSTK-UHFFFAOYSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- PZMXDLWWQHYXGY-UHFFFAOYSA-N 4-amino-1-methyl-3-propylpyrazole-5-carboxamide Chemical compound CCCC1=NN(C)C(C(N)=O)=C1N PZMXDLWWQHYXGY-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029219 regulation of pH Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicinal chemistry, relates to a purification method for high-purity sildenafil freebases, particularly to a purification method for removing new impurities from the sildenafil freebases. The method includes adding 1-6 times (v/w) of organic solvents to sildenafil freebase (II) crude products, stirring fully, warming to 40-60DEG C, stirring for 1-6h with temperature preservation, then cooling to the room temperature, filtering and drying to obtain sildenafil freebase (II) fine products.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a method for purifying sildenafil free alkali, in particular to a purification method for removing new impurities from sildenafil free alkali.
Background
Sildenafil citrate, marketed under the trade name Viagra, by Pesper USA in 1997, under the chemical name 5- [ (2-ethoxy-5 (-4-methylpiperazine-1-sulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [ 4, 3-d ] pyrimidin-7-one, is mainly used clinically for the treatment of sexual dysfunction. The action mechanism is to inhibit the activity of phosphodiesterase V, prevent cGMP and cAMP from being hydrolyzed to generate corresponding 5-nucleotide monophosphate, improve the concentration of cGMP between tissues, inhibit the relaxation of smooth muscle and achieve the purpose of treatment.
The patent of sildenafil citrate compound has expired so far, but the american pfeiffer company has patented the indication of sildenafil for treating ED (10/22/2019), so that the company manufactures wanaike with sildenafil citrate, which is the only drug currently on the market legally with sildenafil as a main ingredient.
Similarly, the only commercial pharmaceutical product for the legal production of sildenafil citrate is the fevered company in the united states, and the main industrial process routes reported by the commercial pharmaceutical product mainly include two types according to the sequence of pyrimidine cyclization and sulfonyl chlorination (Peter, Gree chem., 2004, 6, 43-48).
1. Pyrimidine cyclization was preceded and sulfonyl chlorination was followed (see patent US 5250534, buffere corporation, 1992). The method comprises the steps of condensing o-ethoxybenzoyl chloride (VI) and 4-amino-1-methyl-3-n-propylpyrazole-5-formamide (VII), cyclizing, sulfonating, aminating, and salifying to obtain sildenafil citrate. The yields of the condensation reaction and the sulphonamide reaction are respectively only 40 percent and 49 percent, and the condensation product and the cyclization product need to be separated by column chromatography, so the total yield of the whole route is low and the material consumption is high. After the process of the company is improved, the total yield is improved to 35.9 percent from the original 9.8 percent (calculated by taking a key intermediate VII as a reference), and the method is suitable for industrial production. At present, the route has no legal problems such as patent protection and the like, and the raw material medicine can be researched and declared to be produced in China. The synthetic route is as follows:
2. sulfonyl chlorination precedes pyrimidine cyclization (see patent US5955611, Calif., 1997). According to the method, o-ethoxybenzoic acid (VIII) is used as a raw material, and is subjected to sulfonylchlorination and sulfonylamination reactions, then is subjected to condensation reaction with a key intermediate (VII), then is subjected to cyclization reaction, and finally is salified to obtain sildenafil citrate, wherein the total yield of the process is 75% (both calculated by taking the key intermediate VII as a reference). The synthetic route is as follows:
in combination with the actual legal state of the patent, we have conducted quality studies on the two processes in turn.
Firstly, after a large number of quality research experiments on the improved process (1994, Perey company, USA) of US 5250534, we surprisingly found that in the process route, a new impurity (I08) is found in the compounds (I) to (IV), and the content of the impurity is varied from 0.02 to 2%. And then, by column chromatography separation and combination of spectrograms such as high resolution mass spectrum and nuclear magnetic resonance, the structural formula of the new impurity (I08) is determined as follows:
the research on the impurity source finds that the new impurity I08 is formed in two ways:
1) the subsequent reaction of the impurities carried by the material o-acetoxybenzoyl chloride (VI) is shown as the synthetic route in the method 1.
2) The synthesis route of the reaction Intermediate (IV) as a by-product of sulfonyl chlorination is shown in method 2.
The impurity I08 generated by the method 2 has little polarity difference with the Intermediate (IV), is not easy to be refined and removed, and generally has the content of 0.1-1.5%. The accumulation of impurity I08 by the sulfonyl chloride reaction brings sildenafil free
The content of the crude product of the alkali (II) is generally 0.1-2% according to the different taking-out modes of the crude product.
The method comprises the following steps:
the method 2 comprises the following steps:
then, we also studied the second preparation process route involved in US5955611, and found a new impurity I08 with a content of 0.02-0.5% in the process of (XI) carrying out cyclization reaction to prepare sildenafil free base (II), and the synthetic route is as follows:
at present, no new impurity I08 of sildenafil free base is reported in the literature, and no method for removing the impurity is described in the literature.
In addition, it was found that, because of the large difference in polarity between (II) and I08, the new impurity I08 was relatively easy to purify as the free base; further tests have shown that subsequent purification after salt formation is difficult to remove if the free base is not purified below acceptable limits.
Meanwhile, the existing USP and EP quality standards adopt an isocratic analysis method, the impurity cannot be detected, and a purification method is very necessary to be determined on the quality control of sildenafil free base, so that the content of the impurity is ensured to be not more than 0.1%.
The invention content is as follows:
the invention aims to provide a method for purifying sildenafil free base.
The purification method of the invention is to remove the impurity I08 from the crude sildenafil free base (II) to obtain a fine sildenafil free base product with high purity and high yield.
Specifically, the purification method comprises the following steps: placing the crude product of the sildenafil free base (II) into a reaction bottle, adding 1-6 times (v/w) of organic solvent, fully stirring, heating to 40-60 ℃, preserving heat, stirring for 1-6h, cooling to room temperature, filtering, and drying to obtain the fine product of the sildenafil free base (II).
。
Preferably, the purification method of the present invention comprises the steps of: placing the crude product of the sildenafil free base (II) into a reaction bottle, adding 2-4 times (v/w) of organic solvent, fully stirring, heating to 40-50 ℃, preserving heat, stirring for 2-4h, cooling to room temperature, filtering, and drying to obtain the fine product of the sildenafil free base (II).
Wherein the organic solvent is selected from: one or more of toluene, xylene, acetone, butanone, methanol and ethanol. Preferred organic solvents are toluene, xylene, a mixed solvent of toluene and xylene, and a mixed solvent of toluene and methanol. The volume percentage of the methanol in the mixed solvent of the toluene and the methanol is 5-30%, and the volume percentage of the toluene in the mixed solvent of the toluene and the xylene is 10-30%. Further preferably, the volume percentage of the methanol in the mixed solvent of the toluene and the methanol is 10-20%, and the volume percentage of the toluene in the mixed solvent of the toluene and the xylene is 10-20%.
The content of impurity I08 in the refined sildenafil free alkali (II) is not more than 0.1 percent,
the content of the impurity I08 in the refined sildenafil free alkali (II) is controlled to be 0.025-0.058%.
The crude sildenafil free base (II) of the present invention can be either commercially available or prepared by methods known in the art.
The preparation process route (refer to US 5250534 and optimized) of the crude sildenafil free alkali (II) (the purity of the pure product is more than 95 percent and the impurity I08 is 0.5-2 percent) is as follows:
a) 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide (VII) and o-acetoxybenzoyl chloride (VI) are subjected to condensation reaction in dichloromethane and under the condition of triethylamine acid-binding agent, and then refined to obtain an intermediate (V).
b) And (3) carrying out cyclization reaction on the intermediate (V) in alcohol and strong alkali, and regulating the pH value to obtain an Intermediate (IV).
c) And (3) carrying out sulfonyl chlorination on the Intermediate (IV) in a chlorosulfonic acid system, and carrying out post-treatment by adopting dichloromethane and water to obtain an intermediate (III).
d) And (3) performing sulfonylation amination reaction on the intermediate (III) and N-methylpiperazine in ethanol, and obtaining a sildenafil free base (II) crude product through concentration and pH regulation.
Wherein,
a) in the step, the content of the impurity I08 in the Intermediate (IV) is directly influenced by different refined solvents, but the selectable organic solvents comprise toluene, xylene, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, acetone, butanone, tetrahydrofuran, dioxane and the like.
b) In the step, the alcohol can be methanol, ethanol, isopropanol, tert-butanol and the like; the strong base includes inorganic strong bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide and the like, and organic strong bases such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like. The content of an impurity I08 in the Intermediate (IV) obtained by post-treatment is 0.1-1%.
c) In the step, the feeding molar ratio of the chlorosulfonic acid is at least 10 times of the molar number of the Intermediate (IV), so that the reaction is ensured to be sufficient. The content of the impurity I08 in the intermediate (III) obtained by post-treatment is 0.1-1.5%.
d) In the step, a crude product of sildenafil free base (II) is obtained after simple reaction treatment, wherein the content of impurity I08 is 0.1-1.5%.
According to the invention, a large number of purification experiments show that when the impurity content of the crude product of the sildenafil free base (II) is within 0.5%, the crude product of the sildenafil free base (II) can be directly obtained at one time by adopting organic solvents including aromatic hydrocarbon compounds such as toluene and xylene, ketone solvents such as acetone and butanone, alcohols such as methanol and ethanol, or the solvent mixed solution, wherein the content of the impurity I08 is not more than 0.1%, and then the impurity I08 is directly controlled to be below an acceptable limit through salt formation.
When the impurity content of the crude product of the sildenafil free base (II) is 0.5-2%, the content of the impurity I08 in a common solvent can be controlled to be not more than 0.1% by purifying and refining for many times (namely more than two times).
Wherein, the high yield refers to the yield of more than 90 percent.
Wherein "high purity" means greater than 99% purity by HPLC.
Wherein the room temperature is 20-30 ℃.
According to the invention, through selection of different solvents, several solvents such as toluene, methanol and a mixed solvent (Smix) thereof, particularly a mixed solvent of toluene and methanol, can be found, the content of the impurity I08 can be well controlled to be not more than 0.1% at one time, the purity of the refined sildenafil free base (II) is more than 99%, and the yield is more than 90%. The refined free base product obtained by the method can be directly salified, and a high-quality sildenafil finished product (wherein the content of the impurity I08 is below 0.02%) with the content of more than 99.5% can be obtained without refining.
In the invention, the sildenafil free alkali (II) crude product is self-made (II) with the purity of more than 95% and the content of impurity I08 of 0.5-2%.
Another object of the present invention is to provide a method for detecting sildenafil.
Wherein, the chromatographic conditions are as follows:
A. a chromatographic column: c18Column, Waters Spherisorb ODS 14.6X 250mm 5 μm;
B. mobile phase A: 0.05mol/L triethylamine phosphate solution (7 ml of triethylamine, 1000ml of water, pH adjusted to 3.0 with phosphoric acid) -methanol-acetonitrile (58: 25: 17);
mobile phase B: 0.05mol/L triethylamine phosphate solution (7 ml of triethylamine, 1000ml of water and phosphoric acid for adjusting the pH value to 3.0) -acetonitrile (30: 70);
C. mobile phase gradient procedure
D. Detection wavelength: 290 nm;
E. column temperature: 30 ℃;
F. sample introduction amount: 20 mu l of the mixture;
G. flow rate: 1 ml/min;
H. operating time: 60 min;
the HPLC chromatogram of the refined sildenafil free base (II) (wherein the retention time of 46.392min is the chromatographic peak of impurity I08) is shown in figure 1.
Drawings
FIG. 1 shows HPLC chromatogram of fine sildenafil free base (II)
Detailed Description
The following examples are intended to be illustrative of the present invention and should not be construed as limiting the present patent.
EXAMPLE 1 preparation of crude sildenafil free base (II)
Wherein, the 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide (VII) is from thoroughfare state Yongchu chemical technology Co., Ltd, the o-ethoxybenzoyl chloride (VI) is from Ziboyixin chemical industry Co., Ltd, and other reagents are from Beijing chemical reagent Co., Ltd of the national medicine group.
1) Synthesis of 1-methyl-3-propyl-4- (2-ethoxybenzamido) pyrazole-5-carboxamide (V)
Adding 500ml of dichloromethane into a 2L reaction bottle, then adding 100g of (VII), starting stirring, then adding 83g of triethylamine, then cooling to 0 ℃ in a low-temperature bath, dropwise adding 110g of (VI), keeping the temperature at room temperature for reacting for 4h after the dropwise adding is finished, then adding water for washing for 1 time, standing and separating, directly and averagely dividing the obtained dichloromethane layer into two parts, concentrating and evaporating to dryness.
The method A comprises the following steps: refining 100ml ethyl acetate, filtering and drying to obtain 75g (V)AThe yield thereof was found to be 83%.
The method B comprises the following steps: refining 100ml ethanol, filtering, drying to obtain 60g (V)BThe yield thereof was found to be 66%.
2) Synthesis of 1-methyl-3-propyl-5- (2-ethoxy) phenyl-6, 7-dihydro-1H-pyrazolo [ 4, 3-d ] pyrimidin-7-one (IV)
Adding 180mL of methanol and 10g of sodium hydroxide into a 1L reaction bottle, then adding 60g of (V), heating to reflux reaction for 3h, concentrating and evaporating to dryness, adding 100mL of water, cooling to room temperature, adjusting pH to be neutral by using 2N hydrochloric acid, filtering, and drying to obtain about 50g of (IV), wherein the yield is 88.8%.
The method A comprises the following steps: adopt (V)AAs raw materials, de (IV)AWherein the content of the impurity I08 is 0.85 percent.
The method B comprises the following steps: adopt (V)BAs raw materials, de (IV)BWherein the content of the impurity I08 is 0.18 percent.
3) Synthesis of 1-methyl-3-propyl-5- (2-ethoxy-5-chlorosulfonyl) phenyl-6, 7-dihydro-1H-pyrazolo [ 4, 3-d ] pyrimidin-7-one (III)
160ml of chlorosulfonic acid is added into a 1L reaction bottle, then the bottle is cooled to below 0 ℃ in a low-temperature bath, 40g of (IV) is added, and after the addition is finished, the bottle is reacted at room temperature for more than 4 hours. The reaction mixture was slowly added to a 2L reaction flask containing a prepared mixture of 600mL of ice water and 400mL of methylene chloride, and the resulting methylene chloride layer was washed with salt, dried over anhydrous sodium sulfate, filtered, and distilled to obtain about 36g of a product (III) with a yield of 68.7%.
The method A comprises the following steps: adopt (IV)AAs raw materials, de (III)AWherein the content of the impurity I08 is 1.24 percent.
The method B comprises the following steps: adopt (IV)BAs raw materials, de (III)BWherein the content of the impurity I08 is 0.52 percent.
4): synthesis of 1-methyl-3-propyl-5- [ (2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl ] -6, 7-dihydro-1H-pyrazolo [ 4, 3-d ] pyrimidin-7-one (II)
Pumping 360mL of ethanol into a 1L reaction bottle, adding 36g (III), fully stirring, adding N-methyl piperazine, reacting at room temperature for 3 hours, distilling and concentrating the ethanol, adding 500mL of water, adjusting pH to be neutral by 10% potassium carbonate, filtering, and drying to obtain 39.5g of a product (II), wherein the yield is 95%.
The method A comprises the following steps: adopt (IV)AAs raw material, obtain crude product (II)AWherein the content of the impurity I08 is 1.28 percent, and the purity is 95.4 percent.
The method B comprises the following steps: adopt (IV)BAs raw material, obtain crude product (II)BWherein the content of the impurity I08 is 0.54 percent, and the purity is 96.3 percent.
EXAMPLE 2 preparation of a Fine product of sildenafil free base (II)
Adding 15ml of toluene and 2ml of methanol into a 100ml reaction bottle, adding 5g of crude sildenafil free base (II), fully stirring, heating to 45-50 ℃, keeping the temperature, stirring for 2h, cooling to room temperature, filtering, and drying to obtain the product (II).
The method A comprises the following steps: the yield is 92.8 percent, wherein the content of the impurity I08 is 0.058 percent
The method B comprises the following steps: the yield is 93.4%, wherein the content of the impurity I08 is 0.028%
EXAMPLE 3 preparation of a Fine product of sildenafil free base (II)
Adding 15ml of toluene and 4ml of methanol into a 100ml reaction bottle, adding 5g of crude sildenafil free base (II), fully stirring, heating to 45-50 ℃, keeping the temperature, stirring for 2h, cooling to room temperature, filtering, and drying to obtain the product (II).
The method A comprises the following steps: the yield is 90.6 percent, wherein the content of the impurity I08 is 0.054 percent
The method B comprises the following steps: the yield is 91.2 percent, wherein the content of the impurity I08 is 0.025 percent
Example 4 solvent screening procedure for preparation of fine sildenafil free base (II)
And (3) adding 5ml of solvent into a 50ml reaction bottle, adding 1g of crude sildenafil free base (II), fully stirring, heating to 45-50 ℃, keeping the temperature, stirring for 2 hours, cooling to room temperature, filtering, and drying to obtain the product (II).
The results are as follows:
the single solvent experiment results show that: when toluene or xylene is selected as a single solvent, the product yield is highest, the effect of removing the impurity I08 is achieved, the purification effect of methanol, toluene, xylene, ethanol, acetone and butanone is best, and the obtained purity is highest.
The mixed solvent has the following specific results:
the experimental results show that: toluene and methanol are selected as mixed solvents, the yield is not much different from toluene or xylene, but the content of the impurity I08 is the least, the control is easy, and the purification effect is better than that of a single solvent and other mixed solvents. Meanwhile, when the methanol ratio is excessively increased, the purity is increased, but the yield is remarkably decreased.
Experiments show that the organic solvent is preferably toluene, xylene, a mixed solvent of toluene and xylene, and a mixed solution of toluene and methanol, wherein in the solution of toluene and methanol, the proportion of methanol needs to be controlled, and is 5-30%, preferably 10-20%.
Claims (7)
1. A process for the purification of sildenafil free base comprising the steps of: taking the crude product of the sildenafil free alkali (II), adding 1-6 times (v/w) of organic solvent, fully stirring, heating to 40-60 ℃, keeping the temperature and stirring for 1-6h, then cooling to room temperature, filtering, drying to obtain the fine product of the sildenafil free alkali (II),
wherein the organic solvent is selected from: toluene, xylene, a mixed solvent of toluene and methanol,
wherein the content of the impurity I08 in the refined sildenafil free base (II) is not more than 0.1 percent,
2. the purification method according to claim 1, characterized in that it comprises the following steps: taking the crude product of the sildenafil free base (II), adding 2-4 times (v/w) of organic solvent, fully stirring, heating to 40-50 ℃, keeping the temperature, stirring for 2-4h, cooling to room temperature, filtering, and drying to obtain the fine product of the sildenafil free base (II).
3. The purification method according to claim 1, wherein the volume percentage of methanol in the mixed solvent of toluene and methanol is 5 to 30%, and the volume percentage of toluene in the mixed solvent of toluene and xylene is 10 to 30%.
4. The purification method according to claim 1, wherein the volume percentage of methanol in the mixed solvent of toluene and methanol is 10 to 20%, and the volume percentage of toluene in the mixed solvent of toluene and xylene is 10 to 20%.
5. The purification process according to claim 1, wherein the content of impurity I08 in the fine sildenafil free base (II) is controlled to be 0.025% to 0.058%.
6. The purification method according to claim 1, characterized in that it comprises the following steps: adding 15ml of toluene and 2ml of methanol into a 100ml reaction bottle, adding 5g of crude sildenafil free base (II), fully stirring, heating to 45-50 ℃, keeping the temperature, stirring for 2h, cooling to room temperature, filtering, and drying to obtain the product (II).
7. A method for detecting sildenafil free base is characterized in that,
the chromatographic conditions were as follows:
A. a chromatographic column: c18Column, Waters Spherisorb ODS 14.6X 250mm 5 μm;
B. mobile phase A: 0.05mol/L triethylamine phosphate solution-methanol-acetonitrile 58: 25: 17;
mobile phase B: 0.05mol/L triethylamine phosphate solution-acetonitrile-30: 70;
C. mobile phase gradient procedure
D. Detection wavelength: 290 nm;
E. column temperature: 30 ℃;
F. sample introduction amount: 20 mu l of the mixture;
G. flow rate: 1 ml/min;
H. operating time: and (5) 60 min.
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| CN112798719B (en) * | 2020-12-29 | 2023-03-17 | 植恩生物技术股份有限公司 | Detection method of related substance N-methylpiperazine in sildenafil citrate |
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