CN102993205A - 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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- CN102993205A CN102993205A CN201210581758XA CN201210581758A CN102993205A CN 102993205 A CN102993205 A CN 102993205A CN 201210581758X A CN201210581758X A CN 201210581758XA CN 201210581758 A CN201210581758 A CN 201210581758A CN 102993205 A CN102993205 A CN 102993205A
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- toluene
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- free alkali
- methyl alcohol
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- FBHZQNZDJNQRAN-PLJYCHNVSA-N CCCc1n[n](C)c(C(N)=O)c1NC(/C=C/C=C(/CCl)\C=C(/C)\OCC)=O Chemical compound CCCc1n[n](C)c(C(N)=O)c1NC(/C=C/C=C(/CCl)\C=C(/C)\OCC)=O FBHZQNZDJNQRAN-PLJYCHNVSA-N 0.000 description 1
- BNRNXUUZRGQAQC-UHFFFAOYSA-N CCCc1n[n](C)c2c1N=C(c(cc(cc1)S(N3CCN(C)CC3)(=O)=O)c1OCC)NC2=O Chemical compound CCCc1n[n](C)c2c1N=C(c(cc(cc1)S(N3CCN(C)CC3)(=O)=O)c1OCC)NC2=O BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 1
- 0 CCCc1n[n](C)c2c1N=C(c(ccc(*)c1)c1OCC)NC2=O Chemical compound CCCc1n[n](C)c2c1N=C(c(ccc(*)c1)c1OCC)NC2=O 0.000 description 1
- JYELDIDGIRZNPI-UHFFFAOYSA-N CCOc(cc(cc1)Cl)c1C(O)=O Chemical compound CCOc(cc(cc1)Cl)c1C(O)=O JYELDIDGIRZNPI-UHFFFAOYSA-N 0.000 description 1
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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 pharmaceutical chemistry technical field, relate to a kind of method of purifying Virga free alkali, particularly relate to a kind of purification process of from the Virga free alkali, removing new impurity.
Background technology
Sildenafil citrate; commodity are called viagra; Pfizer Inc. is in Novel phosphoric acid diesterase 5 types (PDE5) inhibitor of exploitation listing in 1997; chemistry 5-(2-oxyethyl group-5(-4-methylpiperazine-1-alkylsulfonyl) phenyl by name)-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones is mainly used in the treatment of sexual dysfunction clinically.Its mechanism of action is to suppress the activity of Phosphodiesterase V, stops cGMP and cAMP hydrolysis to generate corresponding 5-monophosphic acid nucleotide, improves the concentration of cGMP between tissue, suppresses the loose of unstriated muscle, reaches the purpose for the treatment of.
Up to the present, the compound patent of sildenafil citrate is expired, but Pfizer Inc. enjoys patent right (on October 22nd, 2019) to the indication of Virga treatment ED, therefore the said firm is at present unique legal in the medicine of Virga as main component on the market with the viagra of the citrate manufacturing of Virga.
Equally, the producer of unique legal production sildenafil citrate bulk drug is Pfizer Inc. on the market at present, and the major industry metallization processes route of its report mainly divides two kinds of (Peter according to the sequencing of pyrimidine cyclization and sulfonating chlorinating, Gree Chem., 2004,6,43-48).
1, pyrimidine ring is combined in elder generation, sulfonating chlorinating in rear (referenced patent US 5250534, Pfizer Inc., 1992).This route adopts O-ethoxyl formyl chloride (VI) and 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide (VII) condensation, again through cyclization, and sulfonating chlorinating, sulfuryl amine, salify obtains sildenafil citrate.The yield of condensation reaction and sulfonamide reaction only has respectively 40% and 49%, and condensation and cyclization product all need column chromatography for separation, and whole piece route total recovery is low, and material consumption is high.After through after the said firm self process modification, total recovery is brought up to 35.9%(all take key intermediate VII as benchmark from original 9.8%), be applicable to suitability for industrialized production.There have not been the legal issues such as patent protection in this route at present, and domestic can research declared this bulk drug of production.Its synthetic route is as follows:
2, sulfonating chlorinating formerly, pyrimidine ring be combined in after (referenced patent US5955611, Pfizer Inc., 1997).This route is take o-ethoxybenzoic acid (VIII) as raw material, after passing through first sulfonating chlorinating and sulfonamide reaction, carry out condensation reaction with key intermediate (VII) again, then carry out ring-closure reaction, last salify obtains sildenafil citrate, and this technique total recovery is that 75%(is all take key intermediate VII as benchmark).Its synthetic route is as follows:
In conjunction with the actual statutory status situation of patent, we have carried out quality approach to above-mentioned two techniques successively.
At first, through the improvement technique (Pfizer Inc., 1994) of US 5250534 having been carried out a large amount of quality approach test, our surprised discovery is in this operational path, all find a kind of new impurity (I08) in compound (I) ~ (IV), the content of this impurity does not wait from 0.02 ~ 2%.Rear by column chromatography for separation, in conjunction with spectrograms such as high resolution mass spectrum and nucleus magnetic resonance, determined that the structural formula of new impurity (I08) is as follows:
Research by the impurity source finds that the formation approach of this new impurity I08 has dual mode:
1) the adjacent acetoxyl group Benzoyl chloride of material (VI) self with the subsequent reactions that produces of impurity, its route of synthesis is shown in method 1.
2) reaction intermediate (IV) carries out the by product of sulfonating chlorinating reaction, and its route of synthesis is shown in method 2.
The polarity difference of the impurity I08 that method 2 produces and intermediate (IV) is little, is difficult for refining the removal, generally all content 0.1% ~ 1.5%.Impurity I08 is by the accumulation of SULPHURYL CHLORIDE reaction, and to bring Virga into free always
In the crude product of alkali (II), the mode of taking out according to crude product is different, and general content is 0.1% ~ 2%.
Method 1:
Method 2:
Then, we have also studied the related preparation were established two of US5955611, carry out ring-closure reaction at (XI) and prepare in the process of Virga free alkali (II) and found equally new impurity I08, content 0.02 ~ 0.5% does not wait, and its route of synthesis is as follows:
At present, in the existing document not the new impurity I08 to the Virga free alkali report, also remove the method for this impurity without any the document record.
Research is found in addition, because (II) the polarity difference with I08 is very large, this new impurity I08 is relatively easy when free alkali is refining; Test shows that re-refining behind the follow-up salify just is difficult to remove if be not purified at free alkali and can accept below the limit in addition.
Simultaneously equal analytical procedure of the degree such as employings on existing USP and the EP quality standard can't detect this impurity, extremely is necessary to guarantee that at the definite a kind of purification process of the quality control of Virga free alkali this foreign matter content is not more than 0.1%.
Summary of the invention:
The object of the present invention is to provide a kind of purification process of Virga free alkali.
Purification process of the present invention is, removes impurity I08 from Virga free alkali (II) crude product, obtains the Virga free alkali elaboration of a kind of high purity, high yield.
Concrete, purification process of the present invention, may further comprise the steps: get Virga free alkali (II) crude product and place reaction flask, adding 1-6 doubly measures the organic solvent of (v/w), is warming up to 40-60 ℃, insulated and stirred 1-6h after fully stirring, then be cooled to room temperature, filter, drying obtains Virga free alkali (II) elaboration.
。
Preferably, purification process of the present invention, may further comprise the steps: get Virga free alkali (II) crude product and place reaction flask, adding 2-4 doubly measures the organic solvent of (v/w), is warming up to 40-50 ℃, insulated and stirred 2-4h after fully stirring, then be cooled to room temperature, filter, drying obtains Virga free alkali (II) elaboration.
Wherein, described organic solvent is selected from: the mixture of one or more in toluene, dimethylbenzene, acetone, butanone, methyl alcohol, the ethanol.Preferred organic solvent is toluene, dimethylbenzene, the mixed solvent of toluene and dimethylbenzene, the mixed solvent of toluene and methyl alcohol.The volume percent of methyl alcohol is 5% ~ 30% in the mixed solvent of toluene and methyl alcohol, and the volume percent of toluene is 10-30% in the mixed solvent of toluene and dimethylbenzene.The volume percent of methyl alcohol is 10 ~ 20 in the mixed solvent of further preferred toluene and methyl alcohol, and the volume percent of toluene is 10 ~ 20% in the mixed solvent of toluene and dimethylbenzene.
The content of impurity I08 is not more than 0.1% in Virga free alkali of the present invention (II) elaboration,
The content of impurity I08 is controlled at 0.025%-0.058% in Virga free alkali of the present invention (II) elaboration.
Virga free alkali (II) crude product can buy in market among the present invention, perhaps prepares by the method in the background technology.
Virga free alkali (II) crude product among the present invention (sterling purity contains 0.5 ~ 2% impurity I08 greater than 95%), its preparation were established (with reference to US 5250534 and be optimized) is as follows:
A) 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide (VII) carries out condensation reaction with adjacent acetoxyl group Benzoyl chloride (VI), and makes with extra care in methylene dichloride, under the triethylamine acid binding agent condition, gets intermediate (V).
B) intermediate (V) carries out ring-closure reaction in alcohol and highly basic, regulates obtaining intermediate (IV) through PH.
C) intermediate (IV) carries out the sulfonating chlorinating reaction in the chlorsulfonic acid system, adopts methylene dichloride and water aftertreatment, obtains intermediate (III).
D) intermediate (III) carries out sulfonamide reaction with N methyl piperazine in ethanol, regulates with PH through concentrated, obtains Virga free alkali (II) crude product.
Wherein,
A) in the step, the difference of refining solvent, directly affect the content size of impurity I08 in the intermediate (IV), but selectable organic solvent comprises toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol, acetone, butanone, tetrahydrofuran (THF), dioxane etc.
B) in the step, alcohols can be methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Comprise in the highly basic inorganic strong alkali such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide etc. and organic alkali such as sodium methylate, sodium ethylate, potassium tert.-butoxide etc.By impurity I08 content in the aftertreatment gained intermediate (IV) 0.1 ~ 1%.
C) in the step, the molar ratio of chlorsulfonic acid is more than 10 times of intermediate (IV) mole number at least, guarantees sufficient reacting.Content by impurity I08 in the aftertreatment gained intermediate (III) is 0.1 ~ 1.5%.
D) in the step, after the simple reaction processing, obtain the crude product of Virga free alkali (II), wherein the content of impurity I08 is 0.1 ~ 1.5%.
The present invention finds by the large-scale purification experimental study, crude product as Virga free alkali (II), foreign matter content is in 0.5%, adopt organic solvent to comprise that aromatic hydroxy compound is such as toluene, dimethylbenzene etc., ketones solvent is such as acetone, butanone etc., alcohols is such as methyl alcohol, ethanol etc., perhaps above-mentioned solvent liquid, just direct disposable Virga free alkali (II) elaboration (wherein the content of impurity I08 is not more than 0.1%) that obtains, then by salify, directly control impurity I08 to accepting below the limit.
And when the crude product of Virga free alkali (II), foreign matter content is in 0.5 ~ 2%, and the content that general solvent often needs repeatedly purification refine (namely more than twice) could control impurity I08 is not more than 0.1%.
Wherein, " high yield " refers to that yield is greater than 90%.
Wherein, " high purity " refers to that HPLC purity is greater than 99%.
Wherein, " room temperature " refers to 20 ~ 30 ℃.
The present invention, selection by different solvents, find several solvent ratio such as toluene, methyl alcohol with and mixed solvent (Smix), the mixed solvent of toluene and methyl alcohol particularly, content that can fine disposable control impurity I08 is not more than 0.1%, the purity of that non-free alkali (II) elaboration of Virga is more than 99%, and yield is more than 90%.The free alkali elaboration of the method gained, directly salify need not the refining high quality Virga finished product (wherein the content of impurity I08 is below 0.02%) that just can obtain more than 99.5%.
In this invention, Virga free alkali (II) crude product refers to homemadely, and purity is greater than 95%, and the content of impurity I08 is 0.5 ~ 2% (II).
Another object of the present invention is to provide a kind of detection method of Virga.
Wherein, chromatographic condition is as follows:
A. chromatographic column: C
18Post, Waters Spherisorb ODS1 4.6 * 250mm 5 μ m;
B. mobile phase A: 0.05mol/L triethylamine phosphate solution (get triethylamine 7ml, add water 1000ml, transfer pH to 3.0 with phosphoric acid)-methyl alcohol-acetonitrile (58:25:17);
Mobile phase B: 0.05mol/L triethylamine phosphate solution (get triethylamine 7ml, add water 1000ml, transfer pH to 3.0 with phosphoric acid)-acetonitrile (30:70);
C. eluent gradient program
D. detect wavelength: 290nm;
E. column temperature: 30 ℃;
F. sample size: 20 μ l;
G. flow velocity: 1ml/min;
H. working time: 60min;
The HPLC spectrogram of Virga free alkali (II) elaboration (wherein retention time 46.392min is the chromatographic peak of impurity I08) as shown in Figure 1.
Description of drawings
The HPLC spectrogram of accompanying drawing 1, Virga free alkali (II) elaboration
Embodiment
Following instance should not be considered as it restriction to this patent just for the present invention is described.
The preparation of embodiment 1 Virga free alkali (II) crude product
Wherein, 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide (VII) derives from the Quzhou and forever creates Chemical Industry Science Co., Ltd, O-ethoxyl formyl chloride (VI) derives from the new chemical industry company limited of Zibo benefit, and other reagent are all from chemical reagent Beijing company limited of traditional Chinese medicines group.
1) 1-methyl-3-propyl group-4-(2-ethoxy benzamide base) pyrazoles-5-methane amide (V) is synthetic
Add the 500ml methylene dichloride in the reaction flask of 2L, then add 100g (VII), start and stir, add again the 83g triethylamine, then the low temperature bath is cooled to 0 ℃, drip 110g(VI), drip and finish rear room temperature insulation reaction 4h, then add washing 1 time, leave standstill separatory, the gained dichloromethane layer, directly average mark is two parts, concentrated evaporate to dryness.
Method A:100ml ethyl acetate is refining, filters, and dries to get 75g(V)
A, yield 83%.
Method B:100ml ethanol is refining, filters, and dries to get 60g(V)
B, yield 66%.
2) 1-methyl-3-propyl group-5-(2-oxyethyl group) phenyl-6,7-dihydro-1 h-pyrazole be synthesizing of ［ 4,3-d ］ pyrimidin-7-ones (IV) also
In the reaction flask of 1L, add 180mL methyl alcohol and 10g sodium hydroxide, then add 60g(V), then be warming up to back flow reaction 3h, concentrated evaporate to dryness adds 100ml water, is cooled to room temperature, transfers PH to neutral with 2N hydrochloric acid, filter dry (IV) about 50g, the yield 88.8% of getting.
Method A: adopt (V)
ABe raw material, get (IV)
A, wherein the content of impurity I08 is 0.85%.
Method B: adopt (V)
BBe raw material, get (IV)
B, wherein the content of impurity I08 is 0.18%.
3) 1-methyl-3-propyl group-5-(2-oxyethyl group-5-chlorosulfonyl) phenyl-6,7-dihydro-1 h-pyrazole be synthesizing of ［ 4,3-d ］ pyrimidin-7-ones (III) also
In the reaction flask of 1L, add the chlorsulfonic acid of 160ml, then the low temperature bath is cooled to below 0 ℃, then adds 40g(IV), reinforced complete after, then more than the room temperature reaction 4h.Then reaction solution is slowly added in the 2L reaction flask of methylene dichloride mixed solution of ready 600mL frozen water and 400mL, the gained dichloromethane layer, after salt was washed, anhydrous sodium sulfate drying filtered, and distills to get product (III), about 36g, yield 68.7%.
Method A: adopt (IV)
ABe raw material, get (III)
A, wherein the content of impurity I08 is 1.24%.
Method B: adopt (IV)
BBe raw material, get (III)
B, wherein the content of impurity I08 is 0.52%.
4): 1-methyl-3-propyl group-5-［ (2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl) phenyl ］-6,7-dihydro-1 h-pyrazole be synthesizing of ［ 4,3-d ］ pyrimidin-7-ones (II) also
In the 1L reaction flask, suction 360ml ethanol adds 36g (III), adds n-formyl sarcolysine base piperazine after fully stirring, behind the room temperature reaction 3h, then distillation and concentration ethanol add 500mL water, and it is neutral that the salt of wormwood with 10% is transferred PH, filter, dry to get product (II) 39.5g, yield 95%.
Method A: adopt (IV)
ABe raw material, get crude product (II)
A, wherein the content of impurity I08 is 1.28%, purity 95.4%.
Method B: adopt (IV)
BBe raw material, get crude product (II)
B, wherein the content of impurity I08 is 0.54%, purity 96.3%.
The preparation of embodiment 2 Virga free alkali (II) elaboration
In the reaction flask of 100ml, add 15ml toluene and 2ml methyl alcohol, add 5g Virga free alkali (II) crude product, be warming up to 45 ~ 50 ℃ after fully stirring, then insulated and stirred 2h is cooled to room temperature, filters, and dries to get product (II).
Method A: yield 92.8%, wherein the content of impurity I08 is 0.058%
Method B: yield 93.4%, wherein the content of impurity I08 is 0.028%
The preparation of embodiment 3 Virga free alkali (II) elaboration
In the reaction flask of 100ml, add 15ml toluene and 4ml methyl alcohol, add 5g Virga free alkali (II) crude product, be warming up to 45 ~ 50 ℃ after fully stirring, then insulated and stirred 2h is cooled to room temperature, filters, and dries to get product (II).
Method A: yield 90.6%, wherein the content of impurity I08 is 0.054%
Method B: yield 91.2%, wherein the content of impurity I08 is 0.025%
The solvent screening process of the preparation of embodiment 4, Virga free alkali (II) elaboration
In the reaction flask of 50ml, add the 5ml solvent, add 1g Virga free alkali (II) crude product, be warming up to 45 ~ 50 ℃ after fully stirring, then insulated and stirred 2h is cooled to room temperature, filters, and dries to get product (II).
Single solvent, concrete outcome is as follows:
Single solvent experimental result shows: when selecting toluene or dimethylbenzene as single solvent, the yield of product is the highest, removes the effect of impurity I08, methyl alcohol ﹥ toluene〉purification of dimethylbenzene ≈ ethanol ≈ acetone ≈ butanone is best, and gained purity is the highest.
Mixed solvent, concrete outcome is as follows:
Experimental result shows: select toluene and methyl alcohol as mixed solvent, yield and toluene or dimethylbenzene difference are little, but the content of impurity I08 is minimum, are easy to control, and purification effect is better than single solvent and other mixed solvents.Simultaneously, when the methyl alcohol ratio increases when excessive, purity increases, but yield obviously reduces.
Show that by experiment organic solvent is preferably toluene, dimethylbenzene, the mixed solvent of toluene and dimethylbenzene, the mixing solutions of toluene and methyl alcohol, wherein in the solution of toluene and methyl alcohol, the ratio of methyl alcohol need be controlled, and 5 ~ 30%, preferred 10 ~ 20%.
Claims (10)
1. the purification process of a Virga free alkali, it is characterized in that, may further comprise the steps: get Virga free alkali (II) crude product, add the organic solvent that 1-6 doubly measures (v/w), be warming up to 40-60 ℃ after fully stirring, insulated and stirred 1-6h, then be cooled to room temperature, filter drying, obtain Virga free alkali (II) elaboration
2. purification process according to claim 1, it is characterized in that, may further comprise the steps: get Virga free alkali (II) crude product, adding 2-4 doubly measures the organic solvent of (v/w), is warming up to 40-50 ℃, insulated and stirred 2-4h after fully stirring, then be cooled to room temperature, filter, drying obtains Virga free alkali (II) elaboration.
3. purification process according to claim 1 and 2 is characterized in that, described organic solvent is selected from: the mixture of one or more in toluene, dimethylbenzene, acetone, butanone, methyl alcohol, the ethanol.
4. purification process according to claim 1 is characterized in that, described organic solvent is toluene, dimethylbenzene, the mixed solvent of toluene and dimethylbenzene, the mixed solvent of toluene and methyl alcohol.
5. purification process according to claim 4 is characterized in that, the volume percent of methyl alcohol is 5% ~ 30% in the mixed solvent of toluene and methyl alcohol, and the volume percent of toluene is 10-30% in the mixed solvent of toluene and dimethylbenzene.
6. purification process according to claim 4 is characterized in that, the volume percent of methyl alcohol is 10 ~ 20 in the mixed solvent of toluene and methyl alcohol, and the volume percent of toluene is 10 ~ 20% in the mixed solvent of toluene and dimethylbenzene.
7. purification process according to claim 1 is characterized in that, the content of impurity I08 is not more than 0.1% in Virga free alkali (II) elaboration,
8. purification process according to claim 1 is characterized in that, the content of impurity I08 is controlled at 0.025%-0.058% in Virga free alkali (II) elaboration.
9. purification process according to claim 1, it is characterized in that, may further comprise the steps: in the reaction flask of 100ml, add 15ml toluene and 2ml methyl alcohol, add 5g Virga free alkali (II) crude product, be warming up to 45 ~ 50 ℃ after fully stirring, insulated and stirred 2h, then be cooled to room temperature, filter, dry to get product (II).
10. the detection method of a Virga free alkali is characterized in that,
Chromatographic condition is as follows:
A. chromatographic column: C
18Post, Waters Spherisorb ODS1 4.6 * 250mm 5 μ m;
B. mobile phase A: 0.05mol/L triethylamine phosphate solution-methyl alcohol-acetonitrile=58:25:17;
Mobile phase B: 0.05mol/L triethylamine phosphate solution-acetonitrile=30:70;
C. eluent gradient program
D. detect wavelength: 290nm;
E. column temperature: 30 ℃;
F. sample size: 20 μ l;
G. flow velocity: 1ml/min;
H. working time: 60min.
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| CN105334275A (en) * | 2015-12-05 | 2016-02-17 | 常州亚邦制药有限公司 | Detection method for sildenafil citrate related substances |
| CN107759603A (en) * | 2016-08-18 | 2018-03-06 | 四川科伦药物研究院有限公司 | A kind of preparation method of heterocyclic compound |
| CN108226354A (en) * | 2018-01-02 | 2018-06-29 | 上海信谊百路达药业有限公司 | A kind of detection method of budesonide residual solvent |
| CN108558890A (en) * | 2018-06-28 | 2018-09-21 | 重庆康刻尔制药有限公司 | A kind of silaenafil intermediate synthetic method |
| CN112798719A (en) * | 2020-12-29 | 2021-05-14 | 植恩生物技术股份有限公司 | Detection method of related substance N-methylpiperazine in sildenafil citrate |
| CN115097026A (en) * | 2022-06-08 | 2022-09-23 | 河北常山生化药业股份有限公司 | Method for detecting pyrazolopyrimidine benzene sulfonate compound from medicine |
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| CN107759603B (en) * | 2016-08-18 | 2020-09-01 | 四川科伦药物研究院有限公司 | Preparation method of heterocyclic compound |
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| CN112798719A (en) * | 2020-12-29 | 2021-05-14 | 植恩生物技术股份有限公司 | Detection method of related substance N-methylpiperazine in sildenafil citrate |
| CN115097026A (en) * | 2022-06-08 | 2022-09-23 | 河北常山生化药业股份有限公司 | Method for detecting pyrazolopyrimidine benzene sulfonate compound from medicine |
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