CN104130159A - Preparation method of intermediate, namely (Z)-2-chloro[(4-methoxy phenyl)hydrazono]ethyl acetate - Google Patents
Preparation method of intermediate, namely (Z)-2-chloro[(4-methoxy phenyl)hydrazono]ethyl acetate Download PDFInfo
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- CN104130159A CN104130159A CN201410406143.2A CN201410406143A CN104130159A CN 104130159 A CN104130159 A CN 104130159A CN 201410406143 A CN201410406143 A CN 201410406143A CN 104130159 A CN104130159 A CN 104130159A
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Abstract
The invention discloses a preparation method of an apixaban intermediate, namely (Z)-2-chloro[(4-methoxy phenyl)hydrazono]ethyl acetate. The preparation method comprises the following step of reacting a p-methoxyaniline diazonium salt aqueous solution with a water-insoluble organic solution of 2-chloroacetoacetate in the presence of a phase transfer catalyst to prepare the important apixaban intermediate, namely (Z)-2-chloro[(4-methoxy phenyl)hydrazono]ethyl acetate. Compared with the prior art, the preparation method has the advantages that the reaction time is shortened, a post-processing method is simplified, the yield is increased, the obtained product is high in purity, subsequent reaction is facilitated, and the preparation method is more suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of Eliquis intermediate, relate in particular to the preparation method of intermediate (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate.
Background technology
Eliquis (apixaban) is a kind of Selective activation X a factor inhibitors that can be oral, by 100 o'clock Mei-Shi Guibao and Pfizer's cooperative research and development, obtain first the approval of European Union in May, 2011, indication is that venous thromboembolism appears in prevent from accepting the selecting a time adult patients of hip joint or knee replacements.The newly-increased Eliquis of in November, 2012 European Union prevents palsy and systemic embolism for NVAF patient.In December, 2012 28 U.S. approval is for reducing NVAF patient's palsy and the risk of systemic embolism generation.
Eliquis is a kind of highly selective, reversible zymoplasm factor Ⅹa inhibitor.In security, with heparin and warfarin comparison, the total hemorrhage rate of Eliquis is obviously lower.Oral effective.In addition, Eliquis is through the metabolism of liver kidney two channels, thereby can be used for having the patient of light moderate hepatorenal damage.
The chemistry of Eliquis (Apixaban) is by name: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide; No. CAS: 503612-47-3; Its structural formula is as follows:
In Eliquis synthetic, the whole bag of tricks is all used (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] this key intermediate of ethyl acetate (I).
In the method for synthetic (I), the easiest, the most economic method is to take P-nethoxyaniline as raw material, in acidic solution, react with sodium nitrite solution and generate diazonium salt, then under alkaline condition, react with 2-chloroacetyl acetacetic ester, generate key intermediate (I).Reaction minute (a) is two steps (b), and reaction process is as follows:
Below existing bibliographical information about the synthetic method of (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate:
In document WO2003049681, the solvent that step (b) adopts is ethyl acetate, and due to ethyl acetate and water unmixing, this reaction is two phase reaction, and the reaction times is greater than 12h, and the impurity of generation is more, and yield only has 74%.
In document CN101967145, the solvent that step (b) adopts is methyl alcohol, although this reaction is homogeneous reaction, product (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate is insoluble in reaction solution, after reaction, obtain the sticky solid of black, comprise more impurity, product purity is lower, and last handling process first revolves the methyl alcohol evaporating in reaction solution, then by ethyl acetate, extract again, after washing, being dried, obtain crude product again, last handling process is loaded down with trivial details, and yield is only 76%.
In document US20100130543, in step (b), adopting ethanol is reaction solvent, obtains the sticky solid of black after reaction, is surrounded by much impurity, and product purity is lower, and yield only has 60%.
Summary of the invention
Technical problem to be solved by this invention be overcome long reaction time in the preparation method of Eliquis intermediate (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate, post-treating method is loaded down with trivial details, product yield is low and the defect such as purity difference, and provides a kind of Eliquis intermediate new preparation method.Advantage of the present invention is Reaction time shorten, simplifies post-treating method and improve yield, and the product purity of acquisition is high, is conducive to subsequent reactions, is more suitable for suitability for industrialized production.
The invention provides the preparation method of a kind of Eliquis intermediate (Z)-2-chlorine being shown below [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate.
It comprises following steps:
Step (a): take P-nethoxyaniline as starting raw material, react with Sodium Nitrite under acidic conditions, generate its P-nethoxyaniline diazonium salt solution.Wherein the mol ratio of P-nethoxyaniline, concentrated hydrochloric acid and Sodium Nitrite is 1:2.5～5:1～1.6, preferably 1:4:1.4.
Sodium Nitrite is that the form with the aqueous solution adds, and its concentration is 30%～60%, preferably 40%～50%.
Add temperature in fashionable reaction solution and maintain below 15 ℃, preferably below 10 ℃.
Finish 15 ℃ of following insulation reaction of rear reacting liquid temperature, preferably below 10 ℃.
Step (b): 2-chloroacetyl acetacetic ester, under Catalyzed By Phase-transfer Catalyst, reacts with P-nethoxyaniline diazonium salt solution and generates Eliquis important intermediate (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate.
The described phase-transfer catalyst of step (b) is that quaternary ammonium salt is with the known pharmaceutically acceptable of the those skilled in the art phase-transfer catalysts such as quaternary salt class, crown ether-like and polyethylene glycols such as quaternary alkylphosphonium salt, preferably quaternary ammonium salt-type phase transfer catalyst; Described quaternary ammonium salt-type phase transfer catalyst is triethyl benzyl ammonia chloride, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tri-n-octyl methyl ammonium chloride and palmityl trimethyl ammonium chloride etc., preferably triethyl benzyl ammonia chloride.
The 2-chloroacetyl acetacetic ester that step (b) is described and P-nethoxyaniline diazonium salt solution are to carry out in organic solvent a kind of and that water is immiscible; Described organic solvent is non-protonic solvent; Described non-protonic solvent is methylene dichloride, ethyl acetate, chloroform, toluene, normal hexane and sherwood oil etc.; Preferred methylene dichloride, ethyl acetate and methyl acetate, more preferably methylene dichloride.
The mol ratio of the described 2-chloroacetyl acetacetic ester of step (b) and P-nethoxyaniline is 0.9～1.2:1, preferably 1:1.
Described potassium acetate, sodium acetate or the sodium bicarbonate for alkaline condition of step (b) regulates, preferably sodium acetate.The mol ratio of sodium acetate and P-nethoxyaniline is 2～5:1, preferably 3.5:1
While diazonium salt solution being joined described in step (b) in 2-chloroacetyl acetacetic ester solution, the temperature of 2-chloroacetyl acetacetic ester solution is below 15 ℃, preferably below 10 ℃.
Finish rear temperature of reaction below 15 ℃, preferably below 10 ℃.
Compared with prior art, positively effect of the present invention is:
The present invention is applied to phase-transfer catalyst in the preparation of Eliquis important intermediate (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate, compared with prior art, advantage of the present invention is: (1) Reaction time shorten: compare without the method for phase-transfer catalysis with WO2003049681, the reaction times foreshortens to 1～2h above by 12h; (2) simplified post-treating method: comparing last handling process with CN101967145 does not need first to evaporate solvent; (3) improved yield: compare with WO2003049681, CN101967145 and US20100130543, yield is increased to more than 97% by 74%, 76% and 60% respectively; (4) product purity obtaining is high, through HPLC, measures, and product purity is all greater than 96%, is conducive to subsequent reactions.Be more suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 liquid chromatogram
Fig. 2 liquid chromatography interpretation of result figure
Embodiment
Mode by the following examples further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, selects according to conventional method and condition.
The preparation of embodiment 1:(Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate
In reaction flask, add P-nethoxyaniline 5g, 40mL water and concentrated hydrochloric acid 13.5mL, be cooled to 0～10 ℃.Slowly drip 40% sodium nitrite solution 9.80g, obtain the diazonium salt solution of P-nethoxyaniline.In another reaction flask, add 2-chloroacetyl acetacetic ester 6.68g, methylene dichloride 50mL and water 20mL, be cooled to below 10 ℃, add sodium acetate 11.7g and triethyl benzyl ammonia chloride 0.14g.Diazonium salt solution is joined in above-mentioned reaction solution, at 10 ℃, react 1～2h.Separate organic phase, water dichloromethane extraction, merge organic phase, use successively saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness obtains tawny solid 10.22g, yield 98.1%, purity is measured and is greater than 96% (seeing accompanying drawing 1) through HPLC, without purifying, can be directly used in next step reaction.mp:96～98℃.ESI-MS(m/z)＝256.9.
1H-NMR(600MHz,CDCl
3)δ:8.27(s,1H),7.18(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.39(q,J＝7.1Hz,2H),3.81(s,3H),1.41(t,J＝7.1Hz,3H).
The preparation of embodiment 2:(Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate
In reaction flask, add P-nethoxyaniline 5g, 40mL water and concentrated hydrochloric acid 13.5mL, be cooled to 0～10 ℃.Slowly drip 40% sodium nitrite solution 9.80g, obtain the diazonium salt solution of P-nethoxyaniline.In another reaction flask, add 2-chloroacetyl acetacetic ester 6.68g, methylene dichloride 50mL and water 20mL, be cooled to below 10 ℃, add sodium acetate 11.7g and triethyl benzyl ammonia chloride 0.23g.Diazonium salt solution is joined in above-mentioned reaction solution, at 10 ℃, react 1～2h.Separate organic phase, water dichloromethane extraction, merge organic phase, successively with saturated sodium bicarbonate solution and saturated sodium-chloride washing, anhydrous sodium sulfate drying, evaporate to dryness obtains tawny solid 10.18g, yield 97.7%, purity is measured and is greater than 96% through HPLC, without purifying, can be directly used in next step reaction.mp:96～98℃.ESI-MS(m/z)＝256.9.
1H-NMR(600MHz,CDCl
3)δ:8.27(s,1H),7.18(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.39(q,J＝7.1Hz,2H),3.81(s,3H),1.41(t,J＝7.1Hz,3H).
The preparation of embodiment 3:(Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate
In reaction flask, add P-nethoxyaniline 5g, 40mL water and concentrated hydrochloric acid 13.5mL, be cooled to 0～10 ℃.Slowly drip 40% sodium nitrite solution 9.80g, obtain the diazonium salt solution of P-nethoxyaniline.In another reaction flask, add 2-chloroacetyl acetacetic ester 6.68g, ethyl acetate 50mL and water 20mL, be cooled to below 10 ℃, add sodium acetate 11.7g and triethyl benzyl ammonia chloride 0.14g.Diazonium salt solution is joined in above-mentioned reaction solution, at 10 ℃, react 1～2h.Separate organic phase, water extracts by ethyl acetate, merges organic phase, successively with saturated sodium bicarbonate solution and saturated common salt washing, and anhydrous sodium sulfate drying, evaporate to dryness obtains tawny solid 9.8g, yield 94%.mp:96～98℃.ESI-MS(m/z)＝256.9.
1H-NMR(600MHz,CDCl
3)δ:8.27(s,1H),7.18(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.39(q,J＝7.1Hz,2H),3.81(s,3H),1.41(t,J＝7.1Hz,3H).
The preparation of embodiment 4:(Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate
In reaction flask, add P-nethoxyaniline 100g, 800mL water and concentrated hydrochloric acid 270mL, be cooled to 0～10 ℃.Slowly drip 40% sodium nitrite solution 195.6g, obtain the diazonium salt solution of P-nethoxyaniline.In another reaction flask, add 2-chloroacetyl acetacetic ester 133.6g, methylene dichloride 1000mL and water 400mL, be cooled to below 10 ℃, add sodium acetate 234g and triethyl benzyl ammonia chloride 2.77g.Diazonium salt solution is joined in above-mentioned reaction solution, at 10 ℃, react 1～2h, separate organic phase.Water dichloromethane extraction, merges organic phase, successively saturated sodium bicarbonate solution and salt washing, anhydrous sodium sulfate drying, evaporate to dryness obtains tawny solid 202.3g, yield 97.3%, purity is measured and is greater than 96% through HPLC, without purifying, can be directly used in next step reaction.mp:96～98℃.ESI-MS(m/z)＝256.9.
1H-NMR(600MHz,CDCl
3)δ:8.27(s,1H),7.18(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.39(q,J＝7.1Hz,2H),3.81(s,3H),1.41(t,J＝7.1Hz,3H).
The preparation of embodiment 5:(Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate
In reaction flask, add P-nethoxyaniline 100g, 800mL water and concentrated hydrochloric acid 270mL, be cooled to 0～10 ℃.Slowly drip 40% sodium nitrite solution 195.6g, obtain the diazonium salt solution of P-nethoxyaniline.In another reaction flask, add 2-chloroacetyl acetacetic ester 133.6g, methylene dichloride 1000mL and water 400mL, be cooled to below 10 ℃, add sodium acetate 234g and triethyl benzyl ammonia chloride 4.62g.Diazonium salt solution is joined in above-mentioned reaction solution, at 10 ℃, react 1～2h, separate organic phase.Water dichloromethane extraction, merges organic phase, successively saturated sodium bicarbonate solution and salt solution washing, anhydrous sodium sulfate drying, evaporate to dryness obtains tawny solid 201g, yield 96.6%, purity is measured and is greater than 96% through HPLC, without purifying, can be directly used in next step reaction.mp:96～98℃.ESI-MS(m/z)＝256.9.
1H-NMR(600MHz,CDCl
3)δ:8.27(s,1H),7.18(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.39(q,J＝7.1Hz,2H),3.81(s,3H),1.41(t,J＝7.1Hz,3H).
Execute routine 6:(Z) preparation of-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate
In reaction flask, add P-nethoxyaniline 100g, 800mL water and concentrated hydrochloric acid 270mL, be cooled to 0～10 ℃.Slowly drip 40% sodium nitrite solution 195.6g, obtain the diazonium salt solution of P-nethoxyaniline.In another reaction flask, add 2-chloroacetyl acetacetic ester 133.6g, ethyl acetate 1000mL and water 400mL, be cooled to below 10 ℃, add sodium acetate 234g and triethyl benzyl ammonia chloride 2.77g.Diazonium salt solution is joined in above-mentioned reaction solution, at 10 ℃, react 1～2h, separate organic phase.Water extracts by ethyl acetate, merges organic phase, saturated sodium bicarbonate solution and salt solution washing successively, and anhydrous sodium sulfate drying, evaporate to dryness obtains tawny solid 196g, yield 94.2%.mp:96～98℃.ESI-MS(m/z)＝256.9.
1H-NMR(600MHz,CDCl
3)δ:8.27(s,1H),7.18(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.3?9(q,J＝7.1Hz,2H),3.81(s,3H),1.41(t,J＝7.1Hz,3H).
Although above-mentioned, by reference to the accompanying drawings the specific embodiment of the present invention is described; but be not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various modifications that creative work can make or distortion still in protection scope of the present invention.
Claims (9)
1. a preparation method for intermediate (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate, is characterized in that, according to following two steps, carries out successively:
Step (a): take P-nethoxyaniline as starting raw material, react with Sodium Nitrite under acidic conditions, generate its P-nethoxyaniline diazonium salt solution;
Step (b): 2-chloroacetyl acetacetic ester, under Catalyzed By Phase-transfer Catalyst, reacts with P-nethoxyaniline diazonium salt solution and generates Eliquis important intermediate (Z)-2-chlorine [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate.
2. preparation method according to claim 1, is characterized in that, (b) in step, described phase-transfer catalyst is quaternary salt class, crown ether-like or polyoxyethylene glycol compounds.
3. preparation method according to claim 2, is characterized in that, (b) in step, described phase-transfer catalyst is quaternary salt compounds.
4. preparation method according to claim 1, it is characterized in that, (b), in step, described phase-transfer catalyst is triethyl benzyl ammonia chloride, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tri-n-octyl methyl ammonium chloride or palmityl trimethyl ammonium chloride.
5. preparation method according to claim 4, is characterized in that, (b) in step, described phase-transfer catalyst is triethyl benzyl ammonia chloride.
6. preparation method according to claim 1, is characterized in that, (b) in step, described phase-transfer catalyst with to the mol ratio of methyl oxyaniline, be 0.05:1～0.5:1.
7. preparation method according to claim 6, is characterized in that, (b) in step, described phase-transfer catalyst with to the mol ratio of methyl oxyaniline, be 0.1:1～0.2:1.
8. preparation method according to claim 1, is characterized in that, (b) in step, described P-nethoxyaniline diazonium salt solution is to carry out in the solvent of methylene dichloride, ethyl acetate or methyl acetate with reacting of 2-chloroacetyl acetacetic ester.
9. preparation method according to claim 8, is characterized in that, (b) in step, described non-protonic solvent is methylene dichloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105044269A (en) * | 2015-06-30 | 2015-11-11 | 成都百裕科技制药有限公司 | Method for detecting initial material II in apixaban through reversed-phase high performance liquid chromatography |
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| WO2010030983A2 (en) * | 2008-09-15 | 2010-03-18 | Auspex Pharmaceuticals, Inc. | Pyrazole carboxamide inhibitors of factor xa |
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2014
- 2014-08-18 CN CN201410406143.2A patent/CN104130159A/en active Pending
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| WO2002085353A1 (en) * | 2001-04-18 | 2002-10-31 | Bristol-Myers Squibb Company | 1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones as factor xa inhibitors |
| WO2010030983A2 (en) * | 2008-09-15 | 2010-03-18 | Auspex Pharmaceuticals, Inc. | Pyrazole carboxamide inhibitors of factor xa |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105044269A (en) * | 2015-06-30 | 2015-11-11 | 成都百裕科技制药有限公司 | Method for detecting initial material II in apixaban through reversed-phase high performance liquid chromatography |
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