CN114149360B - Preparation method of high-purity nitrendipine bulk drug - Google Patents
Preparation method of high-purity nitrendipine bulk drug Download PDFInfo
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- CN114149360B CN114149360B CN202111414403.7A CN202111414403A CN114149360B CN 114149360 B CN114149360 B CN 114149360B CN 202111414403 A CN202111414403 A CN 202111414403A CN 114149360 B CN114149360 B CN 114149360B
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- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 title claims abstract description 70
- 229960005425 nitrendipine Drugs 0.000 title claims abstract description 70
- 229940079593 drug Drugs 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- YOPMSDPIOQUWFE-XYOKQWHBSA-N ethyl (2e)-2-[(3-nitrophenyl)methylidene]-3-oxobutanoate Chemical compound CCOC(=O)C(\C(C)=O)=C\C1=CC=CC([N+]([O-])=O)=C1 YOPMSDPIOQUWFE-XYOKQWHBSA-N 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 13
- -1 2- (3-nitrobenzylidene) ethyl Chemical group 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 239000002516 radical scavenger Substances 0.000 claims abstract description 10
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 claims abstract description 9
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 4
- CAJHZLUJWVVUSU-UHFFFAOYSA-N ethyl 2-[(3-nitrophenyl)methyl]-3-oxobutanoate Chemical compound CCOC(=O)C(C(C)=O)CC1=CC=CC([N+]([O-])=O)=C1 CAJHZLUJWVVUSU-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 13
- 239000002808 molecular sieve Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 11
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 35
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 abstract description 17
- 230000000052 comparative effect Effects 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 13
- 238000005809 transesterification reaction Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000011208 chromatographic data Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension 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
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 239000002866 dihydropyridine calcium channel blocker Substances 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 1
- GASYWQNGISZARS-UHFFFAOYSA-N ethyl 5-(3-nitrophenyl)-3-oxopent-4-enoate Chemical compound CCOC(=O)CC(=O)C=CC1=CC=CC([N+]([O-])=O)=C1 GASYWQNGISZARS-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- XKORCTIIRYKLLG-UHFFFAOYSA-N methyl 3-aminobut-2-enoate Chemical compound COC(=O)C=C(C)N XKORCTIIRYKLLG-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- PVHUJELLJLJGLN-UHFFFAOYSA-N nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-UHFFFAOYSA-N 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention provides a preparation method of a high-purity nitrendipine bulk drug, which takes ethyl acetoacetate, 98% concentrated sulfuric acid and m-nitrobenzaldehyde as raw materials to prepare crude 2- (3-nitrobenzylidene) ethyl acetoacetate at normal temperature; washing, centrifuging and drying to obtain pure 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester; adding 2- (3-nitrobenzyl) acetoacetic acid ethyl ester into an organic solvent, adding 3-methyl aminocrotonate and a water scavenger, heating to react, removing the water scavenger after the reaction is finished, cooling, stirring, centrifuging, and drying the solid to obtain nitrendipine. The nitrendipine bulk drug obtained by the preparation method of the high-purity nitrendipine bulk drug has the purity of over 99.80 percent, and the impurity B and the impurity C are both less than 0.1 percent.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of a high-purity nitrendipine bulk drug.
Background
Nitrendipine (NTD) was originally developed by Bayer, germany, and began to be produced in the 70 s of the 20 th century. Trade name: bayotensin. Nitrendipine tablet is dihydropyridine calcium channel blocker, can inhibit transmembrane calcium ion inflow of vascular smooth muscle and cardiac muscle, and has strong vascular selectivity due to the main vascular effect. Can cause the expansion of systemic blood vessels such as coronary artery, renal arteriole and the like, and has the function of reducing blood pressure. Since nitrendipine has the advantages of quick response, long duration of drug effect, definite curative effect, small side effect and the like, the nitrendipine is widely applied to the treatment of hypertension and coronary heart disease. The chemical structure of nitrendipine is as follows:
in recent years, a great deal of research on the synthesis of nitrendipine is carried out at home and abroad, and a plurality of synthesis methods are proposed. However, it is reported that a large amount of ester exchange impurities are generated in the synthesis methods, the nitrendipine of the dimethyl ester is an impurity B, the nitrendipine of the diethyl ester is an impurity C, and the structural general formula of the impurities is as follows:
the prior art does not address these transesterification impurities. The pharmacopoeia of each country prescribes the limit of the related substances of the nitrendipine tablet.
The control limits of the related substances of the nitrendipine tablet in the current Chinese pharmacopoeia are looser than those of other pharmacopoeias according to the table.
Comparative researches on related substances of nitrendipine tablets of different manufacturers show that although impurities B and C of the nitrendipine tablets of domestic manufacturers meet the requirements according to the standards of Chinese pharmacopoeia, the limits of impurities B and C of the nitrendipine tablets of domestic manufacturers do not meet the European, japanese and British pharmacopoeia standards, and the quality of the domestic nitrendipine tablets is to be improved.
In the patent CN109734656B, the method comprises the following steps of (1) reacting 3-nitrobenzylidene acetoacetate intermediate and 3-amino methyl butenoate in a molar ratio of 1:1-1.1 at 70-75 ℃ in advance; adding concentrated hydrochloric acid into the reaction system of the step (1), wherein the adding amount of the reacted concentrated hydrochloric acid is 10% -15% of the molar amount of the 3-nitrobenzylidene ethyl acetoacetate intermediate at 70-75 ℃ after the adding is finished, and the step (3) is that the temperature is reduced to 15-20 ℃ after the reaction of the step (2) is finished, and the reaction is continued; and then solid-liquid separation and heavy agglomeration are carried out to obtain the nitrendipine. In the operation, the concentrated hydrochloric acid can accelerate the generation of transesterification, so that impurities are increased more, the concentrated hydrochloric acid can form hydrochloride with nitrendipine, the residue of the hydrochloric acid is not detected, and along with the increase of batches, the impurities are increased further, so that the method is not suitable for industrial production.
Patent CN111072553a is a first reaction solution obtained by adding (E) -ethyl 2- (3-nitrobenzylidene) -3-oxobutyrate and methyl 3-aminocrotonate into a first solvent, and performing a reflux reaction at a first temperature; adding acetic anhydride into the first reaction solution at a second temperature to react to obtain a second reaction solution, wherein the second reaction solution is stirred, reacted and filtered at a third temperature to obtain a nitrendipine crude product; and recrystallizing the nitrendipine crude product to obtain the nitrendipine. The patent uses temperature change and the addition of acetic anhydride to achieve the aim of improving purity, and anhydride residues are left, and acetic anhydride residues are not detected.
Patent CN110551061A discloses (1) adding 3-nitrobenzylidene ethyl acetoacetate and 3-methyl aminocrotonate solvent into a reaction bottle, heating to react, (2) evaporating the solvent to dryness under reduced pressure, and gradually heating to react until the reaction liquid is solidified, (3) controlling the temperature and the reaction time after the reaction liquid is solidified to obtain a crude nitrendipine product, (4) adding the solvent to reflux and cool to room temperature overnight, filtering, washing and drying to obtain a refined nitrendipine product.
Patent CN110066240a discloses a method for controlling impurities by using acetonitrile as a reaction solvent, wherein acetonitrile belongs to a class of solvents, and the residual limit of the solvent is low, and no detection is made for the acetonitrile residue.
Patent CN109232390a reports a three-step method for synthesizing nitrendipine, which does not control impurity B and impurity C, and does not give quality data of nitrendipine.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of high-purity nitrendipine bulk drug, the purity of the prepared nitrendipine bulk drug is over 99.80%, and the impurity B and the impurity C are both less than 0.1%. The content of other single impurities is not more than 0.1%.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
a preparation method of high-purity nitrendipine bulk drug comprises the following synthetic route:
the method comprises the following steps:
preparation of S1, 2- (3-nitrobenzylidene) acetoacetate: using ethyl acetoacetate, 98% concentrated sulfuric acid and m-nitrobenzaldehyde as raw materials, and preparing crude 2- (3-nitrobenzylidene) ethyl acetoacetate at normal temperature; washing, centrifuging and drying to obtain pure 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester;
s2, preparation of nitrendipine: adding the pure 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester prepared in the step S1 into an organic solvent, sequentially adding 3-methyl aminocrotonate and a water scavenger, heating to react, removing the water scavenger after the reaction is finished, cooling, stirring, centrifuging, and drying the obtained yellow solid to obtain the nitrendipine.
In the step S2, the organic solvent is absolute ethanol.
In the step S2, the water scavenger is 10-100% of anhydrous sodium sulfate or molecular sieve activated powder.
Because the byproduct of the cyclization reaction is water with one molecule, under the condition of the existence of water, the exchange speed of methyl ester and ethyl ester can be increased, the water content in the system is increased, the transesterification speed is obviously increased, and the impurity B and the impurity C are obviously increased; the absolute ethyl alcohol is used as a reaction solvent, and the water scavenger is added at the same time, so that the generation of impurities B and C can be effectively reduced.
Further, in the S2, the molar ratio of the ethyl 2- (3-nitrobenzylidene) acetoacetate to the methyl 3-aminocrotonate is 1:1 to 1.5.
Still further, the molar ratio of ethyl 2- (3-nitrobenzylidene) acetoacetate to methyl 3-aminocrotonate was 1:1.3
In the step S2, the temperature is raised to 65-70 ℃ for 6-24 hours.
When the temperature reaches above 70 ℃, the rate of transesterification (the formation rate of the impurity B and the impurity C) is obviously increased, and when the reaction temperature is lower than 65 ℃, the rate of transesterification is obviously reduced, and the yield is reduced. The formation of impurity B and impurity C can be effectively avoided at the reaction temperature of 65-70 ℃, and the high yield can be ensured. The reaction time is preferably 6 to 24 hours, and when the reaction time is less than 6 hours, the yield is lower, the reaction time is more than 24 hours, and the impurities B and C are increased.
In the step S2, after the reaction is finished, the water aqua is removed by adopting a filtering mode, and the filtrate is cooled to 0-10 ℃.
Further, the S1 specifically is:
s1-1, adding ethyl acetoacetate and 98% of concentrated sulfuric acid into reaction equipment, adding m-nitrobenzaldehyde in batches, controlling the temperature in the feeding process, stirring at 20-25 ℃ after the feeding is completed, reacting for 2-8 h, and obtaining crude 2- (3-nitrobenzylidene) ethyl acetoacetate after the reaction is completed;
s1-2, adding water into the system after the reaction of S1-1, pulping and dispersing, centrifugally filtering, adding water again into the obtained solid, pulping and dispersing, centrifugally filtering, and drying the obtained solid at 40-45 ℃ for 12 hours to obtain pure 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester.
Still further, in the S1-1, 85-95 parts of ethyl acetoacetate, 4.5-5.5 parts of 98% concentrated sulfuric acid and 95-105 parts of m-nitrobenzaldehyde are calculated according to parts by weight.
Still further, in the S1-1, 90 parts of ethyl acetoacetate, 5 parts of 98% concentrated sulfuric acid and 100 parts of m-nitrobenzaldehyde are calculated according to parts by weight.
In the step S1-1, water is added to carry out beating dispersion, wherein the water addition amount is 200 parts by mass.
Further, the S2 specifically is:
s2-1, adding 2- (3-nitrobenzyl) acetoacetic acid ethyl ester into ethanol, sequentially adding 3-methyl aminocrotonate and molecular sieve activated powder, heating to 65-70 ℃, and reacting for 16h;
s2-2, filtering out molecular sieve activated powder after the reaction is finished, cooling the filtrate to 0-10 ℃, stirring for 2h, centrifuging, and drying the obtained yellow solid at 60-65 ℃ for 6h to obtain nitrendipine.
Still further, in the S2-1, 148 to 155 parts of 2- (3-nitrobenzylidene) acetoacetate, 475 to 485 parts of ethanol, 82 to 88 parts of 3-aminocrotonic acid methyl ester and 20 to 33 parts of molecular sieve activated powder are calculated according to mass parts.
Still further, in the S2-1, 150 parts of ethyl 2- (3-nitrobenzylidene) acetoacetate, 480 parts of ethanol, 85 parts of 3-aminocrotonic acid methyl ester and 30 parts of molecular sieve activating powder are calculated according to parts by weight.
Compared with the prior art, the preparation method of the high-purity nitrendipine bulk drug has the following advantages:
1) According to the preparation method of the high-purity nitrendipine bulk drug, the purity of the prepared nitrendipine bulk drug is over 99.80 percent, the impurity B and the impurity C are both less than 0.1 percent, and other single impurities are not more than 0.1 percent by improving the preparation process;
2) According to the preparation method of the high-purity nitrendipine bulk drug, the water scavenger is added, and absolute ethyl alcohol is used as a reaction solvent, so that the generation of impurities B and C can be effectively reduced;
3) In the preparation method of the high-purity nitrendipine bulk drug, the preparation of the nitrendipine reacts at 65-70 ℃, and the formation of impurities B and C can be effectively avoided at the reaction temperature, and the high yield can be ensured.
Drawings
Fig. 1 is an HPLC profile of nitrendipine prepared according to example 1 of the present invention;
FIG. 2 is an HPLC chart of nitrendipine prepared in comparative example 1 of the present invention;
FIG. 3 is an HPLC chart of nitrendipine prepared in comparative example 2 of the present invention;
FIG. 4 is an HPLC chart of nitrendipine prepared in comparative example 3 of the present invention;
fig. 5 is an HPLC profile of nitrendipine prepared according to comparative example 4 of the present invention;
fig. 6 is an HPLC profile of nitrendipine prepared according to comparative example 5 of the present invention.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to the following examples and drawings.
Example 1
Pumping 90.0kg of ethyl acetoacetate and 5.0kg of 98% concentrated sulfuric acid into a 1000L kettle, adding 100.0kg of m-nitrobenzaldehyde in batches, heating in the feeding process, and stirring at 20-25 ℃ for reaction for 2-8 h after the addition is completed; gradually solidifying the reaction system, and obtaining crude 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester after the reaction is completed; adding 200kg of water into a reaction kettle for pulping and dispersing, stirring for 20 minutes, discharging, centrifugally filtering, pulping and dispersing the centrifugal solid with 200kg of water, centrifuging again, and drying the centrifugal solid at 40-45 ℃ for 12 hours to obtain about 155.0kg (98.74% of content) of pure 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester with a yield of 89.10%;
150.0kg of ethyl 2- (3-nitrobenzylidene) acetoacetate was added to 480.0kg of ethanol, 85.0kg of methyl 3-aminocrotonate was added thereto, and 30.0kg of molecular sieve activating powder was added thereto; after the material is added, the temperature is raised to 65-70 ℃, the reaction is carried out for 16 hours, after the reaction is finished, the molecular sieve activated powder is filtered, the filtrate is cooled to 0-10 ℃, the mixture is stirred for 2 hours, the system is centrifuged, the yellow solid is obtained after being dried for 6 hours at 60-65 ℃, 187.0kg (the content is 99.84 percent and the yield is 91.02 percent) of nitrendipine is obtained. The chromatographic purity of nitrendipine is 99.88%, impurity B is 0.06%, impurity C is 0.03%, and specific chromatographic data are shown in figure 1.
Comparative example 1
Referring to the preparation method in patent CN109734656B, 100.0g of 3-nitrobenzylidene acetoacetic acid ethyl ester intermediate and 46.0g of 3-amino butenoic acid methyl ester are reacted in advance at 70-75 ℃; after the reaction is carried out for 1.0 hour, 3.16ml of concentrated hydrochloric acid is added into the reaction system, the reaction is carried out at 70-75 ℃ after the addition, the TLC plate detects the completion of the reaction, the temperature is reduced to 15-20 ℃ after the reaction is completed, and the nitrendipine is obtained through filtration and recrystallization. The chromatographic purity of nitrendipine is 90.9659%, impurity B is 4.302%, impurity C is 4.647%, and specific chromatographic data are shown in figure 2.
Comparative example 2
Reference is made to the preparation method of patent CN111072553 a: 100.0g of (E) -2- (3-nitrobenzenemethylene) -3-oxo-butyric acid ethyl ester is added into 250.0ml of absolute ethyl alcohol, 48.0g of 3-aminocrotonic acid methyl ester is added, and the temperature is raised to 75-80 ℃ for reaction for 1.0 hour; adding 3.88g of acetic anhydride into the solution to react, continuously stirring for 30min, filtering, stirring, reacting and filtering to obtain a nitrendipine crude product; and recrystallizing the nitrendipine crude product to obtain the nitrendipine. The chromatographic purity of nitrendipine is 98.85%, the impurity B is 0.43%, the impurity C is 0.35%, and the specific chromatographic data is shown in figure 3.
As can be seen from comparison of example 1 and comparative examples 1-2, the nitrendipine bulk drug obtained by the preparation method provided by the invention has the purity of more than 99.8%, less impurities, 0.06% of impurity B and 0.03% of impurity C, and is superior to comparative examples 1-2.
Influence of moisture in the reaction System:
comparative example 3
100.0g of 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester is added into 405.0ml of absolute ethyl alcohol, 56.7g of 3-methyl aminocrotonate is added into a reaction system, 5.0g of water is added into the reaction system, the temperature is raised to 65-70 ℃, the reaction is carried out for 16 hours, after the reaction is finished, the filtrate is cooled to 0-10 ℃, the temperature is stirred for 2 hours, the system is centrifuged, a yellow solid is obtained, the condition of related substances is detected by HPLC, and the chromatographic purity chart is shown in figure 4.
Comparative example 4
On the basis of comparative example 3, 10.0g of water was added to the reaction system, and the other steps were the same as those of comparative example 3, except that the chromatographic purity map was shown in FIG. 5.
Comparative example 5
On the basis of comparative example 3, except that 15.0g of water was added to the reaction system, the other steps were the same as in comparative example 3, and the chromatographic purity profile was shown in FIG. 6.
The HPLC detection conditions for comparative examples 3 to 5 are shown in Table 1.
TABLE 1
| Numbering device | Water content | Nitrendipine purity | Impurity B | Impurity C |
| Comparative example 3 | 5％ | 98.25％ | 0.78％ | 0.64％ |
| Comparative example 4 | 10％ | 97.11％ | 1.12％ | 1.39％ |
| Comparative example 5 | 15％ | 95.30％ | 1.74％ | 2.51％ |
As can be seen from figures 4-6 and Table 1, the influence of water on the amount of impurity B and impurity C is shown, because the byproduct of the cyclization reaction is water of one molecule, under the condition that water exists, the exchange speed of methyl ester and ethyl ester can be increased, the water content in the system is increased, the transesterification speed is obviously increased, and the increase of impurity B and impurity C is obvious.
Influence of the reaction temperature:
the reaction temperature is also affected, the preferable temperature of the invention is 65-70 ℃, when the temperature reaches over 70 ℃, the speed of transesterification (the formation speed of the impurity B and the impurity C) is obviously increased, and when the reaction temperature is lower than 65 ℃, the speed of transesterification is obviously reduced, and the yield is reduced.
Effect of reaction time:
the reaction time is also affected, the reaction time is lower than 6 hours, the yield is lower, the reaction time is higher than 24 hours, and the impurities B and C are increased.
Influence of free acid in the cyclization system:
the free acid in the cyclization system can also be influenced, and in the operation method according to the patent CN109734656B and the patent CN111072553A, concentrated hydrochloric acid and acetic anhydride are respectively added into the system, so that the impurity B and the impurity C are obviously increased. Experiments show that the free acid exists to accelerate the generation of transesterification impurities.
In conclusion, the preparation method of the invention controls key steps in the reaction process, so that the prepared nitrendipine bulk drug has high purity and low impurity content.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (7)
1. The preparation method of the high-purity nitrendipine bulk drug is characterized by comprising the following steps:
preparation of S1, 2- (3-nitrobenzylidene) acetoacetate: using ethyl acetoacetate, 98% concentrated sulfuric acid and m-nitrobenzaldehyde as raw materials, and preparing crude 2- (3-nitrobenzylidene) ethyl acetoacetate at normal temperature; washing, centrifuging and drying to obtain pure 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester;
s2, preparation of nitrendipine: adding the pure 2- (3-nitrobenzylidene) acetoacetic acid ethyl ester prepared in the step S1 into an organic solvent, sequentially adding 3-methyl aminocrotonate and a water scavenger, heating to react, removing the water scavenger by adopting a filtering mode after the reaction is finished, cooling filtrate to 0-10 ℃, stirring, centrifuging, and drying the obtained yellow solid to obtain nitrendipine; wherein the organic solvent is absolute ethyl alcohol, and the water scavenger is 10-100% w/w of molecular sieve activated powder.
2. The method for preparing high-purity nitrendipine bulk drug according to claim 1, which is characterized in that: in the S2, the molar ratio of the ethyl 2- (3-nitrobenzylidene) acetoacetate to the methyl 3-aminocrotonate is 1:1 to 1.5.
3. The method for preparing high-purity nitrendipine bulk drug according to claim 1, which is characterized in that: in the step S2, the temperature is raised to 65-70 ℃ for 6-24 h.
4. The method for preparing high-purity nitrendipine bulk drug according to claim 1, which is characterized in that: the S1 specifically comprises the following steps:
s1-1, adding ethyl acetoacetate and 98% of concentrated sulfuric acid into reaction equipment, adding m-nitrobenzaldehyde in batches, controlling the temperature in the feeding process, stirring at 20-25 ℃ after the feeding is completed, reacting for 2-8 h, and obtaining crude 2- (3-nitrobenzylidene) ethyl acetoacetate after the reaction is completed;
s1-2, adding water into the system after the reaction of S1-1, pulping and dispersing, centrifugally filtering, adding water again into the obtained solid, pulping and dispersing, centrifugally filtering, and drying the obtained solid at 40-45 ℃ to obtain the pure 2- (3-nitrobenzylidene) acetoacetate.
5. The method for preparing high-purity nitrendipine bulk drug according to claim 4, which is characterized in that: in the S1-1, according to the parts by weight, 85-95 parts of ethyl acetoacetate, 4.5-5.5 parts of 98% concentrated sulfuric acid and 95-105 parts of m-nitrobenzaldehyde are mixed.
6. The method for preparing high-purity nitrendipine bulk drug according to claim 1, which is characterized in that: the step S2 is specifically as follows:
s2-1, adding 2- (3-nitrobenzyl) acetoacetic acid ethyl ester into ethanol, sequentially adding 3-methyl aminocrotonate and molecular sieve activated powder, heating to 65-70 ℃, and reacting for 16h;
s2-2, filtering out molecular sieve activated powder after the reaction is finished, cooling the filtrate to 0-10 ℃, stirring for 2h, centrifuging, and drying the obtained yellow solid at 60-65 ℃ to obtain nitrendipine.
7. The method for preparing high-purity nitrendipine bulk drug according to claim 6, which is characterized in that: in the S2-1, 148-155 parts of 2- (3-nitrobenzyl) acetoacetate, 475-485 parts of ethanol, 82-88 parts of 3-aminocrotonic acid methyl ester and 20-33 parts of molecular sieve activating powder are calculated according to parts by weight.
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