CN112645827A - Method for continuously synthesizing metoprolol and salt thereof - Google Patents
Method for continuously synthesizing metoprolol and salt thereof Download PDFInfo
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- CN112645827A CN112645827A CN202011566316.9A CN202011566316A CN112645827A CN 112645827 A CN112645827 A CN 112645827A CN 202011566316 A CN202011566316 A CN 202011566316A CN 112645827 A CN112645827 A CN 112645827A
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- metoprolol
- isopropylamine
- purity
- methoxyethyl
- ethanol solution
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- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960002237 metoprolol Drugs 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- 150000003839 salts Chemical class 0.000 title claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 98
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims abstract description 55
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- UEOWFGJMGUIGHC-UHFFFAOYSA-N 2-[[4-(2-methoxyethyl)phenoxy]methyl]oxirane Chemical compound C1=CC(CCOC)=CC=C1OCC1OC1 UEOWFGJMGUIGHC-UHFFFAOYSA-N 0.000 claims abstract description 28
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007788 liquid Substances 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000001384 succinic acid Substances 0.000 claims abstract description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 239000000047 product Substances 0.000 claims description 23
- 238000004821 distillation Methods 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- RQZBCLSVVDPFIC-UHFFFAOYSA-N 1-[2-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound COCCC1=CC=CC=C1OCC(O)CNC(C)C RQZBCLSVVDPFIC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000005292 vacuum distillation Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000002425 crystallisation Methods 0.000 abstract description 2
- 230000008025 crystallization Effects 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 238000010517 secondary reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 43
- 239000000543 intermediate Substances 0.000 description 31
- 235000019441 ethanol Nutrition 0.000 description 24
- 239000006227 byproduct Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- 230000003068 static effect Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 8
- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 description 8
- 238000005576 amination reaction Methods 0.000 description 8
- 239000000945 filler Substances 0.000 description 8
- 229960000939 metoprolol succinate Drugs 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- FAYGEALAEQKPDI-UHFFFAOYSA-N 4-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=C(O)C=C1 FAYGEALAEQKPDI-UHFFFAOYSA-N 0.000 description 5
- 239000011552 falling film Substances 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- BMWZKJJCLPAELA-UHFFFAOYSA-N butanedioic acid;ethanol Chemical compound CCO.OC(=O)CCC(O)=O BMWZKJJCLPAELA-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 201000007100 Pharyngitis Diseases 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000005979 thermal decomposition reaction Methods 0.000 description 2
- WPTKISQJQVFSQI-LREBCSMRSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 WPTKISQJQVFSQI-LREBCSMRSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- RZWHKKIXMPLQEM-UHFFFAOYSA-N 1-chloropropan-1-ol Chemical compound CCC(O)Cl RZWHKKIXMPLQEM-UHFFFAOYSA-N 0.000 description 1
- SSZWWUDQMAHNAQ-UHFFFAOYSA-N 3-chloropropane-1,2-diol Chemical compound OCC(O)CCl SSZWWUDQMAHNAQ-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 206010057040 Temperature intolerance Diseases 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000008543 heat sensitivity Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- -1 p-hydroxy phenethyl Chemical group 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
- C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for continuously synthesizing metoprolol, which comprises the following steps: (1) carrying out reduced pressure rectification on a 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene raw material to obtain an ethanol solution with the purity of more than 99 percent; (2) uniformly mixing the ethanol solution obtained in the step (1) with isopropylamine, and then feeding the mixture into a pipeline reactor to react to obtain metoprolol reaction solution; (3) and (3) depressurizing the reaction liquid, and then feeding the reaction liquid into a rectifying tower to recover isopropylamine, wherein tower bottom liquid contains high-purity metoprolol. The raw material purity reaches more than 99 percent through the rectification step, and colored impurities are also removed; when metoprolol is synthesized, a rapid reaction method of isopropylamine in a pipeline reactor is adopted, secondary reactions of secondary condensation are obviously reduced, the purity of the metoprolol reaches more than 98%, and a finished product of the raw material medicine with the purity of more than 99.5% can be obtained by crystallization after the metoprolol is salified with succinic acid. The route has high yield, low cost and simple operation, and is a green, environment-friendly and industrialized production process route.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for continuously synthesizing metoprolol and salt thereof.
Background
Metoprolol (also known as Metoprolol, betamethasone, Metoprolol, etc.) is a commonly used drug for treating various types of hypertension (combined with diuretic and vasodilator) and angina pectoris in clinic. Its chemical name is 1-Isopropylamino-3- [ p- (2-methoxyethyl) phenoxy ] -2-propanol, 1- (Isopropylamino) -3- (4- (2-methoxylethyl) phenoxy) propan-2-ol. Metoprolol is a second generation beta-receptor blocker, can selectively block beta 1 receptors and weaken myocardial damage caused by increase of cardiac adrenergic tension; it also reduces the heart rate, so it can treat irregular heart rate. Metoprolol can also reduce myocardial contractility and hypertension. Metoprolol reduces myocardial oxygen demand by slowing heart rate and myocardial contractile strength. Metoprolol is also helpful in treating sore throats, as it may cause sore throats when oxygen demand exceeds supply.
At present, many documents are reported for synthesizing metoprolol and intermediates, such as patents: us2005107635, us5082969, wo9822426, wo2007141593, cn200810115092.2, cn102503843, cn 102381995. The main synthetic route is as follows:
U.S. Pat. No. 5,50829,69 to synthetic II, under the alkaline condition, p-methoxyethylphenol reacts with epichlorohydrin, and the reaction lasts 15-20 hours at low temperature, and the reaction time is too long, and more ring-opening byproducts are generated; wo9822426 reacts with us2005107635 in water, the reaction temperature is increased, the II is purified by distillation, the reaction time is 3-5 hours, and the production reaction operation is inconvenient. In wo2007141593, after the p-methoxyethyl phenol and the alkali form a salt, the p-methoxyethyl phenol reacts at a low temperature for a long time. cn102381995 is improved, and after salifying at high temperature, the reaction time is shortened to 4 hours by reacting with epichlorohydrin at low temperature, but the reaction time is slightly longer. cn200810115092.2 uses phase transfer catalyst, but also uses a large amount of organic solvent such as dichloromethane or isopropanol, which increases the cost and the risk of environmental pollution.
Chinese patent application publication No. CN 105820057 a discloses a method for preparing metoprolol, which comprises reacting p-methoxyethylphenol with epichlorohydrin in a tubular reactor under alkaline conditions, distilling the reaction solution obtained from the tubular reactor under reduced pressure with slight negative pressure to obtain a mixed solution of II and water, and subjecting the mixed solution of II and water and isopropylamine to amination reaction in water to obtain metoprolol. The applicant finds that metoprolol prepared by the method also contains a plurality of byproducts, and the metoprolol can meet the standard requirements of the raw material medicaments only by more purification operations.
Therefore, it would be of great significance to provide a method for synthesizing metoprolol, so as to overcome the defects of the above reaction for synthesizing metoprolol, etc.
Disclosure of Invention
The invention aims to solve the problems in the process for synthesizing metoprolol, and provides a process route which has the advantages of short reaction time, less by-products, simple operation, environmental protection and industrial production.
In order to achieve the above object, the present invention provides a method for continuously synthesizing metoprolol, comprising the steps of:
(1) carrying out reduced pressure rectification on a 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene raw material to obtain a pure product with the purity of more than 99%, and preparing into an ethanol solution;
(2) uniformly mixing the ethanol solution obtained in the step (1) with isopropylamine, and then reacting in a pipeline reactor to generate 1-isopropylamino-3- [ (2-methoxyethyl) phenoxy ] -2-propanol reaction liquid;
(3) and (3) directly feeding the reaction liquid obtained in the step (2) into a rectifying tower after pressure reduction to recover the isopropylamine, wherein the tower bottom liquid contains high-purity metoprolol.
The inventor finds that when the p-methoxyethylphenol and the epichlorohydrin are subjected to condensation reaction, the main side reaction is that the epoxy in the molecule of the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene is subjected to ring opening under the alkaline condition to generate a diol byproduct (III) (shown in the following formula). Meanwhile, epichlorohydrin can be hydrolyzed into chloropropanol and the like. Therefore, increasing the purity of II by distillation or rectification is advantageous for the subsequent reaction and for increasing the purity of the final product. The exact boiling point of intermediate II is not reported in the literature, but atmospheric boiling points around 300 ℃ are predicted. The boiling point actually measured by experiments is 130 +/-2 ℃/2mmHg, and the purification can be carried out by reduced pressure distillation or reduced pressure rectification. However, since the crude product contains not only the diol byproduct (III) with a higher boiling point, but also a small amount of 3-chloropropanediol, epichlorohydrin byproduct, solvent and the like, only by reduced pressure distillation, the improvement of the purity of the intermediate II is limited, and rectification and purification are required. Meanwhile, in the experimental process, the intermediate II is also found to have heat sensitivity, and the intermediate II is accompanied with thermal decomposition at the temperature of more than 160 ℃. This rectification process must therefore be carried out under high vacuum conditions and the internal temperature needs to be below 160 ℃. In order to reduce the thermal decomposition of the intermediate II in the rectification process, the intermediate II is purified by adopting a falling film rectification technology, so that the purity of the intermediate II reaches more than 99 percent, and then the intermediate II is put into the next step for use.
In the invention, the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene raw material is synthesized by a conventional method, and the content is about 96 percent.
Preferably, in the step (1), the pressure during the vacuum rectification is less than 2mmHg, the temperature of a tower bottom is less than 160 ℃, and the theoretical plate number of the rectification tower is controlled to be 2-5.
Preferably, in the step (1), the concentration of the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene in the ethanol solution is 10-20%.
Preferably, in the step (2), the ethanol solution of the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene is preheated, mixed with preheated isopropylamine through a mixer and then enters a pipeline reactor for reaction.
Further, the ethanol solution of the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene is preheated to 80-95 ℃; preheating the isopropylamine to 50-65 ℃; the reaction temperature of the pipeline reactor is 90-100 ℃.
When II is reacted with isopropylamine, the product I is a secondary amine which can still be reacted with II to form a dimeric by-product IV. The by-product can also form salts with succinic acid or tartaric acid, which affects the quality of the product, and the generation of the by-product needs to be minimized through process optimization. The by-product formation can be reduced to some extent by the amount of isopropylamine used during the reaction, but the reduction ratio is limited. It is also desirable to avoid side reactions of the product with II by increasing the reaction temperature so that isopropylamine reacts rapidly with II in a pipeline reactor at elevated temperatures under plug flow conditions. The using amount of the isopropylamine is increased, and the proportion of a by-product IV is effectively reduced by realizing a plug flow reaction.
Preferably, in the step (2), the molar ratio of the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene to the isopropylamine is 1: 5-1: 15.
as a further preference, in the step (3), the excess isopropylamine is recovered by means of atmospheric distillation; the content of isopropylamine in the recovered tower bottom liquid is less than 0.1 percent.
The invention also provides a preparation method of the metoprolol salt, which comprises the following steps:
(A) obtaining metoprolol in ethanol solution according to the method described above;
(B) mixing the ethanol solution of metoprolol with the ethanol solution of succinic acid or tartaric acid to form salt, and then carrying out post-treatment to obtain the metoprolol salt.
The metoprolol salt is metoprolol succinic acid or metoprolol tartaric acid.
Preferably, in step (B), the molar ratio of metoprolol to succinic acid or tartaric acid is 1: 0.49-1: 0.51.
preferably, in step (B), the post-treatment comprises: filtering to remove insoluble substances, and cooling and crystallizing the filtrate to directly obtain metoprolol.
Compared with the prior art, the invention aims to overcome the defects of reaction synthesis of metoprolol, long reaction time, more byproducts and the like in the prior art. The purity of the intermediate II is improved through rectification, and the high-purity, colorless and transparent intermediate II is obtained, so that the steps of decoloring and recrystallizing in the subsequent production process can be avoided, and the production efficiency is improved; by adopting the measures of increasing the dosage of isopropylamine during amination reaction and carrying out plug flow reaction at high temperature, the generation of a by-product IV is effectively reduced, so that the purity of an aminated compound I synthesized by reaction directly reaches more than 98.5 percent, and the purity of a product directly meets the standard requirement of a raw material medicament through a salt-forming crystallization process with succinic acid or tartaric acid. The continuous reaction is carried out at high temperature in a pipeline way, so that the time is greatly shortened, the quality and the yield of the product are improved, and the operation is simple and environment-friendly.
Detailed Description
In order that those skilled in the art will better understand the present invention, the following examples are provided to further illustrate the present invention, but the scope of the present invention is not limited by these examples.
Example 1
1500kg of crude 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene with a main content of 96.5 percent is put into a 2-square falling film rectifying tower at a time. The filler is 316L stainless steel wire mesh filler with low specific surface area, the height is 2m, the number of theoretical plates is about 5, and the recovery ratio is 1:1. controlling the internal temperature to be lower than 150 ℃ during rectification, controlling the vacuum degree to be 1.5mmHg, and collecting fractions with the top temperature of 115 ℃ and the temperature of 125 ℃ as finished products to obtain 1306kg of an intermediate II with the purity of 99.4 percent. The main component of the front cut is still intermediate II, and the intermediate II can be recovered by rectification again after a certain amount of accumulation. Then the pure product of the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene is prepared into 10 percent (wt) absolute ethyl alcohol solution.
Conveying the prepared 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene 10% absolute ethyl alcohol solution to a heat exchanger by a metering pump according to the flow rate of 208kg/h (0.1kmol/h) per hour for heating, heating to 90-92 ℃, and then entering a static mixer; meanwhile, an ethanol solution (the content of the isopropylamine is about 95 percent) containing 62.11kg/h (1Kmol/h) of the isopropylamine is also sent into another heat exchanger by a metering pump, and is heated to 50-55 ℃ and then enters a static mixer to be efficiently mixed with the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene solution. The mixed reaction solution directly enters a pipeline reactor with the inner diameter of 6mm for reaction, the length of the pipeline reactor is 60 meters, the pipeline reactor is coiled into a round coil with the diameter of 600mm, and the whole pipeline reactor is immersed in hot water with the temperature of 90-92 ℃. The tail end of the pipeline reactor is decompressed to normal pressure by a pressure reducing valve, and is directly connected to an isopropylamine continuous rectifying tower for normal pressure collection, and the fraction with the top temperature of 33-34 ℃ is recovered isopropylamine. Recovering excessive isopropylamine from the tower top by rectification, wherein the recovered isopropylamine contains 5% ethanol, and obtaining an ethanol solution of an amination product I from the tower bottom. The detection of the tower bottoms shows that the isopropylamine is less than 0.1 percent; HPLC analysis shows that the content of amide I is 99.5%, the yield is 98% (based on intermediate II), and the content of impurity IV is 0.2%.
And enabling the tower bottom liquid of the isopropylamine continuous recovery rectifying tower to flow into a 500L salt forming kettle through overflow, conveying by using a pump under the ethanol reflux condition, adding 0.05mol/h of succinic acid ethanol solution, and stirring to form salt. The metoprolol succinate solution is conveyed by a pump, is filtered to remove possible mechanical impurities, and enters a continuous crystallizer to be cooled and crystallized. And carrying out solid-liquid separation and drying to obtain the finished metoprolol succinate. After analysis, the HPLC chromatographic purity of the product reaches 99.85%, the impurity IV is not detected, and the yield is 95.1% (based on the intermediate II).
Example 2
1500kg of crude 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene with a main content of 96.5 percent is put into a 2-square falling film rectifying tower at a time. The filler is 316L stainless steel wire mesh filler with low specific surface area, the height is 2m, the number of theoretical plates is about 5, and the recovery ratio is 1:1. controlling the internal temperature to be lower than 150 ℃ during rectification, controlling the vacuum degree to be 1.5mmHg, and collecting fractions with the top temperature of 115 ℃ and the temperature of 125 ℃ as finished products to obtain 1306kg of an intermediate II with the purity of 99.6 percent. The main component of the front cut is still intermediate II, and the intermediate II can be recovered by rectification again after a certain amount of accumulation. Then the pure product of the obtained 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene is prepared into 13 percent absolute ethyl alcohol solution.
Conveying the prepared 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene 13% absolute ethyl alcohol solution to a heat exchanger by a metering pump according to the flow of 160kg/h (0.1kmol/h) per hour for heating, heating to 90-92 ℃, and then entering a static mixer; at the same time, 31.05kg/h (0.5Kmol/h) of ethanol solution (isopropylamine content is about 95%) is also sent into another heat exchanger by a metering pump, and is heated to 50-55 ℃ and then enters a static mixer to be efficiently mixed with the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene solution. The mixed reaction solution directly enters a pipeline reactor with the inner diameter of 6mm for reaction, the length of the pipeline reactor is 60 meters, the pipeline reactor is coiled into a round coil with the diameter of 600mm, and the whole pipeline reactor is immersed in hot water with the temperature of 90-92 ℃. Reducing the pressure of the tail end of the pipeline reactor to normal pressure by using a pressure reducing valve, directly connecting the tail end of the pipeline reactor to an isopropylamine continuous rectifying tower, and collecting the distillate with the top temperature of 33-34 ℃ at normal pressure as recovered isopropylamine. Recovering excessive isopropylamine from the tower top by rectification, wherein the recovered isopropylamine contains 5% ethanol, and obtaining an ethanol solution of an amination product I from the tower bottom. The detection of the tower bottoms shows that the isopropylamine is less than 0.1 percent; HPLC analysis shows that the content of amide I is 99.5%, the yield is 98.3% (based on intermediate II), and the content of impurity IV is 0.23%.
And enabling the tower bottom liquid of the isopropylamine continuous recovery rectifying tower to flow into a 500L salt forming kettle through overflow, conveying by using a pump under the ethanol reflux condition, adding 0.05mol/h of succinic acid ethanol solution, and stirring to form salt. The metoprolol succinate solution is conveyed by a pump, is filtered to remove possible mechanical impurities, and enters a continuous crystallizer to be cooled and crystallized. And carrying out solid-liquid separation and drying to obtain the finished metoprolol succinate. After analysis, the HPLC chromatographic purity of the product reaches 99.87 percent, the impurity IV is not detected, and the yield is 95.3 percent (based on the intermediate II).
Example 3
1500kg of crude 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene with a main content of 96.5 percent is put into a 2-square falling film rectifying tower at a time. The filler is 316L stainless steel wire mesh filler with low specific surface area, the height is 2m, the number of theoretical plates is about 5, and the recovery ratio is 1:1. controlling the internal temperature to be lower than 150 ℃ during rectification, controlling the vacuum degree to be 1.5mmHg, and collecting fractions with the top temperature of 115 ℃ and the temperature of 125 ℃ as finished products to obtain 1306kg of an intermediate II with the purity of 99.6 percent. The main component of the front cut is still intermediate II, and the intermediate II can be recovered by rectification again after a certain amount of accumulation. Then the pure product of the obtained 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene is prepared into 13 percent absolute ethyl alcohol solution.
Conveying the prepared 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene 15% absolute ethyl alcohol solution to a heat exchanger by a metering pump according to the flow rate of 138.7kg/h (0.1kmol/h) per hour for heating, heating to 90-92 ℃, and then entering a static mixer; at the same time, 49.68kg/h (0.8Kmol/h) of ethanol solution (isopropylamine content is about 95%) is also sent into another heat exchanger by a metering pump, and is heated to 50-55 ℃ and then enters a static mixer to be efficiently mixed with the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene solution. The mixed reaction solution directly enters a pipeline reactor with the inner diameter of 6mm for reaction, the length of the pipeline reactor is 60 meters, the pipeline reactor is coiled into a round coil with the diameter of 600mm, and the whole pipeline reactor is immersed in hot water with the temperature of 90-92 ℃. Reducing the pressure of the tail end of the pipeline reactor to normal pressure by using a pressure reducing valve, directly connecting the tail end of the pipeline reactor to an isopropylamine continuous rectifying tower, and collecting the distillate with the top temperature of 33-34 ℃ at normal pressure as recovered isopropylamine. Recovering excessive isopropylamine from the tower top by rectification, wherein the recovered isopropylamine contains 5% ethanol, and obtaining an ethanol solution of an amination product I from the tower bottom. The detection of the tower bottoms shows that the isopropylamine is less than 0.1 percent; HPLC analysis shows that the content of amide I is 99.6%, the yield is 98.5% (based on intermediate II), and the content of impurity IV is 0.15%.
And enabling the tower bottom liquid of the isopropylamine continuous recovery rectifying tower to flow into a 500L salt forming kettle through overflow, conveying by using a pump under the ethanol reflux condition, adding 0.05mol/h of succinic acid ethanol solution, and stirring to form salt. The metoprolol succinate solution is conveyed by a pump, is filtered to remove possible mechanical impurities, and enters a continuous crystallizer to be cooled and crystallized. And carrying out solid-liquid separation and drying to obtain the finished metoprolol succinate. After analysis, the HPLC chromatographic purity of the product reaches 99.9 percent, the impurity IV is not detected, and the yield is 95.5 percent (based on the intermediate II).
Example 4
1500kg of crude 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene with a main content of 96.5 percent is put into a 2-square falling film rectifying tower at a time. The filler is 316L stainless steel wire mesh filler with low specific surface area, the height is 2m, the number of theoretical plates is about 5, and the recovery ratio is 1:1. controlling the internal temperature to be lower than 150 ℃ during rectification, controlling the vacuum degree to be 1.5mmHg, and collecting fractions with the top temperature of 115 ℃ and the temperature of 125 ℃ as finished products to obtain 1306kg of an intermediate II with the purity of 99.6 percent. The main component of the front cut is still intermediate II, and the intermediate II can be recovered by rectification again after a certain amount of accumulation. Then the obtained pure product of the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene is prepared into 20 percent absolute ethyl alcohol solution.
Conveying the prepared 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene 20% absolute ethyl alcohol solution to a heat exchanger by a metering pump according to the flow rate of 104kg/h (0.1kmol/h) per hour for heating, heating to 90-92 ℃, and then entering a static mixer; meanwhile, an ethanol solution (the content of the isopropylamine is about 95 percent) containing 93.15kg/h (1.5Kmol/h) of the isopropylamine is also sent into another heat exchanger by a metering pump, and is heated to 50-55 ℃ and then enters a static mixer to be efficiently mixed with the 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene solution. The mixed reaction solution directly enters a pipeline reactor with the inner diameter of 6mm for reaction, the length of the pipeline reactor is 60 meters, the pipeline reactor is coiled into a round coil with the diameter of 600mm, and the whole pipeline reactor is immersed in hot water with the temperature of 90-92 ℃. Reducing the pressure of the tail end of the pipeline reactor to normal pressure by using a pressure reducing valve, directly connecting the tail end of the pipeline reactor to an isopropylamine continuous rectifying tower, and collecting the distillate with the top temperature of 33-34 ℃ at normal pressure as recovered isopropylamine. Recovering excessive isopropylamine from the tower top by rectification, wherein the recovered isopropylamine contains 5% ethanol, and obtaining an ethanol solution of an amination product I from the tower bottom. The detection of the tower bottoms shows that the isopropylamine is less than 0.1 percent; HPLC analysis shows that the content of amide I is 99.58%, the yield is 98.7% (based on intermediate II), and the content of impurity IV is 0.12%.
And enabling the tower bottom liquid of the isopropylamine continuous recovery rectifying tower to flow into a 500L salt forming kettle through overflow, conveying by using a pump under the ethanol reflux condition, adding 0.05mol/h of succinic acid ethanol solution, and stirring to form salt. The metoprolol succinate solution is conveyed by a pump, is filtered to remove possible mechanical impurities, and enters a continuous crystallizer to be cooled and crystallized. And carrying out solid-liquid separation and drying to obtain the finished metoprolol succinate. After analysis, the HPLC chromatographic purity of the product reaches 99.92 percent, the impurity IV is not detected, and the yield is 95.6 percent (based on the intermediate II).
Comparative example 1
Preparing a weak alkaline solution with the pH value of 9 by using p-hydroxy phenethyl ether and a 10% sodium hydroxide solution, and heating to 98-100 ℃; adding epoxy chloropropane into an epoxy chloropropane kettle, and heating to 90-92 ℃ for later use; the flow rate of the weak alkaline solution of the p-hydroxyethyl methyl ether is 60kg/h, the flow rate of the epichlorohydrin is 13.9 kg/h, and the molar ratio of the p-hydroxyethyl methyl ether to the epichlorohydrin is 1: 1.4, respectively pumping into a static mixer, reaching the requirement of full mixing when flowing through the static mixer at the speed of 3 m/s, then entering a pipeline reactor, controlling the temperature of the reactor to be 110-115 ℃, controlling the pressure to be 0.2-0.3 MPa, controlling the reaction residence time in the pipeline to be 15min, carrying out steam distillation with slight negative pressure (-0.04-0.08 MPa) after the reaction is finished, and recovering epoxy chloropropane to obtain a mixed solution of water II, wherein the HPLC chromatographic purity of a compound II is 95.2%, and the diol byproduct (III) is about 2.7%; directly feeding the cooled mixed liquid of II and water into an amination reaction kettle, simultaneously pumping 80% of isopropylamine aqueous solution with the flow rate of 11.3 kg/h (the molar theoretical ratio of the material II to the isopropylamine is 1:1.8), feeding into the amination reaction kettle for reaction for 5h, overflowing into the next reaction kettle, continuing the reaction, keeping the reaction temperature at 10 ℃ until the reaction is finished, extracting the reaction solution by using toluene, recovering the isopropylamine from wastewater, concentrating partial toluene to obtain crude metoprolol, wherein the HPLC chromatographic purity of the metoprolol is 94.3%, and the dimerization byproduct IV is about 3.6%; cooling and crystallizing to obtain 20.5 kg/h of metoprolol, the HPLC chromatographic purity of the metoprolol is 98.1 percent, the dimerization byproduct IV is about 0.5 percent, and the yield is 85 percent.
Claims (9)
1. A method for continuously synthesizing metoprolol, which is characterized by comprising the following steps:
(1) carrying out reduced pressure rectification on a 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene raw material to obtain a pure product with the purity of more than 99%, and preparing into an ethanol solution;
(2) uniformly mixing the ethanol solution obtained in the step (1) with isopropylamine, and then reacting in a pipeline reactor to generate 1-isopropylamino-3- [ (2-methoxyethyl) phenoxy ] -2-propanol reaction liquid;
(3) and (3) directly feeding the reaction liquid obtained in the step (2) into a rectifying tower after pressure reduction to recover the isopropylamine, wherein the tower bottom liquid contains high-purity metoprolol.
2. The method for continuously synthesizing metoprolol according to claim 1, wherein in the step (1), the pressure during the vacuum distillation is less than 2mmHg, the temperature of a tower bottom is less than 160 ℃, and the theoretical plate number of the distillation tower is controlled to be 2-5.
3. The method for continuously synthesizing metoprolol according to claim 1, wherein in the step (1), the concentration of 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene in the ethanol solution is 10-20%.
4. The method for continuously synthesizing metoprolol according to claim 1, wherein in the step (2), the ethanol solution of 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene and isopropylamine are heated, mixed by a mixer and then enter a pipeline reactor for reaction.
5. The method for continuously synthesizing metoprolol according to claim 1, wherein in the step (2), the molar ratio of 1- (2, 3-epoxypropoxy) -4- (2-methoxyethyl) benzene to isopropylamine is 1: 5-1: 15.
6. the process for the continuous synthesis of metoprolol according to claim 1 or 5, characterized in that in step (3), the excess isopropylamine is recovered by means of atmospheric distillation; the content of isopropylamine in the recovered tower bottom liquid is less than 0.1 percent.
7. The preparation method of metoprolol salt is characterized by comprising the following steps:
(A) obtaining metoprolol in ethanol according to the method of any one of claims 1 to 6;
(B) mixing the ethanol solution of metoprolol with the ethanol solution of succinic acid or tartaric acid to form salt, and then carrying out post-treatment to obtain the metoprolol salt.
8. The process for the preparation of metoprolol salt according to claim 7, wherein in step (B), the molar ratio of metoprolol to succinic acid or tartaric acid is 1: 0.49-1: 0.51.
9. the process for the preparation of metoprolol salt according to claim 8, wherein in step (B) the post-treatment comprises: filtering to remove insoluble substances, and cooling and crystallizing the filtrate to directly obtain metoprolol.
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