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CAS No. :56718-70-8 MDL No. :MFCD00799225
Formula : C12H16O3 Boiling Point : -
Linear Structure Formula :- InChI Key :UEOWFGJMGUIGHC-UHFFFAOYSA-N
M.W :208.25 Pubchem ID :92515
Synonyms :

Safety of [ 56718-70-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P233-P260-P261-P264-P271-P280-P302+P352-P304-P304+P340-P305+P351+P338-P312-P321-P332+P313-P337+P313-P340-P362-P403-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
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Application In Synthesis of [ 56718-70-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 56718-70-8 ]
  • Downstream synthetic route of [ 56718-70-8 ]

[ 56718-70-8 ] Synthesis Path-Upstream   1~2

  • 1
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  • [ 56718-70-8 ]
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YieldReaction ConditionsOperation in experiment
95%
Stage #1: at 60℃; for 12 h; Sealed tube
Stage #2: With water In N,N-dimethyl-formamide at 60℃; for 12 h; Sealed tube
2-[4-(2-Methoxyethyl)phenoxy]methyl}oxirane (20 g, 93.1 mmol) and propan-2-amine (8.34 g, 139.7 mmol) were combined in DMF and heated to 60 °C in a pressure vessel for 12 h, after which the vessel was allowed to cool to r.t. before adding deionized H2O (32.28 mL, 50 equiv) in one portion. The flask was resealed and allowed to react for an additional 12 h at 60 °C. Solvent and excess amine were removed on a rotary evaporator (35 °C/22.5) to afford 24.5 g (95percent) of metoprolol freebase as a white semi-solid in >95percent purity (1H NMR); Rf = 0.28 (1:9 MeOH/CHCl3). IR (thin film): 3299, 3034, 2966, 1613 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.03 (d, J = 7.1 Hz, 2 H), 6.77 (d, J = 7.1 Hz, 2 H), 4.00 (ddt, J = 7.5, 7.3, 6.8 Hz, 1 H), 3.83–5.09 (m, 2 H), 3.49 (t, J = 7.5 Hz, 2 H), 3.27 (s, 3 H), 3.23 (br s, 1 H), 3.78–3.72 (m, 4 H), 2.71 (dd, J = 6.8, 6.6 Hz, 1 H), 1.03 (d, J = 6.9 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 157.0, 131.0, 129.5, 114.2, 73.6, 70.6, 68.1, 58.4, 59.5, 48.7, 35.1, 22.7, 22.6. ESI-MS: m/z (percent) = (pos) 268.2 ([M + H]+, 100); (neg) 266.2 ([M – H]–, 100).
93.1% at 80℃; Flow reactor The compound (II), water and 70percent of the isopropylamine adding an aqueous solution in the reactor to the ammoniation reaction (material II with isopropylamine mol theoretical ratio of 1: 1.5), raising the temperature to 80 °C, reaction 3 - 4 hours, cooled to 40 - 50 °C, extraction of methylbenzene reaction solution, concentrated part after the toluene, cooling crystallization to get the pure product metoprolol 23.3 kg/hour, yield 93.1percent.
88% at 0 - 30℃; for 3 h; Step 2: Metoprolol base Our currently-preferred temperature during addition of epoxide is 10° to 25°C. Our currently-preferred molar ratio of epoxide: isopropyl amine is 1 : 5.25 A 0.25 ; our most- preferred ratio is 1: 5.25 i 0.05. After addition of epoxide, the epoxide and isopropyl amine mixture is reacted in aqueous
media (e. g. , water) at a temperature of not greater than 30° C. Our currently preferred ratio of water to epoxide is 2: 1 volume: weight. At the maximum temperature of 30° C, the reaction completes in about 3 hours time. In order to achieve high purity it is necessary to maintain a temperature range of about 5° C to not more than about 25° C. The reaction works below 5° C, albeit is sluggish. Formation of impurity at RRT 0.35 (as measured by gas chromatography) is minimized by operating at not more than about 30° C. We have observed that in cases where the temperature rises above the range of 30° C, the impurity increases. We prefer to control the reaction temperature by controlling the rate of epoxide addition; if too much epoxide is added too rapidly, then the reaction becomes exothermic and the temperature can exceed 30°C. Accordingly, we prefer to begin to add epoxide at about 0° to 5°C, and add epoxide at a rate which maintains the exothermic reaction mixture below 25° C. After the epoxide is completely added, then we allow the temperature to raise to not more than 30° C, and then maintain the temperature for approximately four hours, or until the reaction is completed. On completion of reaction, the reaction mixture is cooled to 0° to 5°C. Cooling the reaction mass before the following step (quenching the mass with water) is important because quenching the mass with water is exothermic and so, to maintain a maximum temperature under about 25 °C, the reaction mass must be cooled to less than this. The reaction mass is quenched by 2.25 volume of water, maintaining the temperature at not more than 25 °C. The product is then extracted using 3 volumes of toluene. The toluene layer is washed with water for removal of isopropyl amine; after three water washes, isopropyl amine content is less than 0.5percent. Traces of isopropyl amine are removed by maintaining under vacuum, below 25° C. It is necessary to eliminate traces of isopropyl amine at a temperature below 25° C, as the presence of isopropyl amine during distillation of toluene above 25° C leads to the formation of an impurity at RRT 1.54 (as measured by gas chromatography). By following the process described above, this impurity formation is avoided. In case when isopropyl amine remains in the traces, the impurity is detected at RRT 1.54 (as measured by gas chromatography). Thus, following process as per present invention, formation of the impurities at RRT 0.35 RRT 1.54 are under control, which leads to yield highly pure Metoprolol base in higher yields. The analysis of a sample of the toluene layer confirms the absence of isopropyl amine in the toluene. The toluene is distilled out at temperature 30° to 40° C under vacuum. The residue of metoprolol base so obtained shows a purity of greater than 99percent, and a yield of which is in range of 88 to 89percent of the theoretical stoicheometric maximum yield.
88% at 0 - 30℃; for 3 h; Step 2: Metoprolol base Our currently-preferred temperature during addition of epoxide is 10° to 25°C. Our currently-preferred molar ratio of epoxide: isopropyl amine is 1 : 5.25 A 0.25 ; our most- preferred ratio is 1: 5.25 i 0.05. After addition of epoxide, the epoxide and isopropyl amine mixture is reacted in aqueous
media (e. g. , water) at a temperature of not greater than 30° C. Our currently preferred ratio of water to epoxide is 2: 1 volume: weight. At the maximum temperature of 30° C, the reaction completes in about 3 hours time. In order to achieve high purity it is necessary to maintain a temperature range of about 5° C to not more than about 25° C. The reaction works below 5° C, albeit is sluggish. Formation of impurity at RRT 0.35 (as measured by gas chromatography) is minimized by operating at not more than about 30° C. We have observed that in cases where the temperature rises above the range of 30° C, the impurity increases. We prefer to control the reaction temperature by controlling the rate of epoxide addition; if too much epoxide is added too rapidly, then the reaction becomes exothermic and the temperature can exceed 30°C. Accordingly, we prefer to begin to add epoxide at about 0° to 5°C, and add epoxide at a rate which maintains the exothermic reaction mixture below 25° C. After the epoxide is completely added, then we allow the temperature to raise to not more than 30° C, and then maintain the temperature for approximately four hours, or until the reaction is completed. On completion of reaction, the reaction mixture is cooled to 0° to 5°C. Cooling the reaction mass before the following step (quenching the mass with water) is important because quenching the mass with water is exothermic and so, to maintain a maximum temperature under about 25 °C, the reaction mass must be cooled to less than this. The reaction mass is quenched by 2.25 volume of water, maintaining the temperature at not more than 25 °C. The product is then extracted using 3 volumes of toluene. The toluene layer is washed with water for removal of isopropyl amine; after three water washes, isopropyl amine content is less than 0.5percent. Traces of isopropyl amine are removed by maintaining under vacuum, below 25° C. It is necessary to eliminate traces of isopropyl amine at a temperature below 25° C, as the presence of isopropyl amine during distillation of toluene above 25° C leads to the formation of an impurity at RRT 1.54 (as measured by gas chromatography). By following the process described above, this impurity formation is avoided. In case when isopropyl amine remains in the traces, the impurity is detected at RRT 1.54 (as measured by gas chromatography). Thus, following process as per present invention, formation of the impurities at RRT 0.35 RRT 1.54 are under control, which leads to yield highly pure Metoprolol base in higher yields. The analysis of a sample of the toluene layer confirms the absence of isopropyl amine in the toluene. The toluene is distilled out at temperature 30° to 40° C under vacuum. The residue of metoprolol base so obtained shows a purity of greater than 99percent, and a yield of which is in range of 88 to 89percent of the theoretical stoicheometric maximum yield.

Reference: [1] Synthesis (Germany), 2017, vol. 49, # 6, p. 1231 - 1242
[2] Patent: CN106543015, 2017, A, . Location in patent: Paragraph 0031; 0033; 0034; 0037; 0040
[3] Patent: WO2005/46568, 2005, A2, . Location in patent: Page/Page column 6-8
[4] Patent: WO2005/46568, 2005, A2, . Location in patent: Page/Page column 6-8
[5] Journal of Organic Chemistry, 2011, vol. 76, # 21, p. 8768 - 8780
[6] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 5, p. 738 - 747
[7] European Journal of Pharmaceutical Sciences, 2000, vol. 11, # 2, p. 141 - 155
[8] Patent: US6252113, 2001, B1,
[9] Patent: US2009/247642, 2009, A1, . Location in patent: Page/Page column 3-4
[10] Patent: US2005/107635, 2005, A1, . Location in patent: Page/Page column 2
[11] Chemical Communications, 2015, vol. 51, # 82, p. 15133 - 15136
[12] Catalysis Science and Technology, 2014, vol. 4, # 11, p. 3899 - 3908
  • 2
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YieldReaction ConditionsOperation in experiment
91 %Chromat. at 240℃; for 0.00833333 h; In this example, epoxide aminolysis reactions using a continuous flow microreactor was applied to the synthesis of metoprolol 19.As shown in Table 2, the synthesis of metoprolol 19 centers around the aminolysis of the readily available epoxide 20 with isopropyl amine. The epoxide aminolysis is typically performed using multiple equivalents of isopropyl amine at reflux in a polar protic solvent, with reaction times ranging from 2 to 5 h. In examining batch microwave conditions, it was noted that the amount of 19 and bis-alkylation side product 21 was dependent on reactor headspace due to the low boiling point of isopropyl amine (Table 2, Entries 1 and 2). However, under microreactor conditions, loss of the volatile amine at high temperatures was not a concern. At 500 psi, temperatures up to 240° C. were achieved before flashing of ethanol was observed in the microreactor. Using only 1.2 equiv of isopropyl amine, almost full conversion and 72percent yield of metoprolol were obtained with 1 min residence times (Table 2, Entry 5). Increasing the amount of isopropyl amine to 4 equiv did not hinder the ability to maintain the 240° C. reaction temperature, and excellent conversions (98percent) were obtained in only 15 s (Table 2, Entry 8). The large excess of amine led to a significant decrease in the formation of 21 and a 91percent yield of metoprolol was realized in extremely short reaction times. Under these conditions, a single 120 μL microreactor working under continuous flow operation is capable of delivering 7.0 g/h (61 kg/year) of metoprolol. Operating 17 microreactors in parallel could ultimately produce over 1 metric ton of this important drug per year.
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 2, p. 432 - 440
[2] Organic Process Research and Development, 2010, vol. 14, # 2, p. 432 - 440
[3] Patent: US2011/118469, 2011, A1, . Location in patent: Page/Page column 10-11
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