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A technology for intermediates and compounds, applied in the field of chemical pharmacy, achieves the effects of less environmental pollution, low production cost, mild and safe reaction conditions
Pending Publication Date: 2022-06-03
YANGZHOU ZHONGBAO PHARMA
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[0006] The synthetic routes reported by these two patents are similar, and most of them use highly toxic reagents, Pd / C hydrogenation and high-risk high-pressure reactions in the synthetic process.
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Embodiment 1
[0068] Embodiment 1: the synthesis of refenacin intermediate ( figure 1 )
[0069] (1) Add 76.32g of sodium carbonate to a 2L reaction flask, stir to dissolve with 600mL of water, cool down to 0°C; weigh 82.5g of methylaminoacetaldehyde dimethyl acetal material and add 600mL of 2-methyltetrahydrofuran Make a mixed solution, add it to the reaction bottle, and keep it warm at 0°C; weigh a total of 102.3g of Fmoc-Cl, add it dropwise to the reaction bottle, and keep it warm at 0°C during the dropping process; after 1h of dropping, raise the temperature to 20°C and keep it warm for 5h. Stand for separation and keep the organic phase to obtain formula II. The organic phase is directly used for feeding in the next step.
[0070] (2) The organic phase in step (1) was reacted with 600 mL of 3mol / L hydrochloric acid aqueous solution at 20° C. for 8 h; layer; the aqueous phases were combined, 600 mL of EA was added to stir and extract, and the layers were allowed to stand; the organic ...
Embodiment 2
[0074] The synthetic route of the refenacin intermediate in the present invention has been fully optimized for parameters, and the parameter optimization results are as follows:
[0075] 1. Fmoc protection reaction of amino group
[0076] (1) The Fmoc protection reaction solvent type optimization result of amino group is as follows (table 1), and other parameters are with step (1) in embodiment 1:
[0077] Table 1
[0078]
[0079] From the above results, it can be seen that when 2-methyltetrahydrofuran is used as the Fmoc protection reaction solvent of the amino group, Fmoc-Cl can react completely, while the other three solvents Fmoc-Cl are all remaining.
[0080] (2) The Fmoc protection reaction solvent ratio optimization result of amino group is as follows (table 2), and other parameters are with step (1) in embodiment 1:
[0081] Table 2
[0082]
[0083] From the above results, it can be seen that when the volume ratio of 2-methyltetrahydrofuran is 6:1, Fmoc-Cl c...
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Abstract
The invention discloses a preparation method of a rafenasin intermediate. The preparation method comprises the following steps: (1) carrying out protective reaction on methylaminoacetaldehyde dimethyl acetal as shown in a formula I and a protecting group compound to obtain a compound as shown in a formula II; (2) carrying out hydrolysis reaction on the compound shown in the formula II and a hydrochloric acid solution to obtain a compound shown in a formula III; (3) carrying out reductive amination reaction on the compound as shown in the formula III, piperidine-4-yl [1, 1-biphenyl]-2-carbamate as shown in a formula IV and sodium triacetoxyborohydride to obtain a compound as shown in a formula V; and (4) carrying out deprotection reaction on the compound shown in the formula V to obtain the rafenasin intermediate shown in a formula VI. Fmoc-Cl is adopted as an amino protecting group, a Pd / C hydrogenation high-pressure protecting group removal process is avoided, and the method has the advantages of milder and safer reaction conditions, lower production cost, smaller environmental pollution and the like.
Description
technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of a refenacin intermediate. Background technique [0002] Refenacin was first developed by Ireland's Theravance Biopharmaceutical Company. In 2004, the British GlaxoSmithKline (GSK) Pharmaceutical Group Company obtained the global development license for this product; The incompatibility of the device will return the licensing rights to Theravance Biopharmaceuticals; in January 2015, Theravance Biopharmaceuticals and Mylan Pharmaceuticals of the United States jointly developed refenacin, and on November 13, 2017, the US Food and Drug Administration (FDA) ) filed a new drug marketing application and was approved for marketing on November 9, 2018. The trade name of the preparation is Yupelri. Refenacin is a LAMA, also commonly known as an anticholinergic drug. In the airway, by inhibiting smooth muscle muscarinic M3 receptors, bronchiectasis, sho...
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