Improved preparation method of ketorolac intermediate

An intermediate, ketorolac technology, applied in the field of medicinal chemistry, can solve the problems of unsuitability for large-scale industrial production, difficult removal of high-boiling acetic acid solvent, difficult and cumbersome operation of liquid separation and extraction, etc.

An intermediate, ketorolac technology, applied in the field of medicinal chemistry, can solve the problems of unsuitability for large-scale industrial production, difficult removal of high-boiling acetic acid solvent, difficult and cumbersome operation of liquid separation and extraction, etc.

CN113045471AActive Publication Date: 2021-06-29四川尚锐生物医药有限公司
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  • Improved preparation method of ketorolac intermediate
  • Improved preparation method of ketorolac intermediate
  • Improved preparation method of ketorolac intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Add 25g of 2-benzoylpyrrole, 50.8g of triethyl methanetricarboxylate, 58.7g of manganese acetate dihydrate (trivalent), 24.0g of sodium acetate, and 111.8g of acetic anhydride into 250mL of toluene. , add about 125mL of sodium bisulfite aqueous solution (add 2.5g of sodium bisulfite to 125mL of water for dissolving configuration), separate the liquid, concentrate the organic phase under reduced pressure, directly use 50mL of isopropanol to make a slurry, filter, and dry to obtain 55.2 g Diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolazine-1,1-dicarboxylate (intermediate), yield 94.2%. As detected by HPLC, the purity of the intermediate is 99.733%, and the single largest impurity is 0.091%. The results are shown in Table 1 and figure 1 .

[0043] Table 1 gained intermediate HPLC detection result

[0044] peak number keep time area high area% Resolution (USP) Number of Theoretical Plates (USP) 1 10.553 22554 1758 0.069 -- 15011 2 13.965 11...

Embodiment 2

[0046] Add 56g of 2-benzoylpyrrole, 115.3g of triethyl methanetricarboxylate, 175.4g of manganese acetate dihydrate (trivalent), 53.8g of sodium acetate, and 267.5g of acetic anhydride into 504mL of N-methylpyrrolidone, After heating for complete reaction, add about 280 mL of sodium bisulfite aqueous solution (add 20.4 g of sodium bisulfite to 280 mL of water for dissolving configuration), separate liquids, and concentrate the organic phase under reduced pressure, directly use 280 mL of n-propanol to make a slurry, filter, After drying, 119.5 g of the intermediate 5-benzoyl-2,3-dihydro-1H-pyrrolazine-1,1-dicarboxylate diethyl ester was obtained, with a yield of 91.0%. As detected by HPLC, the purity of the intermediate is 99.570%, and the single largest impurity is 0.208%. The results are shown in Table 2 and figure 2 .

[0047] Table 2 gained intermediate HPLC detection result

[0048] peak number keep time area high area% Resolution (USP) Number of ...

Embodiment 3

[0050] Add 32g of 2-benzoylpyrrole, 49.3g of triethyl methanetricarboxylate, 90.2g of manganese acetate dihydrate (trivalent), 43.2g of sodium acetate, and 165.3g of acetic anhydride into 256mL of toluene. , add 160mL of sodium bisulfite aqueous solution (8.7g of sodium bisulfite is added to 160mL of water for dissolving configuration), liquid separation, after the organic phase is concentrated under reduced pressure, directly use 96mL of isopropanol to beat, filter, and dry to obtain 69.2g Diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolazine-1,1-dicarboxylate, yield 92.3%. As detected by HPLC, the purity is 99.451%, and the largest single impurity is 0.186%.

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Abstract

The invention discloses an improved preparation method of a ketorolac intermediate. The intermediate is (5-Benzoyl-1H-pyrrol-2-yl)methanetricarboxylic acid triethyl ester (M-1). The method comprises the following steps: subjecting 2-benzoylpyrrole, methane tricarboxylic acid triethyl ester, manganese acetate dihydrate (trivalent), sodium acetate and acetic anhydride to reacting in an organic solvent; adding an aqueous sodium hydrogen sulfite solution for extraction and liquid separation; and conducting vacuum concentration on an organic phase and pulping the an organic phase with an alcohol solvent. According to the method, post-treatment problems caused by the existence of a large amount of manganese ion compounds and a large amount of solvent acetic acid are effectively solved; meanwhile, the problems of high energy consumption, long period, high cost and the like caused by later concentration are reduced; and the obtained intermediate has the advantages of high purity, high yield and the like and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing an improved ketorolac intermediate 5-benzoylpyrrole-2-methanetricarboxylic acid triethyl ester. Background technique [0002] Ketorolac tromethamine is a new type of non-steroidal powerful analgesic and moderate anti-inflammatory antipyretic that can be injected. Its mechanism of action is to inhibit the production of prostaglandins (PG) in the periphery and central To reduce PG in the peripheral and central, the chemical structure of its main component, ketorolac, is as follows: [0003] [0004] At present, due to the mild conditions and fast reaction speed of the free radical reaction induced by trivalent manganese, the main route of synthesizing ketorolac trometamol is catalyzed by trivalent manganese ions, through 2-benzoylpyrrole and methane three Triethyl carboxylate undergoes free radical reaction, and then undergoes oxidative cond...

Claims

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Application Information

Patent Timeline
29 Jun 2021
Publication
CN113045471A
IPC
C07D207/337
CPC
C07D207/337
Inventors
刘超; 吴昆