Methods of making high enantioselective secondary alcohols
One compound and one formula technology, applied in the field of manufacturing high mirror-selective secondary alcohols, can solve the problems of patient side effects, limiting the dose of anticancer drugs, etc.
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[0075] In one embodiment, a method for preparing a compound of formula 1 comprises the following steps:
[0076]
[0077] Step (1): in containing borane (BH 3 ), B-Diisopinocampheylborane (B-Chlorodiisopinocampheylborane) (DIP-chloride), (S)-(-)-1,1'-bi-2-naphthol ((S)-(- )-1,1'-Bi-2-naphthol) or sodium borohydride (NaBH 4 ), reacting a compound of formula 2 with a compound of formula 3a; and
[0078]
[0079] Step (2): reacting the product of step (1) with the following compound:
[0080] (A) lipase acrylic resin (lipase acrylic resin), sodium carbonate (Na 2 CO 3 ), and one of isopropyl acetate and 2,2,2-trifluoroethyl butyrate; or
[0081] (B) protease, sodium carbonate, and one of isopropyl acetate and 2,2,2-trifluoroethyl butyrate; and the product of step (B) is mixed with sodium methylate (sodium methoxide) reaction,
[0082] where R is a fatty chain or Rx;
[0083] Wherein Rx is hydrogen, an unsubstituted or substituted cyclic group, an electron withdraw...
example
[0127] Various features and embodiments of the invention are illustrated in the following representative examples. The following examples are illustrative only, and are not intended to limit the content of the present invention. It will be readily understood by those having ordinary skill in the technical field of the invention that the specific examples are provided for purposes of illustration only and a more complete description is set forth in the appended claims. The various embodiments and features described in this application should be understood to be interchangeable and combined with other embodiments of this application.
[0128] The clinical test compound OBI-3424 was first synthesized by "Asymchem" through three steps with a yield of 19% (see route 1 below). In order to improve the yield and reduce possible impurities, the inventors tried to design other synthetic routes (see route 2), and finally selected two methods to achieve the goal. First, a labile phospha...
example 1
[0197] Example 1: Synthesis of compound OBI-3424 intermediate (preparation of compound OBI-3424-5 from compound OBI-3424-3)
[0198] Synthetic compound OBI-3424-3
[0199]
[0200] In a round bottom flask, compound OBI-3424-1 (9 g, 48.6 mmol), dimethylformamide (0.1 g, mmol) and thionyl chloride (SOCl 2 , 30 mL, mmol) was refluxed at 75°C for 3 hours. During reflux, at room temperature (about 25°C), anhydrous MgCl 2 (2.79 g, mmol), dimethyl malonate (5.7 mL, mmol) and triethylamine (14.1 mL, mmol) were mixed in another round flask. The resulting white suspension after mixing was stirred for 1.5 hours to become a white mud. After refluxing for 3 hours, compound OBI-3424-1 and SOCl 2 The reaction mixture was cooled to about 40 °C. The reaction mixture was then concentrated using a rotary evaporator to remove excess solvent. Next, the resulting syrup was diluted with 15 mL of toluene. The resulting toluene solution was added dropwise to the previously prepared white mud...
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