Chloroform → Carbon Dioxide

and L represents a single bond) can be prepared by taking the above compound (4a; wherein X1′ represents a halogen atom, preferably a bromine atom or an iodine atom) as the starting material, converting it into a vinyl derivative (4a; wherein X1′ represents CH2═CH—) by Stille coupling reaction well known to those skilled in the art, carrying out a 1,3-dipolar addition according to the description in K. Achiwa et al., Chem. Pharm. Bull. (1985, Vol. 33, No. 7, p. 2762-2766) to form a N-benzylpyrrolidine ring, and then carrying out the N-benzyl group elimination. The above 1,3-dipolar addition is well known to those skilled in the art, wherein the reaction is carried out in an inert solvent such as dichloromethane, at room temperature, using at least 1 equivalent of commercially available N-benzylic-N-(methoxymethyl)-N-trimethylsilylmethylamine with respect to the starting material vinyl derivative (4a), with the addition of an acid catalyst, most preferably trifluoroacetic acid, and 1,3-dipolar cycloaddition occurs between azothinylide generated in the reaction system under the acidic conditions and vinyl group of the compound (4a), to form the corresponding pyrrolidine ring. As having an electron-attracting functional group on the aromatic ring that is to be bonded to the vinyl group is advantageous for cyclization due to frontier orbital energy reasons necessary for cyclization, as taught in E. Laborde, Tetrahedron Lett., 1992, Vol. 33, No. 44, p. 6607-6610, it is convenient for the present reaction to accomplish the desired reaction when the compound (4a) has nitro group at the o-position of the vinyl group, specifically as will be described in the following Preparation Example 103. The N-benzyl group elimination can be carried out by the reaction well known to those skilled in the art, and examples include catalytic hydrogenation and the like using a noble metal catalyst such as nickel, palladium or platinum; however, to prevent the nitro group from being reduced, it is preferable to use a effective dealkylation agent (preferably 1-chloroethyl chloroformate (ACE-Cl)) that is a tertiary amine, as described in R. A. Olofson et al., J. Org. Chem., 1984, Vol. 49, No. 11, p. 2081-2082. The reaction temperature should be a temperature that is sufficient to complete the 1-chloroethoxycarbonylation that occurs concomitantly with dealkylation, and preferably from 60° C. to 150° C. The solvent used in the present reaction varies depending on the starting material, the reagent and the like, and examples of the preferred solvent include a halogen solvent such as dichloromethane, chloroform or 1,2-dichloroethane, a hydrocarbon solvent such as benzene or toluene, and more preferably 1,2-dichloroethane or toluene. Since 1-chloroethoxycarbonyl group decomposes to produce acetaldehyde dimethylacetal and carbon dioxide by adding methanol and heating (preferably 60° C. to 150° C.), the desired debenzylation can be achieved. When water solubility of the pyrrolidine compound (4b) is high and purification/isolation by extraction operation is difficult, the desired pyrrolidine compound (4b) with high purity is obtained by N-tert-butoxycarbonyl (Boc)-derivatization (refer to the following Preparation Example 19) of the crude product by the method well known to those skilled in the art and purification by the well known column chromatography, and then carrying out the Boc-removal which is well known to those skilled in the art, with an acidic solvent, preferably trifluoroacetic acid (refer to the following Example 215), specifically as will be described in the following Preparation Example 104. [Preparation of Compound (15)]

1. customcan be prepared
2. customby Stille coupling reaction
3. additiona 1,3-dipolar addition
4. custom2762-2766) to form a N-benzylpyrrolidine ring
5. additionThe above 1,3-dipolar addition
6. customto form the corresponding pyrrolidine ring
7. custom6607-6610, it is convenient for the present reaction
8. customspecifically as will be described in the following Preparation Example 103
9. customThe N-benzyl group elimination can be carried out by the reaction
10. custompreferably from 60° C. to 150° C
11. customThe solvent used in the present reaction varies

ORD record

ord-a400e7ed3353432f9ca7bc061aac7bdf

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08399520B2