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【结 构 式】

【分子编号】41002

【品名】2-(2,4-difluorobenzoyl)benzoic acid

【CA登记号】

【 分 子 式 】C14H8F2O3

【 分 子 量 】262.2125264

【元素组成】C 64.13% H 3.08% F 14.49% O 18.31%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIV)

Treatment of the alcohol (I) with MsCl in the presence of TEA, followed by treatment with NaN3 in presence of HMPA yields the azide derivative (II). This species reacts with isobutyraldehide under reductive conditions (H2, Pd/C) leading to the substituted amine (III) which will be further substituted by reaction with the bromine derivative (IV) in basic conditions to yield derivative (V). Derivative (V) can also be obtained by following this pathway: Reduction of azide (II) with PPh3 in THF followed by reaction with refluxing water yields amine derivative (VI). This derivative is reductocondensed with the aldehyde (VII) and NaBH4 providing the substituted amine (VIII). This amine is further substituted by reductocondensation with isobutyraldehyde and NaCNBH3. Reduction of the substituted amine (V) with LiBH4 or LiAlH4 affords the alcohol (IX), which is converted into the corresponding azide (X) as already reported for (II). Reduction of azide (X) by means of SnCl2·2H2O/NaOH in water yields amine (XI), which is condensed with acid (XII) in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrocloride (WSC) and HOBt. Elimination of the protecting group Boc with HCl provides derivative (XIII), which is finally condensed with the aromatic acid (XIV) in the same conditions described for the coupling of (XI) with (XII).

1 Nishi, K.; Seno, K.; Okuno, T.; et al.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. J Med Chem 2000, 43, 6, 1041.
2 Seno, K.; Ohtani, M.; Watanabe, F. (Shionogi & Co. Ltd.); Pyrrolidine derivs. having phospholipase A2 inhibitory activity. EP 0976748; WO 9833797 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(I) 15783 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate C11H19NO5 详情 详情
(II) 15785 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate C11H18N4O4 详情 详情
(III) 40992 1-(tert-butyl) 2-methyl (2S,4R)-4-(isobutylamino)-1,2-pyrrolidinedicarboxylate C15H28N2O4 详情 详情
(IV) 40993 2-(bromomethyl)-1,1'-biphenyl C13H11Br 详情 详情
(V) 40994 1-(tert-butyl) 2-methyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1,2-pyrrolidinedicarboxylate C28H38N2O4 详情 详情
(VI) 15786 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate C11H20N2O4 详情 详情
(VII) 40996 [1,1'-biphenyl]-2-carbaldehyde C13H10O 详情 详情
(VIII) 40995 1-(tert-butyl) 2-methyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)amino]-1,2-pyrrolidinedicarboxylate C24H30N2O4 详情 详情
(IX) 40997 tert-butyl (2R,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-2-hydroxy-1-pyrrolidinecarboxylate C26H36N2O3 详情 详情
(X) 40998 tert-butyl (2S,4R)-2-(azidomethyl)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1-pyrrolidinecarboxylate C27H37N5O2 详情 详情
(XI) 40999 tert-butyl (2S,4R)-2-(aminomethyl)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1-pyrrolidinecarboxylate C27H39N3O2 详情 详情
(XII) 41000 (E)-3-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]-2-propenoic acid C13H9NO4S 详情 详情
(XIII) 41001 tert-butyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-2-[[((E)-3-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]-2-propenoyl)amino]methyl]-1-pyrrolidinecarboxylate C40H46N4O5S 详情 详情
(XIV) 41002 2-(2,4-difluorobenzoyl)benzoic acid C14H8F2O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XI)

Conversion of 4-hydroxy-L-proline (I) into the corresponding cis-N-Boc-4-hydroxy-L-proline methyl ester (II) is performed as follows: Treatment of (I) with SOCl2 in MeOH followed by reaction with Boc2O and Et3N in EtOAc affords the corresponding protected acid chloride; then the methyl ester moiety is formed under Mitsunobu conditions with formic acid, DIAD and PPh3 in THF followed by treatment with NaOH in MeOH. The OH group of (II) is converted into thioether (IV) by first mesylation with MsCl and Et3N in toluene followed by reaction with triphenylmethanethiol (III) in THF in the presence of NaH. Reduction of the methyl ester of (IV) with LiBH4 in THF provides alcohol (V), which is mesylated with MsCl and Et3N in THF and then treated with NaN3 and HMPA to furnish azide (VI). Boc removal in (VI) is performed by treatment with HCl in EtOAc to give derivative (VII), which is then converted into compound (VIII) by condensation with 2-(2,4-difluorobenzoyl)benzoic acid (XI) by means of water-soluble carbodiimide (WSC) and HOBt in DMF (compound (XI) can be obtained by Friedel-Crafts reaction between phthalic anhydride (IX) and 1,3-difluorobenzene (X) in the presence of AlCl3). Reduction of the azido moiety of (VIII) by means of SnCl2 and NaOH in EtOH furnishes amine (XII), which is finally converted into the desired product by condensation with carboxylic acid (XIII) by means of WSC and HOBt (derivative (XIII) can be obtained by Knoevenagel reaction between 4-formyl-benzoic acid (XIV) and 2,4-thiazolidinedione (XV) in refluxing 2-methoxyethanol in the presence of piperidine).

1 Nishi, K.; Seno, K.; Ono, T.; Yamada, K.; Murakami, Y.; Nakamoto, S.; Okuno, T.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2: Synthesis of potent and crystallized 4-triphenylmethylthio derivative "pyrrophenone". Bioorg Med Chem Lett 2001, 11, 4, 587.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 15783 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate C11H19NO5 详情 详情
(III) 18831 tritylhydrosulfide; triphenylmethanethiol 3695-77-0 C19H16S 详情 详情
(IV) 50070 1-(tert-butyl) 2-methyl (2S,4R)-4-(tritylsulfanyl)-1,2-pyrrolidinedicarboxylate C30H33NO4S 详情 详情
(V) 50071 tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate C29H33NO3S 详情 详情
(VI) 50072 tert-butyl (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate C29H32N4O2S 详情 详情
(VII) 50073 (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidine; (3R,5S)-5-(azidomethyl)pyrrolidinyl trityl sulfide C24H24N4S 详情 详情
(VIII) 50074 [(2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone C38H30F2N4O2S 详情 详情
(IX) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(X) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(XI) 41002 2-(2,4-difluorobenzoyl)benzoic acid C14H8F2O3 详情 详情
(XII) 50075 [(2S,4R)-2-(aminomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone C38H32F2N2O2S 详情 详情
(XIII) 50076 4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid C11H7NO4S 详情 详情
(XIV) 18922 4-formylbenzoic acid 619-66-9 C8H6O3 详情 详情
(XV) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
Extended Information