合成路线1

The reaction of D-mannitol (I) with acetone and ZnCl2 gives the diacetonide (II), which is oxidized with Pb(OAc)4 to yield the acetonide of (R)-glyceraldehyde (III). The reduction of (III) with H2 over Pd/C affords the (S)-glycerin acetonide (IV), which is treated with TsCl in pyridine to provide the corresponding tosylate (V). The condensation of (V) with the urea derivative (VI) by means of KOH in DMSO gives the adduct (VII), which is deprotected with HCl in acetone to yield the diol (VIII). Monotosylation of (VIII) with TsCl in pyridine affords the primary tosylate (IX), which is treated with Na in methanol to provide the epoxide (X). Finally this compound is treated with tert-butylamine to furnish the target (R)-enantiomer.

合成路线2

The oxidation of mannitol diacetonide (I) with Pb(OAc)4 in benzene gives the glyceraldehyde acetonide (II), which is reductocondensed with benzylamine (III) by means of H2 over Pd/C in methanol to yield, after acidification with HCl, (S)-3-(benzylamino)propane-1,2-diol (IV). The cyclization of (IV) with benzaldehyde (V) in refluxing toluene affords the chiral oxazolidine (VI), which is treated with tosyl chloride and pyridine to provide the corresponding tosylate (VII). The condensation of (VII) with 4-[2-(cyclopropylmethoxy)ethyl]phenol (VIII) by means of NaH in DMF gives the phenolic ether (IX), which is treated with conc. HCl to open the oxazolidine ring and yield the chiral propanolamine (X). The alkylation of the secondary amino group of (X) with isopropyl iodide (XI) in refluxing ethanol affords the tertiary amine (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the target betaxolol.

合成路线3

The 3-(isopropylamino)propane-1,2(S)-diol (IV) intermediate has been obtained by two different methods: 1. The oxidation of 1,2,5,6-O-diisopropylidene-D-mannitol (I) with Pb(OAc)4 in THF gives (R)-2,3-O-isopropylideglyceraldehyde (II), which is reductocondensed with isopropylamine by means of H2 over Pd/C in methanol to yield (S)-3-(isopropylamino)-1,2-O-isopropylidenepropane-1,2-diol (III). The cleavage of the isopropylidene protecting group of (III) in hot 6N HCl affords the desired 3-(isopropylamino)propane-1,2-diol (IV) intermediate. 2. The reductocondensation of (R)-glyceraldehyde (V) with isopropylamine by means of H2 over Pd/C in methanol gives the desired 3-(isopropylamino)propane-1,2-diol (IV) intermediate. The cyclization of (IV) with benzaldehyde (VI) by heating at 150 C gives the oxazolidine (VII), which is treated with Ts-Cl and K2CO3 in pyridine to yield the tosylate (VIII). Finally, this compound is condensed with 4-[2-(cyclopropylmethoxy)ethyl]phenol (IX) by means of NaH in DMF and hydrolyzed with conc. aq. HCl to provide the target isopropanol derivative.

合成路线4

Horner-Emmons condensation of 2,3-isopropylidene-D-glyceraldehyde (I) with phosphonate (II) produced the unsaturated ester (IIIa-b). Ketal deprotection and lactone ring closure of (II) under acidic conditions, followed by O-silylation afforded (IV). The lactone function of (IV) was reduced with DIBAL and then with NaBH4-CeCl3 to produce the corresponding diol. Further silylation of the primary hydroxyl group furnished (V). Condensation of (V) with triethyl orthoacetate followed by Claisen rearrangement gave rise to the gamma,delta-unsaturated ester (VI). This was reduced to alcohol with LiAlH4 and then alkylated with benzyl bromide to yield benzyl ether (VII). Ozonization of (VII) in methanol at -78 C, followed by decomposition of the ozonide with dimethyl sulfide gave aldehyde (VIII). Horner-Emmons condensation of (VIII) with the sodium salt of triethyl phosphonoacetate (IX) produced the alpha,beta-unsaturated ester (X). Double bond hydrogenation in (X) with simultaneous benzyl group cleavage afforded hydroxy ester (XI), which was then converted to mesylate (XII). This was cyclized to the cyclopentane (XIIIa-b) by means of NaH in refluxing THF.

合成路线5

The glycosyl intermediates (VIIIb) and (VIIIc) can be prepared by several related methods. Wittig condensation of 2,3-O-isopropylidene-D-glyceraldehyde (XVI) with (1-carbethoxyethylidene)triphenylphosphorane (XVII) in dry CH2Cl2 provides the unsaturated ester (XVIII) (7). Diastereoselective dihydroxylation of (XVIII) to give diol (XIX) is accomplished using a variety of reagents, including Sharpless oxidation with AD-mix-beta/methanesulfonamide (7), NMMO or t-BuOOH and catalytic OsO4, K3Fe(CN)6 and catalytic K2OsO2(OH)4, tetradecyltrimethylammonium permanganate (TDTAP) and KMnO4, optionally in the presence of crown ether or RuCl3/CeCl3/NaIO4 (4) and NaMnO4/NaHCO3 (5). After conversion of dihydroxy ester (XIX) to the cyclic sulfite (XX) by means of SOCl2 and Et3N, oxidation employing TEMPO/NaOCl or RuCl3/NaIO4 provides the correspondng sulfate ester (XXI). Ring opening of the cyclic sulfate (XXI) with HF-triethylamine complex or with tetrabutyl- or tetraethylammonium fluoride produces the respective ammonium fluorosulfates (XXIIa-c), which undergo cyclization to fluorolactone (XXXIII) under acidic conditions. Subsequent acylation of the dihydroxy ribonolactone (XXIII) with benzoyl chloride and DMAP followed by reduction of the resulting dibenzoyloxy lactone (XXIV) with either Red-Al or LiAlH(O-t-Bu)3 yields lactol (XXV) (4, 5), which is either acetylated to (VIIIb) using Ac2O and DMAP in THF (4) or chlorinated to (VIIIc) with sulfuryl chloride and TBAB (5). Alternatively, cyclization and deprotection of dihydroxy ester (XIX) with ethanolic HCl leads to 2-methyl-D-arabino-γ-lactone (XXVI), which, after protection as the dibenzoate ester (XXVII) with benzoyl chloride in dry pyridine, is fluorinated to (XXIV) using either diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) in THF (7). In a further method, dihydroxy ester (XIX) is selectively acylated at the secondary hydroxyl group with benzoyl chloride in pyridine to produce compound (XXVIII), which is fluorinated to (XXIX) by treatment with DAST or Deoxofluor in THF. Deprotection and cyclization of compound (XXIX) with TFA in hot CH3CN/H2O gives 3-O-benzoyl-2-methyl-2-deoxy-2-fluoro-D-ribono-γ-lactone (XXX), which is further benzoylated to (XXIV) by means of benzoyl chloride n the presence of DMAP and pyridine in AcOEt (7). Scheme 3.

合成路线6

The synthetic precursor (XXIV) can be prepared by a number of alternative methods.
Condensation of 2,3-O-isopropylidene-D-glyceraldehyde (XVI) with ethyl 2-fluoropropionate (XXXI) by means of LDA in cold THF gives a mixture of diastereomeric fluoro-hydroxy esters (XXXIIa) and (XXXI-Ib) along with minor amounts of isomer (XXXIIc). After removal of the undesired (2S,3R)-isomer (XXXIIb) by selective enzymatic hydrolysis with Candida antarctica lipase form B (CALB), the remaining mixture of fluoro-hydroxy esters (XXXIIa) and (XXXIIc) undergoes cyclization to the respective lactones (XXIII) and (XXXIII) upon heating with aqueous H2SO4 (8). Esterification of the mixture of diols (XXIII) and (XXXIII) with benzoyl chloride and DMAP in Et3N/CH3CN followed by recrystallization of the resulting dibenzoates from isopropanol provides compound (XXIV) (8, 9). Scheme 4.
In a related method, chlorination of 2-fluoropropionic acid (XXXIV) with oxalyl chloride and catalytic DMF in toluene followed by reaction with pyrrolidine leads to amide (XXXV). Subsequent condensation of fluoro-amide (XXXV) with glyceraldehyde acetonide (XVI) by means of LDA in THF produces fluoro-hydroxyamide (XXXVIa), which upon heating with aqueous AcOH generates lactone (XXIII) along with minor amounts of its diastereoisomer (XXXIII). Similarly, condensation of S-phenyl 2-fluoropropanethioate (XXXVII) with aldehyde (XVI) yields hydroxy thioester (XXXVIb), which undergoes cyclization to lactones (XXIII) and (XXXIII) under acidic conditions (9). Scheme 4.
In a further related method, acyl benzoxazolone (XXXIX) —prepared by coupling 2-fluoropropionic acid (XXXIV) with benzoxazolone (XXXVIII) in the presence of DCC and DMAP— is condensed with glyceraldehyde acetonide (XVI) by means of TiCl4 and Et3N in CH2Cl2 to furnish adduct (XL). Subsequent hydrolysis and cyclization of (XL) in AcOH/H2O at 90 °C produces the mixture of lactones (XXIII) and (XXXIII) (9). Scheme 4.

合成路线7

合成路线8

合成路线9