〖目标产物〗Venlafaxine hydrochloride, Wy-45030, Effexor LP, Efexor XL, Efexor XR, Efectin, Trevilor, Vandral, Dobupal, Efexor, Effexor
〖合成路线〗
〖合成方法〗A new process for the production of venlafaxine has been reported: Esterification of 2-(4-methoxyphenyl)-acetic acid (I) with ethanol and sulfuric acid gives the corresponding ethyl ester (II), which is condensed with ethyl formate by means of NaH to yield 2-formyl-3-(4-methoxyphenyl)acetic acid ethyl ester (III). Reaction of (III) with dimethylamine and K2CO3 in EtOH affords 3-(dimethylamino)-2-(4-methoxyphenyl)acrylic acid ethyl ester (IV), which is reduced with either NaBH4, LiAlH4 or H2 over Pd/C or Pt/C in ethanol to provide the corresponding propionic ester (V). Finally, this compound is cyclized with the bismagnesiane (VI) in THF. Alternatively, acrylic ester (IV) can be obtained directly by condensation of acetate (II) with dimethylformamide diethylacetal (VII) at 135 C. Alternatively, propionic ester (V) can be obtained by condensation of acetate (II) with N,N-dimethylmethylene-iminium iodide (VIII) by means of LDA in THF/heptane/ ethylbenzene.
〖参考〗Camps Garcia, P.; Bosch i Llado, J.; Onrubia Miguel, M.C.; Arnalot i Aguilar, C.; Soldevila Madrid, N. (Medichem SA); Venlafaxine production process. WO 0107397
〖目标产物〗S-19812
〖合成路线〗
〖合成方法〗Condensation of (4-methoxyphenyl)acetic acid (I) with anisole (II) in hot PPA produced ketone (III). Subsequent treatment of (III) with the Vilsmeier reagent afforded chloroaldehyde (IV). The required thiophene (VI) was then obtained by cyclization with ethyl mercaptoacetate (V) in the presence of NaOEt. After basic hydrolysis of the ester group of (VI), the resulting acid (VII) was decarboxylated by means of copper in quinoline at 180 C, yielding thiophene (VIII). Stannic chloride-promoted Friedel-Crafts acylation of (VIII) with 3-(methoxycarbonyl)propionyl chloride (IX) gave ketoester (X). The keto group of (X) was further reduced employing triethylsilane in trifluoroacetic acid to afford (XI). Hydrolysis of the methyl ester of (XI), followed by treatment with oxalyl chloride furnished acid chloride (XII). The title hydroxamic acid was then obtained by coupling of (XII) with O-(tert-butyldimethylsilyl)-N-methylhydroxylamine and subsequent acid-catalyzed desilylation.
〖参考〗Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Tordjman, C. (ADIR et Cie.); Thiophene cpds., process for their preparation and pharmaceutical compsns. containing them. EP 0728755; FR 2730996; JP 1996253470
〖目标产物〗LY-426410
〖合成路线〗
〖合成方法〗4-Methoxyphenylacetic acid (VII) was esterified with EtOH and p-toluenesulfonic acid. The resulting ethyl ester (VIII) was brominated by means of N-bromosuccinimide to produce bromoester (IX), which was condensed with 4-nitroimidazole (X) yielding (XI). Reduction of the nitro group of (XI) by catalytic hydrogenation over Pd/C gave amine (XII). This was coupled with acid (VI) by means of EDC and HOBt to afford amide (XIII). Then, hydrolysis of the methyl ester of (XIII) with LiOH gave rise to carboxylic acid (XIV). Finally, coupling of (XIV) with 4-methylpiperidine (XV) generated the title compound.
〖参考〗; Growth hormone secretagogues. EP 0933365; WO 9908699
〖目标产物〗LY-444711
〖合成路线〗
〖合成方法〗4-Methoxyphenylacetic acid (XI) was esterified using EtOH and p-toluenesulfonic acid, and then brominated with NBS to give bromoester (XII). Coupling of (XII) with 4-nitroimidazole (XIII) afforded adduct (XIV), which was alkylated using iodomethane and NaH to yield (XVa-b). Hydrolysis of the ester group of (XVa-b) with LiOH gave the corresponding carboxylic acid, which was converted to acid chloride (XVIa-b) by means of treatment with oxalyl chloride. Reaction of (XVI) with the lithium salt of the chiral oxazolidinone (XVII) provided a diastereomeric mixture of N-acyloxazolidinones, which were separated by silica gel chromatography. Removal of the chiral auxiliary from the desired isomer (XVIII) under basic conditions, followed by treatment with oxalyl chloride provided acid chloride (XIX). Further reaction of (XIX) with pyrrolidine (XX) produced amide (XXI). Reduction of the nitro group of (XXI) using hydrogen and Pd/C generated the aminoimidazole derivative (XXII). This was coupled with the N-Boc-dipeptide (X) affording amide (XXIII). The Boc protecting group of (XXIII) was then cleaved by treatment with trifluoroacetic acid, and the title compound was finally isolated as the dihydrochloride salt.
〖参考〗; Growth hormone secretagogues. EP 0933365; WO 9908699
〖目标产物〗VCP-11177, TH-1177
〖合成路线〗
〖合成方法〗L-Proline methyl ester (I) was coupled with 4-methoxyphenylacetic acid (II) using benzotriazol-1-yloxytripyrrolidinephosphonium to afford amide (III). Subsequent reduction of the amide and ester functions of (III) with LiAlH4 in the presence of AlCl3 in THF produced amino alcohol (IV). This was then coupled with 4-chlorobenzhydrol (V) using p-toluenesulfonic acid in refluxing toluene to produce the title benzhydryl ether.
〖参考〗Haverstick, D.M.; MacDonald, T.L.; Gray, L.S.; Heady, T.N.; Inhibition of human prostate cancer proliferation in vitro and in a mouse model by a compound synthesized to block Ca2+ entry. Cancer Res 2000, 60, 4, 1002
〖目标产物〗D-58
〖合成路线〗
〖合成方法〗The target product can be obtained either by condensation of phloroglucinol (I) with carboxylic acid (II) by means of zinc chloride (ZnCl2) and phosphoryl chloride (POCl3) (1) or by reaction of phloroglucinol (I) with acetonitrile derivative (III), boron trifluoride-etherate (BF3-Et2O) and hydrogen chloride in ether.
〖参考〗Mohanty, S.; Grover, S.K.; An improved procedure for the acylation on phenols using boron trifluoride-etherate. Curr Sci 1988, 57, 10, 537
〖目标产物〗D-58
〖合成路线〗
〖合成方法〗The target product can be obtained either by condensation of phloroglucinol (I) with carboxylic acid (II) by means of zinc chloride (ZnCl2) and phosphoryl chloride (POCl3) (1) or by reaction of phloroglucinol (I) with acetonitrile derivative (III), boron trifluoride-etherate (BF3-Et2O) and hydrogen chloride in ether.
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