methyl 4-oxo-4-phenylbutanoate -Drug Synthesis Database

【结构式】

【分子编号】43101

【品名】methyl 4-oxo-4-phenylbutanoate

【CA登记号】25333-24-8

【分子式】C₁₁H₁₂O₃

【分子量】192.21448

【元素组成】C 68.74% H 6.29% O 24.97%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

The esterification of 3-benzoylpropionic acid (I) with methanol and sulfuric acid gives the corresponding methyl ester (II), which is regioselectively reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in THF, yielding the chiral lactone (III). Ring opening of (III) with ammonia in methanol affords the chiral butyramide (IV), which is treated with iodobenzene diacetate (IBA) in acetonitrile to provide the cyclic carbamate (V). The methylation of (V) with NaH and methyl iodide in DMF gives the expected N-methyl derivative (VI), which is hydrolyzed with NaOH in refluxing ethanol to yield the chiral 3-(methylamino)-1(S)-phenyl-1-propanol (VII). Finally, this compound is condensed with 4-(trifluoromethyl)chlorobenzene (VIII) by means of NaH in DMSO. The intermediate propanol (VII) can also be obtained directly from (V), by reductive cleavage of the carbamate ring with borane/dimethyl sulfide complex in THF.

参考文献中间体

合成目标

【1】 Senanayake, C.H.; Hilborn, J.W.; Jurgens, A.R. (Sepracor Inc.); Fluoxetine process from benzoylpropionic acid. WO 9967196 .

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)	43100	4-oxo-4-phenylbutyric acid; gamma-oxobenzenebutyric acid; 4-oxo-4-phenylbutyric acid; 3-Benzoylpropionic acid	2051-95-8	C₁₀H₁₀O₃	详情	详情
(II)	43101	methyl 4-oxo-4-phenylbutanoate	25333-24-8	C₁₁H₁₂O₃	详情	详情
(III)	43102	(5S)-5-phenyldihydro-2(3H)-furanone	1008-76-0	C₁₀H₁₀O₂	详情	详情
(IV)	43103	(4S)-4-hydroxy-4-phenylbutanamide		C₁₀H₁₃NO₂	详情	详情
(V)	43104	(6S)-6-phenyl-1,3-oxazinan-2-one		C₁₀H₁₁NO₂	详情	详情
(VI)	43105	(6S)-3-methyl-6-phenyl-1,3-oxazinan-2-one		C₁₁H₁₃NO₂	详情	详情
(VII)	10008	(1S)-3-(Methylamino)-1-phenyl-1-propanol	114133-37-8	C₁₀H₁₅NO	详情	详情
(VIII)	11973	1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride	98-56-6	C₇H₄ClF₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The chiral precursor (R)-3-(methylamino)-1-phenyl-1-propanol (XVI) has been prepared by an alternative method. Asymmetric reduction of methyl 3-benzoylpropionate (X) to produce the (R)-lactone (XI) was performed either employing commercial (+)-B-chlorodiisopinocampheylborane or generating in situ this reagent from alpha-pinene, NaBH4 and BCl3. Ammonolysis of lactone (XI) in MeOH afforded hydroxy amide (XII). This chiral intermediate (XII) was alternatively obtained by reduction of keto ester (X) with borane in the presence of the oxaazaborolidine chiral auxiliary (XIII) to produce the (R)-hydroxy ester (XIV), which was subsequently treated with ammonium hydroxyde in MeOH. Hofmann rearrangement of amide (XII) using iodobenzene diacetate led to the cyclic carbamate (XV). The key amino alcohol precursor (XVI) was then obtained by reduction of carbamate (XV) with LiAlH4.

参考文献中间体

合成目标

【1】 Hilborn, J.W.; et al.; A practical asymmetric synthesis of (R)-fluoxetine and its major metabolite (R)-norfluoxetine. Tetrahedron Lett 2001, 42, 51, 8919.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	43101	methyl 4-oxo-4-phenylbutanoate	25333-24-8	C₁₁H₁₂O₃	详情	详情
(XI)	55648	(5R)-5-phenyldihydro-2(3H)-furanone		C₁₀H₁₀O₂	详情	详情
(XII)	55649	(4R)-4-hydroxy-4-phenylbutanamide		C₁₀H₁₃NO₂	详情	详情
(XIII)	28292	(S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole	112022-81-8	C₁₈H₂₀BNO	详情	详情
(XIV)	55647	methyl (4R)-4-hydroxy-4-phenylbutanoate		C₁₁H₁₄O₃	详情	详情
(XV)	55650	(6R)-6-phenyl-1,3-oxazinan-2-one		C₁₀H₁₁NO₂	详情	详情
(XVI)	11972	(1R)-3-(Methylamino)-1-phenyl-1-propanol; (R)-3-Hydroxy-N-methyl-3-phenyl propylamine	42142-52-9	C₁₀H₁₅NO	详情	详情

Extended Information