2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide -Drug Synthesis Database

【结构式】

【分子编号】12335

【品名】2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide

【CA登记号】5455-98-1

【分子式】C₁₁H₉NO₃

【分子量】203.1974

【元素组成】C 65.02% H 4.46% N 6.89% O 23.62%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

The starting compounds (IV) and (VII) are obtained as follows: a) Methyl 4-acetylamino-2-hydroxybenzoate (I) is converted to the 2-ethoxy derivative (II) with ethyl iodide, and then chlorination of (II) with N-chlorosuccinimide followed by alkaline hydrolysis of (III) gives benzoic acid (IV). b) The reaction of 2-[(4-fluorobenzyl)amino]ethanol (V) with N-(2,3-epoxypropyl)phthalimide (VI), followed by treatment with concentrated sulfuric acid, affords intermediate (VII). The condensation of 4-Amino-5-chloro-2-ethoxybenzoic acid (IV) with 4-(4-fluorobenzyl)-2-(methylamino) morpholine (VII) by means of ethyl chloroformate and triethylamine in CHCl3 gives 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl] benzamide, which is converted to mosapride citrate, by treatment with citric acid.

参考文献中间体

合成目标

【1】 Kato, S.; Yoshida, N.; Ito, T.; Mosapride Citrate. Drugs Fut 1993, 18, 6, 513.
【2】 Kato, S.; Morie, T.; Hino, K.; Kon, T.; Naruto, S.; Yoshida, N.; Karasawa, T.; Matsumoto, J.; Novel benzamides as selective and potent gastrokinetic agents. 1. Synthesis and structure-activity relationships of N[4-(2-morpholinyl)alkyl]benzamides. J Med Chem 1990, 33, 5, 1406-13.
【3】 Kato, S.; Morie, T.; Hino, K.; Kon, T.; Naruto, S.; Yoshida, N.; Karasawa, T.; Matsumoto, J.; Novel benzamides as selective and potent gastrokinetic agents. 1. Synthesis and structure-activity relationships of N[4-(2-morpholinyl)alkyl]benzamides. J Med Chem 1990, 33, 5, 1406-13.

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)	12330	methyl 4-(acetamido)-2-hydroxybenzoate		C₁₀H₁₁NO₄	详情	详情
(II)	12331	Methyl 4-acetamido-2-ethoxybenzoate; methyl 4-(acetamido)-2-ethoxybenzoate	59-06-3	C₁₂H₁₅NO₄	详情	详情
(III)	12332	methyl 4-(acetamido)-5-chloro-2-ethoxybenzoate		C₁₂H₁₄ClNO₄	详情	详情
(IV)	12333	4-Amino-5-chloro-2-ethoxybenzoic acid		C₉H₁₀ClNO₃	详情	详情
(V)	12334	2-[(4-Fluorobenzyl)amino]-1-ethanol		C₉H₁₂FNO	详情	详情
(VI)	12335	2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide	5455-98-1	C₁₁H₉NO₃	详情	详情
(VII)	12336	[4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methylamine; [4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methanamine; 2-Aminomethyl-4-(4-fluorobenzyl)morpholine	112914-13-3	C₁₂H₁₇FN₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

2) The reaction of N-(2,3-epoxypropyl)phthalimide (I) with dibenzylamine (II) at 80 C gives 1-(dibenzylamino)-3-(phthalimido)-2-propanol (III), which is hydrolyzed with refluxing concentrated HCl to afford 1-amino-3-(dibenzylamino)-2-propanol (IV). The acylation of (IV) with chloroacetyl chloride (V) in CHCl3 yields the corresponding chloroacetamide (VI), which is cyclized by means of potassium tert-butoxide in refluxing ethanol to give 6-(dibenzylaminomethyl)morpholin-3-one (VII). The debenzylation of (VII) with H2 over Pd(OH)2/C in ethanol yields 6-(aminomethyl)morpholin-3-one (VIII), which is condensed with 4-(acetamido)-5-chloro-2-ethoxybenzoyl chloride (IX) by means of triethylamine in CHCl3 to afford the monoacetylated derivative of metabolite M-2 (X). Finally, this compound is hydrolyzed with HCl in refluxing ethanol/water to give metabolite M-2. The two final steps of this sequence can also be performed in a single step by condensation of morpholinone (VIII) with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of carbonyldiimidazole (CDI) in THF to afford directly the metabolite M-2 after neutralization with aqueous NH4OH.

参考文献中间体

合成目标

【1】 Kato, S.; Yoshida, N.; Morie, T.; Synthesis and biological activities of metabolites of mosapride, a new gastroprokinetic agent. Chem Pharm Bull 1995, 43, 4, 699.

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)	12335	2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide	5455-98-1	C₁₁H₉NO₃	详情	详情
(II)	12361	N,N-Dibenzylamine; Dibenzylamine; N-Benzyl(phenyl)methanamine	103-49-1	C₁₄H₁₅N	详情	详情
(III)	12362	2-[3-(Dibenzylamino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione		C₂₅H₂₄N₂O₃	详情	详情
(IV)	12363	1-Amino-3-(dibenzylamino)-2-propanol		C₁₇H₂₂N₂O	详情	详情
(V)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(VI)	12365	2-Chloro-N-[3-(dibenzylamino)-2-hydroxypropyl]acetamide		C₁₉H₂₃ClN₂O₂	详情	详情
(VII)	12366	6-[(Dibenzylamino)methyl]-3-morpholinone		C₁₉H₂₂N₂O₂	详情	详情
(VIII)	12367	6-(Aminomethyl)-3-morpholinone		C₅H₁₀N₂O₂	详情	详情
(IX)	12368	4-(Acetamido)-5-chloro-2-ethoxybenzoyl chloride		C₁₁H₁₁Cl₂NO₃	详情	详情
(X)	12369	4-(Acetamido)-5-chloro-2-ethoxy-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide		C₁₆H₂₀ClN₃O₅	详情	详情
(XI)	12333	4-Amino-5-chloro-2-ethoxybenzoic acid		C₉H₁₀ClNO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIX)

Alkylation of potassium phthalimide (XXVII) with epichlorohydrin (XXVIII) provided N-glycidyl phthalimide (XXIX). Epoxide ring opening in (XXIX) with aqueous HBr led to bromohydrin (XXX), which was further oxidized to bromo ketone (XXXI) by means of CrO3. Coupling of bromo ketone (XXXI) with diethyl malonate (XXXII) to afford (XXXIII) was accomplished in the presence of NaOEt in EtOH/DMF as the solvent. Acid hydrolysis of the malonate ester (XXXIII), followed by thermal decarboxylation, gave rise to phthalimido levulinic acid (XI). The phthaloyl group of (XI) was finally hydrolyzed under acidic conditions to furnish delta-aminolevulinic acid.

参考文献中间体

合成目标

【1】 Collins, A.; Tschudy, D.P.; Malonic ester synthesis of delta-aminolevulinic acid. The reaction of N-3-bromoacetonylphthalimide with malonic ester. J Org Chem 1959, 24, 556.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	59147	5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid		C₁₃H₁₁NO₅	详情	详情
(XXVII)	27890	Potassium phthalimide	1074-82-4	C₈H₄KNO₂	详情	详情
(XXVIII)	10246	N-Phenyl-2-[(triphenylstannyl)selanyl]benzamide		C₃₁H₂₅NOSeSn	详情	详情
(XXIX)	12335	2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide	5455-98-1	C₁₁H₉NO₃	详情	详情
(XXX)	59158	2-(3-bromo-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione		C₁₁H₁₀BrNO₃	详情	详情
(XXXI)	59159	2-(3-Bromo-2-oxopropyl)isoindole-1,3-dione		C₁₁H₈BrNO₃	详情	详情
(XXXII)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(XXXIII)	59160	diethyl 2-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropyl]malonate		C₁₈H₁₉NO₇	详情	详情

Extended Information