MX-68, -Drug Synthesis Database

【结构式】

【药物名称】MX-68

【化学名称】N-[4-(2,4-Diaminopteridin-6-ylmethyl)-3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl]-L-(3'-homo)glutamic acid
　　　　　　2(S)-[4-(2,4-Diaminopteridin-6-ylmethyl)-3,4-dihydro-2H-1,4-benzothiazin-7-ylcarboxamido]adipic acid

【CA登记号】156579-02-1, 158664-17-6 (HBr salt)

【分子式】C₂₂H₂₄N₈O₅S

【分子量】512.55118

【开发单位】Chugai (Originator)

【药理作用】Antiarthritic Drugs, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Antimetabolites

合成路线1 合成路线2 合成路线3

合成路线1

Carboxilic acid (I) is converted to the correspondig acid chloride (II) and and amidated with dimethyl homoglutamate (III) to give the amide (IV). The benzyloxycarbonyl grouo of the amide (IV) is removed with H2 over Pd/C to give the amide (V), which is effectively alkylated with 6-(bromomethyl)-2,4-diaminopteridine (VI) to produce compound (VII). Finally, compound (VII) is hydrolyzed with 1N NaoH to yield MX-68.

参考文献中间体

【1】 Maruyama, N.; et al.; Antirheumatic agents. Novel methotrexate derivatives which are resistant to polyglutamation. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 090.

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)	19819	4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid		C₁₇H₁₅NO₄S	详情	详情
(II)	19820	benzyl 7-(chlorocarbonyl)-2,3-dihydro-4H-1,4-benzothiazine-4-carboxylate		C₁₇H₁₄ClNO₃S	详情	详情
(III)	19821	dimethyl (2S)-2-aminohexanedioate		C₈H₁₅NO₄	详情	详情
(IV)	19822	dimethyl (2S)-2-[([4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate		C₂₅H₂₈N₂O₇S	详情	详情
(V)	19823	dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate		C₁₇H₂₂N₂O₅S	详情	详情
(VI)	11006	2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine	52853-40-4	C₇H₇BrN₆	详情	详情
(VII)	19825	dimethyl (2S)-2-[([4-[(2,4-diamino-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate		C₂₄H₂₈N₈O₅S	详情	详情

合成路线2

As shown in Scheme 22540502a, initially, starting material (I) is converted to benzothiazol (II) by treatment of sodium thiocyanate in the presence of bromine. Alkali hydrolysis of compound (II) gives thiol (III), which is immediatly submitted to S-alkylation with 1-bromo-2-chloroethane, followed by acid esterification, which gives thioether (IV). After protection of the amino group of compound (IV) with tosyl chloride, treatment of NaOH affords benzothiazine ester (V), and next hydrolysis produces the key intermediate (VI). Subsequently, compound (VI) is converted to the corresponding acid chloride and amidated with dimethyl homoglutamate to give the amide (VII). The tosyl group of the amide (VII) is removed with HBr-AcOH to give the amine (VIII), which is effectively alkilated with 6-(bromomethyl)-,4-diaminopteridine (IX) to produce (X). Finally, compound (X) is hydrolyzed with 1N NaOH to yield MX-68.

参考文献中间体

【1】 Matsuoka, H.; et al.; Antirheumatic agents: Novel methotrexate derivatives bearing a benzoxazine or benzothiazine moiety. J Med Chem 1997, 40, 1, 105.
【2】 Mihara, M.; Matsuoka, H.; The synthesis and biological evaluation of new methotrexate derivatives in rheumatoid arthritis. Drugs Fut 1998, 23, 9, 1015.

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)	20004	p-aminobenzoic acid; 4-aminobenzoic acid	150-13-0	C₇H₇NO₂	详情	详情
(II)	25039	2-amino-1,3-benzothiazole-6-carboxylic acid		C₈H₆N₂O₂S	详情	详情
(III)	25040	4-amino-3-sulfanylbenzoic acid hydrochloride		C₇H₈ClNO₂S	详情	详情
(IV)	25041	methyl 4-amino-3-[(2-chloroethyl)sulfanyl]benzoate hydrochloride		C₁₀H₁₃Cl₂NO₂S	详情	详情
(V)	25042	methyl 4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylate		C₁₇H₁₇NO₄S₂	详情	详情
(VI)	25043	4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid		C₁₆H₁₅NO₄S₂	详情	详情
(VII)	25044	dimethyl 2-[([4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate		C₂₄H₂₈N₂O₇S₂	详情	详情
(VIII)	19823	dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate		C₁₇H₂₂N₂O₅S	详情	详情
(IX)	11006	2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine	52853-40-4	C₇H₇BrN₆	详情	详情
(X)	19825	dimethyl (2S)-2-[([4-[(2,4-diamino-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate		C₂₄H₂₈N₈O₅S	详情	详情

合成路线3

The synthetic scheme of tritiated MX-68 ia also presented in Scheme 22540503a. Treatment of compound (I) with triphenylphosphine, followed by Wittig reaction with 4-ethylbenzoic aldehyde (II) yields an olefin (III). To improve the solubility of (III) in routine organic solvents, the amino group of compound (III) is acylated with anhydride (IV) to give a lipophilic olefin (V). The olefin moiety is next oxidized by treatment of ozone to give an aldehyde (VI). Reduction of compound (VI) with NaBT4 is performed in isopropanol to give the corresponding tritiated alcohol (VII). The alohol (VII) is deacylated to yield acyl-free pteridine (VIII). The conversion of compound (VIII) to HBr salt, followed by bromination of alcohol with dibromotriphenylphosphorane, amination with compound (IX) and alkali hydrolysis produces [9-3H]-MX-68.

参考文献中间体

【1】 Matsuoka, H.; et al.; Synthesis of tritiated N-[4-(2, 4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1, 4-benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68). J Label Compd Radiopharm 1997, 39, 5, 363.
【2】 Mihara, M.; Matsuoka, H.; The synthesis and biological evaluation of new methotrexate derivatives in rheumatoid arthritis. Drugs Fut 1998, 23, 9, 1015.

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)	11006	2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine	52853-40-4	C₇H₇BrN₆	详情	详情
(II)	25045	4-ethylbenzaldehyde	4748-78-1	C₉H₁₀O	详情	详情
(III)	25046	6-(4-ethylstyryl)-2,4-pteridinediamine		C₁₆H₁₆N₆	详情	详情
(IV)	25047	butyric anhydride	106-31-0	C₈H₁₄O₃	详情	详情
(V)	25048	N-[2-(butyrylamino)-6-(4-ethylstyryl)-4-pteridinyl]butanamide		C₂₄H₂₈N₆O₂	详情	详情
(VI)	25049	N-[2-(butyrylamino)-6-formyl-4-pteridinyl]butanamide		C₁₅H₁₈N₆O₃	详情	详情
(VII)	25050	N-[2-(butyrylamino)-6-(hydroxymethyl)-4-pteridinyl]butanamide		C₁₅H₂₀N₆O₃	详情	详情
(VIII)	20068	(2,4-diamino-6-pteridinyl)methanol	945-24-4	C₇H₈N₆O	详情	详情
(IX)	19823	dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate		C₁₇H₂₂N₂O₅S	详情	详情

Extended Information