Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1986-05-23
1987-11-24
Schwartz, Richard A.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548303, C07D23338
Patent
active
047090448
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
In the synthesis of biotin or of so-called decarboxybiotin (in which the carboxy group of biotin has been replaced by a methyl group), the present invention provides an improved, more direct method for the conversion of a 1,3-diacyl-4-(bromomethyl)-5-[(5-alkoxycarbonylpentanoyl) or hexanoyl]-4-imidazolin-2-one, of the formula ##STR2## wherein R is (C.sub.1 -C.sub.5)alkanoyl or (C.sub.2 -C.sub.5)alkoxycarbonyl and X is methyl or (C.sub.2 -C.sub.5)alkoxycarbonyl, to a 1,3-diacyl-4-[(4-alkoxybutanoyl) or pentanoyl]-1H,3Hthieno(3,4-b)imidazoyl-2-one of the formula ##STR3## wherein R and X are as defined above. The present method proceeds via the Bunte salt of the formula ##STR4## wherein R and X are as defined above and Y represents an alkali metal (lithium, sodium or potassium).
Heretofor Mukaiyama et al., Japanese Kokai No. 75-88,086 (Chemical Abstracts 84:31061) transformed compound (I) wherein R is acetyl and X is ethoxycarbonyl by reaction of (I) with thiolacetic acid, forming the 4-(acetylthiomethyl) derivative, followed by cyclization to the thienoimidazolone in acetic acid in the presence of dry HCl--with concurrent hydrolysis of the ethyl ester and loss of the acetyl groups. The latter groups must be replaced in an added step because of their importance in facilitating the next stage (hydrogenation) of biotin synthesis. In like manner, Za'ylov et al. [A], Izv. Akad. Nauk. SSSR, Ser. Khim. 1973, pp. 1679-1681 (Chem. Abstracts 79:105143h) have cyclized the same 4-(acetylthiomethyl) derivative with aqueous NaOH followed by aqueous HCl, again with concurrent hydrolysis and loss of both acetyl groups; see also Russian patent 579,767 where cyclization is accomplished with p-toluenesulfonic acid in methanol, again with loss of both acetyl groups (now with conversion to methyl ester rather than hydrolysis to the carboxylic acid).
Similarly, Zav'yalov et al. [B], Isv. Akad. Nauk. SSSR, Ser. Khim. 1980, pp. 1943-1945 .Chem. Abstracts 94:15640y) transformed the compound (I) wherein R is acetyl and X is methoxycarbonyl by reaction of (I) with N-benzoylthiourea to form the isothiuronium salt [43CH.sub.2 SC(.dbd.NH)NHCOC.sub.6 H.sub.5.HBr], followed by cyclization in methanol-p-toluene sulfonic acid, again with loss of both acetyl groups. The highly noxious odor problems associated with this, as well as the above processes employing acetylthio intermediates, represents another major disadvantage of these processes--a disadvantage which is not shared by the present process.
Although Zav'yalov et al. [B] reacted 4(chloromethyl)-5-(5-ethoxycarbonylpentanoyl)-4-imidazolin-2-one with sodium thiosulfate in ethanol at room temperature, followed by addition of p-toluenesulfonic acid and boiling, to form a poor yield 4-(4-ethoxycarbonylbutanoyl)-1H,3H-thieno[3,4-d]imidazol-2-one requiring chromatographic purification, they report that attempted, analogous cyclization of the acetylated compound of the above formula (III), wherein R is acetyl, X is ethoxycarbonyl and Y is sodium was not successful at all, there being formed instead the deacetylated methyl ether: ##STR5## Zav'yalov et al. offer no specific experimental method for preparation, isolation or characterization of the diacetylated thiosulfate salt derivative which they attempted to cyclize.
SUMMARY OF THE INVENTION
In spite of the above results of Murkaiyama et al. and Zav'yalov et al., we have found mild conditions under which the Bunte salts of the formula (III) are not only readily cyclized to the desired biotin precursors of the above formula (II), but the cyclization occurs in high yield, without loss of N-acyl groups, and without need for chromatography in the isolation of purified products. The cyclization reaction is carried out in a reaction-inert solvent in the presence of at least a catalytic amount of both water and a strong acid catalyst. Although the levels of water and acid catalyst are not critical, it is convenient and advantageous to use about one molar equivalent each of water and strong acid so as to effect clean a
REFERENCES:
patent: 3960884 (1976-06-01), Zavyalov et al.
March, J., Advanced Organic Chemistry, McGraw Hill, New York, 1968, p. 330.
C.A. 94: 15640y; Zavyalov et al., Izv. Akad. Nauk SSSR, Ser. Khim, 1980, pp. 1943-1945 (including original article and translation).
C.A. 84: 31061; Mukaiyama et al., Japan Kokai No. 75 88,086 (1975) (Abstract only).
C.A. 79: 105143h; Zavyalov et al., Izv. Akad. Nauk SSSR, Ser. Khim, 1973, pp. 1679-1681 (Abstract only).
T. Taquchi et al., Chemistry Letters 1974, pp. 729-730.
Blackwood Robert K.
Frost Albert E.
Pfizer Inc.
Richardson Peter C.
Schwartz Richard A.
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