In 4-fluoroisoquinoline-5-sulfonyl chloride, C(9)H(5)ClFNO(2)S, (I), one of the two sulfonyl O atoms lies approximately on the isoquinoline plane as a result of minimizing the steric repulsion between the chlorosulfonyl group and the neighbouring F atom. In (S)-(-)-4-fluoro-N-(1-hydroxypropan-2-yl)isoquinoline-5-sulfonamide, C(12)H(13)FN(2)O(3)S, (II), there are two crystallographically independent molecules (Z' = 2). The molecular conformations of these two molecules differ in that the amine group of one forms an intramolecular bifurcated hydrogen bond with the F and OH groups, whilst the other forms only a single intramolecular N-H···F hydrogen bond. The N-H···F hydrogen bonds correspond to weak coupling between the N(H) and (19)F nuclei, observed in the (1)H NMR solution-state spectra. In (S)-(-)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepan-1-ium chloride, C(15)H(19)FN(3)O(2)S(+)·Cl(-), (III), the isoquinoline plane is slightly deformed, suggestive of a steric effect induced by the bulky substituent on the sulfonyl group.
A practical synthesis of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate has been established for supplying this key intermediate of Rho-kinase inhibitor K-115 in a multikilogram production. The chiral 1,4-diazepane was constructed by intramolecular Fukuyama-Mitsunobu cyclization of a N-nosyl diamino alcohol starting from the commercially available (S)-or (R)-2-aminopropan-1-ol. In the same manner, an enantiomeric pair of a structural isomer were prepared for demonstration of the synthetic utility. (1), K-115 1 (Figure 1), a highly potent and selective Rho-kinase inhibitor having the (S)-2-methyl-1,4-diazepane moiety, is a promising candidate for the treatment of ocular hypertension with intraocular pressure-lowering activity and neuroprotection of retinal ganglion cells injured in glaucoma. 2 The S configuration at the 2-position on the 1,4-diazepane ring of K-115 plays the pivotal role for expressing the physiological feature.
Figure 1Recently, we have reported the practical synthesis of K-115 in a multikilogram production. This straightforward synthesis was accomplished without protection and deprotection steps and was well-acceptable from a synthetic methodology viewpoint (Scheme 1). 3 However, in consideration of the convenience and robust large-scale production of an Active Pharmaceutical Ingredient, many improvements were needed, including a reduction in the number of synthetic steps, control of the impurity profile and improved cost-performance. In particular, the placement of the expensive 4-fluoroisoquinoline-5-sulfonyl chloride (2) in the early step of the linear synthesis was not acceptable to us. Therefore, we had to develop an efficient, alternative synthesis. In order to solve the abovementioned issues, we addressed the convergent synthesis of K-115 and the requisite production of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate [(S)-7] (Scheme 2).
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