Process for the preparation of benzothiazolone compounds

Details Process for the preparation of benzothiazolone compounds Process for the preparation of benzothiazolone compounds

1999-10-01

2001-02-27

Gerstl, Robert (Department: 1613)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

Reexamination Certificate

active

06194614

ABSTRACT:

The present invention relates to a process for the preparation of benzothiazolone compounds and to novel intermediates in the process of the invention. Benzothiazolone compounds are known. For example, WO 93/24473 describes 7-(2-aminoethyl)-benzothiazolone compounds of general formula
wherein
X and Y independently represent —S(O)
n
— or —O—,
n represents 0, 1 or 2,
p, q and r independently represent 2 or 3,
Z represents phenyl optionally substituted by halogen, —OR
1
, NO
2
or NR
2
R
3
; or a 5- or
6-membered N, O, or S containing heterocycle, and
R
1
, R
2
and R
3
independently represent hydrogen or alkyl C
1-6
,
and pharmaceutically acceptable derivatives thereof.
The compounds of WO 93/24473 may be prepared by any of several methods, for example by alkylation of the benzothiazolone compound of formula I
with an alkylating agent of formula
L—(CH
2
)
p
—X—(CH
2
)
q
—Y—(CH
2
)
r
—Z
in which p, q, r, X, Y and Z are as defined above and L represents a leaving group, or alkylation of a compound of formula I, as defined above, with a compound of formula,
O═CH—(CH
2
)
p−1
—X—(CH
2
)
q
—Y—(CH
2
)
r
—Z
in which p, q, r, X, Y and Z are as defined above, in the presence of a reducing agent.
The present invention relates in particular to a novel process for the synthesis of compound I.
Routes for the synthesis of the compound are known, for example from Weinstock et al,
J. Med Chem
., 1987, 30, 1166-1176.
According to the present invention, a process for the preparation of the compound of formula I
comprises converting the chlorobenzothiazole compound of formula II
into the compound or formula I, for example using concentrated hydrobromic acid.
The compound of formula II is novel and may be prepared by halogenating the 2-aminobenzothiazole compound of formula III, for example using copper (II) chloride and copper (I) chloride and optionally ethanol, in HCl, e.g., 20% HCl to which is added sodium nitrite:
The compound of formula III is novel and may be prepared from a thiourea of formula IV,
using a halogenating/oxidising agent, for example N-bromosuccinimide, bromine or N-chlorosuccinimide in an acidic solvent, e.g., a mixed acid solvent e.g. MeSO
3
H/AcOH.
The compound of formula IV is novel and may be prepared by hydrolysis of a compound of formula V
for example in water using a base such as K
2
CO
3
or an alkali metal hydroxide, e.g. NaOH or KOH.
The compound of formula V is novel and may be prepared by reacting an aniline hydrochloride of formula VI
with benzoylisothiocyanate, for example in acetone or methylisobutylketone (MIBK).
The compound of formula VI is novel and may be prepared by hydrogenating a nitroacetamide of formula VII and treating with HCl
in any suitable solvent, for example in ethanol or 2-propanol, in the presence of palladium on charcoal.
The compound of formula VII is novel and may be prepared by nitrating an acetamide of formula VIII
for example using HNO
3
in acetic acid.
The compound of formula VIII may be prepared from a compound of formula IX:
for example using acetic anhydride or acetyl chloride, either as solvent and reagent, or in the presence of dichloromethane and triethylamine.
In another aspect, the present invention provides a process for the preparation of compounds of formula I, comprising (i) converting a compound of formula IX into a compound of formula VIII, for example using acetic anhydride or acetyl chloride, either as solvent and reagent, or in the presence of dichloromethane and triethylamine, and (ii) converting the compound of formula VIII into the compound of formula I, for example by the stepwise preparation of compounds VII, VI, V, IV, III and II as described above.
The process of the present invention provides an easy process for the preparation of compound II, without the need to use undesirable starting materials, and giving the product compound in good yield.
The present invention also provides the novel compounds of formulae II, III, IV, V, VI and VII.


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Chemical Abstracts, vol. 59, p. 1963, “Preparation of tyrosol and 4-methoxyphenethyl alcohol,” Yamada et al. Weinstock et al, “Synthesis and Evaluation of Non-Catechol D-1 and D-2 Dopamine Receptor Agonists: Benzimidazol-2-one . . . ,” J. Med. Chem., vol. 30, pp. 1166-1176 (1987).

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