CZ303499A3 - Process for preparing benzothiazolone compounds - Google Patents

Abstract

Described herein are methods for preparing a compound of Formula I and new intermediates for this method of preparation.

Description

The present invention relates to a process for preparing the benzothiazole compounds and novel intermediates in the process of the invention.

BACKGROUND OF THE INVENTION

The benzothiazole compounds are known. For example, WO 93/24473 discloses 7- (2-aminoethyl) benzothiazolone compounds of the general formula:

CH ₂ CH ₂ -NH- (CH ₂ ) _p -X- (CH ₂ ) _q -Y- (CH ₂ ) _r -Z where

X a

-O-,

Y are independently

I and OH are -S (Q) _n or n is 0, 1 or 2, p, q and r are independently 2 or 3,

Z is phenyl, optionally substituted with halogen, -Or 1, -NO ₂ or NR ² R 4, or a 5- or 6-membered heterocyclic group containing N, O or S; and

? 7

R, R, and R independently represent hydrogen or (C 1 -C 6) alkyl and pharmaceutically acceptable derivatives thereof.

The compounds of WO 93/24473 can be prepared by any of several methods, for example by alkylation of a benzothiazolone compound of formula I:

an alkylating agent of the general formula:

L- (CH ₂ ) _p -X- (CH ₂ ) _q -Y- (CH ₂ ) _r -Z in which p, q, r, X, y and Z have the same meaning as above and

L represents a leaving group or by alkylation of a compound of formula I, as defined above, with a compound of formula

O = CH- (CH _{3) p.,} - X- (CH _{J) q} -Y- (CH ₂₎ -Z wherein

3 p, q, r, X, Y and Z have the same meaning as above in the presence of a reducing agent.

SUMMARY OF THE INVENTION

In particular, the present invention relates to a novel process for the synthesis of compounds of formula I.

Synthesis Methods from Weinstock et al., J of this compound Med. Chem; 30, are known, for example, 1166-1176 (1987).

According to a compound of the present invention of formula I:

includes a method of preparation

chlorobenzothiazole II conversion:

compounds of formula

to a compound of formula (I), for example using

Μ * * · Μ

- 4 concentrated hydrobromic acid.

The compound of formula (II) is novel and can be prepared by halogenating a 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 sodium nitrite is added.

(III)

Compound of formula III from thiourea of formula IV:

is new and can prepare

nc ₃ (IV) using a halogenating / oxidizing agent such as N-bromosuccinimide, bromine or N-chlorosuccinimide in an acidic solvent, for example a mixed acidic solvent such as MeSO ₃ H / AcOH.

The compound of formula IV is novel and can be prepared by hydrolyzing a compound of formula V:

* 4 5 «44 • 4»

(V), for example, in water using a base such as K ₂ CO ₃ or an alkali metal hydroxide such as NaOH or KOH.

The compound of formula V is novel and can be prepared by reaction of aniline hydrochloride of formula VI:

NHCOCH-3 (VI) with benzoyl isothiocyanate, for example in acetone or methyl isobutyl ketone (MIBK).

The compound of formula VI is new and can be prepared by hydrogenation of the nitroacetamide of formula VII and treatment with HCl

in any suitable solvent, for example ethanol or 2-propanol, in the presence of palladium on activated carbon.

The compound of formula VII is new and can be prepared

- 6 by nitration of acetamide of formula VIII:

for example using HNO 2 in acetic acid.

The compound of formula VIII is new and can be prepared from a compound of formula IX:

for example using acetic anhydride or acetyl chloride, which are both solvents and reactants, or in the presence of dichloromethane and triethylamine.

In another aspect, the present invention provides a process for preparing compounds of formula I, comprising (i) converting a compound of formula IX to a compound of formula wine, for example using acetic anhydride or acetyl chloride which are both solvents and reactants or in the presence of dichloromethane and triethylamine; a compound of formula VIII to a compound of formula I, for example by sequentially preparing compounds of formula VII, VI, V, IV, III and II as described above.

The method of the present invention provides an easy method of fringing 9 to 9.

9 9 9 9 9

9 99 99 99 9 99 99 99 99 of the preparation of the compound of formula II, without the need for using unsuitable starting materials and yielding the resulting compound in good yield.

The present invention also provides novel compounds of formulas II, III, IV, V, VI and VII.

The following examples illustrate the invention but are not intended to limit it.

DETAILED DESCRIPTION OF THE INVENTION

a) 2- (4-Methoxyphenyl) ethylamine (100 g) was dissolved in dichloromethane under a nitrogen atmosphere. To this solution was added triethylamine (92.18 mL) and the resulting solution was cooled to 0 ° C. Acetic anhydride (62.40 mL) was added dropwise to the cooled solution over 35 minutes. The highest outside temperature of 6 ° C was observed. The reaction mixture was stirred for 40 min at room temperature. TLC analysis showed no trace of starting material after complete addition.

The reaction mixture was washed with dilute hydrochloric acid (2 x 1 L) and saturated NaHCO ₃ (2 x 1 L) and then dried over anhydrous MgSO ₄ , filtered and evaporated in vacuo to give an off-white solid. This solid was dried under vacuum at 40 ° C.

b) To concentrated nitric acid (339.6 mL) at 20 ° C was added a solution of 2- (4-methoxyphenyl) ethylacetamide (70 g) in glacial acetic acid (350 mL) at 20 ° C over 25 min. The mixture was cooled to maintain the temperature between 18 and 20 ° C. The resulting solution was stirred at room temperature for 45 minutes. The progress of the reaction was monitored by HPLC.

4 44 4 444 44 44 4444

4 4 4 4 4

44 »4 4 4 444

The reaction mixture was poured into ice-water (2.7 L) to give a precipitate as a slurry. The product turned into an oil while stirring at room temperature. The mixture was extracted with dichloromethane (2 x 1 L). The extract sample was washed with NaHCO ₃ , dried and evaporated for analysis. The extract was washed with a saturated Na ₂ CO ₃ solution (2 x 1 L), causing the extract to become saturated with water. The extract was diluted slightly with a small amount of dichloromethane (about 100 mL), then dried over anhydrous MgSO ₄ , filtered and evaporated in vacuo.

c) 2- (4-Methoxy-3-nitrophenyl) ethylacetamide (4.82 g) was dissolved in hot ethyl acetate (9.5 mL) and then allowed to cool to room temperature. Cooling to 0 ° C gave yellow crystals. These crystals were filtered off, washed with cold ethyl acetate and dried under vacuum at 40 ° C.

d) 2- (4-Methoxy-3-nitrophenyl) ethylacetamide (5.98 g) was dissolved in ethanol (150 mL), 10% palladium on activated carbon (0.18 g) was added and the resulting mixture was hydrogenated overnight at a pressure of 0.3 MPa.

The catalyst was filtered off and the filtrate was evaporated to about one third its volume. This solution was bubbled with hydrogen chloride gas until cooling, a pale brown solid precipitating. This mixture was allowed to stir overnight. The off-white solid was filtered off, washed with diethyl ether and then dried in vacuo at 50 ° C.

e) Aniline hydrochloride (40.0 g) was dissolved in water (200 ml) and the solution basified with aqueous sodium hydroxide solution (25% w / v) to a pH of approximately 11, extracted with dichloromethane (3x100 ml), dried (Na). ₂ SO4) and evaporated to dryness under vacuum to give a pink solid. This solid was dissolved in acetone (140 mL).

Ammonium thiocyanate (12.35 g) was dissolved in acetone (p.a., 120 mL) and benzoyl chloride (17.3 mL) was added dropwise over 2 minutes. The temperature rose from 22 ° C to 38 ° C during the dropwise addition and a white precipitate formed. The reaction mixture was stirred for an additional 75 minutes at room temperature and then filtered and washed with acetone (20 mL) to give a benzoyl isothiocyanate solution. This solution was added dropwise to the amine solution with stirring over 40 minutes. The temperature rose from 23 ° C to 36 ° C during the dropwise addition. A thick creamy precipitate formed. The reaction mixture was left under stirring at room temperature for 16 hours and then the product was collected by filtration, washed with water (30 ml), sucked dry and then dried at 60 ° C under vacuum.

f) N-Benzoylthiourea (45.0 g) was suspended in water (330 mL). Sodium hydroxide (25% w / v, 58 ml) was added and the mixture was heated to 75-80 ° C for 20 minutes with stirring.

This mixture was cooled to room temperature using a cold water bath and then acidified to pH 7-8 with hydrochloric acid (about 4N, 80 mL).

The mixture was further cooled in an ice bath with an internal temperature of 5 ° C, stirred cold for 15 minutes and the product collected by filtration, washed with water (50 mL) and sucked dry. The product was dried under vacuum at 50 ° C.

g) To methanesulfonic acid (823 mL) under a nitrogen atmosphere was added glacial acetic acid (112 mL). The mixture was cooled to keep the temperature below 30 ° C. Thiourea (93.5 g) was added to the resulting solution at 28 ° C. The resulting solution was cooled to 2 ° C to add a solution of N-bromosuccinimide (59.14 g) in methanesulfonic acid (187 mL) over 30 minutes. The temperature was maintained at 2 to 5 ° C. The resulting solution was stirred at a temperature of about 2 ° C for one hour and then allowed to stir at room temperature (the highest temperature of 30 ° C was observed) for 22 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was transferred to a separatory funnel and added dropwise to 25% sodium hydroxide solution (4.675 L) at 4 ° C over 3.5 hours. The temperature was maintained below 11 ° C throughout the dropwise addition. After the reaction was stopped, an off-white solid precipitated. The mixture was stirred at a temperature ranging from 7 to 10 ° C for 1.25 hours and then filtered. The solid was washed with water (2x200 mL), aspirated to dryness and vacuum at 50 ° C to give the substance.

dried behind a white solid

h) 2-Aminobenzothiazole (5 g) was dissolved in concentrated hydrochloric acid under a nitrogen atmosphere at 22 ° C. To this solution was added copper (II) chloride (1.26 g), copper (I) chloride (0.93 g) and ethanol (0.32 g). Complete dissolution of the aminobenzothiazole was observed. The solution was cooled to 15 ° C to add dropwise aqueous sodium nitrite solution (3.9 g) dropwise over 1.75 hours - added below the surface of the reaction mixture via syringe. The temperature was maintained between 13 and 18 ° C. Evolution of nitrogen was observed. The progress of the reaction was monitored by HPLC. After stirring at ambient temperature for 1.75 hours, the reaction was quenched in 5 minutes by pouring into water with stirring at room temperature. A milky-yellow solution formed

- 11 to which the product turned to an oil at the end of the addition. The mixture was stirred for approximately 60 hours. The solid was filtered, washed with water (250 mL), air dried to dryness and then dried under vacuum at 55 ° C to give an orange solid.

(i) Chlorobenzothiazole (15.0 g) was suspended in concentrated hydrobromic acid (165 ml) under a nitrogen atmosphere and the mixture was heated under reflux for 7.5 hours. The mixture was allowed to cool overnight and the precipitated product was collected by filtration, washed with isopropanol (20 mL) and sucked dry to give a tan powder which was dried under vacuum at 45 ° C.

j) The hydrobromide salt (13.3 g) was suspended in water (130 ml) under a nitrogen atmosphere and heated to a temperature ranging from 80 to 90 ° C. Additional water (20 mL) was added. Activated charcoal was added and the solution / suspension was stirred at about 70 ° C for 15 minutes and then hot filtered to obtain a clear solution.

To the hydrochloric filtrate (18 N atmosphere by filtration, washed to obtain a yellow temperature of 45 ° C).

Concentrated acid (ml) was added and the mixture was allowed to stir overnight. The solid was collected by isopropanol (20 ml) and sucked dry to a powder which was dried under vacuum at

The product (5.0 g) was suspended in water (50 mL) under a nitrogen atmosphere and heated to about 70 ° C. Charcoal (0.3 g) was added and the mixture was stirred for 10 minutes and then slowly filtered to give a light yellow solution. Concentrated hydrochloric acid (7 ml) was added and the mixture was stirred at room temperature.

- 12 stirring was allowed to cool under a nitrogen atmosphere. The precipitated product was collected by filtration, washed with isopropanol (10 mL), sucked dry to give a pale yellow powder and dried under vacuum at 45 ° C.

Claims (9)

PATENT CLAIMS A process for the preparation of a compound of formula I: which comprises converting a chlorobenzothiazole compound of formula II: (II) to a compound of formula I. A process according to claim 1, wherein the compound of formula II is prepared by halogenating a 2-aminobenzothiazole compound of formula III: 3. A process according to claim 2 wherein the compound of formula IV: Formula III was prepared NHCOCH ₃ using a halogenating / oxidising agent. 4. A process according to claim 3, wherein the compound of formula IV is prepared by hydrolyzing the compound of formula V: A process according to claim 4, characterized in that the compound of formula V is prepared by reaction of aniline hydrochloride of formula VI: nc ₃ (vi) with benzoyl isocyanate. - 15 · · *** *** *** *** 15 *** *** 6. A process according to claim 5, wherein the compound of formula VI is prepared by hydrogenation of the nitroacetamide of formula VII and treatment with HCl. NHCOCH, (VII) in any suitable solvent. A process according to claim 6, characterized in that the compound of formula VII is prepared by nitration of acetamide of formula VIII: ch ₃ o NHCOCH, The method of claim 7, wherein the compound of formula IX: Vill is prepared from CH, O (IX) using, for example, acetic anhydride or acetyl chloride as both solvent and reagent, or in the presence of dichloromethane and triethylamine. A process for preparing a compound of formula vzorce 4 - 16 • 4 4 4 4 4 4 4 · · 44 • 4444 « 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 444 444 4 4 44 4 4 characterized by comprising i) converting a compound of formula IX to a compound of formula VIII; and ii) converting a compound of formula VIIIa to a compound Compound of formula (X): (X) where Y is hydrogen; and X is selected from -NO ₂ , NH ₂ -HCl, NH-CS-NHCOPh and NH-CS-NH ₂ or X and Y together form a five-membered ring, as in Formula II or III.