HK1059775B - Process for the preparation of 9-amino substituted 9,10-dihydropyrrolo [2,1-b][1,3] benzotiazepines - Google Patents

Description

9-amino-substituted 9, 10-dihydropyrrolo [2, 1-b ] [1, 3] benzothiepin * preparation method

The invention described herein relates to a process for the preparation of 9, 10-dihydro-pyrrolo [2, 1-b ] [1, 3] benzothiepin * (thiazepine), particularly 9-amino-substituted 9, 10-dihydro-pyrrolo [2, 1-b ] [1, 3] benzothiepin *.

Background

In international patent application WO00/06579, which is incorporated herein by reference in its entirety, 9, 10-dihydro-pyrrolo [2, 1-b ] [1, 3] benzothiepin * is described as a compound endowed with antipsychotic activity, in particular with regard to the treatment of psychiatric disorders such as: schizophrenia, paranoia states, manic-depressive states, affective disorders, antisocial behavior, personality degeneration and hallucinations.

For the compounds described in the above patent applications, there are provided processes for their preparation, which comprise a cyclization reaction of a derivative containing a phenyl group and a pyrrolyl group, resulting in the formation of a [1, 3] -thiaazepine * ring. Preferably, the pyrrolobenzothiazane * derivative should be formed by cyclization and then converted to the target 9-amino-substituted pyrrolo [2, 1-b ] [1, 3] benzothiazane * by action on the keto group.

A certain number of steps are necessary to convert the keto group to an optionally substituted amine group. As shown in FIG. 2B/2 of the above-mentioned patent application, the keto group is first reduced to a hydroxyl group, which is then replaced with a suitable leaving group such as a bromine atom, and the target amine group is finally inserted. The conversion of the keto group into the final amine group gives rise to a chiral center and the resulting racemic mixture derived therefrom is finally separated into the individual enantiomers by conventional methods. Substitution of the hydroxyl group by a leaving group (bromine in the examples given) necessarily reduces the yield, which cannot be recovered in the next step on a scale preparation plan.

Summary of The Invention

It has now been found that 9-amino-substituted pyrrolo [2, 1-b ] [1, 3] benzothiepin * can be obtained in a single step starting from pyrrolobenzothiepin *, resulting in a much higher final yield of useful target product and containing fewer impurities from an industrial point of view.

An object of the invention described herein is a process for the preparation of the compounds of formula (I) and their salts

Wherein:

R＝H、Cl、Br、F、I、C₁-C₄alkoxy radical, C₁-C₄Alkylthio radical, C₁-C₄Alkyl radical, C₅-C₆A cycloalkyl group,

R₁dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl,

R₂hydrogen and C₁-C₄Alkoxy radical, C₁-C₄An alkylthio group;

said process essentially comprising reacting the radicals R and R₂Substituted pyrrolobenzothiazanes * are converted to compounds of formula (I) via the corresponding enamines and optionally salified with an acid.

Detailed Description

According to the invention described herein, wherein R and R are₂A compound of formula (Ia) as defined above for a compound of formula (I)

And as for R₁Target amine R defined by the group₁H reaction to obtain intermediate product enamine (Ib)

Wherein R is₁As defined above for the compound of formula (I), which is then converted into the final compound (I).

The conversion of the compounds (Ia) to (Ib) is effected by known techniques, but it is known that the reaction is carried out by reacting the compound with an amine R in the presence of a Lewis acid, for example trifluoromethanesulfonic acids, such as trimethylsilyltrifluoromethanesulfonic acid, or protic acids, such as sulfonic acids, for example p-toluenesulfonic acid₁H is conveniently effected by treating compound (Ia).

The reaction is carried out in a solvent which is inert to the reagents and reaction products, or, in a preferred embodiment, an excess of amine R relative to compound (Ia)₁H to constitute the reaction medium. The reaction parameters are not critical and can be determined by a skilled person having ordinary experience in the art on the basis of his or her own general knowledge on the subject. For example, compounds (Ia) with amines R₁The molar ratio of H can range from 1: 1 to an amine excess in the above sense. The reaction temperature can also be chosen in relation to the type of reagents used, their molar ratio and the solvent optionally present, in which case the reaction temperature may even be as high as the boiling temperature of the solvent, provided that this temperature does not lead to decomposition of the reagents themselves. With reaction times in the above-mentioned parametersAnd is selected on a basis to complete the reaction. Attempts to optimize the reaction do not constitute an additional experimental burden and are part of the common techniques used in chemical synthesis.

The conversion of the enamine to the compound of formula (I) is effected by reduction of the enamine double bond, which falls within the ordinary expertise of the skilled artisan. Suitable reducing agents can be found in the relevant literature manuals and do not require any particular expertise. For example, one suitable reducing agent is sodium borohydride. Also for the second step, the above considerations regarding reaction parameters and solvents still apply.

Isolation and purification of the compounds of formula (I) is achieved by conventional, known methods; in particular, the separation of the enantiomers can be accomplished as described in the above-mentioned patent application.

The inventive process described herein can be used to prepare benzothiazanes generally *, and dihydrobenzothiazanes * as enamines continue to be reduced.

In a first preferred embodiment of the invention, the compound of the formula (Ia) is reacted with an amine R₁H reaction, which is used as a reaction medium when the physicochemical properties of the latter permit. The preferred trifluoromethanesulfonic acid is trimethylsilyl trifluoromethanesulfonic acid. The reaction temperature was about 120 ℃ and the reaction time was about 3 hours.

In a second preferred embodiment of the invention, the compound of the formula (Ia) is reacted with an amine R₁The latter, when its physicochemical properties allow it, is used as reaction medium. The preferred sulfonic acid is p-toluenesulfonic acid. The reaction temperature is about 180 ℃ and the reaction time is about 1-2 hours.

Isolation and purification of the compounds of formula (I) is achieved by conventional, known methods; in particular, the separation of the enantiomers may be accomplished as described in the above-mentioned patent application, or by fractional crystallization according to one embodiment of the invention described herein.

The following examples further illustrate the invention.

Examples are provided for the preparation of (. + -.) -7-chloro-9- (4-methylpiperazin-1-yl) -9, 10-dihydropyrrolo [2, 1-b ] [1, 3] benzothiepin * (ST1455), which is one of the preferred compounds described in patent application WO 00/06579.

It is clear that the examples provided herein apply to all compounds of formula (I) and that suitable modifications can be made by a person skilled in the art.

Example 1

a) 7-chloro-9- (4-methyl-1-piperazinyl) pyrrolo [2, 1b ] [1, 3] benzothiepin * (10h)

Method A)

Trimethylsilyltriflic acid (5.7 mL; 31.5mmol) was added dropwise over 5 minutes to a mixture of ketone [9b ] (4.5 g; 18mmol) and N-methylpiperazine (15 mL).

The reaction temperature was raised to 120 ℃. The reaction was monitored by TLC and completed within 3 hours. The reaction mixture was allowed to cool at room temperature and the resulting solid material was dissolved in dichloromethane (50mL) and washed with water (2X 30 mL). The organic phase was dehydrated with sodium sulfate and filtered. The crude reaction product can be recovered by evaporation of the solvent under reduced pressure and chromatographed on silica gel (n-hexane/ethyl acetate 50: 50) to give 4.7g of the title compound.

Yield: 78 percent of

TLC(AcOEt)Rf＝0.25；MP：127-128℃.

¹H-NMR(300MHz，CDCl₃)δ7.6(d，1H，J＝2.1Hz)；7.4(d，1H，J＝8.5Hz)；7.2(dd，1H，J₁＝8.4Hz，J₂＝2.0Hz)；6.7(m，1H)；6.6(m，1H)；6.2(m，1H)；6.1(m，1H)；2.9(m，4H)；2.6(m，4H)；2.3(s，3H)。

¹³C-NMR(300MHz CDCl₃)δ143.8；140.5；137.9；134.8；133.2；129.8；129.6；127.9；123.2；112.7；111.6；111.2；55.2；50.1；46.2。

Elemental analysis: (C)₁₇H₁₈ClN₃S): conform to

Method B)

A mixture of ketone [9b ] (0.15 g; 0.6mmol), N-methylpiperazine (0.18 g; 1.8mmol) and p-toluenesulfonic acid (0.296 g; 1.56mmol) was heated to 180 ℃.

The reaction quickly appeared dark, completed in 1.5 hours, the mixture was left to cool at room temperature, the resulting solid material was dissolved in dichloromethane (10mL) and washed with water (2 × 10 mL). The organic phase was dehydrated with sodium sulfate and filtered. Evaporation of the solvent under reduced pressure gave the crude reaction product which was chromatographed on silica gel (n-hexane/ethyl acetate 50: 50) to give the title compound.

Preparation of Compound b) (+ -) -7-chloro-9- (4-methylpiperazin-1-yl) -9, 10-dihydropyrrolo [2, 1-b ] [1, 3] benzothiepin * (ST1455)

Reacting the compound [10b ]](2.97 g; 8.97mmol) in acetic acid (25 mL); the solution was cooled to 0 ℃ and NaBH was carefully added₄(400 mg). The reaction was completed within 2 hours. The mixture was evaporated under reduced pressure. Dichloromethane was added and washed three times with water and bicarbonate. The organic phase was dehydrated with sodium sulfate, filtered and evaporated under reduced pressure. 2.75g of product of 95% purity are obtained, the purity being calculated by HPLC.

Yield: 87 percent of

The table given below shows the values of the various process steps of the invention described herein (table 1) in comparison with the process described in patent application WO 00/06579; see in particular pages 29-30 of the cited patent application and example 2 (table 2).

TABLE 1

Conversion (substrate → product)	Conversion yield (%)
		[9b]→[10b]	78
[10b]→[ST1455]	87
		Total conversion yield: 9.6

TABLE 2

Conversion (substrate → product)	Conversion yield (%)
		[9b]→[24b]	88
[24b]→[25b]	51
		[25b]→[ST1455]	68
Total conversion yield: 4.3

Example 2

Separation of the racemic mixture by fractional crystallization of ST1455

The racemic mixture obtained was separated into two optically active isomers by fractional crystallization of the diastereomeric salts obtained by salt formation with tartaric acid according to the method described below.

2.5g of ST1455(7.5mmol) were dissolved in ethanol while hot and 1.12g D (-) tartaric acid (7.5mmol) was added. The solution was kept at room temperature overnight. The tartrate crystals thus obtained were filtered and recrystallized from a 3: 1 ethanol/methanol mixture. The solution was kept at room temperature overnight. After filtration, 1.1g of the tartrate salt of the (+) enantiomer was obtained, which exhibited an optical purity of 97.3 in HPLC.

Column: Chiralpack-AD (5m), 4.6X 250 mm; t is 23 ℃; mobile phase: n-hexane-ethanol, TEA (95/5/0.1 v/v); flow rate: 1 ml/min; rt 5.6 min

Yield: 62 percent of

Then through NaHCO₃Work-up and AcOEt extraction converted the tartrate salt to the free base.

Similarly, treatment of ST1455 with L (+) tartaric acid gave the tartrate salt of the corresponding (-) enantiomer.

The separation of the racemic mixture by fractional crystallization is particularly advantageous compared with the separation using a semipreparative chiral column, the amount of the target product at any time being much greater than that conventionally obtained by laboratory synthesis.

Claims (13)

1. Process for the preparation of compounds of formula (I) and salts thereof

Wherein:

R＝H、Cl、Br、F、I、C₁-C₄alkoxy radical, C₁-C₄An alkylthio group;

R₁dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl，

R₂Hydrogen and C₁-C₄Alkoxy radical, C₁-C₄An alkylthio group;

the process comprises reacting a pyrrolobenzothiaza * ketone of formula (Ia)

Wherein:

R＝H、Cl、Br、F、I、C₁-C₄alkoxy radical, C₁-C₄An alkylthio group;

R₂hydrogen and C₁-C₄Alkoxy radical, C₁-C₄An alkylthio group;

with amines R₁H reaction, wherein R₁Di-alkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl to give enamine (Ib)

Wherein:

R＝H、Cl、Br、F、I、C₁-C₄alkoxy radical, C₁-C₄An alkylthio group;

R₁dialkyl amine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl;

R₂hydrogen and C₁-C₄Alkoxy radical, C₁-C₄An alkylthio group;

it is then converted into the final compound (I) and optionally salified with an acid.

2. The process according to claim 1, wherein the compound (Ia) and the amine R₁H is reacted in the presence of a Lewis acid, wherein R₁Dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl.

3. The process according to claim 2, wherein the acid is trifluoromethanesulfonic acid.

4. A process according to claim 3 wherein the triflic acid is trimethylsilyl triflic acid.

5. The process according to claim 1, wherein the compound (Ia) is reacted with an amine R₁H is reacted in the presence of a protic acid, wherein R₁Dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl.

6. The method according to claim 5, wherein the acid is a sulfonic acid.

7. The process according to claim 6, wherein the sulfonic acid is p-toluenesulfonic acid.

8. The process according to any one of claims 1 to 7, wherein an excess of amine R relative to compound (Ia) may be used₁H to form a reaction medium, wherein R₁Dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl.

9. The process according to any one of claims 1 to 8, wherein enamine (Ib) is converted to compound (I) by a reducing agent.

10. The process according to claim 9, wherein the reducing agent is sodium borohydride.

11. The process according to claim 4, wherein the reaction temperature is 120 ℃ and the reaction time is 3 hours.

12. The process according to claim 5, wherein the reaction temperature is 180 ℃ and the reaction time is 1 to 2 hours.

13. A process according to any one of claims 2 to 12 wherein the compound of formula (I) is isolated as its enantiomer.