TECHNICAL FIELD:

The present disclosure is in relation to the preparation of tricyclic antidepressants, in particular to the preparation of Doxepin and Dothiepin and their salts. The present disclosure helps in obtaining high yield of the preferred isomer, i.e E-isomer by controlling the formation of the Z-isomer. The method involves usage of cost effective reagents, few steps and is environmentally benign with mild conditions to beget said compounds economically.

BACKGROUND:

Doxepin Hydrochloride with chemical name- 3-Dibenz[b, e]oxepin-11(6H)-ylidene-N,N'-dimethyl-1-propanamine hydrochloride and Dothiepin Hydrochloride with the chemical name- 3-Dibenzo [b, e] thiepin-11(6H)-ylidene- N, N- dimethyl-1-propanamine Hydrochloride are represented by the formula given below are very well known as anti¬depressants. The compounds have been shown to be helpful in managing depression, insomnia by acting as serotonin reuptake inhibitors. In the recent past they have been shown to be effective at the lower dosage for the sleeping disorder.

Doxepin Hydrochloride and Dothiepin Hydrochloride exists in E and Z isomeric forms because of the presence of the double bond. The E-isomer of the aforementioned compounds have been found to be pharmacologically effective and thus mandates the Z-isomer to be absent or present in acceptable range in their usage.

Synthetic methods adopted for the preparation of unsaturated compounds which can exist in E and Z isomeric form usually provide a mixture of both isomers. Among most of such compounds only one of the isomers is pharmacologically valuable. Hence it will be required to separate the isomers or limit the undesired isomer in the mixture to an acceptable amount, to obtain the valuable form of the compound at a commercially useful scale and by a method compatible in terms of the cost and environmentally safe.

Different methods have been used to prepare such compounds and separate mixtures of E and Z isomers. The methods exploit differences in the crystallization, solubility, boiling point, reactivity, affinity and adsorption properties of the isomers. However, the difference between these properties in E and Z isomers is often relatively small, making such separations difficult and expensive. However better method would be the one wherein the formation of the undesired isomer is controlled thus enriching the product stream with the preferred isomer.

According to the pharmacological standards, the acceptable range of Z isomers of Doxepin hydrochloride and Dothiepin hydrochloride are 13%-18% and less than 7% respectively. The methods available in the literature helps in the preparation of mixture of isomers which later have to be separated for the proper utility of the E-isomer. HPLC or NMR have been used to determine the ratio of E/Z isomer.

The synthesis of Dothiepin hydrochloride has been described in Monatsh. 93, 896 (1962, K. Stach, F. Bickelhaupt; NL 6407758; US 3438981; BE 641498 and US342085. BE 641498 and US 3420851 provides information on separation and activity of isomers.

The synthesis of doxepin hydrochloride is described in, Experientia 18, 326 (1962), M. Protiva et al; BE 618591; US 3527766; Cesk Farm. 11,404 (1962) M. Rajsner, M. Protiva,, C.A. 59,2772g (1963).
The methods disclosed are laborious involving multiple steps and workups, high temperature and low yields. Some of the reagents used are not compatible with the environment and retracted from using on an industrial scale. Further, the methods help in obtaining the target compounds as mixture of isomers which have to be subjected for separation to obtain the favoured isomer or a mixture of isomers in a pharmaceutically acceptable ratio.

The present disclosure is aimed to overcome the drawbacks associated with the prior art methods and provide a method of preparation of the Doxepin hydrochloride and Dothiepin hydrochloride which helps in obtaining the target compounds with isomers in a pharmaceutically acceptable ratio.

STATEMENT OF DISCLOSURE:

Accordingly the present disclosure provides a method for preparation of compound of formula I or its pharmaceutically acceptable salt with E-isomer ranging from about 85% to about 99%, said method comprising acts of,

Wherein X=0 or S
Formula I

preparing a solution of 3-dimethylaminopropyl magnesium chloride, reacting solution of compound of formula II with the solution of 3-dimethylaminopropyl magnesium chloride to obtain a reaction mixture,
Wherein X=0 or S Formula II acidifying the reaction mixture to obtain a solution of compound of formula III,

X=0 or S

Formula III
concentrating and acidifying the solution of compound of formula III with hydrochloric acid at a temperature ranging from about 0° C to about 10°C to obtain solution of compound of formula I, separating the compound of formula I from its solution, and optionally converting the compound of formula I to its pharmaceutically acceptable salt.

BRIEF DESCRIPTION OF FIGURES:

Figure 1: The HPLC chromatogram indicating the E/Z isomeric ratio of Doxepin hydrochloride obtained by example no 1.

Figure 2: The HPLC chromatogram indicating the E/Z isomeric ratio of Doxepin hydrochloride obtained by example no 2.

Figure 3: The HPLC chromatogram indicating the E/Z isomeric ratio of Doxepin hydrochloride obtained by example no 3.

Figure 4: The HPLC chromatogram indicating the E/Z isomeric ratio of Dothiepin hydrochloride obtained by example no 4.

Figure 5: The HPLC chromatogram indicating the E/Z isomeric ratio of Dothiepin hydrochloride obtained by example no 5.

Figure 6: The HPLC chromatogram indicating the E/Z isomeric ratio of Dothiepin hydrochloride obtained by example no 6.

DETAILED DESCRIPTION OF DISCLOSURE:

The present disclosure is in relation to a method for preparation of compound of formula I or its pharmaceutically acceptable salt with E-isomer ranging from about 85% to about 99%, said method comprising acts of,

Wherein X=0 or S Formula I

a) preparing a solution of 3-dimethylaminopropyl magnesium chloride,

b) reacting solution of compound of formula II with the solution of 3-dimethylaminopropyl magnesium chloride to obtain a reaction mixture,

Wherein XO or S Formula II c) acidifying the reaction mixture to obtain a solution of compound of formula III,

X=0 or S
Formula III

d) concentrating and acidifying the solution of compound of formula III with hydrochloric acid at a temperature ranging from about 0° C to about 10°C to obtain solution of compound of formula I.

e) separating the compound of formula I from its solution, and

f) optionally converting the compound of formula I to its pharmaceutically acceptable salt.

In an embodiment of the present disclosure, the E-isomer of compound of formula I

Wherein X=0 Formula I ranges from about 85% to about 87%. In another embodiment of the present disclosure, the E-isomer of compound of formula I

Wherein X=S Formula I ranges from about 97% to about 99 %.

In still another embodiment of the present disclosure, the solution of 3-dimethylaminopropyl magnesium chloride is prepared in a solvent selected from a group comprising tetrahydrofuran, toluene and mixture thereof.

In still another embodiment of the present disclosure, the solution of compound of formula II is prepared in a solvent selected from a group comprising toluene, tetrahydrofuran, methyl tetrahydrofuran, tert-butyl methyl ether, dimethoxy ethane, benzene and mixture thereof.

In still another embodiment of the present disclosure, the acidification is carried out using acids selected from a group hydrochloric acid, aqueous ammonium chloride solution, sulphuric acid, phosphoric acid, citric acid or mixture thereof

In still another embodiment of the present disclosure, the pharmaceutically acceptable salt of the compound of formula I is of hydrogen chloride.

In yet another embodiment of the present disclosure the compound of formula I is obtained in a yield ranging from about 75% to about 85%.

Dothiepin and Doxepin exist in E/Z isomeric forms. In the case of Doxepin, Z-Isomer content varies from about 13%-40%. In the case of Dothiepin Z-isomer content is about 7%. As the E-isomer of both the compounds is the pharmacologically preferred isomer it is necessary to have pharmaceutically acceptable amounts of the Z-isomer in the preparations. The pharmaceutically acceptable value of Z-isomer of Doxepin is about 13% to about 18% and that of Dothiepin Z-isomer is less than 7%. According to the methods available in the literature it is difficult to restrain the formation of Z-isomer in accordance with the pharmaceutically acceptable amounts of E and Z isomers. Thus separation of isomers have to be performed involving additional reagents and time.

Further, both the compounds are known to interconvert preferably to more Z-isomer under acidic conditions at higher temperature. In most of the methods temperature of about 100°C is adopted, this aids degradation of the compound product. The aforementioned step reduces the yield of the E-isomer.
The present disclosure provides an improved method for the synthesis of Doxepin and Dothiepin wherein the proportion of E-isomer is high. The amount of Z-isomer is in accordance with the pharmacological standards. Thus the method helps in overcoming the shortcoming related preferential preparation of E-isomer without involving physical or chemical separation of the isomers.

The method utilizes the suitable ketone, Doxepinone or Dothiepinone along with dimethylaminopropylchloride in a Grignard reaction to obtain the corresponding carbinol which is treated with hydrochloric acid for dehydration at a low temperature, preferably from about 0°C to about 10°C, basified to obtain Dothiepin / Doxepin base. The said compounds are optionally converted to their salt form. The reaction is schematically represented as given below (Scheme-1).

Cis/Z-isomer Trans/E-isomer Cis/Z-isomer Trans/E-isomer
wherein X=OorS

Scheme-1
The low temperature adopted from about 0° C to about 10°C provides control over the Z-isomer formation, the amount of Z-isomer in the final product varies from 0% to about 3% in case of Dothiepin from 13% to about 16% in case of Doxepin. The overall yield of Doxepin and Dothiepin obtained by the process varies from 75 % to about 85 %.

Thus the method helps in obtaining pharmaceutically valuable isomer of Doxepin, Dothiepin and their pharmaceutically acceptable salts, preferably hydrochloride salt by a simple method with cost effective reagents in only two steps resulting in high yield.

The present disclosure is now described with reference to the following examples. However it should not be construed that the disclosure is limited thereto.

Example 1: Synthesis of Doxepin Hydrochloride
3-Dimethylaminopropylchloride (133 g in toluene ) is added to a slurry of magnesium (27 g) in tetrahydrofuran (1 Lt) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture is cooled to about 10-15 °C and a solution of Doxepinone (210 g) in toluene (400 mL) added over a period of 2 h. The reaction mass is stirred at room temperature for about 8 h and the reaction mass is acidified with molar equivalent of hydrochloric acid (100 g, 35% aqueous HC1). The toluene-THF layer thus obtained is filtered and concentrated to about 50%. The toluene layer thus obtained is added to cold concentrated HC1 (600 mL) at about 0°C -10°C and stirred for 4h. Organic layer separated and the aqueous layer is basified with sodium carbonate and extracted with toluene (500 mL) and concentrated to get Doxepin base (260 g). The Doxepin base thus obtained is dissolved in acetone (1200 mL), charcolized and treated with HC1 in isopropyl alcohol to get white Doxepin HC1 (255 g) comprising Z-isomer content of 14-15% (Yield- 80%).

Example Al: Synthesis of Doxepin Base
3-Dimethylaminopropylchloride (133 g in toluene) is added to a slurry of magnesium (27 g) in tetrahydrofuran (1 Lt) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture is cooled to about 10-15 °C and a solution of Doxepinone (210 g) in toluene (400 mL) added over a period of 2 h. The reaction mass is stirred at room temperature for about 8 h and the reaction mass is acidified with molar equivalent of hydrochloric acid (100 g, 35% aqueous HC1). The toluene-THF layer thus obtained is concentrated under vacuum below 100 °C. The viscous residue thus obtained in added to 250 mL of methanol and cooled to about 10 °C and stirred at the same temperature for 1 h. The crystals thus separated was filtered and dried at 55-60 °C to get Doxepin Base as almost white crystalline solid (255 g, 86%).

Example 2: Synthesis of Doxepin Hydrochloride
3-Dimethylaminopropylchloride (133 g in toluene ) is added to a slurry of magnesium ( 28 g) in tetrahydrofuran ( 500 mL) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture is cooled to about 10 °C and a solution of Doxepinone (210 g) in toluene (750 mL) is added over a period of 4 h. The reaction mass is stirred at room temperature for about 5-6 h and the reaction mass is acidified with ammonium chloride (150 g in 500ml water). The toluene-THF layer thus obtained is filtered and concentrated. The residue is added to methanol. On cooling crystals of hydroxyl Doxepin separates out and it is filtered and dried (275 g). This is dissolved in toluene (1 Lt) added to cold concentrated HC1 (600 mL) below 10°C and stirred for 3-4h. Aqueous layer is basified with sodium carbonate and extracted with toluene (100 mL) and concentrated to get Doxepin base (240 g). The Doxepin base thus obtained is dissolved in acetone and charcolized and treated with HC1 in isopropyl alcohol to get white Doxepin HC1 which is having Z-isomer content of 14-15% (Yield 240 g, 76%).

Example 3: Synthesis of Doxepin Hydrochloride
3-Dimethylaminopropylchloride (135 g in toluene ) added to a slurry of magnesium (28 g) in tetrahydrofuran (750 mL) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture is cooled to about 10-15 °C and a solution of Doxepinone (210 g) in toluene (500 mL) added over a period of 4 h. The reaction mass is stirred at room temperature for about 10 h and the reaction mass was acidified with molar equivalent of hydrochloric acid ( 100 mL, about 35% aqueous HC1). The toluene-THF layer thus obtained is filtered and cooled to about 10°C and treated with concentrated HC1 (700 mL) and stirred for 3-4h. Aqueous layer is basified with sodium carbonate and extracted with toluene (750 mL) and concentrated to get Doxepin base ( 270 g). The Doxepin base thus obtained is dissolved in acetone (1 Lt), charcolized and treated with HC1 in isopropyl alcohol to get white Doxepin HC1 having Z-isomer content of 14-15% (yield: 258 g, 82%).

Example 4: Synthesis of Dothiepin Hydrochloride
3-Dimethylaminopropylchloride (133 g in toluene) is added to a slurry of magnesium (27 g) in tetrahydrofuran (lLt) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture is cooled to about 5 °C and a solution of Dothiepinone (226 g) in toluene (750 mL) added over a period of 4 h. The reaction mass is stirred at the same temperature for 1 h and then at room temperature for about 6 h and the reaction mass was acidified with molar equivalent of hydrochloric acid (100 mL, 35% aqueous HC1). The toluene-THF layer thus obtained is filtered and concentrated to about 50%. The toluene layer thus obtained is added to cold concentrated HC1 (1000 mL) at about 0 °C-5°C and stirred for 3-4h. Aqueous layer is basified with sodium carbonate and extracted with toluene, concentrated to get Dothiepin base (260 g). The Dothiepin base thus obtained is dissolved in acetone, charcolized and treated with HC1 in isopropyl alcohol to get white Dothiepin HC1 having Z-isomer content of less than 3% (Yield: 265 g, 79.93%).

Example 4A: Synthesis of Dothiepin Base
3-Dimethylaminopropylchloride (133 g in toluene) is added to a slurry of magnesium (27 g) in tetrahydrofuran (lLt) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture is cooled to about 5 °C and a solution of Dothiepinone (226 g) in toluene (750 mL) added over a period of 4 h. The reaction mass is stirred at the same temperature for 1 h and then at room temperature for about 6 h and the reaction mass was acidified with molar equivalent of hydrochloric acid (100 mL, 35% aqueous HC1). The toluene-THF layer thus obtained is concentrated completely under vacuum below 100 °C. The viscous mass thus obtained is added to methanol (250 mL) and cooled to about 5-10°C for 1 h. The crystals thus separated was filtered and dried at 50-60 °C for 4 h, to get Dothiepin base as pale yellow crystalline solid (260 g, 83%).

Example 5: Synthesis of Dothiepin Hydrochloride
3-Dimethylaminopropylchloride (133 g in toluene ) is added to a slurry of magnesium (28 g) in tetrahydrofuran (500 mL) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture was cooled to about 5 °C and a solution of Dothiepinone (226 g) in toluene (500 mL) is added over a period of 4 h. The reaction mass is stirred at room temperature for about 5 h and the reaction mass is acidified with ammonium chloride (150 g in 500 mL water). The toluene-THF layer thus obtained is filtered, concentrated and the residue is added to methanol (500 mL). On cooling, crystals of hydroxyl Dothiepin separates out and it is filtered and dried (290 g). This is dissolved in toluene (1 Lt) added to cold concentrated HC1 (750 mL) at about 0°C- 10°C and stirred for 3-4h. Aqueous layer is basified with sodium carbonate and extracted with toluene and concentrated to get Dothiepin base (280 g). The Dothiepin base thus obtained is dissolved in acetone, charcolized and treated with HC1 in isopropyl alcohol to get white Dothiepin HC1 having Z-isomer content of <3% (yield: 273 g, 82%).

Example 6: Synthesis of Dothiepin Hydrochloride
3-Dimethylaminopropylchloride (133 g in toluene) is added to a slurry of magnesium (28 g) in tetrahydrofuran (400 mL) and generated 3-dimethylaminopropyl magnesium chloride. The reaction mixture is cooled to about 5 °C and a solution of Dothiepinone (226 g) in toluene (500 mL) is added over a period of 6 h. The reaction mass is stirred at room temperature for 5-6 h and the reaction mass is acidified with molar equivalent of hydrochloric acid (100 mL, aqueous HC1). The toluene-THF layer thus obtained is filtered and concentrated to about 50%. The toluene layer thus obtained is cooled to about 10°C and treated with concentrated HC1 (100 mL) and stirred for 3-4h. Aqueous layer is basified with sodium carbonate and extracted with toluene and concentrated to get Dothiepin base (290 g). The Dothiepin base thus obtained is dissolved in acetone, charcolized and treated with HC1 in isopropyl alcohol to get white Dothiepin HC1 having Z-isomer content of less than 3% (Yield: 267 g, 80%).

While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the appended claims.

WE CLAIM:

1). A method for preparation of compound of formula I or its pharmaceutically acceptable salt with E-isomer ranging from about 85% to about 99%, said method comprising acts of,

Wherein X=0 or S Formula I

a) preparing a solution of 3-dimethylaminopropyl magnesium chloride,

b) reacting solution of compound of formula II with the solution of 3-dimethylaminopropyl magnesium chloride to obtain a reaction mixture,

Wherein X=0 or S Formula II c) acidifying the reaction mixture to obtain a solution of compound of formula III,

X=0 or S Formula III

d) concentrating and acidifying the solution of compound of formula III with hydrochloric acid at a temperature ranging from about 0° C to about 10°C to obtain solution of compound of formula I,

e) separating the compound of formula I from its solution, and

f) optionally converting the compound of formula I to its pharmaceutically acceptable salt.
2) The method as claimed in claim 1, wherein the E-isomer of compound of formula I
Wherein X=0 Formula I ranges from about 85% to about 87%. 3) The method as claimed in claim 1, wherein the E-isomer of compound of formula I

Wherein X=S Formula I

ranges from about 97% to about 99 %.

4) The method as claimed in claim 1, wherein the solution of 3-dimethylaminopropyl magnesium chloride is prepared in a solvent selected from a group comprising tetrahydrofuran, toluene and mixture thereof.

5) The method as claimed in claim 1, wherein the solution of compound of formula II is prepared in a solvent selected from a group comprising Toluene, tetrahydrofuran, methyl tetrahydrofuran, tert-butyl methyl ether, dimethoxy ethane, benzene and mixture thereof.

6) The method as claimed in claim 1 (c), wherein the acidification is carried out using acids selected from a group comprising hydrochloric acid, aqueous ammonium chloride solution, sulphuric acid, phosphoric acid, citric acid or mixture thereof.

7) The method as claimed in claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is of hydrogen chloride.

8) The method as claimed in claim 1, wherein the compound of formula I is obtained in a yield ranging from about 75% to about 85%.