DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF SARECYCLINE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT NO.1, SURVEY NO.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
HYDERABAD, 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a simple and cost effective process for the purification of Sancycline of Formula – II.

Sancycline of Formula – II is the key starting material of Sarecycline of Formula – I or pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Sarecycline of Formula – I is chemically known as (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-[(methoxy-(methyl)-amino)methyl] 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide. Sarecycline has been approved by FDA as its hydrochloride salt under the brand name Seysara® in the form of oral Tablets. Sarecycline is an anti-inflammatory drug substance used for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older.

US 8318706 (herein after referred as US ‘706) disclosed substituted tetracycline class antibiotics such as Sarecycline of Formula – I or pharmaceutically acceptable salt thereof. The ‘706 patent further disclosed the process for the preparation of Sarecycline hydrochloride by reacting 7-formylsanscyline of Formula – V as trifluoroacetic acid salt with N-methoxy methanamine followed by the addition of methanolic HCl to obtain Sarecycline hydrochloride of Formula – Ia. The process is depicted below, as Scheme – I:

Scheme – I

US 20210017123 disclosed a process for the preparation of Sarecycline hydrochloride of Formula – Ia from Sancycline of Formula – II by reacting Sancycline of Formula – II with N-iodo succinimide to obtain 7-iodosancycline of Formula – VI followed by reacting with carbon monoxide to obtain 7-formylsancycline of Formula – V, then reacting with N-methoxy methanamine followed by treating with hydrochloric acid to obtain Sarecycline hydrochloride of Formula – Ia. The process is depicted below, as Scheme – II:

Scheme – II
CN 106831479 disclosed a process for the preparation of Sancycline of Formula – II from demeclocycline of Formula – IV. The process involves reducing demeclocycline of Formula – IV by using palladium catalyst to obtain demecycline of Formula – III, and then undergoes reduction in the presence of rhodium catalyst to obtain Sancycline Formula – II. The process is depicted below, as Scheme – III:

Scheme-III
The major disadvantages associated with the above process is the use of expensive reagents for reduction such as rhodium, tedious work up methods, which are not feasible at an industrial scale.

Hence, there is a need of an improved process for the preparation of Sancycline of Formula – II which is the key intermediate in the preparation of Sarecycline of Formula – I or pharmaceutically acceptable salt thereof.

The inventors of the present invention found an improved process to prepare Sancycline of Formula – II. The process of the present invention is industrially feasible, avoids the use of expensive reagents and overcomes the above disadvantages and provides Sancycline of Formula – II with higher yields and purity.
OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a simple and cost effective process for the purification of Sancycline of Formula – II.

.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a process for the purification of Sancycline of Formula – II,
,
which comprises:

(i) treating Sancycline of Formula – II with an acid to obtain Sancycline acid addition salt thereof of Formula – IIa;

,
(ii) treating Sancycline acid addition salt thereof of Formula – IIa with a base to obtain Sancycline of Formula – II;
(iii) purifying Sancycline of Formula – II by using a solvent or mixture thereof.

In another embodiment, the present invention provides a process for the preparation of Sarecycline of Formula – I or pharmaceutically acceptable salts thereof from Sancycline of Formula – II prepared by the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the purification of Sancycline of Formula – II.

The process for purification of Sancycline of Formula – II comprises, treating Sancycline of Formula – II with an acid to obtain a Sancycline acid addition salt thereof of Formula – IIa, treating Sancycline acid addition salt thereof of Formula – IIa with a base to obtain Sancycline of Formula – II, purifying Sancycline of Formula – II by using a solvent or mixture thereof.

Acid addition salt thereof of Formula – IIa comprises sulphate, bisulphate, para toluene sulphonate, methane sulphonate, hydrochloride and hydrobromide.

Acid used to obtain Sancycline acid addition salt thereof of Formula – IIa comprises sulphuric acid, para toluene sulphonic acid, methane sulphonic acid, hydrochloric acid, hydrobromic acid and like.

The above obtained Sancycline acid addition salt thereof of Formula – IIa can be isolated, purified by known methods or can be proceed further without isolating.

The base used to obtain Sancycline of Formula – II comprises an organic base selected from lithium methoxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethylamine, diisopropyl methyl amine, methyl amine, dimethyl amine or mixtures thereof or an inorganic base selected from alkaline or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and similar; alkaline or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate and similar or mixtures thereof.

Purification of Sancycline of Formula – II is carried out using a solvent or mixture thereof.

The solvent used for the above purification step comprises water, alcohols, nitriles, halogenated hydrocarbons, hydrocarbons, amides, sulphoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols comprises C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; nitrile solvent selected from acetonitrile, propionitrile, and the like; halogenated hydrocarbons selected from methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons selected from hexane, cyclohexane, toluene, xylene and the like; amides selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulphoxides selected from but are not limited to dimethyl sulphoxide and the like; nitriles selected from acetonitrile, propionitrile and the like; esters comprises, ethyl acetate and butyl acetate and the like; ethers selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones selected from acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The purification is carried out at a temperature of 0 – 50 °C.

Sancycline used in the present invention can be obtained by reducing demeclocycline of Formula – IV or pharmaceutically acceptable salts thereof to obtain demecycline of Formula – III or pharmaceutically acceptable salts thereof; further reducing demecycline of Formula – III to obtain Sancycline of Formula – II or pharmaceutically acceptable salts thereof.

Reduction of demeclocycline of Formula – IV or pharmaceutically acceptable salts thereof is carried out in the presence of a reducing agent, a base and a solvent to obtain demecycline of Formula – III or pharmaceutically acceptable salts thereof.

The reducing agent used in above reduction comprises lithium aluminium hydride, raney nickel, palladium on carbon, sodium borohydride, sodium amalgam, zinc amalgam, diborane, iron sulphate, tin chloride, dithionates, thiosulphates, diisobutyl aluminium hydride.

The base and solvent used in above reduction are as defined above.

The above reduction step is carried out at a temperature of 10 – 50 °C.

Reduction of demecycline of Formula – III or pharmaceutically acceptable salts thereof is carried out in the presence of a reducing agent, acid and a solvent to obtain Sancycline of Formula – II, wherein the reducing agent, acid and the solvent used in the above reaction are as defined above.

The above reduction reaction is carried out at a temperature of 0 – 20 °C.

The pure Sancycline of Formula – II obtained from the present invention is converted to Sarecycline of Formula – I or pharmaceutically acceptable salts thereof, by any of the known methods.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLE - 1:

PREPARATION OF DEMECYCLINE [FORMULA – III]

Methanol (1500 ml) was added to demeclocycline hydrochloride (500 grams) to obtain suspension. Triethyl amine (315 grams, 3.12 mmol) was added to the above suspension at 20-30 °C. The resulting reaction mass was stirred for 15 – 20 minutes till the clear solution was obtained. Palladium on carbon (25 grams, 5% w/w) suspended in methanol (500 ml) was added to the reaction mass in autoclave at 20-30 °C. After completion of the reaction, pH was adjusted with concentrated hydrochloric acid (225 ml, 2.55 mmol) and then with aqueous ammonia (100 ml, 1.49 mmol) to obtain demecycline.

Yield: 390 gm;
HPLC Purity: 98.07%.

EXAMPLE - 2:

PREPARATION OF SANCYCLINE BISULPHATE [FORMULA – IIa]

Mixture of methanol (4550 ml) and water (350 ml) were added to demecycline (350 grams) to obtain a suspension. Methanesulphonic acid (74.2 grams) was added to the above suspension at 20-30 °C. The resulting reaction mass was stirred for 15 – 20 minutes till the clear solution was obtained. Palladium on carbon (175 grams, 5% w/w) and methanol (350 ml) were added to the reaction mass in autoclave at 2-8 °C. After completion of the reaction, sulphuric acid solution (350 grams, contains 175 grams sulphuric acid and 175 grams water) was added and maintained at 2-8 °C for 3 hours. The product was filtered, washed with methanol (350 ml), acetone (700 ml) to obtain wet filtered mass of sancycline bisulphate (250 grams).

EXAMPLE - 3:

PURIFICATION OF SANCYCLINE [FORMULA – II]
Mixture of acetone (1050 ml) and water (875 ml) was added to the above obtained wet mass of sancycline bisulphate (250 grams) at 20 – 30 °C to obtain suspension. Dimethylformamide (175 ml) was added to the above suspension followed by adding triethylamine (157.5 ml, 1.38 mmol) and stirred for 15 – 20 mins at 20 – 30 °C to obtain a clear solution, pH of 9.0. The pH of the solution was adjusted to 7 by adding concentrated hydrochloric acid (35 ml). Reaction mass was stirred for 4 hours at 20 – 30 °C and then filtered. The filtered mass was washed with aqueous acetone (200 ml, contains 100 ml acetone & 100 ml water) to obtain sancycline.

Yield: 95 grams;
HPLC Purity: 98.69%. ,CLAIMS:CLAIMS
We claim,
1. A process for the purification of sancycline of Formula – II,
,
which comprises:
(i) treating sancycline of Formula – II with an acid to obtain sancycline acid addition salt thereof of Formula – IIa;
,
(ii) treating sancycline acid addition salt thereof of Formula – IIa with a base to obtain sancycline of Formula – II;
(iii) purifying sancycline of Formula – II by using a solvent or mixture thereof.

2. The process according to claim 1, wherein the acid addition salt of step (i) comprises sulphate, bisulphate, para toluene sulphonate, methane sulphonate, hydrochloride and hydrobromide.

3. The process according to claim 1, wherein an acid used in step (i) comprises sulphuric acid, para toluene sulphonic acid, methane sulphonic acid, hydrochloric acid, hydrobromic acid.

4. The process according to claim 1, wherein the base used in step (ii) comprises an organic base selected from lithium methoxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethylamine, diisopropyl methyl amine, methyl amine and dimethyl amine or an inorganic base selected from alkaline or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and similar; alkaline or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate or mixtures thereof.

5. The process according to claim 1, wherein the solvent at step (iii) is selected from water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulphoxides, nitriles, esters, ethers, ketones or mixtures thereof.

6. The process according to claim 1, further comprises converting of sancycline of Formula – II to sarecycline of Formula – I or pharmaceutically acceptable salt thereof,
.