WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone

Lurasidone – it having been developed and launched by Sumitomo Dainippon Pharma. Lurasidone was launched for schizophrenia in the US by Sumitomo's US subsidiary Sunovion Pharmaceuticals.

WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone

An improved process for the preparation of lurasidone and its intermediate

PIRAMAL ENTERPRISES LIMITED [IN/IN]; Piramal Tower Ganpatrao Kadam Marg, Lower Parel Mumbai 400013 (IN)

GHARPURE, Milind; (IN).
TIWARI, Shashi Kant; (IN).
WAGH, Ganesh; (IN).
REVANAPPA, Galge; (IN).
WARPE, Manikrao; (IN).
ZALTE, Yogesh; (IN).

From left: Anand Piramal, executive director, Piramal Group; Swati Piramal, vice-chairperson, Piramal Group; Ajay Piramal, chairman, Piramal Group; Nandini Piramal, executive director, Piramal Enterprises; and Peter DeYoung, president, Piramal Enterprises

Improved process for preparing pure (3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piperazin]-1'-ium methanesulfonate, useful as a key intermediate in the synthesis of lurasidone. Also claims a process for purifying lurasidone hydrochloride, useful for treating schizophrenia and bipolar disorders. In July 2016, Newport Premium™ reported that Piramal Enterprises was capable of producing commercial quantities of lurasidone hydrochloride and holds an active US DMF for the drug since March 2015.

Lurasidone (the Compound-I), is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorders.The drug is marketed as hydrochloride salt (the compound-I.HCl) by Sunovion Pharms Inc.under the tradename"LATUDA", in the form of oral tablets. Latuda is indicated for the treatment of patients with schizophrenia. Lurasidone hydrochloride has the chemical name ((3aR,4S,7R,7aS)-2-[((lR,2R)-2-{ [4-(l,2-benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)-methyl]hexahydro-lH-4,7-methanisoindol-l,3-dione hydrochloride, and is structurally represented as follows;

Compound-I.HCl

Lurasidone being an important antipsychotic agent; a number of processes for its preparation as well as for its intermediates are known in the art.

US Patent No. 5,532,372 describe a process for the synthesis of Lurasidone, which is illustrated below in Scheme-I. In the process, the compound, cyclohexane- l,2-diylbis(methylene) dimethanesulfonate(referred to as the compound-Ill) is reacted with 3-(l-piperazinyl-l,2-benzisothiazole(referred to as the compound-IV) in acetonitrile, and in the presence of sodium carbonate to provide corresponding quaternary ammonium salt as 4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2, r-piperazin]-l'-ium methanesulfonate (the compound-II). The compound-II is further treated with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in xylene, in the presence of potassium carbonate and dibenzo-18-crown-6-ether to provide lurasidone.

Scheme-I

US Published Patent Application 2011/0263848 describes a process for the preparation of the quaternary ammonium salt (the compound-II) which comprises reacting 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)- cyclohexane in a solvent such as toluene in the presence of a phosphate salt.

Indian Published Patent Application 2306/MUM/2014 (" the IN'2306 Application") describes a process for the synthesis of lurasidone and the intermediates thereof, comprising reacting (R,R) trans l,2-bis(methane sulphonyl methyl)cyclohexane with 3-(Piperazine-l-yl)benzo[d]isothiazole in presence of a mixture of two or more polar aprotic solvents selected from acetonitrile, N,N-dimethyl formamide (DMF) and/or Ν,Ν-dimethyl acetamide (DMAc), and a base at reflux temperature to obtain the quaternary ammonium salt (the compound II), which is then converted to lurasidone. The IN'2306 application demonstrated preparation of the compound II using the solvent combination such as acetonitrile-DMF and acetonitrile-DMAc.

US Published Patent Application 2011/0263847 describes a process for the preparation of the quaternary ammonium salt (the compound-II) comprising reacting 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent such as toluene, wherein the piperazine compound is used in an excess amount i.e. 1.8 to 15 moles with respect to ( 1R,2R)- 1 ,2-bis(methanesulfonyloxymethyl)cyclohexane.

Chinese Published Patent Application 102731512 describes a process for the preparation of the quaternary ammonium salt (the compound-II) comprises reaction of 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent such as toluene in the presence of a phase transfer catalyst.

In addition to the afore discussed patent documents, there are a number of patent documents that describe a process for the preparation of the quaternary ammonium salt (the compound-II), the key intermediate for the synthesis of lurasidone. For instance, Published PCT application WO2012/131606 A 1, Indian Published patent application 217/MUM/2013, Chinese published patent applications 102863437, 103864774 and 102827157 describe a process for the preparation of the quaternary ammonium salt (compound-II) comprises reaction of 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent or a solvent mixture such as acetonitrile, acetonitrile : water solvent mixture, toluene or DMF, in the presence of a base.

It is evident from the discussion of the processes for the preparation of the quaternary ammonium salt (the compound-II), described in the afore cited patent documents that the reported processes primarily involve use of acetonitrile either as the single solvent or in a mixture of solvents. Acetonitrile is a relatively toxic, and not an environment friendly solvent. Due to its toxic nature, it can cause adverse health effects also. Acetonitrile is covered under Class 2 solvents i.e. solvents to be limited, and residual solvent limit of acetonitrile is 410 ppm in a drug substance as per the ICH (International Conference on Harmonisation) guidelines for residual solvents. Moreover, acetonitrile is a costlier solvent, which renders the process costlier and hence, is not an industrially feasible solvent.

It is also evident from the discussion of the processes described in afore cited patent documents that some of the reported processes involve use of high boiling solvents such as toluene and dimethylformamide as reaction solvent, which subsequently require high reaction temperatures, and this in turn leads to tedious workup procedures. In view of these drawbacks, there is a need to develop an industrially viable commercial process for the preparation of lurasidone and its intermediates; which is simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.

Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic and/or costly solvents. Moreover, the process does not require additional purification steps and critical workup procedure. Accordingly, the present invention provides a process for the preparation of lurasidone and its intermediates, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.

Scheme-II

Scheme-Ill

EXAMPLES

Example-1: Preparation of (3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,l'-piperazin]-l'-ium methanesulfonate(the compound II)

Charged 150.0 mL (3v) of isopropyl alcohol (IPA) in a flask followed by the addition of the compound-Ill (50.0 g) , 3-(l-Piperazinyl)-l, 2-Benzisothiazole (32.84 g), sodium carbonate granular (10.79 g) and water 50 mL (lv). The reaction mixture was heated at a temperature of 82-85 °C for 24 to 25 h. Cooled the reaction mixture to room temperature, filtered on Buchner funnel and the filtrate was collected.

The filtrate was evaporated under vacuum at 55-65°C till visible solid appears in the reaction mass. The solid was stirred in 75 mL of toluene at room temperature and the solid was filtered. The wet cake was transferred to a flask and added 125 mL of acetone to it; followed by stirring at room temperature. The resulting solid was filtered to yield the pure title compound (II).

Yield: 63.4 g (90 %)

Purity (by HPLC): 99.79 %

Unreacted compound-IV as impurity in 0.05 % .

Example-2: Preparation of Lurasidone free base.

Charged 150.0 mL of Ν,Ν-dimethylformamide (DMF) in a flask followed by the addition of 50.0 g of the compound-II (as obtained in the above example-1), 19.5 g (3aR,4S,7R,7aS)-4,7-methano-lH-isoindole-l,3(2H)-dione and 19.5 g of potassium carbonate. The reaction mixture was heated at a temperature of about 125 °C for 24 h. The reaction mixture was cooled to room temperature and 400 mL of water was added to it. The reaction mixture was stirred, and the precipitated product was filtered. The wet cake was washed with IPA and Lurasidone free base is obtained as the pure product. [Yield: 46.52 g (80 %)]

Example-3: Purification of Lurasidone hydrochloride.

Charged water (200 ml) and IPA (200 ml) in flask followed by the addition of Lurasidone hydrochloride (50 gm, residual acetone: 5769 ppm). The reaction mixture was heated at a temperature of 75-80 °C for about 30 min. The reaction mixture was cooled to 20-30 °C and stirred for about 2 hours. The precipitated solid was filtered and isolated as pure Lurasidone hydrochloride (residual acetone: 2 ppm)

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

///////////////WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

FOR Cancer; Parasitic infection; Plasmodium falciparum infection; Viral infection

WO-2016110874

KUMAR, Ashok; (IN).
SINGH, Dharmendra; (IN).
MAURYA, Ghanshyam; (IN).
WAKCHAURE, Yogesh; (IN)

Dr. Ashok Kumar, President - Research and Development (Chemical) at IPCA LABORATORIES LTD

IPCA LABORATORIES LIMITED [IN/IN]; 48, Kandivli Industrial Estate, Charkop, Kandivali (West), Mumbai 400067 (IN)

Novel process for preparing artemisinin or its derivatives such as dihydroartemisinin, artemether, arteether and artesunate. Also claims novel intermediates of artemesinin such as artemisinic acid or dihydroartemisinic acid. Discloses the use of artemisinin or its derivatives, for treating malaria, cancer, viral and parasitic infections.

In July 2016, Newport Premium™ reported that IPCA was capable of producing commercial quantities of artemether, arteether and artesunate; and holds an inactive US DMF for artemether since February 2009. In July 2016, IPCA's website lists artemether, arteether and artesunate under its products and also lists artemether and artesunate as having EDMF and WHO certificates. The assignee also has Canada HPFB certificate for artemether.

The Central Drug Research Institute (CDRI) in collaboration with IPCA is developing CDRI-97/78 (1,2,4 trioxane derivative), a synthetic artemisinin substitute for treating drug resistant Plasmodium falciparum infection. In July 2016, CDRI-97/78 was reported to be in phase 1 clinical development. IPCA in collaboration with CDRI was also investigating CDRI-99/411, a synthetic artemisinin substitute for treating malaria; but its development had been presumed to have been discontinued; however, this application's publication would suggest otherwise.

Writeup

Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant's anti-malarial application was first described in a Chinese pharmacopeia, titled "Chinese Handbook of Prescriptions for Emergency Treatments," written at around 340 A.D.

Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.

Artemisinin and its derivatives - dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.

Dihydroartemisinin Artesunate

The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.

Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.

Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme- 1.

acid

In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane ( δΗι ΒΗ followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrCb/ifcSC^. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.

Amorpha -4, 11-diene

A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene - 11, 12 - epoxide) is further reduced to get amorph- 4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.

Amorphadiene-11,12-epoxide

This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.

Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.

Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.

DHAA methyl ester

Scheme 2

Method 4 (From compound of formula IV (R = CI)):

In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30^°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30^°C followed by heating and maintaining the temperature for 40 hours at 80^°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water

(100 ml) and toluene (100 ml) to the reaction mass with stirring for 30 minutes at 28^°C. The layers were separated out and aqueous layer was back extracted with toluene (2 X 100 ml). The organic layer was washed with water (100 ml) and saturated brine solution (100 ml). Solvent was distilled out under vacuum at 50^°C, and the crude mass degassed under vacuum at 50-55^°C. IPA (40 ml) was charged to the mass. Simultaneous addition of hydrazine hydrate (65% in aqueous solution) (3.8 g) and hydrogen peroxide (50% in aqueous solution) (2.5 ml) was done at 30-32^°C over a period of 3.25 hours. After completion, reaction mass was cooled up to 5-10^°C and water (100ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with dilute 8% aqueous HC1 (24 ml) at 10^°C. Ethyl acetate (60 ml) was added to the reaction mass at 10^°C and stirred for 15 minutes at 15-20^°C. The layers were separated. Aqueous layer was back extracted with ethyl acetate (2 X 20 ml). The combined organic layer was washed with 10%) sodium metabisulfite solution (50 ml), water (50 ml) and saturated brine solution (50 ml). The organic layer was distilled out under vacuum at 45^°C and the obtained crude mass was degassed at 50-55^°C. To this was added DME (40 ml), Biphenyl (0.9 g) and Li-metal (1.63 g) and the reaction mass was maintained for 10 hours at 80-85^°C till reaction completion. The reaction mass was cooled up to 0-5^°C followed by drop wise addition of water within one hour, and the reaction stirred for two hours at 20-25^°C. Toluene (35 ml) was charged with stirring and layers were separated. The aqueous layer was washed with toluene (35 ml) and the combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15^°C and pH adjusted to 3.5-4 with dilute 16% aqueous HC1. MDC (50 ml) was charged and stirred 30 minutes at 20-25^°C followed by separation of layers. The aqueous layer extracted with MDC (25 ml) and the combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). The solvent was distilled out under vacuum at 40-45^°C and the crude mass (Purity: 70-80%>) was degassed at 65-70°C. The crude product (10 g) was dissolved in ethyl acetate (200 ml). 10%> aqueous NaOH (100 ml) was charged to the reaction mass and stirred one hour at 20^°C followed by layer separation. Again 10%> aqueous NaOH (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaOH solution wash was adjusted to 4.0 with dilute 16%> aqueous HC1 at 5-10^°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml) and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55^°C to obtain Dihydroartemisinic acid (Purity: 90-95%).

b) Methyl ester of Dihydroartemisinic acid:

To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass.

Weight: 41.88 gm

Yield = 98%

c) Artemisinin:

Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The

mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm

Yield= 70.7%

Purification of Artemisinin:

Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.

Weight: 4 gm

Yield: 40%

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India


////////New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd, malaria, Cancer,  Parasitic infection,  Plasmodium falciparum infection,  Viral infection, artemether artemisinin,  artemotil,  artenimol,  artesunate,

NEW PATENT, WO 2016108172, OSPEMIFENE AND FISPEMIFENE, OLON S.P.A.

Ospemifene is useful for treating menopause-induced vulvar and vaginal atrophy; while fispemifene is useful for treating symptoms related with male androgen deficiency and male neurological disorders.

In July 2016, Newport Premium™ reported that Olon was potentially interested in ospemifene and holds an active US DMF for ospemifene since September 2015. Olon's website also lists ospemifene under R&D APIs portfolio.

WO2016108172

PROCESS FOR THE PREPARATION OF OSPEMIFENE AND FISPEMIFENE

OLON S.P.A. [IT/IT]; Strada Rivoltana, Km. 6/7 20090 Rodano (MI) (IT)

CRISTIANO, Tania; (IT). ALPEGIANI, Marco; (IT)

WO2016108172

Process for preparing ospemifene or fispemifene, by reacting a phenol with an alkylating agent.

Ospemifene, the chemical name of which is 2-{4-[(lZ)-4-chloro-l,2-diphenyl-l-buten-l-yl]phenoxy}ethanol (Figure), is a non-steroidal selective oestrogen-receptor modulator (SERM) which is the active ingredient of a medicament recently approved for the treatment of menopause-induced vulvar and vaginal atrophy.

The preparation of ospemifene, which is disclosed in WO96/07402 and WO97/32574, involves the reaction sequence reported in Scheme 1 :

 

Ospemifene

Scheme 1

The first step involves alkylation of 1 with benzyl-(2-bromoethyl)ether under phase-transfer conditions. The resulting product 2 is reacted with triphenylphosphine and carbon tetrachloride to give chloro-derivative 3, from which the benzyl protecting group is removed by hydrogenolysis to give ospemifene.

A more direct method of preparing ospemifene is disclosed in WO2008/099059 and illustrated in Scheme 2.

Ospemifene

Scheme 2

Intermediate 5 (PG = protecting group) is obtained by alkylating 4 with a compound X-CH2-CH2-O-PG, wherein PG is a hydroxy protecting group and X is a leaving group (specifically chlorine, bromine, iodine, mesyloxy or tosyloxy), and then converted to ospemifene by removing the protecting group.

Alternatively (WO2008/099059), phenol 4 is alkylated with a compound of formula X-CH2-COO-R wherein X is a leaving group and R is an alkyl, to give a compound of formula 6, the ester group of which is then reduced to give ospemifene (Scheme 3)

 

Ospemifene

Scheme 3

Processes for the synthesis of ospemifene not correlated with those reported in schemes 2 and 3 are also disclosed in the following documents: CN104030896, WO2014/060640, WO2014/060639, CN103242142 and WO201 1/089385.

Fispemifene, the chemical name of which is (Z)-2-[2-[4-(4-chloro-l,2-diphenylbut-l-enyl)phenoxy]ethoxy]ethanol (Figure) is a non-steroidal selective oestrogen-receptor modulator (SERM), initially disclosed in WOO 1/36360. Publications WO2004/108645 and WO2006/024689 suggest the use of the product in the treatment and prevention of symptoms related with male androgen

deficiency. The product is at the clinical trial stage for the treatment of male neurological disorders.

According to an evaluation of the synthesis routes for ospemifene and fispemifene described in the literature, those which use compound 4 (Schemes 2 and 3) are particularly interesting, as 4 is also a key intermediate in the synthesis of toremifene, an oestrogen-receptor antagonist (ITMI20050278).

Leaving group X of the compound of formula 7 is preferably a halogen, such as chlorine, bromine or iodine, or an alkyl or arylsulphonate such as mesyloxy or tosyloxy.

In one embodiment of the invention, in the compound of formula 7, X is a leavmg group as defined above and Y is -(OCH2CH₂)_nOH wherein n is zero, and the reaction of 7 with 4 provides ospemifene, as reported in Scheme 4.

 

Scheme 4

In another embodiment of the invention, in the compound of formula 7, X and Y, taken together, represent an oxygen atom, the compound of formula 7 is ethylene oxide, and the reaction of 7 with 4 provides ospemifene, as reported in Scheme 5.

 

Scheme 5

In another embodiment of the invention, X is a leaving group as defined above and n is 1, and the reaction of 7 with 4 provides fispemifene, as reported in Scheme 6.

Scheme 6

The reaction between phenol 4 and alkylating reagent 7, wherein X is a leaving group as defined above and Y is the -(OCHbCEh^OH group as defined above, can be effected in an aprotic solvent preferably selected from ethers such as tetrahydrofuran, dioxane, dimethoxyethane, tert-butyl methyl ether, amides such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide and N-methylpyrrolidone, nitriles such as acetonitrile, and hydrocarbons such as toluene and xylene, in the presence of a base preferably selected from alkoxides, amides, carbonates, oxides or hydrides of an alkali or alkaline-earth metal, such as potassium tert-butoxide, lithium bis-trimethylsilylamide, caesium and potassium carbonate, calcium oxide and sodium hydride.

The reaction can involve the formation in situ of an alkali or alkaline earth salt of phenol 4, or said salt can be isolated and then reacted with alkylating reagent 7. Examples of phenol 4 salts which can be conveniently isolated are the sodium salt and the potassium salt. Said salts can be prepared by known methods, for example by treatment with the corresponding hydroxides (see preparation of the potassium salt of phenol 4 by treatment with aqueous potassium hydroxide as described in document ITMI20050278), or from the corresponding alkoxides, such as sodium methylate in methanol for the preparation of the sodium salt of phenol 4, as described in the examples of the present application.

Example 1

Sodium hydride (4.2 g) is loaded in portions into a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (10 g) in tetrahydrofuran (120 ml) in an inert gas environment, and the mixture is maintained under stirring at room temperature for 1 h. 2-Iodoethanol (11 ml) is added dropwise, and the reaction mixture is refluxed for about 9 h. Water is added, and the mixture is concentrated and extracted with ethyl acetate. The organic phase is washed with sodium carbonate aqueous solution and then with water, and then concentrated under vacuum. After crystallisation of the residue from methanol-water (about 5: 1), 9.9 g of crude ospemifene is obtained.

Example 2

A solution of sodium methylate in methanol (6.25 ml) is added to a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (10 g) in methanol (100 ml) in an inert gas environment, and maintained under stirring at room temperature for 1 h. The mixture is concentrated under vacuum and taken up with tetrahydrofuran (100 ml). A solution of 2-iodoethanol (3.5 ml) in tetrahydrofuran (30 ml) is added dropwise, and the reaction mixture is refluxed for about 3 h. Water is added, and the mixture is concentrated and extracted with ethyl acetate. The organic phase is washed with a saturated sodium hydrogen carbonate aqueous solution, and finally with water. The resulting solution is then concentrated under vacuum and crystallised from methanol-water to obtain 5.8 g of crude ospemifene.

Example 3

Potassium tert-butylate (2.0 g) is added to a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (5 g) in tert-butanol (75 ml) in an inert gas environment, and maintained under stirring at room temperature for 1 h. The solvents are concentrated under vacuum, and the concentrate is taken up with tetrahydrofuran (50 ml). A solution of 2-iodoethanol (1.7 ml) in tetrahydrofuran (15 ml) is added in about 30 minutes, and the reaction mixture is then refluxed for about 2 h. The process then continues as described in Example 1, and 2.9 g of crude ospemifene is obtained.

Example 4

A 50% potassium hydroxide aqueous solution (4.4 ml) is added to a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (2 g) in toluene (20 ml) in an inert gas environment, and maintained under stirring at room temperature for 15

minutes. 2-Iodoethanol (2.2 ml) is added in about 30 minutes, and the reaction mixture is refluxed and maintained at that temperature for about 7 h. After the addition of water, the phases are separated. The organic phase is washed with a saturated sodium hydrogen carbonate aqueous solution, and finally with water. The organic phase is then concentrated under vacuum. After crystallisation of the residue from methanol-water (about 5:1), 0.85 g of crude ospemifene is obtained.

//////NEW PATENT, WO 2016108172, OSPEMIFENE AND FISPEMIFENE, OLON S.P.A.

WO 2016092561, Ivacaftor, New patent, Laurus Labs Pvt Ltd

WO-2016092561, Ivacaftor, NEW PATENT

https://www.google.com/patents/WO2016092561A2?cl=en

Novel polymorphs of ivacaftor, process for its preparation and pharmaceutical composition thereof

Laurus Labs Pvt Ltd

LAURUS LABS PRIVATE LIMITED [IN/IN]; Plot No. DS1, IKP Knowledge Park, Genome Valley Turkapally, Shameerpet Mandal, Ranga District Hyderabad 500078 (IN)

Ram Thaimattam, Venkata Srinivasa Rao DAMA, Venkata Sunil Kumar Indukuri, Seeta Rama Anjaneyulu GORANTLA,Satyanarayana Chava, Less «
Applicant	Laurus Labs Private Limited

THAIMATTAM, Ram; (IN).
DAMA, Venkata Srinivasa Rao; (IN).
INDUKURI, Venkata Sunil Kumar; (IN).
GORANTLA, Seeta Rama Anjaneyulu; (IN).
CHAVA, Satyanarayana; (IN)

Novel crystalline forms of ivacaftor (designated as forms L1 to L14), processes for their preparation and composition comprising them are claimed.

Vertex, in research collaboration with Cystic Fibrosis Foundation Therapeutics, had developed and launched ivacaftor.

Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula I:

Formula I

Ivacaftor was approved by FDA and marketed by Vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO^® in the form of 150 mg oral tablets.

WO2006/002421 publication discloses modulators of ATP-binding cassette transporters such as ivacaftor. This patent generally discloses a process for the preparation of modulators of ATP-binding cassette transporters such as quinoline compounds; however, specific process for the preparation of ivacaftor and its solid state details were not specifically disclosed.

WO2007/079139 publication discloses Form A, Form B and amorphous form of ivacaftor characterized by PXRD, DSC and TGA and process for their preparation. Further this publication discloses ethanol crystalate of ivacaftor in example part.

WO2009/038683 publication discloses the solid forms of ivacaftor, which are designated as Form-I (2-methylbutyric acid), Form-II (propylene glycol), Form-HI (PEG400.KOAc), Form-IV (lactic acid), Form-V (isobutyric acid), Form-VI (propionic

acid), Form- VII (ethanol), Form- VIII (2-propanol), Form-IX (monohydrate), Form-X (besylate Form A), Form-XI (besylate Form B), Form-XII (besylate Form D), Form-XIII (besylate Form E), Form-XIV (besylate Form F), Form-XV (besylate (2: 1)), Form-XVI (besylate mono hydrate). This publication also discloses the characterization details like PXRD, DSC and TGA for the above forms and process for their preparation.

WO201 1/1 16397 publication discloses crystalline Form C of ivacaftor, process for its preparation and pharmaceutical composition comprising the same. Also discloses characterization details of Form C, such as PXRD, IR, DSC and ¹³CSSNMR.

WO2013/158121 publication discloses solvated forms of ivacaftor, which are designated as Form D (acetonitrile or acetonitrile/water (75/25) solvate), Form E (Methyl ethyl ketone (MEK), MEK/water (90/1), MEK/water (90/10), MEK/water (80/20) solvate), Form F (acetonitrile/water (75/25) solvate), Form G (isopropyl acetate solvate), Form H (isopropyl acetate/water (95/5) solvate), Form I (MEK solvate), Form J (MEK/water (99/1) solvate), Form K (MEK or MEK/water (99/1) or MEK/water (90/10) or MEK/water (80/20) solvate), Form L (isopropyl acetate/water (95/5) solvate), Form M (MEK or MEK/water (99/1) solvate), Form N (MEK water (90/10) or MEK/water (80/20) solvate), Form O (MEK or MEK/water (99/1) solvate), Form P (MEK water (90/10) or MEK water (80/20) solvate), Form Q (MEK/water (80/20) solvate), Form R (acetonitrile solvate), Form S (MEK/water (80/20) solvate), Form T (isopropyl acetate/water (95/5) solvate), Form W (acetonitrile/water (90/10) solvate), Form XX (from 10% water/ acetonitrile) and hydrate B (hydrated form). This patent further discloses characterization details like PXRD and TGA for the above forms and process for their preparation.

WO2014/118805 publication discloses crystalline forms of ivacaftor designated as Form D, Form E, Form El, Form G and Form G'; amorphous ivacaftor designated as Form I and Form II; crystalline ivacaftor solvates such as n-butanol solvate, methanol solvate, propylene glycol solvate, DMF solvate, THF solvate, DMF:ethylacetate solvate. This publication further discloses the process for the preparation of said forms along with their characterization details.

WO2015/070336 publication discloses polymorphic form APO-I and MIBK solvate of ivacaftor along with its characteristic PXRD details, process for its preparation and pharmaceutical composition comprising them.

CN 104725314A publication discloses ivacaftor new polymorph D, which is obtained by crystallization of ivacaftor from acetonitrile/water. This publication further discloses characteristic details such PXRD, IR and DSC of ivacaftor new polymorph D.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.

Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound, like ivacaftor, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. New polymorphic forms of the ivacaftor have now been discovered and have been designated as ivacaftor Form-Ll, Form-L2, Form-L3, Form-L4, Form-L5, Form-L6, Form-L7, Form-L8, Form-L9, Form-LlO, Form-Ll 1, Form-Ll 2 A, Form-Ll 2B, Form-Ll 3 and Form-Ll 4.

EXAMPLE 1 : Preparation of Ivacaftor Form-Ll

A suspension of ivacaftor ethanolate (5 g) in n-heptane (200 mL) was heated to 95-100°C and stirred for 5 hrs at the same temperature. Then the reaction mixture was cooled to 25-35°C and stirred for an hour. The solid obtained was filtered, washed with n-heptane and suck dried. The wet solid was further dried at 60-65°C for 16 hrs under vacuum yielded ivacaftor Form-Ll . The XRPD is set forth in Figure- 1.

In a similar manner, ivacaftor Form-Ll was prepared from different solvates of ivacaftor in place of ivacaftor ethanolate as input using the following conditions;

Ivacaftor cyclopentyl methyl ether (0.5 g) n-heptane (20 mL) 50°C/8 hr

Ivacaftor methyltertiarybutyl ether (0.5 g) n-heptane (20 mL) 50°C/8 hr

 

Dr Satyanarayana Chava

Chief executive officer (CEO)

Laurus Labs Private Limited

When Dr Satyanarayana Chava started Laurus Labs in 2007, he invested nearly Rs 60 crore of his own money into it. His confidence in its success was neither bravado nor bluster, but defined by his knowledge of the pharmaceutical industry. Eight years on, the Hyderabad-based company is on track to reach revenues of Rs 2,000 crore by the end of FY2016.

Chava, now 52, has more than two decades of experience in the pharmaceutical industry; in his last job, he was chief operating officer (COO) of the successful startup, Matrix Laboratories. Of his 10 years there, he says with pride, “I never skipped a promotion and got to work in all departments.” His dedication, coupled with a sound understanding of what it takes to start a pharmaceutical company, is what makes Laurus Labs among the hottest startups in this sector.

Initially, Chava planned the business around research and development (R&D). He wanted Laurus Labs to focus on contract research and make money from royalties. “In India, companies start with manufacturing and then get into R&D,” he explains. “I did it the other way round.” He focussed his fledgling company’s resources on developing formulations for medicines, and licensed them to other pharmaceutical players. In the early months, Laurus Labs had 10 people in manufacturing and 300 in R&D.

In June 2007, Aptuit, a US-based contract research organisation (CRO), signed it on for a $20 million (then Rs 80 crore) contract. But despite this injection of funds, Chava was unable to sustain his original idea of developing technologies for other companies. At the time of the Aptuit deal, Laurus Labs’s annual revenues were not even $20,000 (Rs 8 lakh at the time). In 2008, Chava decided to start manufacturing active pharmaceutical ingredients (API), which, as the name suggests, are chemicals or key ingredients in drugs required to make the medication work. His early investment into R&D benefitted Laurus Labs; it maintains a large repository of research-based knowledge that forms the bedrock of any successful pharmaceutical business.

Today, it is a key manufacturer supplier of APIs and holds its own against better-known competitors like US generic drug giant Mylan, which, incidentally, acquired a controlling stake in Matrix around the time Chava founded Laurus Labs. It has also carved a niche for itself by supplying antiretroviral or ARVs (used to fight infections caused by retroviruses like HIV) and oncology drugs. And despite being a relatively new player, its clients include giants like Pfizer, Teva Pharmaceutical Industries and Merck.

The person behind it
A Master’s degree in chemistry was never on the cards for Chava. In the early 1980s, the best students usually studied physics, and he had planned to do the same. But when he went to his college in Amravati (Andhra Pradesh) to enroll, his elder sister’s friend suggested he study chemistry too. Chava took up the subject on a whim. He ended up liking chemistry so much so that in his final year he topped his batch despite not having written one out of the four required papers. He went on to complete his PhD in the subject in 1991.

Upon graduating, he was hired by Ranbaxy Laboratories in Delhi as a researcher. In those early years itself Chava knew he’d spend a lifetime in the industry. He enjoyed the work and gained valuable experience as a young researcher in what was then India’s finest pharmaceutical company.

But through his years in the industry, Chava was conscious of the fact that he needed to broaden his experience outside of research. His stint at Matrix Laboratories afforded him that opportunity. As it was a startup, he was able to rise through the ranks quickly and got the opportunity to work in key departments from sales and marketing to finance and accounts. Within eight years of joining Matrix, he became its COO.

This experience was to come in handy when, due to differences with the board—he refused to elaborate on this—he decided to leave Matrix and set up Laurus Labs. And though he is the company’s chief executive officer (CEO), Chava remains true to his calling as a chemist. He has strived to build an organisation that is not very hierarchical. It is not uncommon to see him interacting with the chemists in the company and discussing formulations with them—something unheard of in an industry where most CEOs are from a sales and marketing background.

Chandrakanth Chereddi

VP Synthesis Business Unit

Prior to his current assignment at Laurus Labs India, Chandra headed the Project Management division for all scientific projects at the Laurus R&D center. Chandra previously worked for McKinsey & Company in India as a member of the healthcare practice and at Google Inc. as a software engineer in Google’s Mountain View, CA office. Chandra holds a BE from the College of Engineering, Osmania University, Hyderabad, and MS from University of Illinois at Urbana-Champaign, and an MBA from Indian School of Business, Hyderabad.