Maralixibat Chloride, ماراليكسيبات كلوريد , 氯马昔巴特 , Мараликсибата хлорид

Maralixibat chloride

Maralixibat Chloride,  ماراليكسيبات كلوريد ,  氯马昔巴特 , Мараликсибата хлорид

SHP625, Maralixibat chloride, Molecular Formula C40-H56-N3-O4-S.Cl, Molecular Weight, 710.4184

4-Aza-1-azoniabicyclo(2.2.2)octane, 1-((4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl)-, chloride (1:1)

1-[4-({4-[(4R,5R)-3,3-Dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxido-2,3,4,5-tetrahydro-1-benzothiepin-5-yl]phenoxy}methyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride

4-Aza-1-azoniabicyclo[2.2.2]octane, 1-[[4-[[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-, chloride

(4R.5R)-1- r.4- r _4- .3.3 -Dibutyl-7- (dimethylamino) -2.3 ,4.5- tetrahydro-4-hydroxy-1, l-dioxido-l-benzothiepin-5- yl] henoxy] ethyl] phenyl1methyl] -4-aza-l- azoniabicyclo [2.2.2] octane

(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane Chloride Salt

(4R,5R)- 1 -((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -diυxido- 1 -benzithiepin-5-yl)pheπoxy)methyl)phenyl)methyl-4-aza- 1 - azoniabicyclo[2.2.2]octane chloride

Cas: 228113-66-4, Free form 716313-53-0
UNII: V78M04F0XC, LUM 001, Lopixibat chloride, Treatment of Cholestatic Liver Diseases

Inventors	James Li, Ching-Cheng Wang, David B. Reitz, Victor Snieckus, Horng-Chih Huang,Andrew J. Carpenter, Less «
Applicant	G.D. Searle & Co.

Several drawings of Maralixibat chloride

It is well established that agents which inhibit the 20 transport of bile acids across the ileum can also cause a decrease in the level of cholesterol in blood serum. Stedronski, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biophysica Acta, 1210 (1994) 255- 25287, discusses biochemistry, physiology, and known active agents affecting bile acids and cholesterol.

A class of ileal bile acid transport-inhibiting compounds which was recently discovered to be useful for influencing the level of blood serum cholesterol is 30 tetrahydrobenzothiepine-l,l-dioxides (THBDO compounds). (U.S. Patent Application No. 08/816,065)

Some classes of compounds show enhanced potency as pharmaceutical therapeutics after they have been enantiomerically-enriched (see, for example, Richard B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press, 1992, pp. 76-82) . Therefore, THBDO compounds that have been enantiomerically-enriched are of particular interest.

A class of chemistry useful as intermediates in the preparation of racemic THBDO compounds is tetrahydrobenzothiepine-1-oxides (THBO compounds) . THBDO compounds and THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring. A method of preparing enantiomerically-enriched samples of another phenyl/seven-member fused ring system, the benzothiazepines, is described by Higashikawa (JP 59144777) , where racemic benzothiazepine derivatives are optically resolved on a chromatographic column containing chiral crown ethers as a stationary phase. Although optical resolution is achieved, the Higashikawa method is limited to producing only small quantities of the enantiomerically-enriched benzothiazepine derivatives. Giordano (CA 2068231) reports the cyclization of (2S, 3S) -aminophenylthiopropionates in the presence of a phosphonic acid to produce (2S, 3S) -benzothiazepin-4-ones . However, that preparation is constrained by the need to use enantiomerically-enriched starting materials rather than racemic starting materials. In addition, the Giordano method controls the stereochemistry of the seven-member ring of the benzothiazepin-4-one only at the 2- and 3 -positions. The 4- and 5-positions of the seven-member ring of the benzothiazepin-4-one are not asymmetric centers, and the stereochemistry at these sites therefore cannot be controlled by the Giordano method. A method by which enantiomerically-enriched 1,5- benzothiazepin-3-hydroxy-4 (5H) -one compounds have been produced is through the asymmetric reduction of 1,5- benzothiazepin-3,4 (2H, 5H) -dione compounds, reported by Yamada, et al . (J^". Org. Chem. 1996, 61 (24), 8586-8590). The product is obtained by treating the racemic 1,5- benzothiazepin-3,4 (2H, 5H) -dione with the reaction product of an optically active alpha-amino acid and a reducing agent, for example sodium borohydride. Although a product with high optical purity was achieved, the method is limited by the use of a relatively expensive chemical reduction step.

The microbial reduction of racemic 1, 5-benzothiazepin- 3 , 4 (2H, 5H) -dione compounds to produce enantiomerically- enriched 1, 5-benzothiazepin-3-hydroxy-4 (5H) -one compounds is reported by Patel et al . , U.S. Patent 5,559,017. This method is limited by the inherent problems of maintaining a viable and pure bacterial culture of the appropriate species and variety. In addition, that method is limited in scale, producing only microgram quantities of the desired product. Until now, there have been no reported processes for preparing enantiomerically-enriched THBDO compounds or enantiomerically-enriched THBO compounds. Furthermore, there have been no reported processes for controlling the stereochemistry at the 4- and 5-positions of the seven- member rings of THBDO compounds or THBO compounds

FDA Grants Breakthrough Designation to Shire's Rare GI Therapies

Tue, 06/14/2016

Shire announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for two investigational products for rare diseases: SHP621 (budesonide oral suspension, or BOS) for eosinophilic esophagitis (EoE), and SHP625 (maralixibat) for progressive familial intrahepatic cholestasis type 2 (PFIC2).

“Receiving Breakthrough Therapy Designation on two pipeline products this past week reflects the potential of our strong and innovative pipeline of more than 60 programs,” said Flemming Ornskov, M.D., MPH, and CEO, Shire. “Shire is committed to bringing innovation to the rare and specialty areas we focus on. We persevere to see compounds through the many stages of development through their challenges and successes, and always keep patients with unmet needs top of mind.”

EoE is a serious, chronic and rare disease that stems from an elevated number of eosinophils, a type of white blood cell, that infiltrate the walls of the esophagus. EoE is characterized by an inflammation of the esophagus that may lead to difficulty swallowing (dysphagia). The diagnosed prevalence of EoE ranges from approximately 15-55 cases per 100,000 persons, with high-end estimates reported by studies in Western regions.

PFIC refers to a group of autosomal-recessive liver disorders of childhood that disrupt bile formation and present with cholestasis. The symptoms of PFIC include severe itching of the skin (pruritus), and jaundice. PFIC is estimated to affect 1 in 50,000 to 1 in 100,000 births. PFIC2 is the most common type of PFIC, accounting for around half of cases.

According to the FDA, Breakthrough Therapy Designation is granted to a therapy that is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically significant endpoints over current standard of care. Under the designation, the FDA provides intensive guidance, organizational commitment involving senior managers, and eligibility for rolling and priority review of the application; this process helps ensure patients have access to therapies as soon as possible, pending approval. Breakthrough Therapy Designation does not guarantee that FDA will ultimately approve BOS for EoE or maralixibat for PFIC2, and the timing of any such approval is uncertain.

“On behalf of patients in the United States with EoE and PFIC2, we are so pleased that the FDA has granted Breakthrough Therapy Designation to BOS and maralixibat,” said Philip J. Vickers, Ph.D., Head of R&D, Shire. “We look forward to working with the agency to continue their development and, pending FDA approval, deliver these therapeutic options to the patients who need them most.”

Source: Shire

Patent

WO 2003022804

It is well established that agents which inhibit the transport of bile acids across the tissue of the ileum can also cause a decrease in the levels of cholesterol in blood serum. Stedronski, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biophysica Acta, 1210 (1994) 255-287 discusses biochemistry, physiology, and known active agents surrounding bile acids and cholesterol. Bile acids are actively transported across the tissue of the ileum by an apical sodium co-dependent bile acid transporter (ASBT), alternatively known as an ileal bile acid transporter (IBAT).
A class of ASBT-inhibiting compounds that was recently discovered to be useful for influencing the level of blood serum cholesterol comprises tetrahydrobenzothiepine oxides (THBO compounds, PCT Patent Application No. WO 96/08484). Further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 97/33882.
Additional THBO compounds useful as ASBT inhibitors are described in U.S. Patent No. 5,994,391. Still further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 99/64409. Included in the THBO class are tetrahydrobenzo-thiepine-l -oxides and tetrahydrobenzothiepine- 1,1 -dioxides. THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring.

Published methods for the preparation of THBO compounds include the synthesis through an aromatic sulfone aldehyde intermediate. For example l-(2,2-dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene (29) was cyclized with potassium t-butoxide to form tetrahydrobenzothiepine- 1,1 -dioxide (svn-24) as shown in Eq. 1.

Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acid chloride with anisole in the presence of aluminum trichloride to produce a chlorobenzophenone compound; the chlorobenzophenone compound was reduced in the presence of trifluoromethanesulfonic acid and triethylsilane to produce a chlorodiphenylmethane compound; the
chlorodiphenylmethane compound was treated with lithium sulfide and 2,2-dibutyl-3-(methanesulfonato)propanal to produce l-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene (40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29. The first step of that method of preparing compound 29 requires the use of a corrosive and reactive carboxylic acid chloride that was prepared by the reaction of the corresponding carboxylic acid with phosphorus pentachloride.
Phosphorus pentachloride readily hydrolyzes to produce volatile and hazardous hydrogen chloride. The reaction of 2,2-dibutyl-3-(methanesulfonato)propanal with the lithium sulfide and the chlorodiphenylmethane compound required the intermediacy of a cyclic tin compound to make the of 2,2-dibutyl-3-(methanesulfonato)propanal. The tin compound is expensive and creates a toxic waste stream.
In WO 97/33882 compound syn-24 was dealkylated using boron tribromide to produce the phenol compound 28. Boron tribromide is a corrosive and hazardous material that generates hydrogen bromide gas and requires special handling. Upon hydrolysis, boron tribromide also produces borate salts that are costly and time-consuming to separate and dispose of.

An alternative method of preparing THBO compounds was described in WO
97/33882, wherein a 1,3-propanediol was reacted with thionyl chloride to form a cyclic sulfite compound. The cyclic sulfite compound was oxidized to produce a cyclic sulfate compound. The cyclic sulfate was condensed with a 2-methylthiophenol that had been deprotonated with sodium hydride. The product of the condensation was a (2-methylphenyl) (3'-hydroxypropyl)thioether compound. The thioether compound was oxidized to form an thioether aldehyde compound. The thioether aldehyde compound was further oxidized to form an aldehyde sulfone compound which in turn was cyclized in the presence of potassium t-butoxide to form a 4-hydroxytetrahydrobenzothiepine 1,1 -dioxide compound. This cyclic sulfate route to THBO compounds requires an expensive catalyst. Additionally it requires the use of SOCI2, which in turn requires special equipment to handle.
PCT Patent Application No. WO 97/33882 describes a method by which the phenol compound 28 was reacted at its phenol hydroxyl group to attach a variety of functional groups to the molecule, such as a quaternary ammonium group. For example, (4R,5R)-28 was reacted with l,4-bis(chloromethyl)benzene (?,??'-dichloro-p-xylene) to produce the chloromethyl benzyl- ether (4R,5R)-27. Compound (4R,5R)-27 was treated with diazabicyclo[2.2.2]octane (DABCO) to produce (4R,5R)-l-((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro-4-hydroxy-l , 1 -dioxido-1 -benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-l-azomabicyclo[2.2.2]octane chloride (41). This method suffers from low yields because of a propensity for two molecules of compound (4R,5R)-28 to react with one molecule of l,4-bis(chloromethyl)benzene to form a bis(benzothiepine) adduct. Once the bis-adduct forms, the reactive chloromethyl group of compound (4R,5R)-27 is not available to react with an amine to form the quaternary ammonium product.

A method of preparing enantiomerically enriched tetrahydrobenzothiepine oxides is described in PCT Patent Application No. WO 99/32478. In that method, an aryl-3- hydroxypropylsulfide compound was oxidized with an asymmetric oxidizing agent, for example (lR (->(8,9-dichloro-10-camphorsulfonyl)oxaziridine, to yield a chiral aryl-3-hydroxypropylsulfoxide. Reaction of the aryl-3-hydroxypropylsulfoxide with an oxidizing agent such as sulfur trioxide pyridine complex yielded an aryl-3-propanalsulfoxide. The aryl- 3-propanalsulfoxide was cyclized with a base such as potassium t-butoxide to
enantioselectively produce a tetrahydrobenzothiepine- 1 -oxide. The tetrahydrobenzothiepine- 1 -oxide was further oxidized to produce a tetrahydrobenzothiepine- 1 , 1 -dioxide. Although this method could produce tetrahydrobenzothiepine- 1,1 -dioxide compounds of high enantiomeric purity, it requires the use of an expensive asymmetric oxidizing agent.
Some 5-amidobenzothiepine compounds and methods to make them are described in

PCT Patent Application Number WO 92/18462.
In Svnlett. 9, 943-944(1995) 2-bromophenyl 3-benzoyloxy-l-buten-4-yl sulfone was treated with tributyl tin hydride and AIBN to produce 3-benzoyloxytetrahydrobenzothiepine-1,1 -dioxide.
In addition to forming the desired ASBT inhibitors, it is also desirable to form such

ASBT inhibitors of higher purity and having lower levels of residual solvent impurities. This is especially so with respect to ASBT inhibitors having a positively charged substituent, for example, the compounds designated as 41 (supra) and 60 (infra).
It is further desirable to provide methods for making such high purity ASBT inhibitors.

Example 11.

Preparation of (4R,5R)- 1 -((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -diυxido- 1 -benzithiepin-5-yl)pheπoxy)methyl)phenyl)methyl-4-aza- 1 - azoniabicyclo[2.2.2]octane chloride,
41

41

Ste l. Preparation of (4R.5R1-26.

( 4R, 5R) -26
A 1000 mL 4 neck jacketed Ace reactor flask was fitted with a mechanical stirrer, a nitrogen inlet, an addition funnel or condenser or distilling head with receiver, a
thermocouple, four internal baffles and a 28 mm Teflon turbine agitator. The flask was purged with nitrogen gas and charged with 25.0 grams of (4R,5R)-28 and 125 mL of N,N-dimethylacetamide (DMAC). To this was added 4.2 grams of 50% sodium hydroxide. The mixture was heated to 50°C and stiπed for 15 minutes. To the flask was added 8.3 grams of 55 dissolved in 10 mL of DMAC, all at once. The temperature was held at 50°C for 24 hrs. To the flask was added 250 mL of toluene followed by 125 mL of dilution water. The mixture was stiπed for 15 minutes and the layers were then allowed to separate at 50°C. The flask was then charged with 125 mL of saturated sodium chloride solution and stiπed 15 minutes. Layers separated cleanly in 30 seconds at 50°C. Approximately half of the solvent was distilled off under vacuum at 50°C. The residual reaction mixture contained (4R,5R)-26.

Step 2. Preparation of (4R.5RV27.

( 4R, 5R) -27
Toluene was charged back to the reaction mixture of Step 1 and the mixture was cooled to 35°C. To the mixture was then added 7.0 grams of thionyl chloride over 5 minutes. The reaction was exothermic and reached 39°C. The reaction turned cloudy on first addition of thionyl chloride, partially cleared then finally remained cloudy. The mixture was stirred for 0.5 hr and was then washed with 0.25N NaOH. The mixture appeared to form a small amount of solids that diminished on stirring, and the layers cleanly separated. The solvent was distilled to a minimum stir volume under vacuum at 50°C. The residual reaction mixture contained (4R,5R)-27.

Step 3. Preparation of 41.
To the reaction mixture of Step 2 was charged with 350 mL of methyl ethyl ketone (MEK) followed by 10.5 mL water and 6.4 grams of diazabicyclo[2.2.2]octane (DABCO) dissolved in 10 mL of MEK. The mixture was heated to reflux, and HPLC showed <0.5% of (4R,5R)-27. The reaction remained homogenous initially then crystallized at the completion of the reaction. An additional 5.3 mL of water was charged to the flask to redissolve product. Approximately 160 mL of solvent was then distilled off at atmospheric pressure. The mixture started to form crystals after 70 mL of solvent was distilled. Water separated out of distillate indicating a ternary azeotrope between toluene, water and methyl ethyl ketone (MEK). The mixture was then cooled to 25°C. The solids were filtered and washed with 150 mL MEK, and let dry under vacuum at 60°C. Isolated 29.8.0 g of off-white crystalline 4 Example 11a.
Alternate Preparation of (4R,5R)-l-((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro- 4-hydroxy- 1 , 1 -dioxido- 1 -benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza- 1 - azoniabicyclo[2.2.2]octane chloride, Form II of 41

A 1000 mL 4 neck jacketed Ace reactor flask is fitted with a mechanical stiπer, a nitrogen inlet, an addition funnel or condenser or distilling head with receiver, a
thermocouple, four internal baffles and a 28 mm Teflon turbine agitator. The flask is purged with nitrogen gas and charged with 25.0 grams of (4R,5R)-28 and 100 mL of N,N-dimethylacetamide (DMAC). The mixture is heated to 50°C and to it is added 4.02 grams of 50% sodium hydroxide. The mixture is stiπed for 30 minutes. To the flask is added 8.7 grams of 55 dissolved in 12.5 mL of DMAC, all at once. The charge vessel is washed with 12.5 mL DMAC and the wash is added to the reactor. The reactor is stiπed for 3 hours. To the reactor is added 0.19 mL of 49.4% aq. NaOH and the mixture is stirred for 2 hours. To the mixture is added 0.9 g DABCO dissolved in 12.5 mL DMAC. The mixture is stiπed 30 to 60 minutes at 50°C. To the flask is added 225 mL of toluene followed by 125 mL of dilution water. The mixture is stiπed for 15 minutes and the layers are then allowed to separate at 50°C. The bottom aqueous layer is removed but any rag layer is retained. The flask is then charged with 175 mL of 5% hydrochloric acid solution and stiπed 15 minutes. Layers are separated at 50°C to remove the bottom aqueous layer, discarding any rag layer with the aqueous layer. Approximately half of the solvent is distilled off under vacuum at a maximum pot temperature of 80°C. The residual reaction mixture contains (4R,5R)-26.

Step 2. Preparation of (4R.5RV27.

Toluene (225 mL) is charged back to the reaction mixture of Step 1 and the mixture is cooled to 30°C. To the mixture is then added 6.7 grams of thionyl chloride over 30 to 45 minutes. The temperature is maintained below 35°C. The reaction turns cloudy on first addition of thionyl chloride, then at about 30 minutes the layers go back together and form a clear mixture. The mixture is stiπed for 0.5 hr and is then charged with 156.6 mL of 4% NaOH wash over a 30 minute period. The addition of the wash is stopped when the pH of the mixture reaches' 8.0 to 10.0. The bottom aqueous layer is removed at 30°C and any rag layer is retained with the organic layer. To the mixture is charged 175 mL of saturated NaCl wash with agitation. The layers are separated at 30°C and the bottom aqueous layer is removed, discarding any rag layer with the aqueous layer. The solvent is distilled to a minimum stir volume under vacuum at 80°C. The residual reaction mixture contains (4R,5R)-27.

Step 3. Preparation of 41.
To the reaction mixture of Step 2 is charged 325 mL of methyl ethyl ketone (MEK) and 13 mL water. Next, the reactor is charged 6.2 grams of diazabicyclo[2.2.2]octane (DABCO) dissolved in 25 mL of MEK. The mixture is heated to reflux and held for 30 minutes. Approximately 10% of solvent volume is then distilled off. The mixture starts to form crystals during distillation. The mixture is then cooled to 20°C for 1 hour. The off-white crystalline 41 (Form U) is filtered and washed with 50 mL MEK, and let dry under vacuum at 100°C.

Example lib.
Alternate Preparation of (4R,5R)-1 -((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 4-hydroxy- 1 , 1 -dioxido- 1 -benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza- 1 - azoniabicyclo[2.2.2]octane chloride, Form II of 41

A 1000 mL 4 neck jacketed Ace reactor flask is fitted with a mechanical stiπer, a nitrogen inlet, an addition funnel or condenser or distilling head with receiver, a
thermocouple, four internal baffles and a Teflon turbine agitator. The flask is purged with nitrogen gas and charged with 25.0 grams of (4R,5R)-28 and 125 mL of N,N-dimethylacetamide (DMAC). The mixture is heated to 50°C and to it is added 7.11 grams of 30% sodium hydroxide over a period of 15 to 30 minutes with agitation. The mixture is stiπed for 30 minutes. To the flask is added 9.5 grams of solid 55. The reactor is stiπed for 3 hours. To the mixture is added 1.2 g of solid DABCO. The mixture is stiπed 30 to 60 minutes at 50°C. To the flask is added 225 mL of toluene followed by 125 mL of water. The mixture is stirred for 15 minutes and the layers are then allowed to separate at 50°C. The bottom aqueous layer is removed but any rag layer is retained with the organic layer. The flask is then charged with 175 mL of 5% hydrochloric acid solution and stirred 15 minutes. Layers are separated at 50°C to remove the bottom aqueous layer, discarding any rag layer with the aqueous layer. The flask is then charged with 225 mL of water and stirred 15 minutes. The layers are allowed to separate at 50°C. The bottom aqueous layer is removed, discarding any rag layer with the aqueous layer. Approximately half of the solvent is distilled off under vacuum at a maximum pot temperature of 80°C. The residual reaction mixture contains (4R,5R)-26.

Step 2. Preparation of (4R.5RV27.

Toluene (112.5 mL) is charged back to the reaction mixture of Step 1 and the mixture is cooled to 25°C. To the mixture is then added 7.3 grams of thionyl chloride over 15 to 45 minutes. The temperature of the mixture is maintained above 20°C and below 40°C. The reaction turns cloudy on first addition of thionyl chloride, then at about 30 minutes the layers go back together and form a clear mixture. The mixture is then charged with 179.5 mL of 4% NaOH wash over a 30 minute period. The mixture is maintained above 20°C and below 40°C during this time. The addition of the wash is stopped when the pH of the mixture reaches 8.0 to 10.0. The mixture is then allowed to separate at 40°C for at least one hour.

The bottom aqueous layer is removed and any rag layer is retained with the organic layer. To the mixture is charged 200 mL of dilution water. The mixture is stiπed for 15 minutes and then allowed to separate at 40°C for at least one hour. The bottom aqueous layer is removed, discarding any rag layer with the aqueous layer. The solvent is distilled to a minimum stir volume under vacuum at 80°C. The residual reaction mixture contains (4R,5R)-2 .

Step 3. Preparation of 41.
To the reaction mixture of Step 2 is charged 350 mL of methyl ethyl ketone (MEK) and 7 mL water. The mixture is stiπed for 15 minutes and the temperature of the mixture is adjusted to 25°C. Next, the reactor is charged with 6.7 grams of solid
diazabicyclo[2.2.2]octane (DABCO). The mixture is maintained at 25°C for three to four hours. It is then heated to 65°C and maintained at that temperature for 30 minutes. The mixture is then cooled to 25°C for 1 hour. The off-white crystalline 41 (Form II) is filtered and washed with 50 mL MEK, and let dry under vacuum at 100°C.

Example 12. 
Alternate preparation of (4R,5R)-1 -((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 4-hydroxy- 1 , 1 -dioxido- 1 -benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza- 1 - azoniabicyclo[2.2.2]octane chloride, Form I of 41

(4R,5R)-27 (2.82 kg dry basis, 4.7 mol) was dissolved in MTBE (9.4 L). The solution of (4R,5R)-22 was passed through a 0.2 mm filter cartridge into the feeding vessel. The flask and was rinsed with MTBE (2 x 2.5 L). The obtained solution as passed through the cartridge filter and added to the solution of (4R,5R)-2 in the feeding vessel. DABCO
(diazabicyclo[2.2.2]octane, 0.784 kg, 7.0 mol) was dissolved in MeOH (14.2 L). The DABCO solution was passed through the filter cartridge into the 100 L nitrogen-flushed reactor. The Pyrex bottle and the cartridge filter were rinsed with MeOH (7.5 L) and the solution was added to the reactor. The (4R,5R)-22 solution was added from the feeding vessel into the reactor at 37°C over a period of 10 min, while stirring. Methanol (6.5 L) was added to the Pyrex bottle and via the cartridge filter added to the feeding vessel to rinse the remaining (4R,5R)-2 into the reactor. The reaction mixture was brought to 50-60°C over 10-20 min and stiπed at that temperature for about 1 h. The mixture was cooled to 20-25°C over a period of 1 h. To the reaction mixture, methyl t-butyl ether (MTBE) (42 L) was added over a period of 1 h and stiπed for a minimum of 1 h at 20 - 25°C. The suspension was filtered through a Buchner funnel. The reactor and the filter cake were washed with MTBE (2 x 14 L). The solids were dried on a rotary evaporator in a 20 L flask at 400 - 12 mbar, 40°C, for 22 h. A white crystalline solid was obtained. The yield of 4 . (Form I) was 3.08 kg (2.97 kg dry, 93.8 %) and the purity 99.7 area % (HPLC; Kromasil C 4, 250 x 4.6 mm column; 0.05% TFA in H₂O/0.05% TFA in ACN gradient, UV detection at 215 nm).

Example 12a.
Conversion of Form I of Compound 41 into Form II of Compound 41.

To 10.0 grams of Form I of 4 . in a 400 mL jacketed reactor is added 140 mL of MEK. The reactor is stirred (358 φm) for 10 minutes at 23 °C for 10 minutes and the stirring rate is then changed to 178 φm. The suspension is heated to reflux over 1 hour using a programmed temperature ramp (0.95°C/minute) using batch temperature control (cascade mode). The delta T_maχ is set to 5°C. The mixture is held at reflux for 1 hour. The mixture is cooled to

25°C. After 3 hours at 25°C, a sample of the mixture is collected by filtration. Filtration is rapid (seconds) and the filtrate is clear and colorless. The white solid is dried in a vacuum oven (80°C, 25 in. Hg) to give a white solid. The remainder of the suspension is stirred at 25°C for 18 hours. The mixture is filtered and the cake starts to shrink as the mother liquor reaches the top of the cake. The filtration is stopped and the reactor is rinsed with 14 mL of MEK. The reactor stirrer speed is increased from 100 to 300 φm to rinse the reactor. The rinse is added to the filter and the solid is dried with a rapid air flow for 5 minutes. The solid is dried in a vacuum oven at 25 in. Hg for 84 hours to give Form II of 4

PATENT

WO 2014144650

Scheme 3:

PAPER

Journal of Medicinal Chemistry (2005), 48(18), 5853-5868

Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)

Horng-Chih Huang ,*^† Samuel J. Tremont ,*^‡ Len F. Lee ,^‡ Bradley T. Keller ,^§ Andrew J. Carpenter ,^† Ching-Cheng Wang ,^† Shyamal C. Banerjee ,^‡ Scott R. Both ,^‡ Theresa Fletcher ,^† Danny J. Garland ,^† Wei Huang ,^†Claude Jones ,^‡ Kevin J. Koeller ,^‡ Steve A. Kolodziej ,^† James Li ,^† Robert E. Manning ,^† Matthew W. Mahoney ,^†Raymond E. Miller ,^‡ Deborah A. Mischke ,^† Nigam P. Rath ,^# Emily J. Reinhard ,^† Michael B. Tollefson ,^† William F. Vernier ,^† Grace M. Wagner ,^‡ Steve R. Rapp ,^§ Judy Beaudry ,^§ Kevin Glenn ,^§ Karen Regina ,^§ Joe R. Schuh ,^§Mark E. Smith ,^§ Jay S. Trivedi ,^‖ and David B. Reitz ^†

Department of Discovery Chemistry and Department of Cardiovascular Disease, Pharmacia, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, Office of Science and Technology, Chemical Science Division, Pharmacia, 800 Lindbergh Boulevard, Creve Coeur, Missouri 63167, Department of Pharmaceutical Sciences, Pharmacia, Skokie, Illinois, and Department of Chemistry, University of Missouri, St. Louis, Missouri

J. Med. Chem., 2005, 48 (18), pp 5853–5868

DOI: 10.1021/jm0402162

http://pubs.acs.org/doi/abs/10.1021/jm0402162

Abstract

In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure−activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.

compd

R

IC50 (nM)b

hygroscp I wt gain (%)c

hygroscp II % wt gain (%)d

crystallinitye

74

OCH2C6H4(p)CH2(N+)DB

0.28

1.59

2.1

yes

(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane Chloride Salt (74). Following a similar procedure as in General Method B, the title compound 74 was prepared from the corresponding chloromethyl benzyl ether and DABCO as a white solid, mp 223−230 °C (dec); ¹H NMR (CDCl₃) δ 0.89 (m, 6H), 1.27−1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, J_AB = 15.1 Hz, J = 43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J = 7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.87 (d, J = 8.9 Hz, 1H). HRMS calcd for C₄₀H₅₆N₃O₄S:  674.3992; found, 674.4005. Anal. Calcd for C₄₀H₅₆N₃O₄S:  ‘ C, 67.62; H, 7.95; N, 5.92; S, 4.51. Found:  C, 67.48; H, 8.32; N, 5.85; S, 4.60.

^a All compounds were prepared using method B in Scheme 3.^b Taurocholate is transported across the baby hamster kidney cell membrane.^c % weight gain in a 25 °C, 57% humidity chamber for 2 weeks.^d % weight gain in a 40 °C, 80% humidity chamber for 2 weeks.^e Crystallinity as determined by X-ray powder diffraction analysis.^f (N⁺)DB is a DABCO terminal group with the quaternary ammonium attached to the linke

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PATENT

https://www.google.com/patents/WO1999032478A1?cl=en

Inventors	James Li, Ching-Cheng Wang, David B. Reitz, Victor Snieckus, Horng-Chih Huang,Andrew J. Carpenter,
Applicant	G.D. Searle & Co.

Example 10. Preparation of enantiomerically-enriched (4R.5R)-1- r.4- r _4- .3.3 -Dibutyl-7- (dimethylamino) -2.3 ,4.5- tetrahydro-4-hydroxy-1, l-dioxido-l-benzothiepin-5- yl] henoxy] ethyl] phenyl1methyl] -4-aza-l- azoniabicyclo [2.2.2] octane chloride ( (4R,5R) -XXVII) ♦

( (4R,5R) -XXVII) * = chiral center

Step 1. Preparation of 4-flUoro-2- ( (4- methoxyphenyl) methyl) -phenol To a stirred solution of 23.66 g of 95% sodium hydride (0.94 mol) in 600 mL of dry toluene was added 100.0 g of 4- fluorophenol (0.89 mol) at 0°C. The mixture was stirred at 90°C for 1 hour until gas evolution stopped. The mixture was cooled down to room temperature and a solution of 139.71 g of 3 -methoxybenzyl chloride (0.89 mol) in 400 mL of dry toluene was added. After refluxing for 24 hours, the mixture was cooled to room temperature and quenched with 500 mL of water. The organic layer was separated, dried over MgS0₄, and concentrated under high vacuum. The remaining starting materials were removed by distillation. The crude dark red oil was filtered through a layer of 1 L of silica gel with neat hexane to yield 53.00 g (25.6%) of the product as a pink solid: *H NMR (CDC1₃) d 3.79 (s, 3H) , 3.90 (s, 2H) , 4.58 (s, IH) , 6.70-6.74 (m, IH) , 6.79-6.88 (m, 4H) , 7.11-7.16 (m, 2H) .

Step 2. Preparation of 4-fluoro-2- ( (4- methoxyphenyl) methyl) -thiophenol

Step 2a. Preparation of thiocarbamate To a stirred solution of 50.00 g (215.30 mmol) of 4- fluoro-2- ( ( -methoxyphenyl) methyl) -phenol in 500 mL of dry DMF was added 11.20 g of 60% sodium hydride dispersion in mineral oil (279.90 mmol) at 2°C. The mixture was allowed to warm to room temperature and 26.61 g of dimethylthiocarbamoyl chloride (215.30 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with 100 mL of water in an ice bath. The solution was extracted with 500 mL of diethyl ether. The ether solution was washed with 500 mL of water and 500 mL of brine. The ether solution was dried over MgS0₄ and stripped to dryness. The crude product was filtered through a plug of 500 mL silica gel using 5% ethyl acetate/hexane to yield 48.00 g (69.8%) of the product as a pale white solid: ^XH NMR (CDC1₃) d 3.21 (s, 3H) , 3.46 (s, 3H) , 3.80 (s, 3H) , 3.82 (s, 2H) , 6.78-6.86 (m, 3H) , 6.90- 7.00 (m, 2H) , 7.09 (d, J = 8.7 Hz, 2H) .

Step 2b. Rearrangement and hydrolysis of thiocarbamate to 4-fluoro-2- ( (4 -methoxyphenyl) methyl) -thiophenol A stirred solution of 48.00 g (150.29 mmol) of thiocarbamate (obtained from Step 2a) in 200 mL of diphenyl ether was refluxed at 270°C overnight. The solution was cooled down to room temperature and filtered through 1 L of silica gel with 2 L of hexane to remove phenyl ether. The rearrangement product was washed with 5% ethyl acetate/hexane to give 46.00 g (95.8%) of the product as a pale yellow solid: ^XH NMR (CDC1₃) d 3.02 (s, 3H) , 3.10 (s, 3H) , 3.80 (s, 3H) , 4.07 (s, 2H) , 6.82-6.86 (m, 3H) , 6.93 (dt, J = 8.4 Hz, 2.7 Hz, IH) , 7.08 (d, J = 8.7 Hz, 2H) , 7.49 (dd, J = 6.0 Hz, 8.7 Hz, IH) . To a solution of 46.00 g (144.02 mmol) of the rearrangement product (above) in 200 mL of methanol and 200 mL of THF was added 17.28 g of NaOH (432.06 mmol) . The mixture was refluxed under nitrogen overnight . The solvents were evaporated off and 200 mL of water was added. The aqueous solution was washed with 200 mL of diethyl ether twice and placed in an ice bath. The aqueous mixture was acidified to pH 6 with concentrated HCl solution. The solution was extracted with 300 mL of diethyl ether twice. The ether layers were combined, dried over MgS0₄ and stripped to dryness to afford 27.00 g (75.5%) of the product as a brown oil: ^XH NMR (CDC1₃) d 3.24 (s, IH) , 3.80 (s, 3H) , 3.99 (s, 2H) , 6.81-6.87 (m, 4H) , 7.09 (d, J = 8.7 Hz, 2H) , 7.27- 7.33 (m, IH) .

Step 3. Preparation of dibutyl cyclic sulfate

Step 3a. Preparation of 2 , 2-dibutyl-l, 3-propanediol . To a stirred solution of di-butyl-diethylmalonate (Aldrich) (150g, 0.55 mol in dry THF (700ml) in an acetone/dry ice bath was added LAH (1 M THF) 662 ml (1.2 eq. , 0.66 mol) dropwise maintaining the temperature between -20 to 0°C. The reaction was stirred at RT overnight. The reaction was cooled to -20°C and 40 ml of water, and 80 mL of 10% NaOH and 80 ml of water were added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulphate and concentrated in vacuo to give diol 598.4 g (yield 95%) as an oil. MS spectra and proton and carbon NMR spectra were consistent with the product.

Step 3b. Preparation of dibutyl cyclic sulfite

A solution of 2 , 2-dibutyl-l, 3-propanediol (103 g, 0.548 0 mol, obtained from Step 3a) and triethylamine (221 g, 2.19 mol) in anhydrous methylene chloride (500 ml) was stirred at 0°C under nitrogen. To the mixture, thionyl chloride (97.8* g, 0.^'82 mol) was added dropwise and within 5 min the solution turned yellow and then black when the addition was 5 completed within half an hour. The reaction mixture was stirred for 3 hrs. at 0°C. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice . The organic phase was dried over magnesium sulfate and concentrated under vacuum 0 to give 128 g (100%) of the dibutyl cyclic sulfite as a black oil. Mass spectrum (MS) was consistent with the product .

Step 3c. Oxidation of dibutyl cyclic sulfite to ⁵ dibutyl cyclic sulfate

To a solution of the dibutyl cyclic sulfite (127.5 g , 0.54 mol, obtained from Step 3b) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium (III) chloride (1 g) and sodium periodate 0 (233 g, 1.08 mol) . The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The organic phase was dried over magnesium sulfate and passed through celite. The filtrate was 5 concentrated under vacuum and to give 133 g (97.8%) of the dibutyl cyclic sulfate as an oil. Proton and carbon NMR and MS were consistent with the product.

Step 4. Preparation of aryl-3-hydroxypropylsulfide

10 To a stirred solution of 27.00 g (108.73 mmol) of 4- fluoro-2- ( (4-methoxyphenyl) methyl) thiophenol (obtained from Step 2) in 270 mL of diglyme was added 4.35 g of 60% sodium-, hydride dispersion in mineral oil (108.73 mmol) at 0°C. After gas evolution ceased, 29.94 g (119.60 mmol) of the

15 dibutyl cyclic sulfate (obtained from Step 3c) was added at 0°C and stirred for 10 minutes. The mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated and 200 mL of water was added. The solution was washed with 200 mL of diethyl ether and added

2025 mL of concentrated sulfuric acid to make a 2.0 M solution that was refluxed overnight. The solution was extracted with ethyl acetate and the organic solution was dried over MgS0₄ and concentrated in vacuo. The crude aryl-3 - hydroxypropylsulfide was purified by silica gel

25 chromatography (Waters Prep 500) using 8% ethyl acetate/hexane to yield 33.00 g (72.5%) of the product as a light brown oil: E NMR (CDC1₃) d 0.90 (t, J = 7.1 Hz, 6H) , 1.14-1.34 (m, 12H) , 2.82 (s, 2H) , 3.48 (s, 2H) , 3.79 (s, 3H) , 4.10 (s, 2H) , 6.77-6.92 (m, 4H) , 7.09 (d, J = 8.7 Hz,

302H) , 7.41 (dd, J = 8.7 Hz, 5.7 Hz, IH) . Step 5. Preparation of enantiomerically-enriched aryl-3 - hydroxypropylsulfoxide

To a stirred solution of 20.00 g (47.78 mmol) of aryl- 53 -hydroxypropylsulfide (obtained from Step 4) in 1 L of methylene chloride was added 31.50 g of 96% (12?) - ( -) - (8 , 8- dichloro-10-camphor-sulfonyl) oxaziridine (100.34 mmol, Aldrich) at 2°C. After all the oxaziridine dissolved the mixture was placed into a -30 °C freezer for 72 hours. The

10 solvent was evaporated and the crude solid was washed with 1 L of hexane. The white solid was filtered off and the hexane solution was concentrated in vacuo. The crude oil was purified on a silica gel column (Waters Prep 500) using 15% ethyl acetate/hexane to afford 19.00 g (95%) of the

15 enantiomerically-enriched aryl-3 -hydroxypropylsulfoxide as a colorless oil: ^lH NMR (CDC1₃) d 0.82-0.98 (m, 6H) , 1.16-1.32 (m, 12H) , 2.29 (d, J - 13.8 Hz, IH) , 2.77 (d, J = 13.5 Hz, IH) , 3.45 (d, J = 12.3 Hz, IH) , 3.69 (d, J = 12.3 Hz, IH) , 3.79 (s, 3H) , 4.02 (q, J = 15.6 Hz, IH) , 6.83-6.93 (m, 3H) ,

207.00 (d, J = 8.1 Hz, 2H) , 7.18-7.23 (m, IH) , 7.99-8.04 (m, IH) . Enantiomeric excess was determined by chiral HPLC on a (2?,2?) -Whelk-0 column using 5% ethanol/hexane as the eluent. It showed to be 78% e.e. with the first eluting peak as the major product.

25

Step 6. Preparation of enantiomerically-enriched aryl-3- propanalsulfoxide

To a stirred solution of 13.27 g of triethylamine (131.16 mmol, Aldrich) in 200 mL dimethyl sulfoxide were

30 added 19.00 g (43.72 mmol) of enantiomerically-enriched aryl-3 -hydroxypropylsulfoxide (obtained from Step 5) and 20.96 g of sulfur trioxide-pyridine (131.16 mmol, Aldrich) at room temperature. After the mixture was stirred at room temperature for 48 hours, 500 mL of water was added to the mixture and stirred vigorously. The mixture was then 5 extracted with 500 mL of ethyl acetate twice. The ethyl acetate layer was separated, dried over MgS0₄, and concentrated in vacuo. The crude oil was filtered through 500 mL of silica gel using 15% ethyl acetate/hexane to give 17.30 g (91%) of the enantiomerically-enriched aryl-3-

10 propanalsulfoxide as a light orange oil: ^lE NMR (CDC1₃) d 0.85-0.95 (m, 6H) , 1.11-1.17 (m, 4H) , 1.21-1.39 (m, 4H) , 1.59-1.76 (m, 4H) , 1.89-1.99 (m, IH) , 2.57 (d, J = 14.1 Hz, IH) , 2.91 (d, J = 13.8 Hz, IH) , 3.79 (s, 3H) , 3.97 (d, J = 15.9 Hz, IH) , 4,12 (d, J = 15.9 Hz, IH) , 6.84-6.89 (m, 3H) ,

157.03 (d, J = 8.4 Hz, 2H) , 7.19 (dt, J = 8.4 Hz, 2.4 Hz, IH) , 8.02 (dd, J = 8.7 Hz, 5.7 Hz, IH) , 9.49 (s, IH) .

Step 7. Preparation of the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (4R, 5R)

20 To a stirred solution of 17.30 g (39.99 mmol) of enantiomerically-enriched aryl-3 -propanalsulfoxide (obtained from Step 6) in 300 mL of dry THF at -15°C was added 48 mL of 1.0 M potassium t-butoxide in THF (1.2 equivalents) under nitrogen. The solution was stirred at -15°C for 4 hours.

25 The solution was then quenched with 100 mL of water and neutralized with 4 mL of concentrated HCl solution at 0°C. The THF layer was separated, dried over MgS0₄, and concentrated in vacuo. The enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (4R,5R) was purified by

30 silica gel chromatography (Waters Prep 500) using 15% ethyl acetate/hexane to give 13.44 g (77.7%) of the product as a white solid: 'H NMR (CDC1₃) d 0.87-0.97 (m, 6H) , 1.16-1.32 (m, 4H) , 1.34-1.48 (m, 4H) , 1.50-1.69 (m, 4H) , 1.86-1.96 (m, IH) , 2.88 (d, J = 13.0 Hz, IH) , 3.00 (d, J = 13.0 Hz, IH) , 3.85 (s, 3H) , 4.00 (s, IH) , 4.48 (s, IH) , 6.52 (dd, J = 9.9 5Hz, 2.4 Hz, IH) , 6.94 (d, J = 9 Hz, 2H) , 7.13 (dt, J = 8.4 Hz, 2.4 Hz, IH) , 7.38 (d, J = 8.7 Hz, 2H) , 7.82 (dd, J = 8.7 Hz, 5.7 Hz, IH) .

Step 8. Preparation of enantiomerically-enriched

10 tetrahydrobenzothiepine-1, 1-dioxide (4R, 5R)

To a stirred solution of 13.44 g (31.07 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (obtained from Step 7) in 150 mL of methylene chloride was added 9.46 g of 68% m-chloroperoxybenzoic acid (37.28 mmol,

15 Sigma) at 0 °C. After stirring at 0 °C for 2 hours, the mixture was allowed to warm up to room temperature and stirred for 4 hours. 50 mL of saturated Na₂S0₃ was added into the mixture and stirred for 30 minutes. The solution was then neutralized with 50 mL of saturated NaHC0₃ solution.

20 The methylene chloride layer was separated, dried over MgS0₄, and concentrated in vacuo to give 13.00 g (97.5%) of the enantiomerically-enriched tetrahydrobenzothiepine-1, 1- dioxide (4R,5R) as a light yellow solid: 'H NMR (CDC1₃) d 0.89-0.95 (m, 6H) , 1.09-1.42 (m, 12H) , 2.16-2.26 (m, IH) ,

253.14 (q, J = 15.6 Hz, IH) , 3.87 (s, 3H) , 4.18 (s, IH) , 5.48 (s, IH) , 6.54 (dd, J = 10.2 Hz, 2.4 Hz, IH) , 6.96-7.07 (m, 3H) , 7.40 (d, J = 8.1 Hz, 2H) , 8.11 (dd, J = 8.6 Hz, 5.9 Hz, IH) .

30 Step 9. Preparation of enantiomerically-enriched 7-

(dimethylamino) tetrahydrobenzothiepine-1 , 1-dioxide (4R.5R) - To a solution of 13.00 g (28.98 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1, 1- dioxide (obtained from Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor was added ca . 20 5 mL of neat dimethylamine . The mixture was sealed and stirred at 110 °C overnight, and cooled to ambient temperature. The excess dimethylamine was evaporated. The crude oil was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water, dried over MgS0₄ and

10 concentrated in vacuo. Purification on a silica gel column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g (90.5%) of the enantiomerically- enriched 7- (dimethylamino) tetrahydrobenzothiepine-1, 1-dioxide (4R, 5R) as a colorless solid: *H NMR (CDC1₃) d 0.87-0.93 (m, 6H) ,

151.10-1.68 (m, 12H) , 2.17-2.25 (m, IH) , 2.81 (s, 6H) , 2.99 (d, J = 15.3 Hz, IH) , 3.15 (d, J = 15.3 Hz, IH) , 3.84 (s, 3H) , 4.11 (d, J = 7.5 Hz, IH) , 5.49 (s, IH) , 5.99 (d, J = 2.4 Hz, IH) , 6.51 (dd, J = 8.7 Hz, 2.4 Hz, IH) , 6.94 (d, J = 8.7 Hz, 2H) , 7.42 (d, J = 8.4 Hz, 2H) , 7.90 (d, J = 8.7 Hz,

20 IH) . The product was determined to have 78% e.e. by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. Recrystallization of this solid from ethyl acetate/hexane gave 1.70 g of the racemic product. The remaining solution was concentrated and recrystallized to

25 give 9.8 g of colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. It showed to have 96% e.e with the first eluting peak as the major product.

30 Step 10: Demethylation of 5- (4 ' -methoxyphenyl) -7-

(dimethylamino) tetrahydrobenzothiepine-1.1-dioxide (4R, 5R) To a solution of 47 g (99 mmol) of enantiomeric- enriched (dimethylamino) tetrahydrobenzothiepine-1, 1-dioxide (obtained from Step 9) in 500 mL of methylene chloride at -10 °C was added dropwise a solution of boron tribromide (297 mL, 1M in methylene chloride, 297 mmol), and the resulting solution was stirred cold (-5 °C to 0 °C) for 1 hour or until the reaction was complete. The reaction was cooled in an acetone-dry ice bath at -10 °C, and slowly quenched with 300 mL of water. The mixture was warmed to 10 °C, and further diluted with 300 mL of saturated sodium bicarbonate solution to neutralize the mixture. The aqueous layer was separated and extracted with 300 mL of methylene chloride, and the combined extracts were washed with 200 mL of water, brine, dried over MgS0₄ and concentrated in vacuo. The residue was dissolved in 500 mL of ethyl acetate and stirred with 50 mL of glacial acetic acid for 30 minutes at ambient temperature. The mixture was washed twice with 200 mL of water, 200 mL of brine, dried over MgS0₄ and concentrated in vacuo to give the crude 4-hydroxyphenyl intermediate. The solid residue was recrystallized from methylene chloride to give 37.5 g (82%) of the desired (4R, 5R) -5- (4' - hydoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepine-1, 1- dioxide as a white solid: *H NMR (CDC1₃) d 0.84-0.97 (m, 6H) , 1.1-1.5 (m, 10H) , 1.57-1.72 (m, IH) , 2.14-2.28 (m, IH) , 2.83 (s, 6H) , 3.00 (d, J = 15.3 Hz, IH) , 3.16 (d, J - 15.3 Hz, IH) , 4.11 (s, 2H) , 5.48 (s, IH) , 6.02 (d, J - 2.4 Hz, IH) , 6.55 (dd, J^" = 9, 2.4 Hz, IH) , 6.88 (d, 8 , 7 Hz , 2H) , 7.38 (d, J - 8.7 Hz, 2H) , 7.91 (d, J^" = 9 Hz, 2H) .

Step 11: Preparation of enantiomerically-enriched chlorobenzyl intermediate Treat a solution of enantiomerically-enriched (4R,5R)- 5- (4' -hydoxypheny1) -7- (dimethylamino) tetrahydrobenzothiepine-1, 1-dioxide (5.0 g, 10.9 mmol, obtained from Step 10) in acetone (100 mL) at 25 °C under N₂ with powdered 5 K₂C0₃ (2.3 g, 16.3 mmol, 1.5 eq.) and a, a' -dichloro-p-xylene (6.7 g, 38.1 mmol, 3.5 eq.) . Stir the resulting solution at 65 °C for about 48 hours. Cool the reaction mixture to 25 °C and concentrate to 1/5 of original volume. Dissolve the residue in EtOAc (150 mL) and wash with water (2 x 150 mL) .

10 Extract the aqueous layer with EtOAc (2 x 150 mL) and wash the combined organic extracts with saturated aqueous NaCI (2 x 150 mL. Dry the combined extracts with MgS0₄ and concentrate in vacuo to provide the crude product . Purification by flash chromatography (5.4 x 45 cm silica,

1525-40% EtOAc/hexane) will afford the enantiomerically- enriched chlorobenzyl intermediate .

Step 12: Preparation of enantiomerically-enriched (4R.5R)- 1- r [4- [ [4- [3 , 3-Dibutyl-7- (dimethylamino) -2,3 , 4 , 5-tetrahvdro-

204 -hydroxy-1.1-dioxido-1-benzothiepin-5- yl] phenoxy] methyll phenyl! methyl] -4-aza-l- azoniabicyclo f2.2.2] octane chloride (XXVII)

Treat a solution of the enantiomerically-enriched chlorobenzyl intermediate (4.6 g, 7.7 mmol, obtained from

25 above in Step 11) in acetonitrile (100 mL) at 25 °C under N₂ with diazabicyclo [2.2.2] -octane (DABCO, 0.95 g, 8.5 mmol, 1.1 eq.) and stir at 35 °C for 2 hours. Collect the precipitated solid and wash with CH₃CN. Recrystallization from CH₃OH/Et₂0 will give the desired title compound (XXVII) .

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///////////FDA, Breakthrough Designation,  Shire, Rare GI Therapies, SHP625, maralixibat, progressive familial intrahepatic , Maralixibat chloride, 228113-66-4, UNII: V78M04F0XC, LUM 001, Lopixibat chloride, cholestasis type 2 (PFIC2), Maralixibat Chloride,  ماراليكسيبات كلوريد ,  氯马昔巴特 , Мараликсибата хлорид

CCCCC1(CS(=O)(=O)c2ccc(cc2[C@H]([C@H]1O)c3ccc(cc3)OCc4ccc(cc4)C[N+]56CCN(CC5)CC6)N(C)C)CCCC.[Cl-]

GSK-2881078

GSK-2881078

(R)-1-[1-(Methylsulfonyl)propan-2-yl]-4-(trifluoromethyl)-1H-indole-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

Phase I

A selective androgen receptor modulator potentially for the treatment of cachexia.

Inventors	Philip Stewart Turnbull, Rodolfo Cadilla
Applicant	Glaxosmithkline Intellectual Property (No.2) Limited

CAS Number	1539314-06-1
Chemical Name	GSK-2881078
Synonyms	GSK-2881078
Molecular Formula	C14H13NF3N2O2S
Formula Weight	330.33

• Originator GlaxoSmithKline
• Mechanism of Action Selective androgen receptor modulators

• Phase I Cachexia

Most Recent Events

• 03 Sep 2015 GlaxoSmithKline initiates enrolment in a phase I trial for Cachexia (In volunteers) in USA (NCT02567773)
• 01 Mar 2015 GlaxoSmithKline completes a phase I trial in Cachexia (In volunteers) in USA (NCT02045940)
• 31 Jan 2014 Phase-I clinical trials in Cachexia (In volunteers) in USA (PO)

GSK2881078 is a selective androgen receptor modulator (SARM) that is being evaluated for effects on muscle growth and strength in subjects with muscle wasting to improve their physical function. Part A of this study will evaluate the safety, efficacy and pharmacokinetics of GSK2881078 in healthy, older men and post-menopausal women who will take daily dosing for 28 days and be followed for a total of 70 days. Part B of this study will characterize the effect of Cytochrome P450 3A4 (CYP3A4) inhibition on the GSK2881078 pharmacokinetics. Part B will only be conducted if safe and efficacious dose is identified in Part A. Part A will include healthy older males and post-menopausal females; and randomize approximately 60 subjects (about 15 per cohort [4 cohorts]) to complete approximately 48 (about 12 per cohort). Part B will enroll one cohort of approximately 15 healthy male subjects to complete approximately 12. The study duration will be approximately 115 days for Part A and 122 days for Part B.

Steroidal nuclear receptor (NR) ligands are known to play important roles in the health of both men and women. Testosterone (T) and dihydrotestosterone (DHT) are endogenous steroidal ligands for the androgen receptor (AR) that appear to play a role in every tissue type found in the mammalian body. During the development of the fetus, androgens play a role in sexual differentiation and development of male sexual organs. Further sexual development is mediated by androgens during puberty. Androgens play diverse roles in the adult, including stimulation and maintenance of male sexual accessory organs and maintenance of the musculoskeletal system. Cognitive function, sexuality, aggression, and mood are some of the behavioral aspects mediated by androgens. Androgens have a physiologic effect on the skin, bone, and skeletal muscle, as well as blood, lipids, and blood cells (Chang, C. and Whipple, G. Androgens and Androgen Receptors. Kluwer Academic Publishers: Boston, MA, 2002)

Many clinical studies with testosterone have demonstrated significant gains in muscle mass and function along with decreases in visceral fat. See, for example,

Bhasin (2003) S. J. Gerontol. A Biol. Sci. Med. Sci. 58:1002-8, and Ferrando, A. A. et al. (2002) Am. J. Phys. Endo. Met. 282: E601-E607. Androgen replacement therapy (ART) in men improves body composition parameters such as muscle mass, strength, and bone mineral density (see, for example, Asthana, S. et al. (2004) J. Ger, Series A: Biol. Sci. Med. Sci. 59: 461 -465). There is also evidence of improvement in less tangible parameters such as libido and mood. Andrologists and other specialists are increasingly using androgens for the treatment of the symptoms of androgen deficiency. ART, using T and its congeners, is available in transdermal, injectable, and oral dosage forms. All current treatment options have contraindications (e.g., prostate cancer) and side-effects, such as increased hematocrit, liver toxicity, and sleep apnoea. Side-effects from androgen therapy in women include: acne, hirsutism, and lowering of high-density lipoprotein (HDL) cholesterol levels, a notable side-effect also seen in men.

Agents that could selectively afford the benefits of androgens and greatly reduce the side-effect profile would be of great therapeutic value. Interestingly, certain NR ligands are known to exert their action in a tissue selective manner (see, for example, Smith et al. (2004) Endoc. Rev. 2545-71 ). This selectivity stems from the particular ability of these ligands to function as agonists in some tissues, while having no effect or even an antagonist effect in other tissues. The term "selective receptor modulator" (SRM) has been given to these molecules. A synthetic compound that binds to an intracellular receptor and mimics the effects of the native hormone is referred to as an agonist. A compound that inhibits the effect of the native hormone is called an antagonist. The term "modulators" refers to compounds that have a spectrum of activities ranging from full agonism to partial agonism to full antagonism.

SARMs (selective androgen receptor modulators) represent an emerging class of small molecule pharmacotherapeutics that have the potential to afford the important benefits of androgen therapy without the undesired side-effects. Many SARMs with demonstrated tissue-selective effects are currently in the early stages of development See, for example, Mohler, M. L. et al. (2009) J. Med. Chem. 52(12): 3597-617. One notable SARM molecule, Ostarine™, has recently completed phase I and II clinical studies. See, for example, Zilbermint, M. F. and Dobs, A. S. (2009) Future Oncology 5(8):121 1-20. Ostarine™ appears to increase total lean body mass and enhance functional performance. Because of their highly-selective anabolic properties and demonstrated androgenic-sparing activities, SARMs should be useful for the prevention and/or treatment of many diseases in both men and women, including, but not limited to sarcopenia, cachexias (including those associated with cancer, heart failure, chronic obstructive pulmonary disease (COPD), and end stage renal disease (ESRD), urinary incontinence, osteoporosis, frailty, dry eye and other conditions associated with aging or androgen deficiency. See, for example, Ho et al. (2004) Curr Opin Obstet Gynecol. 16:405-9; Albaaj et al. (2006) Postgrad Med J 82:693-6; Caminti et al. (2009) J Am Coll Cardiol. 54(10):919-27; lellamo et al. (2010) J Am Coll Cardiol. 56(16): 1310-6; Svartberg (2010) Curr Opin Endocrinol Diabetes Obes. 17(3):257-61 , and Mammadov et al. (201 1 ) Int Urol Nephrol 43:1003-8. SARMS also show promise for use in promoting muscle regeneration and repair (see, for example, Serra et al. (Epub 2012 Apr 12)

doi:10.1093/Gerona/gls083),in the areas of hormonal male contraception and benign prostatic hyperplasia (BPH), and in wound healing (see, for example, Demling (2009) ePIasty 9:e9).

Preclinical studies and emerging clinical data demonstrate the therapeutic potential of SARMs to address the unmet medical needs of many patients. The demonstrated advantages of this class of compounds in comparison with steroidal androgens (e.g. , tissue-selective activity, oral administration, AR selectivity, and lack of androgenic effect) position SARMs for a bright future of therapeutic applications.

Although amorphous forms of SARMs may be developed for some uses, compounds having high crystallinity are generally preferred for pharmaceutical use due to their improved solubility and stability. Accordingly, there remains a need in the art for crystalline form of SARMs for therapeutic use.

Patent

WO 2015110958

EXAMPLES

Example 1 - Synthesis of (R)-1 -(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)- -indole-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)^-(trifluoromethyl)-1 H-indole-5-carbonitrile

Method 1 :

A. (R)-1 -(Methylthio)propan-2 -amine

Step 1

To a solution of commercially available (R)-2-aminopropan-1 -ol (5 g, 66.6 mmol) in MeCN (20 mL), in an ice bath, is added very slowly, dropwise, chlorosulfonic acid (4.46 mL, 66.6 mmol) (very exothermic). The reaction mixture is kept in the cold bath for ~10 min, and then at rt for ~ 30 min. After stirring for another ~ 10 minutes, the solids are collected by filtration, washed sequentially with MeCN (40 mL) and hexanes (100 mL), and dried by air suction for ~ 40 min. to produce the intermediate ((R)-2-aminopropyl hydrogen sulfate.

Step 2:

To a solution of sodium thiomethoxide (5.60 g, 80 mmol) in water (20 mL) is added solid NaOH (2.66 g, 66.6 mmol) in portions over ~ 10 min. Then the intermediate from step 1 is added as a solid over ~ 5 min. The mixture is then heated at 90 °C for ~10 h. The reaction mixture is biphasic. Upon cooling, MTBE (20 mL) is added, and the organic phase (brownish color) is separated. The aqueous phase is extracted with MTBE (2 x 20 mL). The original organic phase is washed with 1 N NaOH (15 mL). The basic aqueous phase is re-extracted with MTBE (2 x 20 mL). All the ether phases are combined, dried over Na₂S0₄, filtered, and concentrated (carefully, since the product is volatile) to afford the crude product as a light yellow oil.

Method 2

(R)-1-(methylthio)propan-2 -amine hydrochloride

A. (R)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

Step 1

Commercially available (R)-2-aminopropan-1 -ol (135 g, 1797 mmol) is dissolved in MeOH 1350 mL). The solution is cooled to 5°C with an icebath, then Boc₂0 (392 g, 1797 mmol) is added as a solution in MeOH (1000 mL). The reaction temperature is kept below 10°C. After the addition, the cooling bath is removed, and the mixture is stirred for 3 h. The MeOH is removed under vacuum (rotavap bath: 50°C). This material is used as is for the next step.

Step 2

The residue is dissolved in CH₂CI₂ (1200 mL) and NEt₃ (378 mL, 2717 mmol) is added, then the mixture is cooled on an ice bath. Next, MsCI (166.5 mL, 2152 mmol) is added over ~2 h, while keeping the reaction temperature below 15°C. The mixture is stirred in an icebath for 1 h then the bath was removed. The mixture is stirred for 3 d, then washed with a 10% NaOH solution (500 mL 3 x), then with water. The organic phase is dried with MgS0₄, filtered, then stripped off (rota, 50°C waterbath. The impure residue is dissolved in a mix of 500mL EtOAc (500 mL) and MTBE (500 mL) and then extracted with water to remove all water-soluble salts. The organic phase is dried with MgS0₄, filtered, then stripped off to afford a white solid residue.

B. (R)-tert-Butyl (1 -(methylthio)propan-2-yl)carbamate

NaSMe (30 g, 428 mmol) is stirred with DMF (200 mL) to afford a suspension. Next, (R)-2-((tertbutoxycarbonyl)amino)propyl methanesulfonate (97 g, 383 mmol) is added portionwise while the temperature is kept below 45°C (exothermic). After the addition, the mixture is stirred for 2 h, then toluene (100 mL) is added. The mixture is washed with water (500 mL, 4 x), then dried with MgS0₄, and filtered. The filtrate is stripped off (rotavap) to a pale yellow oil.

C. (R)-1 -(Methylthio)propan-2 -amine hydrochloride

Acetyl chloride (150 mL,) is added to a stirred solution of MeOH (600 mL) cooled with an icebath. The mixture is stirred for 30 min in an icebath, then added to (R)-tert-butyl (1 -(methylthio)propan-2-yl)carbamate (78 g, 380 mmol). The mixture is stirred at rt for 2 h, (C0₂, (CH₃)₂C=CI-l2 evolution) and then stripped off to a white solid.

D. 4-Fluoro-3-iodo-2-(trifluoromethyl)benzonitrile

To a freshly prepared solution of LDA (1 19 mmol) in anhyd THF (250 mL) at -45°C is added a solution of commercially available 4-fluoro-2-(trifluoromethyl)benzonitrile (21 .5 g, 1 14 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained < -40°C (became dark brown during addition). The mixture is stirred 30 min at -45°C, cooled to -70°C and iodine (31 .7 g, 125 mmol) is added in one portion (-70°C→ -52°C). The mixture is stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na₂S₂0₃ (ca. 250 mL) and 1 N HCI (ca. 125 mL). The mixture is extracted with EtOAc (x3). Combined organics are washed (water, brine), dried over Na₂S0₄ and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc / hexanes, gradient elution) followed by

recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (15.79 g, 50.1 mmol, 44.1 % yield) as a pale yellow solid.

E. 4-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile

A 20 mL vial is charged with 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile,(0.315 g, 1 .00 mmol), Pd(PPh₃)₂CI₂ (0.014 g, 0.020 mmol) and Cul (0.0076 g, 0.040 mmol), and sealed with a rubber septum. Anhyd PhMe (5 mL) and DIPA (0.210 mL, 1 .500 mmol) are added via syringe and the mixture is degassed 10 min by sparging with N₂while immersed in an ultrasonic bath. Ethynyltrimethylsilane (0.155 mL, 1 .100 mmol) is added dropwise via syringe and the septum is replaced by a PTFE-faced crimp top. The mixture is stirred in a heating block at 60°C. Upon cooling the mixture is diluted with EtOAc and filtered through Celite. The filtrate is washed (satd NH₄CI, water, brine), dried over Na₂S0₄ and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc / hexanes, gradient elution) affording 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile .

F. (R)-1 -(1 -(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

A mixture of 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (1 .16 g, 4.07 mmol), (R)-1 -(methylthio)propan-2-amine (0.599 g, 5.69 mmol) and DIEA (1 .42 mL, 8.13 mmol) in DMSO (7 mL) is heated (sealed tube) at 100°C for 50 min. Upon cooling, the reaction mixture is diluted with EtOAc (50 mL) and washed with water (30 mL). The organic phase is washed with water and brine, dried over Na₂S0₄, filtered and concentrated to give the intermediate aniline. This intermediate is dissolved in NMP (7 mL), treated with KOtBu (1 M in THF) (5.69 mL, 5.60 mmol) and heated at 50°C. The reaction is monitored by LCMS, and deemed complete after 40 min. Upon cooling, the reaction mixture is diluted with EtOAc (40 mL) and washed with water (30 mL). The organic phase is washed with more water and brine, dried over Na₂S0₄, filtered and concentrated. The residue is chromatographed over silica gel using a 5-40% EtOAc-hexane gradient to give the thioether intermediate:

G. (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

To an ice-cold solution of (R)-1 -(1 -(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (0.560 g, 1.88 mmol) in MeOH (10 mL) is added a solution of Oxone (4.04 g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture is diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue is chromatographed over silica gel using 100% CH₂CI₂ to give (R)-1-(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-l H-indole-5-carbonitrile as a white foam that is crystallized from

CH₂CI₂/hexanes to afford a white solid.

Example 2- Preparation of crystalline form 1 of (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .74kg, 1wt) was dissolved in ethyl acetate (12.0 Kg, 6.9 wt) at 20-30°C. The solution was transferred into a clean reaction vessel via an in-line cartridge filter. The solution was concentrated to ~3.0-5.0 volumes under reduced pressure, keeping the temperature below 50°C. The solution was cooled to 20-30°C, and n-heptane (23.0 Kg, 13.2 wt) was added slowly over ~1 hour. The solution was stirred 1 -2 hrs at 20-30°C, heated to 50-55°C for 2-3 hours, cooled back to 20-30°C and stirred for 1 -2 hours. The slurry was sampled and analyzed by XRPD. The solid was collected by filtration, washed with n-heptane (1 .4 Kg, 0.8 wt), and dried in vacuo at 40-50 °C to provide crystalline

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .54 Kg, Form 1 ; 88.5 % yield, 99.5% purity) as a slightly colored solid.

Example 3- Preparation of crystalline form 2 of (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

Crude (R)-1 -(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .54 g [theoretical], 1 wt) was dissolved in dichloromethane (5mL, 3.25 vol) and loaded onto a 12-g ISCO column (Si0₂). The column was eluted with DCM (-500 mL, 325 vol) and the product-containing fractions were combined and concentrated in vacuo. The resulting residue was triturated in n-heptane. The solid was collected by filtration, air-dried, and placed under high vacuum for 3 h to provide GSK2881078A (1 .009 g, Form 2; 65.1 % yield, 100% AUC HPLC-UV) as a white solid.

PATENT

https://www.google.com/patents/WO2014013309A1?cl=en22

Example 26

1-(1-(Methylsulfonyl)propan-2-yl)-4-(trifiuoromethyl)-1H-indole-5-carbonitrile Synthesized in a manner similar to Example 9 using 1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (Example 25): MS (ESI): m/z 331 (MH+).

Example 27

(R)-1 -(1 -(Methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

A. (R)-1-(Methylthio)propan-2-amine

Step l

To a solution of commercially available (R)-2-aminopropan-1-ol (5 g, 66.6 mmol) in MeCN (20 mL), in an ice bath, was added very slowly, dropwise, chlorosulfonic acid (4.46 mL, 66.6 mmol) (very exothermic). A gummy beige precipitate formed. The reaction mixture was kept in the cold bath for -10 min, and then at rt for ~ 30 min. The reaction mixture was scratched with a spatula to try to solidify the gummy precipitate. After a few minutes, a beige solid formed. After stirring for another ~ 10 minutes, the solids were collected by filtration, washed sequentially with MeCN (40 mL) and hexanes (100 mL), and dried by air suction for ~ 40 min. The intermediate ((R)-2-aminopropyl hydrogen sulfate, weighed 0.46 g (~ 96% yield).

Step 2:

To a solution of sodium thiomethoxide (5.60 g, 80 mmol) in water (20 mL) was added solid NaOH (2.66 g, 66.6 mmol) in portions over - 10 min. Then the intermediate from step 1 was added as a solid over ~ 5 min. The mixture was then heated at 90 °C for -10 h. The reaction mixture was biphasic. Upon cooling, MTBE (20 mL) was added, and the organic phase (brownish color) was separated. The aqueous phase was extracted with MTBE (2 x 20 mL). The original organic phase is washed with 1 NaOH (15 mL) (this removes most of the color). The basic aqueous phase was re-extracted with MTBE (2 x 20 mL). All the ether phases are combined, dried over Na₂S0₄, filtered, and

concentrated (carefully, since the product is volatile) to afford the crude product as a light yellow oil: ¹H NMR (400 MHz, DMSO-cf₆) δ 2.91-2.87 (m, 1 H), 2.43-2.31 (m, 2 H), 2.04 (s, 3 H), 1.50 (bs, 2 H), 1.01 (d, J = 6.3 Hz, 3 H).

Alternative synthesis of example 27A:

(R)-1 -(Methylthio)propan-2 -amine hydrochloride

A. (R)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

Step 1

Commercially available (R)-2-aminopropan-1-ol (135 g, 1797 mmol) was dissolved in MeOH 1350 mL). The solution was cooled to 5°C with an icebath, then Boc₂0 (392 g, 1797 mmol) was added as a solution in MeOH (1000 mL). The reaction temperature was kept below 10°C. After the addition, the cooling bath was removed, and the mixture was stirred for 3 h. The MeOH was removed under vacuum (rotavap bath: 50°C). The resulting residue was a colorless oil that solidified overnight to a white solid. This material was used as is for the next step.

Step 2

The residue was dissolved in CH₂CI₂ (1200 mL) and NEt₃ (378 mL, 2717 mmol) was added, then the mixture was cooled on an ice bath. Next, MsCI (166.5 mL, 2152 mmol) was added over ~2 h, while keeping the reaction temperature below 15°C. The mixture was stirred in an icebath for 1 h then the bath was removed. The mixture was stirred for 3 d, then washed with a 10% NaOH solution (500 mL 3 x), then with water. The organic phase was dried with MgS0 , filtered, then stripped off (rota, 50°C waterbath. The impure residue was dissolved in a mix of 500mL EtOAc (500 mL) and MTBE (500 mL) and then, extracted with water to remove all water-soluble salts.The organic phase was dried with MgS0₄, filtered, then stripped off to afford a white solid residue: ¹H NMR (400 MHz, DMSO-d_s) δ 6.94-6.92 (m, 1 H), 4.02 (d, J = 5.8 Hz, 2 H), 3.78-3.71 (m, 1 H), 3.16 (s, 3 H), 1.38 (s, 9 H), 1.06 (d, J = 6.8 Hz, 3 H).

B. (R)-tert-Butyl (1-(methylthio)propan-2-yl)carbamate

NaSMe (30 g, 428 mmol) was stirred with DMF (200 mL) to afford a suspension. Next, (R)-2-((tertbutoxycarbonyl)amino)propyl methanesulfonate (97 g, 383 mmol) was added

portionwise while the temperature was kept below 45°C (exothermic).. After the addition, the mixture was stirred for 2 h, then toluene (100 ml_) was added. The mixture was washed with water (500 ml_, 4 x), then dried with MgS0₄, and filtered. The filtrate was stripped off (rotavap) to a pale yellow oil: ¹H NMR (400 MHz, DMSO-d₆) δ 6.77-6.75 (m, 1 H), 3.60-3.54 (m, 1 H), 2.54-2.50 (m, 1 H), 2.43-2.38 (m, 1 H), 2.05 (s, 3 H), 1.38 (s, 9 H), 1.08 (d, J = 7.8 Hz, 3 H).

C. (R)-1-(Methylthio)propan-2-amine hydrochloride

Acetyl chloride (150 mL,) was added to a stirred solution of MeOH (600 mL) cooled with an icebath. The mixture was stirred for 30 min in an icebath, then added to (R)-tert-butyl (1-(methylthio)propan-2-yl)carbamate (78 g, 380 mmol). The mixture was stirred at rt for 2 h, (C0₂, (CH₃)₂C=CH₂ evolution) and then stripped off to a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (bs, 3 H), 3.36-3.29 (m, 1 H), 2.80-2.75 (m, 1 H), 2.64-2.59 (m, 1 H (d, J = 6.6 Hz, 3 H).

D. (R)-1 -(1 -(Methylthio)propan-2-yl)-4-(trif luoromethy l)-1 H-indole-5-carbonitrile

A mixture of 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (Example 21 D,1.16 g, 4.07 mmol), (R)-1-(methylthio)propan-2-amine (0.599 g, 5.69 mmol) and DIEA (1.42 mL, 8.13 mmol) in DMSO (7 mL) was heated (sealed tube) at 100°C for 50 min. Upon cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL). The organic phase was washed with water and brine, dried over Na₂S0₄, filtered and concentrated to give the intermediate aniline. This intermediate was dissolved in NMP (7 mL), treated with KOtBu (1 M in THF) (5.69 mL, 5.60 mmol) and heated at 50°C. The reaction was monitored by LCMS, and deemed complete after 40 min. Upon cooling, the reaction mixture was diluted with EtOAc (40 mL) and washed with water (30 mL). The organic phase was washed with more water and brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed over silica

gel using a 5-40% EtOAc-hexane gradient to give the thioether intermediate: MS (ESI):

E. (R)-1-(1-(Methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

To an ice-cold solution of (R)-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (0.560 g, 1.88 mmol) in MeOH (10 mL) was added a solution of Oxone (4.04 g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed over silica gel using 100% CH₂CI₂ to give (R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-l H-indole-5-carbonitrile as a white foam that was crystallized from CH₂CI₂/hexanes to afford a white solid (0.508 g, 79% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J = 8.6 Hz, 1 H), 8.12 (d, J = 3.5 Hz, 1 H), 7.81 (d, J - 8.5 Hz, 1 H), 6.87-6.84 (m, 1 H), 5.43-5.35 (m, 1 H), 4.01 (dd, J = 14.8, 8.6 Hz, 1 H), 3.83 (dd, J = 14.8, 4.9 Hz, 1 H), 2.77 (s, 3 H), 1.59 (d, J = 6.8 Hz, 3 H); MS (ESI): m/z 331 (M+H).

Philip Turnbull

Director of Chemistry

https://www.linkedin.com/in/philip-turnbull-21266a8

Experience

Director of Chemistry

Receptos, a wholly-owned subsidiary of Celgene

June 2015 – Present (1 year 1 month)Greater San Diego Area

Director

GSK

April 2010 – June 2015 (5 years 3 months)RTP

Section Head

GSK

April 2007 – April 2010 (3 years 1 month)RTP

Group Manager

GlaxoSmithKline

April 2003 – April 2007 (4 years 1 month)RTP

Investigator

GSK

June 1998 – April 2003 (4 years 11 months)RTP

Research Associate

Biophysica Foundation

February 1988 – September 1991 (3 years 8 months)La Jolla, Ca

Education

The Scripps Research Institute

post doc, Organic chemistry

1996 – 1998

University of California, Irvine

Doctor of Philosophy (Ph.D.), Organic synthesis

1991 – 1996

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