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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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New patent, Opicapone, WO 2019123066, Unichem


New patent, Opicapone, WO 2019123066, Unichem

WO-2019123066

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019123066&tab=PCTDESCRIPTION

Process for the preparation of opicapone and its intermediates, useful for treating parkinson’s disease. Bial-Portela  has developed and launched opicapone, for treating Parkinson’s disease.

Opicapone is a selective and reversible catechol-O-methyltransferase (COMT) inhibitor, use as adjunctive therapy for parkinson’s disease. Opicapone was approved by European Medicine Agency (EMA) on June 24, 2016 and it is developed and marketed as ONGENTYS® by Bial-Portela in Europe. Opicapone is chemically described as 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-l-oxide and depicted below as compound of formula (I).

Opicapone and a process for preparation of it is disclosed in US 8,168,793. The process disclosescondensation of 3, 4-dibenzyloxy-5-nitrobenzoic acid with (Z)-2, 5-dichloro-N’-hydroxy-4, 6-dimethylnicotinimidamide in presence of N, N’-Carbonyl diimidazole in N, N’-dimethylformamide. The crude condensation intermediate was subjected to tetrabutylammonium fluoride (TBAF) mediated cyclization in tetrahydrofuran to give l,2,4-oxadiazole derivative, purifying it by precipitating in 1:1 mixture of dichloromethane: diethyl ether and recrystallized it in isopropyl alcohol. Oxidation of l,2,4-oxadiazole compound is carried out using 10 fold excess of urea hydrogen peroxide complex and trifluoroacetic anhydride in dichloromethane and was purified by column chromatography. Obtained N-oxide compound was converted into opicaponecompound of formula (I) by deprotection O-benzoyl groups by exposure it to boron tribromide (BBr3) in dichloromethane at -78°C to room temperature. Final product was purified in mixture of toluene and ethanol. Above synthetic stepsare outline in scheme 1.


c eme

This process has several drawbacks like cyclization reaction involve use of TBAF and THF. Use of expensive TBAF, leads to high cost in the production and therefore uneconomical for industrial production, whereas use of THF during this reaction has limitation due to peroxide contents. . Similarly diethyl ether is a potential fire hazard and can form peroxides rapidly and thus should be avoided in commercial scale production. Above cyclization is also carried out in presence of DMF and CDI at l20°C.

Similar approach was reported in W02008094053 which describes preparation of opicapone by one pot cyclization of 3,4-dibenzyloxy-5-nitrobenzoic acid with (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide using N,N’-Carbonyl diimidazole in N,N’-dimethylformamide followed by heating the reaction mixture at l35°C for 5 hours to obtain l,2,4-oxadiazole derivative. This oxadiazole derivative was purified by recrystallization from isopropyl alcohol. Further oxidation using urea hydrogen peroxide complex followed by o-debenzylation using boron tribromide (BBr3) was achieved to obtain Opicapone.

This process also suffers from drawback like use of elevated temperature (l35°C) and use of expensive BBr3.

US 9,126,988 also disclose process for the preparation of opicapone, whichinvolves several chemical steps: 1) nitrating vanillic acid in presence of nitric acid in acetic acidfollowed by recrystallization with acetic acid to get nitro compound with yield 40-46%; 2)which converted into acid chloride compoundby treating it with thionyl chloride in presence of catalytic amount of N, N-dimethylformamide in dichloromethane or l,4-dioxane; 3) condensing acid chloride compound with (Z)-2, 5-dichloro-N’-hydroxy-4, 6-dimethylnicotinimidamide in presence of excess amount of pyridine in N,N-dimethyl acetamide/ tetrahydrofuran/ dichloromethane or l,4-dioxane at 5-10 °C and then heating the reaction mixture at H0-l l5°C for 5-6 hours to get 1,2,4-oxadiazole compound; 4) which was oxidized using urea hydrogen peroxide complex and trifluoroacetic anhydride in dichloromethane to get N-oxide product which was purified by repeated recrystallization (2 or more times) using mixture of formic acid and toluene to get pure product with 59% yield; 5) O-methyl group was deprotected using aluminium chloride and pyridine in N-Methyl pyrrolidone at 60 C to obtain opicapone. After completion of reaction, the crude product was isolated by quenching the reaction mixture in mixture cone. HC1: water followed by filtration, washing with water: isopropyl alcohol and recrystallization from ethanol. Final purification was done in mixture of formic acid and isopropyl alcohol. Above synthetic steps are outline in scheme 2.

Scheme 2

As described above, cited literature processes suffers from some drawbacks like elevated reaction temperature and longer duration, use of excess amount of pyridine for cyclization reaction which is difficult to handle on large scale preparation. Another drawback of reported procedure is unsafe workup procedures for isolation of N-oxide as residual peroxides were not quenched by any peroxide quenching reagent. Also repeated crystallizations (more than two) are required for purification of N-oxide derivative to remove unreacted starting material which is tedious and time consuming process. Also for its purification mixture of solvent i.e. formic acid and toluene are used which hamper its recovery and is not cost effective process.

US 9,126,988 also disclosed process for the preparation of 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide compound of formula (IV), in which 2,5-dichloro-4,6-dimethylnicotinonitrile compound of formula (VIII) was reacted with hydroxyl amine solution in the presence of catalytic amount of 1,10-phenanthroline in methanokwater at 70-80°C for 6 hrs. After completion reaction mixture was cooled, filtered and dried to get 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV) (88%).

Bioorganic & Medicinal Chemistry 13 (2005) 5740-5749, Karl Bailey et.al. disclosed process for preparation of 3,4-dimethoxy-5-nitro benzoic acid compound of formula (Ilia). In which a solution of Cr03, concentrated H2S04 and water was added to solution of 3,4-dimethoxy-5-nitro benzaldehyde in acetone and water. The obtained solution was stirred for 24 hrs and then isopropanol was added to eliminate any unreacted Cr(VI) species to obtained crude green sludge, which was extracted into ethyl acetate and washed with 1M HC1 to remove remaining Cr(III) species. Obtained product is then recrystallized from water and ethanol to yield 69 % of 3,4-dimethoxy-5-nitro benzoic acid compound of formula (Ilia).

US 5,358, 948 also disclosed process for preparation of 3,4-dimethoxy-5-nitro benzoic acid compound of formula (Ilia). In which a solution of potassium permanganate was added to a solution of 3,4-dimethoxy-5-nitro benzaldehyde in acetone. The mixture was then stirred at 20°C for 18 hrs togives 3,4-dimethoxy-5-nitro benzoic acid compound of formula (Ilia) with 72% yield.

Disadvantage of the above cited literature (Karl Bailey et.al and US’ 948) processes are harsh, acidic condition and involve expensive reagents. The process is both uneconomical and time consuming, (18-24 hrs) hence not suitable for commercial production.

Oxidation of aldehydes to the corresponding carboxylic acids, on the other hand, are commonly carried out using KMn04 in acidic or basic media, or K2Cr207 in acidic medium or chromic acid. These heavy metal-based reagents are hazardous and the protocols produce metal wastes that require special handling owing to their toxicities.

It is therefore, desirable to provide efficient, robust, alternative simple process, cost effective process which is used on a large scale and allows product to be easily workup, purified and isolate without the disadvantages mentioned above.

Example 1: Preparation of 3, 4-dimethoxy-5-nitro benzoic acid (Ilia).

To a cooled solution of 3,4-dimethoxy-5-nitro benzaldehyde (lOOg, 0.474 mole) in DMF (500 ml) was added Oxone (294.1 g, 0.478 mole) lot wise at 5-10 °C. Reaction mixture was stirred for 30 minutes at same temperature, allowed to warm to room temperature and stirred for 2-3 hours. After completion, the reaction mixture was diluted with 1500 ml of water and filtered. The solid was washed with water until all peroxides removed and drying at 50°C under vacuum afforded 3,4-dimethoxy-5-nitro benzoic acid of formula (Ilia) (l02g, 95%).

Example 2: Preparation of 2 ,5-dichloro-N’ {[(3,4-dimethoxy-5-nitrophenyl) carbonyl]oxy}-4, 6-dimethylpyridine-3-carboximidamide (Va)

To a solution of 3,4-dimethoxy-5-nitro benzoic acid of formula (Ilia) (5 g, 0.022 mole)in 60 ml of acetonitrile was added N,N’-Carbonyldiimidazole (4.28g, 0.026 mole) in portions and the reaction mixture was stirred at room temperature for 1.5 hours. Then was added 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV) (5.4g, 0.023 mole) and stirring was continued for 3 hours. After completion, the reaction mixture was diluted with 240 ml of water and 300 ml of dichloromethane. Organic layer was separated and washed with water (200 ml x 3), concentrated under reduced pressure to obtain 2,5-dichloro-N'{ [(3,4-dimethoxy-5-nitrophenyl)carbonyl]oxy}-4,6-dimethylpyridine-3-carboximidamide of formula (Va) (8.67g, 88.9%).

Example 3: Preparation of 2, 5-dichloro-3-[5-(3, 4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine (Via)

To a solution of 2,5-dichloro-N'{ [(3,4-dimethoxy-5-nitrophenyl)carbonyl]oxy}- 4,6-dimethylpyridine-3-carboximidamide of formula (Va) (0.5g, 0.0011 mole)in 10 ml of dichloromethane was added isopropyl alcohol (1 ml) followed by KOH (0.075g, 0.001 lmole) dissolved in 0.1 ml of water. After stirring for 1 hour at room temperature the reaction mixture was diluted with 30 ml of dichloromethane and washed with water (lOml x 2). The reaction mixture was concentrated under reduced pressure to obtain 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine of formula (Via) (0.4 g, 83%).

Example 4: Preparation of 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine (Via) (One pot cyclization procedure)

To a stirred solution of 3,4-dimethoxy-5-nitro benzoic acid formula (Ilia) (lOOg, 0.44 mol)in 1000 ml of dichloromethane was added N,N’-Carbonyldiimidazole (86g, 0.53 mole) in portions and the reaction mixture was stirred at room temperature for 1.5 hours. Then was added 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV) (l08g, 0.46 mole) and stirring was continued for 3 hours. Isopropyl alcohol (200 ml) and KOH (30g, 0.53 mole) dissolved in 30 ml of water was then added to the reaction mixture. After stirring for 1 hour at room temperature the organic layer was washed with water (1000 ml x 2). Solvent was distilled out at atmospheric pressure, added 1000 ml of isopropyl alcohol and suspension was stirred at 55-60°C for 2 hours. The reaction mixture was allowed to cool to room temperature, stirred for 2 hours and filtered. The solid was washed with isopropyl alcohol (100 ml x 2) and dried at 50-60°C under vacuum to obtain 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine of formula (Via) (l60g, 85%).

Example 5: Preparation of 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine (Via) (cyclization procedure using thionyl chloride)

To a stirred solution of 3,4-dimethoxy-5-nitro benzoic acid of formula (Ilia) (lOOg, 0.44 mol) in 500 ml of dichloromethane was added 0.4 ml of N,N-dimethyl formamide followed bythionyl chloride (82g, 0.69 mole) drop wise at room temperature and the reaction mixture was heated at 40°C for 4 hours. After completion, dichloromethane and excess of thionyl chloride was distilled out under reduced pressure at 40°C. The obtained residue was dissolved in 500 ml of dichloromethane and was added to pre-cooled mixture of 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV) (l03g, 0.44 mole) and triethyl amine (73 ml, 0.53 mole) in 500 ml of dichloromethane at 5°C. After addition, the reaction mixture was allowed to warm to 25-30°C and stirred for 2 hours. Then was added isopropyl alcohol (200 ml) followed by KOH (62g, 1.1 mole) dissolved in 62 ml of water and stirring was continued for 2 hours at room temperature. The reaction mixture was washed with 1000 ml of water, 1N aqueous HC1 solution (500ml x 2) followed by 500 ml of 5% aqueous sodium bicarbonate solution. Solvent was distilled out at atmospheric pressure at 40°C. To the residue was added 1200 ml of methanol and the suspension was stirred at 55-60°C for 2 hours. The reaction mixture was allowed to cool to room temperature, maintained for 2 hours and filtered. The solid product was washed with methanol (100 ml x 2) and dried at 50°C under vacuum to obtain 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)- 1, 2, 4-oxadiazol-3-yl]-4, 6-dimethyl pyridine of formula (Via) (l65g, 88%).

Example 6: Preparation of 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine-l-oxide (Vila)

To a cooled solution of 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine of formula (Via) (25g, 0.0588 mole) in 300 ml of dichloromethane was added urea hydrogen peroxide complex (l8.26g, 0.194 mole) in portions followed by trifluoroacetic anhydride (37g, 0.176 mole) maintaining temperature below l0°C. After stirring at 5-l0°C for 1 hour, the reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was washed with water (300 ml x 2), 300ml of 5% aqueous sodium sulphite solution to quench residual peroxides and finally with 300 ml of water. Dichloromethane layer was distilled out at atmospheric pressure. The obtained solid was suspended in 250 ml of ethyl acetate and 12.5 ml of cone. HC1 was added at room temperature. The resulting suspension was then stirred at 65-70°C for 1 hour and allowed to cool to room temperature. After stirring for 2 hours, the reaction mixture was filtered, solid was washed with ethyl acetate (50 ml x 2) followed by water (50 x 3) and dried at 50°C under vacuum to obtain (5-(3,4-bis(methoxy)-5-nitrophenyl)-l,2,4-oxadiazol-3-yl)-2,5-dichloro-4,6-dimethylpyridine 1 -oxide of formula (Vila) (18g, 69%).

Example 7: Preparation of 5-[3-(2,5-Dichloro-4,6-dimethyl-l-oxido-3-pyridinyl)-l,2,4-oxadiazol-5-yl]-3-nitro-l,2-benzenediol (Opicapone, I)

To a cooled solution of 2,5-dichloro-3-[5-(3,4-dimethoxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine-l-oxide of formula (Vila) (25g, 0.056 mole) in 200 ml of N,N-Dimethylformamide was added AlCl3 (l l.34g, 0.085 mol) at 5-l0°C in portions. The reaction mixture was then heated at 85 °C for 6 hours. After completion, the reaction mixture was cooled to room temperature and poured onto cold mixture of cone. HC1 (200 ml) and water (400 ml). The reaction mixture was filtered, solid washed with water (100 ml X 3) followed by methanol (50 ml x2) and dried at 50°C under vacuum to obtain 5-[3-(2,5-Dichloro-4, 6-dimethyl- l-oxido-3-pyridinyl)- 1,2, 4-oxadiazol-5-yl]-3-nitro- 1,2-benzenediol of formula (I) (22 g, 94%).

Example 8: Preparation of 2, 5-dichloro-N’-hydroxy-4, 6-dimethyl nicotinimidamide of formula (IV)

To a suspension of 2,5-dichloro-4,6-dimethylnicotinonitrile of formula (VIII) (lOOg, 0.497 mole) in l,4-dioxane (400 ml) and water (900 ml) was added 50% aqueous solution of hydroxyl amine (l30g) and N-methyl morpholine (50.2g, 0.497) at room temperature. The reaction mixture was then stirred at 70-80°C for 10 hours. After completion, water (1100 ml) was added to the reaction mixture at 70-80°C and allowed to cool to room temperature. After stirring for 2 hours the reaction mixture was filtered, solid was washed with water (200ml x 3) and dried at 50°C under vacuum to obtain 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV) (68 g, 58%).

Example 9:Preparation of 2,5-dichloro-N’-hydroxy-4, 6-dimethylnicotinimidamide of formula (IV)

To a suspension of 2,5-dichloro-4,6-dimethylnicotinonitrile of formula (VIII) (lOOg, 0.497 mole) in methanol (600 ml) and water (800 ml) was added 50% aqueous solution of hydroxyl amine (l30g) and 2-methylpyrazine (7.02g, 0.0746) at room temperature. The reaction mixture was then stirred at 70-80°C for 6-8 hours. After completion, water (800 ml) was added to the reaction mixture at 70-80°C and allowed to cool to room temperature. After stirring for 2 hours the reaction mixture was filtered, solid was washed with water (200ml x 3) and dried at 50°C under vacuum to obtain 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV) (82 g, 70%).

Example 10: Preparation of 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV)

To a solution of hydroxylamine hydrochloride (86.4g, 1.243 mole) in 400 ml of water was added LiOH.H20 (52.7g, 1.25 mole) at room temperature and heated at 50°C for 30 minutes. To the reaction mixture was added 300 ml of methanol, 2-methylpyrazine (3.5 lg, 0.037 mole) and 2,5-dichloro-4,6-dimethylnicotinonitrile of formula (VIII) (50g, 0.248 mole) at 50°C. The reaction mixture was then stirred at 70-80°C for 6 hours. After completion, water (500 ml) was added to the reaction mixture at 70-80°C and allowed to cool to room temperature. After stirring for 2 hours the reaction mixture was filtered, solid was washed with water (lOOml x 3) and dried at 50°C under vacuum to obtain 2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide of formula (IV) (37.6 g, 64%).

Example 11: Purification of 5-[3-(2,5-Dichloro-4,6-dimethyl-l-oxido-3-pyridinyl)-l,2,4-oxadiazol-5-yl]-3-nitro-l,2-benzenediol (Opicapone, I)

The crude 5-[3-(2,5-Dichloro-4, 6-dimethyl- l-oxido-3-pyridinyl)- 1,2, 4-oxadiazol-5-yl]-3-nitro-l,2-benzenediol of formula (I)(25.0g) was suspended in 250 ml of N,N-dimethylformamide and reaction mixture was heated at 60-65°C to obtain clear solution. Then was added 500 ml of methanol and reaction mixture was cooled to room temperature. After stirring for 2-3 hours, the reaction mixture was filtered, solid was washed with methanol and dried at 50°C under vacuum to obtain 5-[3-(2, 5-Dichloro-4, 6-dimethyl- l-oxido-3-pyridinyl)- 1,2, 4-oxadiazol-5-yl]-3-nitro-l,2-benzenediol of formula (I) (22.0 g, 88%).

/////////////New patent, Opicapone, WO 2019123066, Unichem, WO2019123066

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VIXOTRIGINE, NEW PATENT, WO-2019071162, BIOGEN INC


VIXOTRIGINE, NEW PATENT, WO-2019071162, BIOGEN INC

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019071162&redirectedID=true

vixotrigine

Process for preparing α-carboxamide pyrrolidine derivatives (particularly vixotrigine ) and its intermediates are modulators of use-dependent voltage-gated sodium channels

Biogen, following the acquisition of Convergence Pharmaceuticals, that previously acquired clinical assets from  GSK is developing vixotrigine a voltage-gated sodium channel 1.7 inhibitor, for the oral treatment of neuropathic pain, primarily trigeminal neuralgia.

CHEN, Weirong; US
COUMING, Vinny; US
IRDAM, Erwin; US
KIESMAN, William, F.; US
KWOK, Daw-long, A.; US
MACK, Tamera, L.; US
OPALKA, Suzanne, M.; US
PATIENCE, Daniel, B.; US
WALKER, Donald, G.; US
LIANG, Wenli; US

The invention relates to a novel process for preparing a-carboxamide pyrrolidine derivatives, in particular (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide, and to novel intermediates for use in said process along with processes for preparing said intermediates.

(2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide:

is described in WO 2007/042239 as having utility in the treatment of diseases and conditions mediated by modulation of use-dependent voltage-gated sodium channels. The synthetic preparation of (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide is described in both WO 2007/042239 and WO 2011/029762.

Description 1a: Methyl (S)-5-(4-(benzyloxy)phenyl)-2-((iert-butoxycarbonyl)amino)-5-oxopentanoate (D1a) (Batch Process using Grignard Procedure)

A reactor was charged with THF (350 kg) and the solvent was degassed by nitrogen sparging for about 30 min at 20 – 30 °C. To the degassed THF was charged l-(benzyloxy)- 4- bromobenzene (137 kg (1.78 equiv)). The solids were dissolved at 20 – 30 °C with agitation and under an inert atmosphere of nitrogen.

A reactor was charged with Mg (21.3 kg (3.0 equiv)) and THF (131 kg) and the mixture was degassed by nitrogen sparging for about 30 min at 20 – 30 °C. To this mixture was added -5% of the 1-(benzyloxy)-4-bromobenzene – THF solution followed by heating to 50 – 60 °C under an inert atmosphere of nitrogen. With good agitation, DIBAL-H in toluene (1 M; 2.5 kg (0.01 equiv)) was added followed by heating the mixture to 60 – 70 °C and aging for about 1 h. The remaining amount of the 1-(benzyloxy)-4-bromobenzene – THF solution was added followed by a THF rinse (36 kg) of the reactor. The mixture was aged for about 1 h at 60 – 70 °C and was cooled to 20 – 30 °C under an inert atmosphere of nitrogen.

A reactor was charged with THF (382 kg) and the solvent was degassed by nitrogen sparging for about 30 min at 20 – 30 °C. To the degassed THF was charged l-(ferf-butyl) 2-methyl (S)- 5- oxopyrrolidine 1 ,2-dicarboxylate (71 kg (1.0 equiv)), and the resulting solution was cooled to -60 to -70 °C under an inert atmosphere of nitrogen. To this solution was added the Grignard solution while maintaining a reaction temperature of <-60 °C. The reactor that contained the Grignard solution was rinsed with THF (61 kg) and the reaction was aged at -60 to -70 °C for about 1 h. The progress of the reaction was monitored (HPLC).

Upon completion, 2-propanol (56 kg) was added while maintaining a reaction temperature of -60 to -70 °C, and the reaction was aged for about 30 min. Water (296 kg) was added while maintaining a reaction temperature of <10 °C; the contents of the reactor were warmed to 20 – 30 °C following the addition. The pH of the mixture was adjusted to 6 – 7 by addition of 51 wt% acetic acid in water (70 kg). MTBE (220 kg) was added and the mixture was agitated for about 30 min. The layers were separated, the organic layer was clarified by filtration and was concentrated to about 3 – 4V. MTBE (220 kg) was added and the resulting solution was concentrated to about 3 – 4V. MTBE (150 kg) was added and the resulting solution was heated to 35 – 45 °C. n-Heptane (250 kg) was added slowly while maintaining a reaction temperature of 35 – 45 °C, the mixture was aged for 1 – 2 h, cooled to 0 – 5 °C and aged for 3 – 5 h. The solids were isolated by filtration, washed with n-heptane (74 kg) and dried in vacuo at 50 – 60 °C to constant weight to afford 96.7 kg (77.5%) of the title compound.

Description 1 b: Methyl (S)-5-(4-(benzyloxy)phenyl)-2-((iert-butoxycarbonyl)amino)-5-

oxopentanoate (D1 b) (Batch Process using Grignard Procedure) (Alternative

Procedure)

A reactor was charged with degassed THF (1090 kg) and 1-(benzyloxy)-4-bromobenzene (329 kg (1.46 equiv)). The solids were dissolved at 20 – 25 °C with agitation and under an inert atmosphere of nitrogen.

A reactor was charged with Mg turnings (31.9 kg (1.53 equiv)) and degassed THF (389 kg) under an inert atmosphere of nitrogen. To this mixture was added -5% of the l-(benzyloxy)-4-bromobenzene – THF solution (-70 kg) followed by heating to 50 – 60 °C. With good agitation, DIBAL-H in toluene (1.5M; 4.55 kg (0.0093 equiv)) was added followed by addition of toluene (2.16 kg) into the reactor through the charging line. The mixture was heated to 60

– 70 °C and aged for about 1 h. The remaining amount of the 1-(benzyloxy)-4-bromobenzene

– THF solution was added followed by a degassed THF rinse (51 kg) of the reactor. The mixture was aged for about 1 h at 60 – 70 °C and was cooled to 20 – 30 °C under an inert atmosphere of nitrogen.

A reactor was charged with degassed THF (1090 kg) and 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (208 kg (1.0 equiv)), and the resulting solution was cooled to -60 to -70 °C under an inert atmosphere of nitrogen. To this solution was added the Grignard solution while maintaining a reaction temperature of <-50 °C. The reactor that contained the Grignard solution was rinsed with degassed THF (208 kg) and the reaction was aged at -60 to -70 °C for about 1 h. The progress of the reaction was monitored (HPLC).

Upon completion, 2-propanol (164 kg) was added while maintaining a reaction temperature of <-40 °C, and the reaction was aged for 20 – 30 min. Water (100 kg) was added while maintaining a reaction temperature of <-20 °C; the contents of the reactor were warmed to -10 to -20 °C following the addition. The mixture was transferred into another reactor and water (940 kg) was added while maintaining a reaction temperature of <10 °C; the contents of the reactor were warmed to 20 – 30 °C following the addition. The pH of the mixture was adjusted to 6.0 – 7.0 by addition of 50 wt% acetic acid in water (-170 kg). MTBE (647 kg) was added and the mixture was agitated for 20 – 30 min. The layers were separated, and the organic layer was stirred for 20 – 30 min with a brine solution prepared from NaCI (48 kg) and water (390 kg). The layers were separated, the organic layer was clarified by filtration and the filtration apparatus was washed with THF (30 kg). The solution was concentrated to about 5.5 – 6X the input mass of 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate at a temperature of 45 – 50 °C. MTBE (647 kg) was added and the resulting solution was concentrated to about 5.5 – 6X the input mass of 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate at a temperature of 45 – 50 °C. MTBE (661 kg) was added and the resulting solution was concentrated to about 5.5 – 6X the input mass of 1 -(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate at a temperature of 45 – 50 °C. MTBE (77 kg) was added, the solution was sampled and analysed for residual THF content (if the result was >15%, MTBE (661 kg) was added and the solution was concentrated at 45 – 50 °C to about 5.5 – 6X the input mass of 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate). The solution was cooled to 35 – 45 °C and n-Heptane (726 kg) was added slowly while maintaining a reaction temperature of 35 – 45 °C. The mixture was aged for 1 – 2 h, cooled to 15 – 25 °C over 2 – 3 h, cooled to 0 – 5 °C and aged for 3 – 5 h. The solids were isolated by centrifugation and washed with n-heptane (214 kg). The wet solids (-328 kg) were dissolved in THF (683 kg) at 40 – 50 °C. The solution was cooled to 35 – 45 °C and n-heptane (564 kg) was added slowly while maintaining a reaction temperature of 35 – 45 °C. The mixture was aged for 1 -2 h, cooled to 15 – 25 °C over 2 – 3 h, cooled to 0 – 5 °C and aged for 3 – 5 h. The solids were isolated by centrifugation, washed with n-heptane (167 kg) and dried in vacuo at 50 – 60 °C to constant weight to afford 252 kg (69%) of the title compound.

Description 1c: Methyl (S)-5-(4-(benzyloxy)phenyl)-2-((fert-butoxycarbonyl)amino)-5-oxopentanoate (D1c) (Batch Process using Magnesium “ate” Procedure)

A reactor was charged with THF (249 kg) and the solvent was degassed by nitrogen sparging for about 30 min at 20 – 30 °C. To the degassed THF was charged l-(ferf-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (71 kg (1.0 equiv)), and the resulting solution was stirred at 20 to 30 °C under an inert atmosphere of nitrogen.

A reactor was charged with THF (460 kg) and the mixture was degassed by nitrogen sparging for about 30 min at 20 – 30 °C. To the degassed THF was charged 1-(benzyloxy)-4-bromobenzene (93 kg (1.2 equiv)) and the solution was degassed in triplicate. The solution was cooled to -40 to -50 °C under an inert atmosphere of nitrogen. To this solution was added /-PrMgCI – THF solution (51.3 kg, 2M; 0.36 equiv) while maintaining a reaction temperature of <-40 °C. To this solution was added n-BuLi – hexane solution (71.3 kg, 2.5M; 0.90 equiv) while maintaining a reaction temperature of <-40 °C. The contents of the reactor were aged at -40 to -50 °C for 1 – 1.5 h. The solution was cooled to -60 to -70 °C under an inert atmosphere of nitrogen.

The 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate – THF solution was added to the reactor containing the organomagnesium “ate” solution while maintaining a reaction temperature of -60 to -70 °C; the contents of the reactor were aged for about 1 h. The progress of the reaction was monitored (HPLC).

Upon completion, 10% NH4CI solution (389 kg) was added while maintaining a reaction temperature of < -40 °C. Following the addition, the contents of the reactor were warmed to 20 – 30 °C. The pH of the mixture was adjusted to 6 – 7 by addition of 50 wt% acetic acid in water (24.4 kg). n-Heptane (97 kg) was added and the mixture was agitated for 20 – 30 min at 20 – 30 °C. The layers were separated and the organic layer was concentrated in vacuo to about 270 L at <50 °C. The contents of the reactor were cooled to 20 – 30 °C and n-heptane (490 kg) was added followed by slurry aging for 2 – 3 h. The slurry was cooled to 0 – 5 °C and aged for 2 – 3 h. The solids were isolated by filtration, washed with a solution composed of n-heptane (58 kg) and THF (25 kg) and were dried in vacuo at 50 – 60 °C to constant weight to afford 102.95 kg (82.5%) of the title compound.

A reactor was charged with the title compound (102.95 kg) and THF (469 kg). The contents of the reactor were warmed to 40 – 50 °C, aged for 1 – 2 h, cooled to 20 – 30 °C and concentrated to a volume of about 250 L. n-Heptane (490 kg) was added and the mixture was agitated for 2 – 3 h at 20 – 30 °C. The mixture was cooled to 0 – 5 °C and aged for 2 – 3 h. The solids were isolated by filtration, washed with n-heptane (213 kg) and dried in vacuo at 50 – 60 °C to constant weight to afford 87.95 kg (70.5%) of the title compound.

Description 1d: Methyl (S)-5-(4-(benzyloxy)phenyl)-2-((fert-butoxycarbonyl)amino)-5-oxopentanoate (Did) (Batch Process using Turbo Grignard Procedure)

A clean 100 mL EasyMax reactor was swept with dry nitrogen, the flow was reduced and /-PrMgCI-LiCI complex in THF (41.7g, 1.3M, 1.0 eq) was added to the reactor and the temperature was set to 20 °C. Bis(dimethylamino)ethyl ether (9.13 g, 1.0 eq) was added in a single portion, the mixture was stirred for 5 min, and 4-benzyloxybromobenzene (15.0 g, 1.0 eq) was added in a single portion. The reaction was heated to 40°C under an inert atmosphere of nitrogen and held at this temperature until full conversion was observed (ca. 3.5h).

A clean 100 mL EasyMax reactor was swept with dry nitrogen, the flow was reduced and dry THF (45 mL). 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (5.0 g, 1.0 eq) was charged in a single portion and the solution was cooled to -35 °C under an inert atmosphere of nitrogen. The Grignard solution (26.4 mL, 0.85M, 1.1 eq) was then added at a rate of 0.5 mL/min while maintaining a reaction temperature of <-30°C. The progress of the reaction was monitored (HPLC). Upon completion the reaction was neutralized by the addition of a 14.6 wt% AcOH/water solution (24 mL). The reaction was then warmed to -10 °C, then to 0 °C. A 20% aqueous NH4CI solution (10.3 g) was added followed by a pH adjustment with 1 M HCI (14 mL), then with 6M HCI to an endpoint of pH 1. The reaction mixture was transferred to a separatory funnel with the aid of 25 ml of THF. The phases were separated and the organic layer washed with saturated aqueous NaCI solution (16 g). The organic layer was concentrated under reduced pressure at <50°C to afford a crude product solution (19.4 g).

The crude product solution was transferred to a clean 100 mL EasyMax reactor and was heated to 35 °C. Heptane (20 mL) was then added over about 30 sec. The mixture was cooled to 10°C and held for about 30 min. The solids were filtered, washed twice with 2: 1 heptane/MTBE mixture (14 mL) and dried to constant weight to afford 4.147 g (47%) of the title compound.

Description 1e: Methyl (S)-5-(4-(benzyloxy)phenyl)-2-((fert-butoxycarbonyl)amino)-5-oxopentanoate (Die) (Flow Process using Intermittent Continuous Stirred Tank Reactor)

Reactor 1 was charged with 1-(benzyloxy)-4-bromobenzene (145 g (1.0 eq)) and the reactor was flushed with nitrogen. THF (490 g) was added and solids were dissolved at 20 – 30 °C by agitation; the solution was kept under an inert atmosphere of nitrogen.

Reactor 2 was charged with Mg (13.66 g (1.02 eq relative to reactor 1 charge)) and the reactor was flushed with nitrogen. Iodine (0.14 g (0.001 eq relative to the 1-(benzyloxy)-4-bromobenzene charge)) was charged followed by addition of 5% of the prepared 1-(benzyloxy)-4-bromobenzene – THF solution. The contents of the reactor were warmed to 50 – 65 °C and after color dissipation, the remainder of the prepared 1-(benzyloxy)-4-bromobenzene – THF solution (Reactor 1) was added while maintaining a reaction temperature of 50 – 70 °C. The contents of the reactor were stirred at 60 – 70 °C for about 1 h, cooled to 20 – 30 °C and held under an inert atmosphere of nitrogen.

Grignard Solution Batch 1

Reactor 3 was charged with 1-(benzyloxy)-4-bromobenzene (2.755 kg (1.0 eq)) and the reactor was flushed with nitrogen. THF (9.29 kg) was added and solids were dissolved at 20 – 30 °C by gentle agitation; the solution was kept under an inert atmosphere of nitrogen. Reactor 4 was charged with Mg (259.2 g (1.02 eq relative to the reactor 3 charge)) and the reactor was flushed with nitrogen. The contents of Reactor 2 were charged and the mixture was warmed to 50 – 65 °C. The prepared 1-(benzyloxy)-4-bromobenzene – THF solution in Reactor 3 was added while maintaining a reaction temperature of 50 – 70 °C. The contents of the reactor were stirred at 60 – 70 °C for about 1 h and cooled to 20 – 30 °C. About 95% of this Grignard solution was transferred into Reactor 5 and held under an inert atmosphere of nitrogen. A sample was pulled from Reactor 5 for analysis (residual 1-(benzyloxy)-4-bromobenzene (HPLC); Grignard reagent concentration). The remaining 5% of this Grignard solution was held in Reactor 4 under an inert atmosphere of nitrogen.

Grignard Solution Batch 2

Reactor 3 was charged with 1-(benzyloxy)-4-bromobenzene (2.90 kg (1.0 eq)) and the reactor was flushed with nitrogen. THF (9.78 kg) was added and solids were dissolved at 20 – 30 °C by gentle agitation; the solution was kept under an inert atmosphere of nitrogen.

Reactor 4 was charged with Mg (273.1 g (1.02 eq relative to the reactor 3 charge)) and the mixture was warmed to 50 – 65 °C. The prepared 1-(benzyloxy)-4-bromobenzene – THF solution in Reactor 3 was added while maintaining a reaction temperature of 50 – 70 °C. The contents of the reactor were stirred at 60 – 70 °C for about 1 h and cooled to 20 – 30 °C. About 95% of this Grignard solution was transferred into Reactor 6 and held under an inert atmosphere of nitrogen. A sample was pulled from Reactor 6 for analysis (residual 1-(benzyloxy)-4-bromobenzene (HPLC); Grignard reagent concentration). The remaining 5% of this Grignard solution was held in Reactor 4 under an inert atmosphere of nitrogen.

Grignard Solution Batch 3

Reactor 3 was charged with 1-(benzyloxy)-4-bromobenzene (2.90 kg (1.0 eq)) and the reactor was flushed with nitrogen. THF (9.78 kg) was added and solids were dissolved at 20 – 30 °C by gentle agitation; the solution was kept under an inert atmosphere of nitrogen.

Reactor 4 was charged with Mg (273.2 g (1.02 eq relative to the reactor 3 charge)) and the mixture was warmed to 50 – 65 °C. The prepared 1-(benzyloxy)-4-bromobenzene – THF solution in Reactor 3 was added while maintaining a reaction temperature of 50 – 70 °C. The contents of the reactor were stirred at 60 – 70 °C for about 1 h, cooled to 20 – 30 °C and held under an inert atmosphere of nitrogen. A sample was pulled for analysis (residual 1-(benzyloxy)-4-bromobenzene (HPLC); Grignard reagent concentration).

Reaction of Grignard Reagent with l-(ferf-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate

The reaction was performed in 12 cycles; a representative cycle is described below. In total, 6.46 kg of 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate was processed forward to the title compound.

Reactor 7 was charged with 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (2.21 kg) and THF (5.89 kg) and the solids were dissolved at 20 – 30 °C by gentle agitation under an inert atmosphere of nitrogen.

Reactor 8 was charged with THF (0.98 kg) and the solvent was cooled to about -10 °C under an inert atmosphere of nitrogen. Solutions of the Grignard reagent (3.2 kg) in Reactor 6 and the 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate – THF solution (2.0 kg) in Reactor 7 were simultaneously pumped into Reactor 8 over 15 min while maintaining a reaction temperature of <30 °C. The contents of Reactor 8 were stirred for an additional 15 min; the final reaction temperature was 0 – 10 °C. The contents of Reactor 8 were transferred to Reactor 9, cooled to about -5 °C and the reaction was quenched by addition of 1 M aqueous H2SO4 solution (1.20 equiv) while maintaining a reaction temperature of <10 °C. The mixture was stirred for 30 min, was transferred to Reactor 10 and was heated to 25 – 30 °C. The mixture was transferred to Reactor 1 1 , toluene (2.39 kg) was charged and the mixture was agitated. The mixture was transferred to Settler 1 and the organic layer was transferred to Reactor 12 using a metering pump. Water (1.65 kg) wash charged to Reactor 12, the mixture was agitated, transferred to Settler 2 and the organic layer was transferred to a storage container using a metering pump.

Product Isolation

The contents of the storage container (organic streams from 12 reaction cycles) was concentrated in Reactor 13 to an endpoint of 65 °C (pot temperature) at 200 torr. The contents of the reactor were cooled to 30 °C, then to 0 to -10 °C and aged for 0.5 – 2 h. The solids were isolated by filtration, washed with toluene (7.50 kg) and dried in vacuo at 50 °C and < 10 torr to give 8.76 kg (77%) of the title compound.

Description 1f: Methyl (S)-5-(4-(benzyloxy)phenyl)-2-((fert-butoxycarbonyl)amino)-5-oxopentanoate (D1f) (Flow Process using Plug Flow Reactor)

A flow reactor with two reagent inputs, ¾ inch tubing for reagent transfer, and two ½ inch jacketed static mixers connected in series (35 mL volume) was assembled. Gear pumps were used to transfer reagents to the flow reactor. Mass flow meters were used to measure the flow rates of the reagents. Thermocouples were placed to monitor the temperature of the (4-benzyloxy)phenylmagnesium bromide (Grignard) and l-(terf-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate solutions prior to entering the tube-in-tube mixer T, as well as the out-flowing reaction stream from the static mixers. A fourth thermocouple measured the

temperature of the collection vessel. A peristaltic pump was used to transfer an aqueous acetic acid quench solution to the reaction stream as it exited from the static mixers. A standard T-mixer was used to join these reaction streams. The quenched reaction mixture flowed through a cooled coil into a jacketed collecting vessel. The approximate residence time through the static mixers was calculated to be -4.5 seconds.

Solution A: 0.57M (4-benzyloxy)phenylmagnesium bromide (Grignard) solution in THF (1.3 equiv used).

Solution B: 0.44M l-(ferf-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (0.750 kg) in THF (6.5 L)

Solution C: 2.9M glacial acetic acid (517 g) in water (3.013 L) to provide a 2.9 M solution. The quenched reaction mixture flowed into a collecting vessel containing 20% aqueous NH4CI (1.465 kg) at 0 °C.

The pre-cooling loop for Solution B was set to a bath temperature of -20 to -22 °C. The static mixer jacket coolant was set to a temperature of -25 °C. The pre-cooling loop for Solution A was set to a jacket temperature of -5 °C. The continuous quench tube reactor was set to a bath temperature of 0 °C.

After the jacket temperatures and cooling baths were allowed to reach desired temperatures, Solution A was pumped at a rate of -250 mL/min through the outside tube of the tube-in-tube mixer and met the Solution B that was pumped through the inner tube at a rate of 250 mL/min. Simultaneously to the reagent streams, the flow rate of the 2.9M aqueous acetic acid solution was initiated and set to approximately 130 mL/min. Reagent flow rates were measured with mass flow meters and temperatures were measured with thermocouples.

The reaction was run for about 20 min; a total of 5.663 kg of Solution B, 6.237 kg of Solution A and 3.530 kg of 2.9M aqueous acetic acid solution were charged during the reaction. The lines were rinsed with THF (1.252 kg) immediately after the reaction was finished.

The pH of the aqueous layer in the collection vessel was measured at 6.08. The pH was adjusted to 5.05 with 1 N HCI (2.05 kg) followed by the addition of 1V: 1V AcOH/water (162 g). The reactor jacket temperature was set to 10 °C and the contents of the reactor were stirred for 12 h. The pH of the mixture was further adjusted to 2.06 by adding 37% HCI (0.301 kg) and the mixture was stirred at 0 – 10 °C for 15 to 30 min.

The aqueous layer was separated and the organic layer was stirred for 20 min with a 25% brine solution (1.995 kg). The aqueous layer was separated; the organic layer was held at 10 °C overnight. The organic layer was concentrated at 35 – 40 °C (jacket temperature) and 25-30 mm Hg. Upon reaching a volume of about 9.5 L, a well developed slurry was noted. The concentration was continued to a volume of about 4.5 L. The slurry was warmed to 31 °C and heptane (3.145 kg) was added. The slurry was heated to 35 °C, stirred for 30 min, and was cooled to and held at 20 to 22 °C. The slurry was cooled to 10 °C and stirred for at least 2 h. Solids were collected by filtration and washed with 2: 1 heptane/MTBE (2 x 1.5 L). The solids were dried to constant weight in vacuo to yield 990 g (86.8%) of the title compound.

Description 1g: methyl (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate

A reactor was charged with degassed THF (1 199 kg) and 1-(benzyloxy)-4-bromobenzene (450 kg). The solids were dissolved at 20 – 25 °C with agitation and under an inert atmosphere of nitrogen. The mixture was heated to reflux for 15 min, then cooled to 20 – 30 °C.

A reactor was charged with Mg turnings (43.6 kg) and degassed THF (399 kg) under an inert atmosphere of nitrogen. To this mixture, a solution of DIBAL-H (25% in toluene, 6.2 kg) was added followed by addition of toluene (3.7 L) into the reactor through the charging line. The mixture was heated to reflux for 10 – 15 minutes followed by charging of 5% of the 1-(benzyloxy)-4-bromobenzene – THF solution. The contents of the reactor were held for 1 h under reflux; reaction initiation was confirmed. The remainder of the 1-(benzyloxy)-4-bromobenzene – THF solution was added over 3 – 4 h. Following the charge, the temperature was adjusted to 20 – 30 °C.

A reactor was charged with degassed THF (760 kg) and 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (284.9 kg), and the resulting solution was heated to reflux under an inert atmosphere of nitrogen, maintained at reflux for 10 – 15 min, then cooled to -60 °C to -70 °C. To this solution was added the Grignard solution while maintaining a reaction temperature of <-50 °C. The reactor which contained the 1-(benzyloxy)-4-bromobenzene -THF solution was rinsed with degassed THF (22 kg) and the rinse was charged into the reaction. The contents of the reactor were aged at -60 to -70 °C for about 1 h. The progress of the reaction was monitored for completion (HPLC).

A reactor was charged with 2-propanol (285 L) and THF (253 kg). With good agitation the reaction was quenched into this THF – 2-propanol solution while keeping the temperature between -20 °C and 0 °C. The reactor was rinsed forward with THF (53 kg), and the mixture was stirred vigorously for 5 – 10 min. Water (712 L) was added while maintaining a reaction temperature of <20 °C; the pH of the mixture was adjusted to 6.0 – 7.0 by addition of 50 wt% acetic acid in water (-170 kg) while controlling the temperature below 20 °C. The reaction mixture was warmed to 20 – 30 °C, stirred for 20 – 30 min and the phases were separated. Sodium chloride (42 kg) and water (255 L) were charged, the mixture was stirred for 55 – 65 min, and the phases were separated. THF (125 kg) was charged and the solution was concentrated by distillation under vacuum at a temperature of 40 – 45 °C. The distillation was stopped when the weight of the reaction mixture was between 5.5 – 6. OX the weight of the input mass of 1-(te/f-butyl) 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate. The reaction mixture was heated to 35 – 45 °C. Heptane (994 kg) was charged to the reaction mixture, the contents of the reactor were maintained at 35 – 45 °C, aged for 1 – 2 h, cooled to 15 – 25 °C over 2 – 3 h, cooled to 0 – 5 °C and aged for 3 – 5 h. The solids were isolated by centrifugation in three portions; each portion was washed with heptane (97 kg) followed by acetonitrile (59 kg) to give 389 kg of wet product. Based on LOD measurements, 375.3 kg (76.6 %) of the title compound was obtained.

Description 1 h: benzyl (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate

A reactor was charged with 1-benzyl 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (69.3 g) and anhydrous THF (450 g) and the resulting solution was cooled to about -65 °C under an

inert atmosphere of nitrogen. A solution of 0.8M (4-benzyloxy)phenylmagnesium bromide in THF (1.1 eq) was added over about 2 h, and the progress of the reaction was monitored by HPLC. Upon completion, the reaction was quenched by simultaneous addition of 1 M sulfuric acid (1.1 eq) and toluene (264 g) over about 30 min. The resulting mixture was warmed from -10 °C to ambient temperature and was aged for about 30 min. The phases were separated, and the organic layer was washed with 10 wt% brine (180 g) and water (180 g). The organic solution was concentrated to about 6V at about 50 °C and <170 mbar (distillate: 650 g / 710 ml_). The resulting solution was heated to about 65 °C and a solution of toluene (105 g) and methylcyclohexane (200 g) was added dropwise while maintaining a temperature of about 65 °C. The solution was cooled to 0 – 5 °C and aged for about 1 h. The solids were isolated by filtration, washed with cold (0 – 5 °C) methylcyclohexane (200 g in 6 portions) and dried at 45 °C in vacuo to constant weight to give 76.6 g (66%) of the title compound.

Description 1 i: methyl (S)-2-(((benzyloxy)carbonyl)amino)-5-(4-(benzyloxy)ph oxopentan

Solution A: 0.8M (4-benzyloxy)phenylmagnesium bromide solution in THF

Solution B: 0.88M 1 -benzyl 2-methyl (S)-5-oxopyrrolidine 1 ,2-dicarboxylate (25.0 g) solution in anhydrous THF

Solution C: 1 M aqueous sulfuric acid

Equipment: plug flow reactor with a Y-mixer; 10 ml_ reaction loop

Reaction conditions:

· reagent flow rates:

o solution A: 5.27 ml_ / min (1.3 eq)

o solution B: 4.72 ml_ / min (1.0 eq)

o solution C: 5.75 ml_ / min (1.5 eq)

• residence time: 1 min

· reaction temperature: 25 °C

• collection time: 2 h (theory: 0.36 mol title product)

• the quenched reaction mixture flowed into a collecting vessel

Following collection of the quenched reaction mixture, the phases were separated and the upper organic layer was concentrated to dryness in vacuo. The solids were dissolved in fresh THF (5.5V) at 45 °C. The solution was cooled to -5 °C over about 160 min and was aged overnight. The solids were collected by filtration, washed with heptane (5.5V, total) and dried to constant weight at 55 °C in vacuo to afford 18.61 g (45%) of the title product.

The combined filtrate and wash containing additional solids was transferred to a reactor, cooled to -5 °C over 2 h and aged for an additional 4 h. The solids were collected by filtration, washed with heptane (2 X 2V) and dried to constant weight at 55 °C in vacuo to afford 1 1.37 g (27%) of the title product.

Description 1j: methyl (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate – flow chemistry procedure

The CSTR flow setup consists of one 1 L stirred tank for reaction, one 1 L settling tank and one 10L Schlenk type collection vessel. The stirred tank was equipped with a solid addition device, a reflux condenser, and a dip-tube (set to a 500 ml_ working volume) with an inner transfer line.

Step 1 : A stirred tank reactor was pre-charged with THF (70 ml), and magnesium (50.8 g, 5 eq), and stirred at room temperature overnight. The solid addition device was filled with magnesium. The reaction was initiated by adding (4-(benzyloxy)phenyl)magnesium bromide 0.77M solution (7.7 g, 5.9 mmol). The jacket temperature was increased to 55 °C. A solution of 1-bromo-4-benzylphenol (0.85 M in THF) was added at a rate of 7.8 ml/min to the stirred reaction vessel. After seven minutes, solid addition of magnesium started at a rate of 0.161 g/min. The total amount of magnesium for the entire run was (175 g, 7.18 mol,

1 equiv) and was calculated to keep 5 eq of magnesium in the stirred tank reactor over the course of the run. When the liquid level in the tank reached the level of the dip tube, a pump activated pulling material to the settling tank at a rate to maintain the 500 mL filling level in the CSTR. The approximate residence time of the solution in the jacketed reactor was 62 minutes. The product was transferred into the settling tank (unstirred), held for another residence time (1 hour), and subsequently transferred to a final collection vessel. The entire process was run for 18 hours.

Step 2: Grignard Addition: The equipment consists of tubular pipe reactor, heat exchanger, and a series of centrifugal phase separators. The tubular reactor accommodates mixing of two reagents for the conversion to methyl (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate and quenching of the product solution with an acid solution. The centrifugal phase separators separate the product containing organic phase from the waste aqueous phase. The reagent (methyl-N-boc-pyroglutamate, Grignard, and sulfuric acid solutions were transferred continuously at controlled flowrates from their respective storage tank to pass through the tubular pipe reactor, heat exchanger and finally to the centrifugal extractors.

Reaction/Quench/Work-up: The 0.82 M Grignard solution was fed continuously from the storage tank at a flow rate of 32.6 mL/min (1.19 eq), simultaneously a 0.817 M methyl N-boc-pyroglutamate solution stream was fed continuously at 27.4 ml/min through a heat exchanger to pre-cool it to -8°C. The tubular reactor where the reaction between the reagent N-boc-pyroglutamate and Grignard solution occurred was attached to a heat exchange unit with chiller fluid set at 10°C. After passing through the reaction zone, 1.0 M sulfuric acid was introduced at a rate 22.4 ml/min. The residence time of the solution from reagent introduction to acid quench was 8 seconds. From sulfuric acid introduction to phase split the residence time was ca. 80 seconds. The quenched mixture passed through another heat exchanger to increase the temperature to 30°C for phase split. This material was directly fed into a centrifugal extractor to remove the aqueous component. The obtained organic layer was subsequently mixed with a solution of brine and sodium bicarbonate (14.5 ml/min) in a second centrifugal extractor. The final product containing organic layer was collected into a glass bottle. The process was run for 3.7 hours.

Crystallization: The product-containing organic layer above was transferred to a 10 L reactor for solvent switch to a lower water content THF-Heptane solvent system by vacuum distillation. A total of 6867 mL THF (appx. 9.5% v/v) in Heptane was added to the reactor and

subsequently distilled in appx. 2 equal portions maintaining distillation under reduced pressure (appx. 600-700 mbar) at temperature within 60-65°C to replace the original solvent (water-containing THF).3 The final solution obtained (appx. 11.5L) was cooled to 0-5°C with a cooling rate 0.5C/min and the resulting slurry was filtered, washed with Heptane and dried under vacuum at 60°C to obtain 1.765 kg of product.

Description 2a: Methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate

A reactor was charged with methyl (S)-5-(4-(benzyloxy)phenyl)-2-((te/f-butoxycarbonyl)amino)-5-oxopentanoate (180 kg) and ACN (486 kg) and the slurry temperature was adjusted to 10 – 15 °C. A solution of methanesulfonic acid (117.5 kg (2.9 eq)) in ACN (75 kg) was added while maintaining a reaction temperature of <25 °C. The reaction temperature was adjusted to 22 – 26 °C and the contents of the reactor were stirred for 1 – 1.5 h. The progress of the reaction was monitored (HPLC). Upon completion, the contents of the reactor were cooled to 10 – 15 °C and a solution of 4. ON NH4OH (299 kg) was added to a pH of 7 – 8 while maintaining a reaction temperature of <25 °C. The phases were separated and the upper organic layer was heated to 30 – 40 °C. While maintaining a reaction temperature of 30 – 40 °C, 2-propanol (101 kg) and water (430 kg) were added to the reactor. The solution was cooled to 17 – 19 °C and was seeded (1.8 kg). The slurry was stirred for 1 – 2 h at 14 – 19 °C, cooled to 7 – 12 °C, aged for 1 – 2 h and cooled to 2 – 7 °C. Water (890 kg) was added and the slurry was aged for 2 – 3 h at 2 – 7 °C. The solids were isolated by filtration, washed with a solution composed of 2-propanol (61 kg) and water (270 kg) and dried in vacuo at 50 – 60 °C to constant weight to afford 1 19.6 kg (90%) of the title compound.

Description 2b: Methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D2b) (Alternative Procedure)

A reactor was charged with methyl (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (532 kg) and ACN (1670 kg) and the slurry temperature was adjusted to 20 – 25 °C. Methanesulfonic acid (346 kg (2.9 eq)) was added while maintaining a reaction temperature of <26 °C. The contents of the reactor were stirred for 1 h; the progress of the reaction was monitored (HPLC). Upon completion, the contents of the reactor were cooled to <10 °C and a solution of 4.6N NH40H (773 kg) was added until a pH of 7 – 8 was reached while maintaining a reaction temperature of <25 °C. The phases were separated and the upper organic layer was heated to 30 – 35 °C. The organic layer was filtered through a plate filter to remove small particulates. While maintaining a reaction temperature of 30 – 35 °C, 2-propanol (301 kg) and water (1277 kg) were added to the reactor. The solution was cooled to 18 – 22 °C and precipitation occurred. The slurry was stirred for at least 30 minutes at 18 – 22 °C and then cooled to 0 – 10 °C. While maintaining a temperature of 0 – 10 °C, water (2128 kg) was added and the reaction mixture was aged for not less than 2 hours at 0 – 10 °C. The solids were isolated by filtration, washed with a solution composed of 2-propanol (188 kg) and water (798 kg) and dried in vacuo at 50 – 55 °C to constant weight to afford 319 kg (83%) of the title compound.

Description 2c: methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate – flow chemistry procedure with MsOH/ACN

Solution A: 0.79M methanesulfonic acid in anhydrous ACN

Solution B: 0.25M l-(terf-butyl) (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate solution in anhydrous THF

Solution C: 4.6N NH4OH solution in water

Equipment: plug flow reactor with a Y-mixer; 10 ml_ stainless steel reaction loop

Reaction equivalents:

· solution A: 3.0 (3.764 mL / min)

• solution B: 1.0 (3.946 mL / min)

• solution C: 2.7 (0.579 mL / min)

Residence time: 1.3 min

Reaction temperature: 130 °C

After reaching steady state, the reaction stream was collected for 102 min in a 1 L flask immersed in an ice water bath. The base solution from pump C and the reaction stream

were simultaneously collected with good stirring. Following the run, the pH was adjusted to 7 with by charging additional 4.6N ammonium hydroxide solution (about 15 mL). The phases were split, and the organic layer was concentrated to dryness by rotary evaporation in vacuo. The resulting residue was dissolved in ACN (120 mL) and distilled water (5 mL) at 25 °C and 500 rpm in a 100 mL EZMax reactor. The solution was cooled to 22 °C and water – I PA solution (2/1 (v/v), 80 mL) was added over about 30 min. The solution was further cooled to 18 °C, seeded (5 wt%) and cooled to about 0 °C over 2 h. Water (139 mL) was added to the slurry over about 30 min, and the mixture was aged for about 20 min. The temperature of the slurry was raised to 20 °C, held for about 40 min, re-cooled to about 0 °C over 90 min and aged for an additional 90 min. The solids were collected by filtration and dried to constant weight in vacuo at 55 °C to give 28.9 g (92%, corrected for seed) of the title compound.

Description 2d: methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate – flow chemistry procedure with H2SO4/ACN

Three solutions were prepared for the flow reaction. Solution A: 0.25M l-(terf-butyl) (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate solution in anhydrous THF; Solution B: 0.75M sulfuric acid in anhydrous ACN;

A plug flow reactor with a Y-mixer and a 10 mL reaction loop was used with 1 reaction equivalent of solution A, and 2 reaction equivalents of solution B; a residence time of 7.5 minutes; a reaction temperature of 95 °C; and a collection time: 73.7 minutes (theory: 22.1 mmol title product).

The collected product stream was neutralized to pH 7 – 8 using 4.6N NH4OH solution in water. HPLC analysis of the organic layer showed it contained 98.0 area% of the desired product. The lower organic layer was removed, and the organic layer was cooled to about 22 °C, aged for about 30 min and cooled to 0 – 5 °C over about 1 h. Water (38 mL) was added over 10 min, and the resulting slurry was filtered, and was washed with a solution composed of IPA (0.45V) and water (1.5V). The solids were dried in vacuo at 55 °C to yield 2.62 g (38%) of the title compound.

Description 2e: methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate – flow chemistry procedure with MsOH/THF-PhMe

Solution A: 1.5M methanesulfonic acid in 1 : 1 (v/v) anhydrous THF – anhydrous PhMe Solution B: 0.25M l-(terf-butyl) (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate solution in anhydrous THF

Solution C: 4.6N NH4OH solution in water

Equipment: plug flow reactor with a Y-mixer; 10 ml_ PFA coil reactor

Reaction equivalents:

• solution A: 3.0 (1.667 mL / min)

· solution B: 1.0 (3.333 mL / min)

• solution C: 6.0 (1.087 mL / min)

Residence time: 2.0 min

Reaction temperature: 150 °C

After reaching steady state, the reaction stream was collected for 1 17 min in a 1 L flask immersed in an ice water bath. The base solution from pump C and the reaction stream were simultaneously collected with good stirring for the first 60 min; for the remainder of the collection time, only the reaction stream was collected. Following the run, the pH was adjusted to 7 with by charging additional 4.6N ammonium hydroxide solution. The phases were split, and the organic layer was concentrated to dryness by rotary evaporation in vacuo. The resulting residue was transferred to a 400 mL EZMax reactor using ACN (120 mL) and the temperature of the mixture was raised to 35 °C. To the mixture was added water – IPA solution (2/1 (v/v), 78 mL) over about 10 min. The resulting solution was cooled to 18 °C over about 30 min, seeded (208 mg), further cooled to about 0 °C over 2 h and aged overnight. Water (135 mL) was added to the slurry over about 1 h, and the mixture was aged for about 4 h. The temperature of the slurry was raised to 13 °C, re-cooled to about 0 °C over 3 h and aged overnight. The solids were collected by filtration and dried to constant weight in vacuo at 55 °C to give 8.18 g (27%, corrected for seed) of the title compound.

Description 2f: methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate – method A

A reactor was charged with methyl (S)-5-(4-(benzyloxy)phenyl)-2-((te/f-butoxycarbonyl)amino)-5-oxopentanoate (100.0 g) and ACN (400 ml_) and the reaction temperature was adjusted to about 25 °C. Concentrated sulfuric acid (45.3 g) was added over about 10 min while maintaining a reaction temperature of <50 °C. The contents of the reactor were stirred at 40 – 50 °C; the progress of the reaction was monitored for completion (HPLC). Upon completion, the reaction was cooled to about 25 °C. A solution of 4.6N NH4OH (215 ml_) was added with good stirring to a pH of about 7. The phases were separated, and the organic layer was split into two equal portions of about 256 ml_ for product isolation studies.

Portion A

To one portion was added a solution composed of 2-propanol (36.5 ml_) and water (120 ml_) with good stirring at about 22 °C. The resulting slurry was aged briefly at 22 °C, then cooled to 5 °C over about 1 h. Water (100 ml_) was added to the slurry while maintaining a reaction temperature of <10 °C. The solids were filtered, washed with a solution composed of 2-propanol (27.5 ml_) and water (75 ml_) and dried to constant weight in vacuo to give 30.87 g (85%) of the title compound.

Portion B

To one portion was added water (150 ml_) with good stirring at about 22 °C. The resulting slurry was aged briefly at 22 °C, then cooled to 5 °C over about 1 h. Water (100 ml_) was added to the slurry while maintaining a reaction temperature of <10 °C. The solids were filtered, washed with a solution composed of 2-propanol (27.5 ml_) and water (75 ml_) and dried to constant weight in vacuo to give 31.90 g (88%) of the title compound.

Description 2g: methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate – method B

A reactor was charged with methyl (S)-5-(4-(benzyloxy)phenyl)-2-((te/f-butoxycarbonyl)amino)-5-oxopentanoate (776.5 kg) and ACN (1743.5 kg) and the slurry temperature was adjusted to 15 – 25 °C. Methanesulfonic acid (482.1 kg) was added while maintaining a reaction temperature of <26 °C. The contents of the reactor were stirred at 20 – 25 °C for about 1 h. The progress of the reaction was monitored (HPLC); while awaiting results, the contents of the reactor were cooled to 0 – 10 °C. A solution of 4.6N NH4OH (590 kg) was added over about 25 min to a pH of 2 – 3 while maintaining a reaction temperature of <30 °C. Additional 4.6N NH4OH solution (519 kg) was added to a final pH of 7 – 8 while maintaining a reaction temperature of <25 °C. The phases were separated and the upper organic layer was heated to 25 – 30 °C. The organic layer was filtered and the filtrate was cooled to 20 – 25 °C. While maintaining this temperature range, a solution of 2-propanol (362.8 kg) and water (924.3 kg) were added to the reactor. The solution was cooled to 15 -20 °C and was seeded (3.7 kg, 0.5 wt%). The slurry was cooled to 0 – 5 °C over at least 2 h and aged for at least 30 min. Water (2403.1 kg) was added while maintain a reaction temperature of <20 °C. The slurry was cooled to 0 – 5 °C and aged for 30 – 40 min. The slurry was warmed to 15 – 20 °C, aged for 30 – 40 min, cooled to 0 – 5 °C over at least 1 h and aged for at least 2 h. The solids were isolated by filtration, washed with a solution composed of 2-propanol (283.2 kg) and water (1079.5 kg) and dried in vacuo at 50 – 55 °C to constant weight to afford 466.0 kg (87%) of the title compound.

Description 3a: l-(ferf-butyl) 2-methyl (2S, 5 ?)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate (D3)

A hydrogenation reactor was charged with methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (30 kg) and MeOH (120 kg), and the slurry was heated to solution at 30 – 40 °C. The solution was cooled to 15 – 25 °C followed by addition of d -tert-butyldicarbonate (21.8 kg, 1.03 eq) and water wet 20% Pd(OH)2/C (0.9 kg, 3 wt%). The

contents of the reactor were degassed under vacuum followed by pressurization with nitrogen. The contents of the reactor were degassed under vacuum followed by pressurization with hydrogen (3 – 4 bar). After 2 h at 22 – 27 °C, the reactor was vented and re-pressurized with hydrogen (3 – 4 bar). The progress of the reaction was monitored for completion (HPLC). After 4.5 h, the reactor was vented and MeOH (90 kg) was charged. The contents of the reactor were warmed to 32 – 42 °C and held for 20 – 30 min. The catalyst was removed by filtration through a bed of diatomite (13 kg) and the spent filter cake was washed with warm (40 – 45 °C) MeOH (25 kg). The combined filtrate and wash was concentrated in vacuo to 2 volumes at <40 °C and MeOH was charged (56 kg). The slurry was heated to 50 – 56 °C and the solution was aged for about 1.5 h. The solution was cooled to 20 – 30 °C, the slurry was aged for about 1 h, water (60 kg) was added and the slurry was aged for about 2 h. The slurry was cooled to about -5 °C and aged for about 8 h. The solids were isolated by centrifugation, washed with 1 :4 (v/v) MeOH – water (57.5 kg) and dried in vacuo at 50 – 60 °C to constant weight to afford 27.6 kg (88.5%) of the title compound.

Description 3b: 1 -(tert-butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate – method A

A hydrogenation reactor was charged with 20% Pd(OH)2/C (water wet; 5.7 kg), methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (186.4 kg), MeOH (8.85V), water (20 kg) and di-te/f-butyldicarbonate (132 kg). The reactor was pressurized with nitrogen followed by venting (three times). The reactor was pressurized with hydrogen followed by venting (three times). The reactor was pressurized with hydrogen (15 bar). After about 2 h at 25 °C, the reactor was vented and re-pressurized with hydrogen (15 bar). The progress of the reaction was monitored for completion (HPLC). After about 4.25 h, the reactor was vented and its contents were filtered, and the filtrate was concentrated in vacuo to about 4.4 volumes at about 35 °C and at about 240 mbar. The contents of the reactor were reheated to 55 – 60 °C, the solution was cooled to 20 – 30 °C over about 2 h and the slurry was aged for about 1 h. Water (285 kg) was added over about 1 h and the slurry was aged for about 1 h. The slurry was cooled to 3 – 7 °C over about 2 h and aged for about 3 h. The solids were isolated by filtration, washed with 1 :4 (v/v) MeOH – water (359 kg) and dried in vacuo at 50 – 55 °C to constant weight to afford 174.6 kg (90%) of the title compound.

Description 3c: l-(tert-butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate – method B

A hydrogenation reactor was charged with 20% Pd(OH)2/C (water wet; 3 wt%), methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (100 g), MeOH (4.5V), water (5 g) and 90 wt% di-te/f-butyldicarbonate in THF (1.00 eq). The reactor was pressurized with nitrogen followed by venting (three times). The reactor was pressurized with hydrogen followed by venting (three times). The reactor was pressurized with hydrogen (15 bar). After 1 h at 25 °C, the reactor was vented and re-pressurized with hydrogen (15 bar). The progress of the reaction was monitored for completion (HPLC). After 5 h, the reactor was vented and its contents were warmed to about 45 °C. The catalyst was removed by filtration through a warmed filter, and the filtrate was re-heated to 45 – 55 °C and held for about 30 minutes. The filtrate was concentrated in vacuo to about 4.4 volumes at 30 – 40 °C. The residue was cooled to 20 – 30 °C over at least 1 h, water (1.5V) was added over about 45 minutes and the slurry was aged for about 1 h. The slurry was cooled to 3 – 7 °C over about 2 h and aged for about 3 h. The solids were isolated by filtration, washed with 1 :4 (v/v) MeOH – water (2V) and dried in vacuo at 50 – 60 °C to constant weight to afford 88.9 g (86%) of the title compound.

Description 3d: 1 -(tert-butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate – flow chemistry procedure

reaction 2

The flow direction was from top to bottom (feed solution and hydrogen); and the hydrogen flow rate was 50 ml_ / min (while maintaining desired reaction pressure).

A 25 ml_ tube was packed with glass wool, sand, spherical catalyst beads (3% Pd/0-AI203 (1.0 – 1.2 mm spherical pellets)), sand and glass wool to give a 10 ml_ packed bed volume. 4 wt% methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate and di-ferf- butyldicarbonate (1.2 eq) in MeOH at -5 °C (feed solution 1) was then passed through the flow reactor at 0.08 – 0.10 ml_ / min, at a temperature of 53 – 61 °C and at a pressure of 10 – 15 bar. The collected solution contained a mixture of 1-(te/f-butyl) 2-methyl (2S,5f?)-5-(4- (benzyloxy)phenyl)pyrrolidine-1 ,2-dicarboxylate and 1-(te/f- butyl) 2-methyl (2S, 5f?)-5-(4- hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate in MeOH (feed solution 2) was passed through the flow reactor at 0.10 mL / min, at a temperature of 78 – 81 °C and at a pressure of 3 bar to produce about 600 g of a methanol solution primarily containing 1-(te/f-butyl) 2-methyl (2S, 5f?)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate. This solution was concentrated in vacuo at a temperature of about 40 °C to a net weight of about 3.6X the amount of the input methyl (S)-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. After stirring the mixture at ambient temperature for 15 – 20 min, water (2V) was added over about 30 min, the resulting mixture was aged for about 30 min, cooled to about 0 °C and aged for about 30 min. Solids were isolated by filtration, washed with ice cold 1 :4 (v/v) MeOH – water (2 X 1V) and dried to constant weight in vacuo at 55 °C to afford 23.51 g (88%) of the title compound.

Description 4a: iert-butyl (2S, 5/?)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (D4a) (K2CO3 / ACN procedure using 2-fluorobenzyl bromide)

A reactor was charged with 1-(te/f-butyl) 2-methyl (2S, 5f?)-5-(4-hydroxyphenyl)pyrrolidine- 1 ,2-dicarboxylate (1 10 kg), powdered K2CO3 (71.5 kg (1.5 equiv)) and ACN (429 kg). With good stirring, 2-fluorobenzyl bromide (68.2 kg (1.05 equiv)) and ACN (15 kg) were charged and the mixture was heated to 86 – 94 °C; the progress of the reaction was monitored (HPLC). Upon completion, the slurry was cooled to 40 – 50 °C, filtered and the spent filter cake was washed with fresh ACN (175 kg).

To the ACN filtrate was charged powdered K2CO3 (94.6 kg (2.0 equiv)) and formamide (308 kg (20 equiv)) and the mixture was heated to 86 – 94 °C; the progress of the reaction was monitored (HPLC). Upon completion, the slurry was cooled to 70 – 75 °C and water (1 150 kg) was added while maintaining a reaction temperature of >70 °C. Following the addition the solution was aged for about 30 min, cooled to 65 – 70 °C, seeded (0.55 kg) and aged for 3 – 4 h. The slurry was cooled to 50 – 60 °C, aged 3 – 4 h, cooled to 20 – 30 °C and aged for 3 – 4 h. The solids were isolated by centrifugation, washed twice with water (220 kg) and dried in vacuo at 30 – 40 °C for 4 – 8 h and at 50 – 60 °C for 4 – 8 h to yield 128.75 kg (87.5%) of the title compound.

Description 4b: iert-butyl (2S, 5 ?)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (D4b) (NaOMe – MeOH procedure using 2-fluorobenzyl bromide in DMF)

A reactor was charged with 1-(te/f-butyl) 2-methyl (2S, 5f?)-5-(4-hydroxyphenyl)pyrrolidine- 1 ,2-dicarboxylate (1.0 kg), anhydrous DMF (2.9 L), 2-fluorobenzyl bromide (430 mL (1.12 equiv)) and anhydrous DMF (0.1 L). The solution was cooled to about 15 °C. With good stirring, 741 mL (1.05 equiv) 4.4M NaOMe-MeOH solution was added while maintaining a temperature of <20 °C. Following the charge, the contents of the reactor were warmed to about 25 °C, aged for about 1 h and 44 mL (0.06 equiv) 4.4M NaOMe-MeOH solution was added over about 5 min. The progress of the reaction was monitored (HPLC).

Upon completion, formamide (2.5 L) was charged followed by addition of 81 1 mL (1.15 equiv) 4.4M NaOMe-MeOH solution while maintaining a temperature of <25 °C. The contents of the reactor were aged for about 1 h and 516 mL (0.73 equiv) 4.4M NaOMe-MeOH solution was added while maintaining a temperature of <25 °C. The progress of the reaction was monitored (HPLC). Upon completion, a solution of glacial acetic acid (350 mL (2.0 equiv) in water (2.2 L)) was added over about 10 min. The slurry was heated to about 70 °C and aged for about 1 h. Water (1.8 L) was added over about 1 h and the slurry was cooled to about 3 °C over 3 h and aged for about 10 h. The solids were isolated by filtration, washed twice with water (2 L) and dried to constant weight in vacuo at 80 °C to afford 1.21 kg (94%) of the title compound.

Description 4c: iert-butyl (2S, 5 ?)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (D4c) (NaOMe – MeOH procedure using 2-fluorobenzyl bromide in DMF) (Alternative Procedure)

A reactor was charged with 1-(te/f-butyl) 2-methyl (2S, 5f?)-5-(4-hydroxyphenyl)pyrrolidine- 1 ,2-dicarboxylate (100 g), anhydrous DMF (290 mL), 2-fluorobenzyl bromide (42.2 mL (1.10 equiv)) and anhydrous DMF (10 mL). The solution was cooled to about 15 °C. With good stirring, 75 mL (1.06 equiv) 4.4M NaOMe-MeOH solution was added over a period of approximately 30 min while maintaining a temperature of <20 °C. Following the charge, the contents of the reactor were warmed to about 25 °C and aged for about 2 h. The progress of the reaction was monitored (HPLC).

Upon completion, formamide (250 mL) was charged followed by addition of 133 mL (1.88 equiv) 4.4M NaOMe-MeOH solution over approximately 45 min while maintaining a temperature of <25 °C. The contents of the reactor were aged for about 4 h. The progress of the reaction was monitored (HPLC). Upon completion, a solution of glacial acetic acid (35 mL (2.0 equiv) in water (100 mL) was added over about 30 min. The slurry was heated to about 60 °C. Water (300 mL) was then charged to the reactor over about 1 h, and the slurry was aged for about 1 h. The slurry was cooled to about 3 °C over 3 h and aged for about 1 h. The solids were isolated by filtration, washed twice with water (200 mL) and dried to constant weight in vacuo at 80 °C to afford 120.0 g (93%) of the title compound.

Description 4d: iert-butyl (2S, 5/?)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (D4d) (NaOMe – MeOH procedure using 2-fluorobenzyl chloride in DMF)

A reactor was charged with 1-(te/f- butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine- 1 ,2-dicarboxylate (7.50 g), anhydrous DMF (22.5 mL) and 2-fluorobenzyl chloride (3.20 mL (1.15 equiv)). The solution was cooled to about 15 °C. With good stirring, 5.6 mL (1.06 equiv) 4.4M NaOMe-MeOH solution was added while maintaining a temperature of <25 °C. Following the charge, the contents of the reactor were warmed to about 45 °C over 20 min. The progress of the reaction was monitored (HPLC).

Upon completion, the contents of the reactor were cooled to about 25 °C over about 10 min. Formamide (19 mL) was charged followed by addition of 5.8 mL (1.1 equiv) 4.4M NaOMe- MeOH solution while maintaining a temperature of <25 °C. The contents of the reactor were aged for about 1 h and 3.7 mL (0.7 equiv) 4.4M NaOMe-MeOH solution was added while maintaining a temperature of <25 °C. The progress of the reaction was monitored (HPLC). Upon completion, a solution of glacial acetic acid (2.6 mL (2.0 equiv)) in water (7.5 mL) was added over about 25 min. The slurry was heated to about 65 °C and water (22.5 mL) was added to the solution over about 1 h. The slurry was aged for about 30 min, was cooled to 0 – 5 °C over about 3 h and aged for about 30 min. The solids were isolated by filtration, washed twice with water (7.5 mL) and dried to constant weight in vacuo at 80 °C to afford 8.39 g (90%) of the title compound.

Description 4e: iert-butyl (2S, 5/?)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (D4e) (NaOMe – MeOH procedure using 2-fluorobenzyl chloride in DMSO)

A reactor was charged with 1-(te/f- butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate (7.50 g), anhydrous DMSO (22.5 mL) and 2-fluorobenzyl chloride (3.20 mL (1.15 equiv)). The solution was cooled to about 15 °C. With good stirring, 5.5 mL (1.06 equiv) 4.5M NaOMe-MeOH solution was added while maintaining a temperature of <25 °C. Following the charge, the contents of the reactor were warmed to about 25 °C over 5 min. The progress of the reaction was monitored (HPLC).

Upon completion, formamide (19 mL) was charged followed by addition of 9.73 mL (1.88 equiv) 4.5M NaOMe-MeOH solution over about 45 min. The progress of the reaction was monitored (HPLC). Upon completion, a solution of glacial acetic acid (2.6 mL (2.0 equiv)) in water (7.5 mL) was added over about 25 min. The slurry was heated to about 65 °C and water (22.5 mL) was added to the solution over about 1 h. The slurry was aged for about 30 min, was cooled to 0 – 5 °C over about 3 h and aged for about 30 min. The solids were isolated by filtration, washed twice with water (7.5 mL) and dried to constant weight in vacuo at 80 °C to afford 8.72 g (90%) of the title compound.

Description 4f: iert-butyl (2S, 5/?)-2-carbamoyl-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (D4f) (f-BuOK procedure using 2-fluorobenzyl bromide in ACN – formamide)

f-BuOK 

A reactor was charged with 1-(te/f- butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate (10.0 g), anhydrous ACN (30 mL), 2-fluorobenzyl bromide (4.18 mL (1.05 equiv)) and formamide (10 mL). The solution was cooled to 0 – 5 °C. With good stirring, 3.67 g (1.05 equiv) f-BuOK was added followed by warming the contents of the reactor to about 15 °C. The progress of the reaction was monitored (HPLC).

Upon completion, the contents of the reactor were cooled to 0 – 5 °C and 4.71 g (1.35 equiv) f-BuOK was added followed by warming the contents of the reactor to about 15 °C. The progress of the reaction was monitored (HPLC). Upon completion, the contents of the reactor were warmed to about 65 °C and a solution of glacial acetic acid (4.14 mL (2.3 equiv)) in water (10 mL) was added. Additional water (40 mL) was added over about 30 min. The contents of the reactor were cooled to 0 – 5 °C and filtered. The filter cake was washed twice with water (10 mL) and dried to constant weight in vacuo at 80 °C to afford 10.93 g (85%) of the title compound.

Description 4g: iert-butyl (2S, 5 ?)-2-carbamoyl-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (D4g) (f-BuONa procedure using 2-fluorobenzyl bromide in ACN – formamide)

f-BuONa-THF

A reactor was charged with 1-(te/f- butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate (10.0 g), anhydrous ACN (30 mL), 2-fluorobenzyl bromide (4.18 mL (1.05 equiv)) and formamide (1.5 mL). The solution was cooled to 0 – 5 °C. With good stirring, 16.4 mL (1.05 equiv) 2M f-BuONa – THF solution was added followed by warming the contents of the reactor to about 15 °C. The progress of the reaction was monitored (HPLC).

Upon completion, the contents of the reactor were cooled to 0 – 5 °C and formamide (8.5 mL) was added, followed by 21 mL (1.35 equiv) 2M f-BuONa – THF solution, and the contents of the reactor were warmed to about 15 °C. The progress of the reaction was monitored (HPLC). Upon completion, the contents of the reactor were warmed to about 65 °C and a solution of glacial acetic acid (4.14 mL (2.3 equiv)) in water (10 mL) was added. Additional water (40 mL) was added over about 30 min. The contents of the reactor were cooled to 0 – 5 °C and filtered. The filter cake was washed twice with water (10 mL) and dried to constant weight in vacuo at 80 °C to afford 11.06 g (86%) of the title compound.

Description 4h: tert-butyl (2S, 5S)-2-carbamoyl-5-(4-((2-

A reactor was charged with 1-(te/f-butyl) 2-methyl (2S, 5f?)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate (264 Kg), anhydrous DMF (748 kg) and 2-fluorobenzyl bromide (171 Kg (1.10 eq)). The solution was cooled to about 15 °C. With good stirring, 157 Kg (1.06 eq) 30% NaOMe-MeOH solution was added over at least 30 min while maintaining a temperature between 20 – 30 °C. Following the charge, the line was rinsed forward with MeOH (18 kg), and the batch was maintained at about 25 °C for at least 1 h. The progress of the reaction was monitored for completion (HPLC).

Upon completion, formamide (749 Kg) was charged followed by a line rinse with MeOH (18 kg). 279 Kg (1.88 eq) 30% NaOMe-MeOH solution was added over at least 45 min while maintaining a temperature of about 25 °C followed by a line rinse with MeOH (18 kg). The contents of the reactor were maintained at about 25 °C with agitation for about 4 h. The progress of the reaction was monitored for completion (HPLC). Upon completion, the batch was transferred to a second reactor and the equipment was rinsed forward with MeOH (155 Kg). Glacial acetic acid (97 Kg) was added to the batch over at least 15 min while maintaining a temperature of 20 – 30 °C followed by the addition of water (264 Kg). The batch was heated to 60 °C and water (792 Kg) was added over at least 2 h with good agitation. The batch was maintained at 60 °C with agitation for at least 1 h. The batch was cooled to about 2 °C over at least 3 h and aged for at least 1 h. The solids were isolated by filtration and washed twice with water (528 Kg per wash). The wet cake was dried to constant weight in vacuo at 67 °C to afford 315.4 kg (93%) of the title compound.

Description 4i: tert-butyl (2S, 5S)-2-carbamoyl-5-(4-((2-

A reactor was charged with 1-(te/f-butyl) 2-methyl (2S, 5f?)-5-(4-hydroxyphenyl)pyrrolidine-1 ,2-dicarboxylate (70 g), anhydrous DMF (198.2 g) and 2-fluorobenzyl bromide (45.3 g (1.10 equiv)). With good agitation, 41.4 g (1.06 equiv) 30% NaOMe-MeOH solution was added over about 60 min while maintaining a temperature of 20 – 30 °C. The addition funnel was rinsed forward into the reactor with MeOH (2.4 g). The batch was maintained at about 25 °C for at least 1 h; the progress of the reaction was monitored for completion (HPLC).

Upon completion, formamide (238.1 g) was charged followed by rinsing forward the charging equipment with MeOH (2.4 g). 30% NaOMe-MeOH solution (66.5 g (1.70 equiv)) was added over 45 min while maintaining temperature at about 25 °C. The addition funnel was rinsed forward into the reactor with MeOH (2.4 g). The batch was stirred for about 4 h at 25 °C; the progress of the reaction was monitored for completion (HPLC). Upon completion, the batch was transferred to a second reactor and the equipment was rinsed forward with MeOH (20.6 g). Glacial acetic acid (25.7 g) was added while maintaining a temperature of 20 – 30 °C. Water (70 g) was added over about 20 min and the batch was heated to 60 °C. Water (280 g) was added over at least 2 h with good agitation. The batch was maintained at 60 °C with agitation for at least 1 h, cooled to 0-3 °C over at least 3 h and aged for at least 1 h. The solids were isolated by filtration, washed with water/MeOH 70:30 v/v (140 ml_) and water (140 g). The wet cake was dried to constant weight in vacuo at 80 °C to afford 83.7 g (93%) of the title compound.

Description 5a: (2S,5 ?)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide (E1)

A reactor was charged with te/f-butyl (2S, 5f?)-2-carbamoyl-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (which may be prepared as described in Description 4) (375.1 kg) and ACN (825.6 kg). With good agitation, methanesulfonic acid (1 14.8 kg (1.3 equiv) was added while maintaining a reaction temperature of 20 – 25 °C followed by ACN (50 kg). The contents of the reactor were warmed to 40 – 50 °C and aged for 2 – 3 h. The progress of the reaction was monitored (HPLC). Upon completion, a solution of 1.0N NH4OH (377 kg) was added while maintaining a reaction temperature of 40 – 50 °C. The reaction temperature was raised to 48 – 52 °C and 1.0N NH4OH (1495 kg) was added slowly with good stirring while maintaining the reaction temperature within this range. The slurry was cooled to -3 to 3 °C over 3 – 4 h and was aged for 1 – 2 h. The solids were isolated by centrifugation (3 drops) and each portion was washed twice with water (182 – 189 kg). The solids were dried in vacuo at 30 °C for 4 h, at 50 °C for 4 h and to constant weight at 80 °C (10 h) to afford 256.4 kg (90.5%) of the title compound.

Description 5b: (2S,5 ?)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide hydrochloride (1 :1 ) (E2)

A reactor was charged with 2-propanol (672 kg) and the solvent was cooled to -10 to 0 °C. With good agitation, HCI (90 kg) was introduced while maintaining a reaction temperature of -10 – 0 °C. A sample of the solution was removed for concentration determination.

A reactor was charged with te/f-butyl (2S, 5f?)-2-carbamoyl-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (which may be prepared as described in Description 4) (160 kg) and 2-propanol (1280 kg). Wth good agitation, the prepared HCI – 2- propanol solution (5.3 eq) was added while maintaining a reaction temperature of 20 – 30 °C. The contents of the reactor were warmed to 30 – 35 °C and aged for 12 – 16 h. The progress of the reaction was monitored (HPLC). Upon completion, the contents of the reactor were cooled to 0 – 10 °C, concentrated and aged for 2 – 3 h at 0 – 10 °C. The solids were filtered, washed with 2-propanol (105 kg) and dried in vacuo at 60 – 70 °C for 15 – 20 h to afford 132 kg (96%) of the title compound.

Description 5c: (2S,5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide – method A

A reactor was charged with terf-butyl (2S, 5S)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (307 Kg) and acetonitrile (612 Kg). With good agitation, methanesulfonic acid (30 Kg (1.28 equiv)) was added over at least 30 min while maintaining a reaction temperature of 20 – 30 °C. The batch was warmed to 30 °C, aged for about 30 min and heated to 45 °C over about 30 min. The batch was maintained at 45°C for 2 h; the progress of the reaction was monitored for completion (HPLC). Upon completion, the batch was transferred to a second reactor, rinsed forward with acetonitrile (108 Kg) and 1.7% aqueous NH4OH solution (304 Kg) was added while maintaining a temperature of about 40 – 50 °C. The reaction temperature was raised to about 46 – 52 °C and 1.7% NH4OH solution (1216 Kg) was added slowly over 2 h with good stirring while maintaining the reaction temperature within this range. The batch was aged at 50 °C for about 1 h, cooled to 0 °C over at least 3 h and aged for about 1 h. The solids were isolated by filtration and washed twice with water (614 Kg per wash). The solids were dried in vacuo at 70 °C to constant weight to afford 218 Kg (94%) of the title compound.

Description 5d: (2S,5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide – meth

A reactor was charged with terf-butyl (2S, 5S)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (100 g) and ACN (199.5 g). With good agitation, methanesulfonic acid (29.7 g (1.28 equiv)) was added while maintaining a reaction temperature of 20 – 30 °C. The batch was warmed to 30 °C, aged for at least 30 min and heated to 45 °C over at least 30 min. The batch was maintained at 45 °C for 2 h; the progress of the reaction was monitored for completion (HPLC). Upon completion, the batch was transferred to a second reactor; the first reactor was rinsed forward with ACN (35.4 g). A solution of 1.7% aqueous NH4OH (99.0 g) was added at 40 – 50 °C over at least 15 min. The reaction temperature was raised to 49 °C and 1.7% NH4OH solution (396.0 g) was added slowly over at least 2 h with good stirring while maintaining the reaction temperature at about 49 °C. The slurry was aged for 30 – 90 min, cooled to 0°C over 3 h and aged for at least 1 h. The solids were isolated by filtration and washed with water/acetonitrile 90: 10 v/v (200 mL) and water (200 g). The solids were dried in vacuo at 70 °C to constant weight to afford 71.6 g (94%) of the title compound.

Description 5e: (2S,5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide hydrochloride

A reactor was charged with terf-butyl (2S, 5S)-2-carbamoyl-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (160 kg) and isopropanol (1280 kg) at 20 -30 °C. A solution of 2.6M HCI in isopropanol (5.3 eq) was added over about 2 h at 20 – 35 °C. The contents of the reactor were warmed to 30 – 35 °C, and the progress of the reaction was monitored for completion (HPLC). The contents of the reactor were cooled to about 10 °C over about 3 h, concentrated in vacuo for about 1 h and aged at 5 – 10 °C for about 2 h under an inert atmosphere of nitrogen. Solids were filtered, washed with isopropanol (125 kg) and dried to constant weight in vacuo at 60 – 70 °C to give 132.05 kg (96%) of the title compound.

Description 6a: l-(tert-butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrol

dicarbo

A hydrogenation reactor was charged with 10% Pd(OH)2/C (water wet; 1.06 g), benzyl (S)-5-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (23 g), MeOH (140

ml_) and di-te/f-butyldicarbonate (1 1.3 g, 1.02 eq). The reactor was pressurized with hydrogen (8 bar) and stirred (300 rpm) for 3 h at ambient temperature followed by stirring at 50 °C for an additional 5 h. The contents of the reactor were cooled to ambient temperature and filtered. The filtrate was concentrated to dryness and the residue was reconstituted in warm MeOH (30 ml_). The contents of the flask were cooled to ambient temperature. The solids were isolated by filtration and dried in vacuo at 60 °C to constant weight to afford 9.6 g (60%) of the title compound.

Description 6b: 1 -(tert-butyl) 2-methyl (2S, 5R)-5-(4-hydroxyphenyl)pyrrolidine-1,2-dicarbo

A hydrogenation reactor was charged with 20% Pd(OH)2/C (water wet; 2.25 g), benzyl (S)-5-(4-(benzyloxy)phenyl)-2-((terf-butoxycarbonyl)amino)-5-oxopentanoate (74.59 g (71.00 g activity)), di-terf-butyldicarbonate (35.27 g, 1.01 eq) and MeOH (415 g). Following three vacuum / nitrogen break cycles, the reactor was pressurized with hydrogen (4 bar) and stirred (-2200 rpm) for about 105 min at 25 °C, then heated to 35 °C and held for an additional 1 h. The reactor was vented, additional MeOH (59 g) was charged, and the reduction was continued at 35 °C, 4 bar and -2200 rpm. The progress of the reaction was monitored for completion (HPLC). Celite® (2.5 g) was added, and the mixture was filtered through a pad of Celite® (2.5 g) and the spent pad was washed with warm MeOH (59 g). The filtrate was concentrated at 40 °C and 200 mbar to a net weight of about 179 g. The contents of the flask were warmed to solution at about 55 °C, slowly cooled to ambient temperature and aged for about 30 min. Water (100 g) was added over about 1 h, and the mixture was aged overnight at ambient temperature. The mixture was cooled to 0-5 °C, aged for about 3 h and filtered. The solids were washed with cold 1 :4 (v/v) MeOH – water (2 X 48 g) and dried in vacuo at 55 °C to constant weight to afford 43.98 g (89%) of the title compound.

///////////VIXOTRIGINE, NEW PATENT, WO-2019071162, BIOGEN INC

WO 2018066004, NEW PATENT, INDOCO REMEDIES LIMITED, DORZOLAMIDE


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 (WO2018066004) PROCESS FOR THE PREPARATION OF DORAOLZMIDE HYDROCHLORIDE

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018066004&redirectedID=true

Applicants: INDOCO REMEDIES LIMITED [IN/IN]; Indoco House, 166 C.S.T. Road, Santacruz (East) Mumbai, Maharashtra 400098 (IN)
Inventors: SHETH, Nilima; (IN).
KUDUVA, Srinivasan Subramanian; (IN).
RAMESAN, Palangat Vayalileveetil; (IN).
PANANDIKAR, Aditi Milind; (IN)

nilima sheth

SHETH, Nilima

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Aditi Kare Panandikar, Managing Director, Indoco Remedies

Process for preparing dorzolamide hydrochloride is claimed. It is disclosed that dorzolamide hydrochloride is a carbonic anhydrase inhibitor. 

Trusopt is an ophthalmic solution containing the carbonic anhydrase inhibitor dorzolamide hydrochloride for treating intraocular pressure in patients with ocular hypertension or open-angle glaucoma, which was developed and launched by Merck & Co , and is also now marketed by Santen Pharmaceuticals and Mundipharma International . 

In April 2018, Newport Premium™ reported that Indoco Remedies was capable of producing commercial quantities of dorzolamide hydrochloride and holds an active US DMF since 2010

Dorzolamide hydrochloride is a carbonic anhydrase (CA) inhibitor. It is chemically represented by (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride; and is structurally represented

Formula I

It acts as an anti -glaucoma agent, in open-angle glaucoma and ocular hypertension. It is used in ophthalmic solutions to lower intraocular pressure (IOP).

The compound dorzolamide hydrochloride has been in the market for very long time. It is administered as a topical ophthalmic in the form of a solution and marketed under the brand name T rusopt.

Dorzolamide hydrochloride and process for its preparation are first described in the patent, US 4,797,413 (US 413 Patent) and its corresponding European patent, E P 0296879. The process described in US 413 patent involves reacting thiophene-2-thiol with but-2-enoic acid and further proceeds with formation of racemic 4- ( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide (dorzolamide base).

A number of further processes for the preparation of dorzolamide hydrochloride have been devised and in many of these, as well as in the above US 413 Patent, the last step of the process involves the removal of diastereomeric impurity from the racemic mixture of dorzolamide base. To obtain pure dorzolamide hydrochloride devoid of the diastereomeric impurity of cis-isomer from the racemic compound, as per the patent US ~413, racemic mixture of dorzolamide base is subjected to column chromatography and then resolution is carried out using resolving agent di-p-tol uoyl-L -tartaric acid monohydrate in n-propanol. The salt formed is treated with base to get dorzolamide free base, which is reacted with ethanolic hydrochloric acid to get dorzolamide hydrochloride. The compound is further recrystallised from mixture of solvents viz., methanol and isopropanol to get pure dorzolamide hydrochloride.

US 5,688,968 describes a process for preparation of dorzolamide hydrochloride, wherein chiral hydroxyl sulfone compound having fixed chirality, proceeds via Ritter reaction to obtain dorzolamide base having mixture of cis- and trans-isomer. The compound dorzolamide base is reacted with maleic acid to isolate maleate salt of dorzolamide. The salt is again converted to free base and then reacted with hydrochloric acid in ethyl acetate to get required pure trans-isomer of dorzolamide hydrochloride.

The PCT patent publication W 02006038222 discloses the preparation of dorzolamide hydrochloride, wherein the cis- and trans-isomer of racemic dorzolamide base is separated using resolution via chiral salt formation with di benzoyl -L -tartaric acid monohydrate or di-p-tol uoyl-L -tartaric acid monohydrate in methanol which on neutralization results in dorzolamide base. The base is then reacted with hydrochloric acid in isopropanol to give

dorzol amide hydrochloride which is recrystalised in isopropanol to obtain pure dorzol amide hydrochloride.

Another US patent US 7,109,353 discloses the process for preparation of dorzolamide hydrochloride, wherein racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with mineral acid to form the corresponding salt, which is then converted to racemic trans-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide and resolved with di-p-toluoyl-D -tartaric acid followed by neutralization of the chiral salt to isolate trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in ethanol results in required trans-dorzolamide hydrochloride.

PCT patent publication WO2007122130 discloses the process for preparation of (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, wherein racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide having trans:cis diastereomeric mixture of 80:20 is treated with maleic acid in acetone to isolate racemic trans-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide maleate salt having trans:cis diastereomeric mixture of 95:5. The isolated maleate salt is then treated with base and reacted with (1 S)-(+)-10-camphorsulfonic acid to get corresponding (4S,6S)-4-(ethylamino)-6-methyl-5, 6-di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di ox i de ( 1 S ) -( + )- 10-camphorsulfonate salt, which is neutralized to give pure (4S,6S)-4-(ethylamino)-6- methyl -5, 6-di hydro-4H -thi eno[2,3- b] thi opyran-2-sulf onami de 7, 7-di oxi de.

PCT patent publication W 02008135770 discloses the process for the preparation of dorzolamide hydrochloride, wherein the racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with

carboxylic acid selected from the group consisting of fumaric acid, benzoic acid, acetic acid, salicylic acid and p-hydroxybenzoic acid, which selectively forms an acid addition salt with the trans- isomer and removes the undesirable c is- isomer from the mixture of cis and trans- isomers. The trans-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide acid addition salt is converted to trans-(e)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide by conventional methods. The compound trans-(e)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is resolved with di-p-toluoyl-L -tartaric acid followed by neutralization of the chiral salt yields the compound (4S,6S)4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, which on reaction with hydrochloric acid in isopropanol results in the required (4S,6S)4-( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide hydrochloride.

PCT patent publication WO2010061398 discloses the process for the preparation of dorzolamide hydrochloride, wherein the racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with maleic acid in water to get trans-dorzolamide maleate salt. The maleate salt is further neutralized and then resolution with di-p-toluoyl-L -tartaric acid followed by neutralization of the chiral salt yields (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in isopropanol results in the required pure trans-dorzolamide hydrochloride.

PCT patent publication WO2011101704 and corresponding Indian Patent application 426/C H E/2010 describes the process for the preparation of trans-dorzolamide hydrochloride by forming the maleate salt of racemic 4-( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide. The maleate salt is further neutralized and then resolution with di-p-

toluoyl-L -tartaric acid followed by neutralization of the chiral salt yields trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound trans-(4S,6S)-4-(ethylamino)-6-methyl- 5.6- dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in isopropanol results in the required trans-(S,S)-dorzol amide hydrochloride.

Indian Patent application 3431 /M U M/2012 discloses the process wherein racemic 4-( ethyl ami no) -6- methyl – 5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de

7.7- dioxide is resolved using di benzoyl- L -tartaric acid monohydrate or di-p-toluoyl-L -tartaric acid monohydrate in methanol followed by neutralization of the chiral salt and then the (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide thus obtained is treated with hydrochloric acid in isopropanol to result in the required trans-(S,S)-dorzolamide hydrochloride. The compound is further recrystallised in isopropanol to isolate pure dorzol amide hydrochloride.

The prior art processes disclosed as above have several drawbacks in the preparation of pure trans-dorzolamide hydrochloride viz.,

1. involves column chromatography for separation of the desired diastereomer;

2. involves preparation of corresponding diastereomeric salts and converting again to base before preparation and isolation of pure trans-dorzolamide hydrochloride;

3. involves additional step of reacting the racemic dorzolamide base with mineral acid to isolate corresponding dorzolamide salt which is again converted to dorzolamide base and further resolved using resolving agent to form the corresponding salt, neutralization and isolation of the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride; and

4. involves an additional step of reacting the racemic dorzolamide base with carboxylic acid to isolate corresponding dorzolamide salt which is again converted to dorzolamide base and resolved using resolving agent to form the corresponding salt, neutralization and isolation of the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride.

As is evident from the cursory review of the prior arts that the preparation of pure dorzolamide hydrochloride involves either column chromatography for isolation of trans- isomer followed by use of resolving agent or involves repeated preparations of chiral or diastereomeric salts, use of resolving agent followed by converting into dorzolamide base and then isolating pure dorzolamide hydrochloride devoid of the diastereomeric impurity of cis-isomer.

Therefore, there remains a need in the art to develop a simple and cost effective process for the preparation of dorzolamide hydrochloride which ameliorates the above drawbacks of the prior arts and makes the process industrially viable and economically advantageous. The present invention therefore seeks to address these issues by providing an improved and cost-effective process that can easily be scaled for industrial production of dorzolamide hydrochloride.

The present inventors have developed an alternative process for isolating pure dorzolamide hydrochloride substantially free from the cis-isomer without using the time consuming column chromatography technique, repeated preparation of chiral salts, diastereomeric salts and converting into base before hydrochloride salt formation to isolate pure trans-(S,S)-dorzolamide hydrochloride.

E xamples:

E xample 1 : Preparation of (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride:

In a dry flask charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (50.0 gm) in acetone (700 ml) under stirring and cooled to OeC. Maintaining the temperature at OeC to 5eC purged hydrochloric acid gas to adjust the pH to acidic between the range of 1-2. After attaining desired pH, maintained the reaction mass for two hours at OeC to 5eC under stirring. Filtered the precipitated compound (6S)-4-(ethylamino)-6-methyl-5, 6-di hydro-4H -thi eno[2,3- b] thi opyran-2-sulf onami de 7,7-di oxi de hydrochl ori de and washed the solid mass with chilled acetone (50 ml). Dried the compound at 60-65eC till constant weight.

Dry weight: 50 g

H PL C purity: 77.62% [cis-isomer: 22.11 % ]

E xample 2: Preparation of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride [C rude dorzolamide hydrochloride]:

In a dry flask charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (19.0 g) and methanol (190 ml) at temperature of 25eC to 30eC. Under stirring raised the temperature of the reaction mass to reflux and maintained at reflux temperature for a period of two hours. After maintaining cooled the reaction mass gradually to 10eC to 15eC. Filtered the compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride and washed the solid mass with chilled methanol. Dried the compound at 60-65eC till constant weight.

Dry weight: 12.8 g

H PL C purity: 99.33% [cis-isomer: 0.5% ]

E xample 3: Purification of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride: In a dry flask charged trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (11.0 g), acetone (11 ml) and purified water (5.5 ml) at the temperature of 25eC to 30eC. Raised the temperature of the reaction slurry to reflux and maintained at reflux for one hour. Diluted the reaction mass with fresh acetone (44 ml) maintaining the temperature at reflux and continued maintaining at reflux temperature further for one hour. Cooled the reaction mass gradually to 10eC to 15eC and maintained. Filtered the compound pure (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride solid mass and washed the pure compound with chilled acetone (11 ml). Dried at 55eC to 60eC till constant weight.

Dry weight: 8.8 g

H PL C purity: 99.89% [cis-isomer: not detected]

[T otal impurities: 0.11 % ]

E xample 4: Preparation of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride [C rude dorzolamide hydrochloride]:

Charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (5.0 g), methanol (22.5 ml) and 2.5 ml purified water at temperature of 25eC to 30eC. Under stirring raised the temperature of the reaction mass to reflux and maintained at reflux temperature for a period of two hours. After maintaining cooled the reaction mass gradually to 30eC to 35eC. Filtered the solid compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride and washed with methanol (10 ml). Dried the compound at 60eC to 65eC till constant weight.

Dry weight: 3.2 g

H PL C purity: 99.47% [cis-isomer: 0.43% ]

////////WO 2018066004, NEW PATENT, INDOCO REMEDIES LIMITED, DORZOLAMIDE

WO 2018067805, NEW PATENT, SOTAGLIFLOZIN, TEVA


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WO-2018067805

(WO2018067805) SOLID STATE FORMS OF SOTAGLIFLOZIN

TEVA PHARMACEUTICAL INDUSTRIES LTD.

GIAFFREDA, Stefano Luca; (IT).
MODENA, Enrico; (IT).
IANNI, Cristina; (IT).
MUTHUSAMY, Anantha Rajmohan; (IN).
KANNIAH, Sundara Lakshmi; (IN)

Stefano Luca Giaffreda at PolyCrystallineStefano Luca Giaffreda

Enrico Modena at PolyCrystallineEnrico Modena

Sundara Lakshmi KanniahSundara Lakshmi Kanniah
Novel crystalline forms of sotagliflozin (designated as Forms A and E) and their hydrate and monohydrate, processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating diabetes. Sotagliflozin is known to be an inhibitor of sodium glucose transporter-1 and -2, useful for treating insulin dependent diabetes and non-insulin dependent diabetes

Sotagliflozin has the chemical name (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H- pyran-3,4,5-triol. Sotagliflozin has the following chemical structure:

[0003] Sotagliflozin is an orally available L-xyloside based molecule that apparently inhibits both sodium-glucose transporter type 1 (SGLT1) and type 2 (SGLT2). SGLT1 is primarily responsible for glucose and galactose absorption in the gastrointestinal tract, and SGLT2 is responsible for most of the glucose reabsorption performed by the kidney.

[0004] Sotagliflozin is known from WO 2008/109591. Amorphous forms and crystalline forms (i.e. Form 1 and Form 2) of Sotagliflozin are disclosed in WO2010/009197.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Sotagliflozin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving

formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Sotagliflozin.

EXAMPLES

Sotagliflozin Form-2 may be prepared according to WO2010/009197. Sotaglifiozin Form-2 may also be prepared according to Example 16 below.

Working examples:

Example- 1 : Preparation of Sotagliflozin (Amorphous Form)

[0080] 2 g of Sotagliflozin (Form-2) was taken in 250ml round bottom flask and applied vacuum (approx. 50 mbar) with continuous rotation of the flask. The flask was externally heated by hot air flow maintained at few centimetres from the rotating flask wall for few minutes until the compound melts at around 130°C and the melt was quenched to room temperature (25°C) with water bath. The amorphous solid (1.8 g) was scratched from the walls of the flask.

Example-2: Preparation of Sotagliflozin Form A

[0081] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of water, was left at variable temperature as follows: heating from 10°C to 50°C at the rate of 20°C/hr, held at 50°C for 3 hrs; cooling from 50°C to 10°C at the rate of 20°C/hr, held at 10°C for 3hrs; again heating from 10°C to 50°C at the rate of 10°C/hr, held at 50°C for 3hrs; again cooling from 50°C to 10°C at the rate of 10°C/hr, held at 10°Cfor 3hrs; further heating from 10°C to 50°C at the rate of 5°C/hr, held at 50°C for 3hrs; further cooling from 50°C to 10°C at the rate of 5°C/hr, held at 10°C for 3hrs; followed by raising the temperature from 10°C to 25°C at the rate of 10°C/hr, held at 25°C for 24hrs. The suspension was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form A has been confirmed by PXRD as presented in figure 1.

Example-3 : Preparation of Sotagliflozin Form B

[0082] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Toluene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD as presented in figure 2.

Example-4: Preparation of Sotagliflozin Form B

[0083] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Heptane at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-5 : Preparation of Sotagliflozin Form B

[0084] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Mesitylene at room temperature (20-25°C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-6: Preparation of Sotagliflozin Form B

[0085] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of p-Xylene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-7: Preparation of Sotagliflozin Form C

[0086] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Water at 50°C. The suspension was stirred for 72hrs which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form C has been confirmed by PXRD as presented in figure 3.

Example-8: Preparation of Sotagliflozin Form D

[0087] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of ethanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20 ml vial and left open to allow evaporation of the solvent (25°C/1 atm). Solid was observed after 3 days; it was collected and analyzed by PXRD. Sotagliflozin Form D has been confirmed by PXRD as presented in figure 4.

Example-9: Preparation of Sotagliflozin Form E

[0088] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of isopropyl acetate. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. The crystals were observed after 9 days; it was collected and analyzed by PXRD. Sotagliflozin Form E has been confirmed by PXRD as presented in figure 5.

Example-9: Preparation of Sotagliflozin Form F

[0089] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 2-propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened to allow evaporation of the solvent (4-7°C/l atm). The crystals were observed after 13 days; it was collected and analyzed by PXRD. Sotagliflozin Form F has been confirmed by PXRD as presented in figure 6.

Example- 10: Preparation of Sotagliflozin Form G

[0090] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 1 -propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. Solid was observed after 24 days; it was collected and analyzed by PXRD.

Sotagliflozin Form G has been confirmed by PXRD as presented in figure 7.

Example- 11 : Preparation of Sotagliflozin Form H

[0091] 15 mg of Sotagliflozin (Form- A) was kept in DVS (dynamic vapor sorption) instrument. The kinetic sorption measurement was performed at 25 °C in two full cycle of sorption and desorption as follows, from 40%RH to 90%RH, 90%RH to 0%RH then again from 0% to 90%RH, 90%RH to 0%RH. After completion of experiment, the powder was collected and analyzed by PXRD. Sotagliflozin Form H has been confirmed by PXRD as presented in figure 8.

Example- 12: Preparation of Sotagliflozin Form I

[0092] Procedure to prepare saturated solution: 1500 mg of Sotagliflozin were dissolved in 1ml of 2-Methoxyethanol and the solution was stirred overnight at 25°C; the solution was then filtered. Taken ΙΟΟμί from above saturated stock solution, 500μί of Diisopropylether was added drop by drop, no solid was observed left the solution overnight under stirring, added again 500μί of Diisopropylether into the entire solution. The solid was precipitated, stirred for 30min and filtered under vacuum. Sotagliflozin Form I has been confirmed by PXRD as presented in figure 9.

Example-13: Preparation of Sotagliflozin Form K

[0093] 10-20mg of Sotagliflozin (Form D) was kept for drying in a natural air convection oven (MPM instruments modelM40-VN) at 60°C for lh. Sotagliflozin Form K has been confirmed by PXRD as presented in figure 10.

Example-14: Preparation of Sotagliflozin Form E:

[0094] Sotagliflozin (2g) and ethyl acetate (6ml) were heated to reflux temperature (71-74°C). Heptane (6ml) was added at reflux, reaction mass was stirred for additional 15 minutes and then cooled to room temperature. Solid was precipitated out during cooling at about 57°C. A mixture of ethyl acetate and heptane (1 : 1 v/v, 24 ml) was added and the reaction mixture was heated to reflux temperature (71-74°C) to obtain a clear solution which was maintained for 15 minutes. Reaction mass was cooled to room temperature (25-30°C) and stirred for 3 hours. The slurry was filtered, washed with a mixture of ethyl acetate and heptane (l : lv/v, 8ml) and dried under vacuum at 50°C for 2Hrs. The obtained solid (1.8g) was analyzed by PXRD-Form E.

Example-15: Preparation of Sotagliflozin Form D:

[0095] 2g of sotagliflozin Form F was kept in glass petri-dish and exposed to 80%RH for 60hrs at room temperature. Solid was collected (2g) and analyzed for PXRD-Form D.

Example-16: Preparation of Sotagliflozin Form 2:

[0096] 50 gm of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(Methylthio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (SOT-1) and 500ml of methanol were charged in round bottom flask, the slurry was cooled to 20°C then added sodium methoxide solution prepared in methanol (2.45gm of sodium methoxide in 50ml of methanol) at 20°C

over the period of 10 min and stirred the mass for 2hr at 20°C.The reaction completion was ensured by HPLC. Once the reaction is completed added 2.5gm Norit carbon to the reaction mass at 23°C and stirred for 30min. Filtered the reaction mass through Hyflo bed and washed with 20ml of methanol. Taken the filtrate into the flask and concentrated under vacuum at 45°C up to 3 volumes with respect to SOT-1 then cooled to 21°C over the period of 60 min, added 560ml of Water at 21°C over the period of 30min and stirred for 30min at 21 °C, the reaction mass left overnight (without stirring) and stirred for lhr. The obtained slurry was filtered under vacuum and washed with 55ml*3times of water then kept for suction at 20-30°C for 30min. The material was dried at 50-60°C for 9hrs under vacuum to obtain 35gm of Sotagliflozin. 5.7gm of Sotagliflozin (5.7gr, Sotagliflozin) and 28.5ml of Methyl ethyl ketone (28.5ml) were charged in round bottom flask, the slurry was stirred at 22-25°C for 5-10min gradually raised the temperature to 78°C then added 114 ml of n-Heptane (114ml) at 78°C over the period of 55min. Once the addition of n-heptane was completed, seeds of Form-2 (20 mg) were added, the slurry was gradually cooled down to 25-27°C over the period of 60 min. The obtained slurry was stirred for 2-3hrs at 25-27°C and the mass was kept overnight (without stirring) at 25-27°C then stirred for 3hr at 23 °C. The mass was filtered under vacuum and washed with 10ml of n-Heptane then kept for suction for 30min at 25-30°C. The material was dried at 50°C for 2hrs under vacuum to obtain Form-2 of Sotagliflozin.

Preparation of Form 2- Seeds

[0097] Sotagliflozin (2gr, amorphous) was dissolved in methyl ethyl ketone (10ml) The slurry was heated to 80°C, then n-Heptane (40ml) was added over 60mins. The hazy solution was cooled to 20-30° over 60mins and stirred for 3hr. The slurry was kept overnight at 20-30°C (without stirring). The obtained slurry was filtered under vacuum and washed with n-Heptane (10ml) . The material was dried at 50 °C for 4hrs under vacuum to obtain the 1.9gm of Sotagliflozin Form -2 as confirmed by PXRD.

///////////WO 2018067805, NEW PATENT,  SOTAGLIFLOZIN, TEVA

DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent


DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent

CRYSTAL FORM OF ANDROGEN RECEPTOR ANTAGONIST MEDICATION, PREPARATION METHOD THEREFOR, AND USE

张晓宇 [CN]

一种式(I)所示ODM-201的晶型B,其特征在于,其X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°处有特征峰。

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Novel crystalline forms of an androgen receptor antagonist medication, particularly ODM-201 (also known as darolutamide; designated as Forms B and C), processes for their preparation and compositions comprising them are claimed. Represents a first filing from Crystal Pharmaceutical Co Ltd and the inventors on this API.

Orion and licensee Bayer are codeveloping darolutamide, an androgen receptor antagonist, for treating castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer.

专利CN102596910B公开了ODM-201的制备方法,但并未公开任何的晶型信息。专利WO2016120530A1公开了式(I)(CAS号:1297538-32-9)所示的晶型I,式(Ia)(CAS号:1976022-48-6)所示的晶型I’和式(Ib)(CAS号:1976022-49-7)所示的晶型I”。文献Expert Rev.Anticancer Ther.15(9),(2015)已报道:ODM-201是由1:1比例的(Ia)和(Ib)两种非对应异构体组成,即为式(I)所示结构。因此,现有关于ODM-201的晶型只有晶型I报道。

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Prostate cancer has become an important disease threatening the health of men. Its incidence is higher in western countries and shows a year-by-year upward trend. In the past, Asian countries with a lower incidence of the disease have also seen an increase in the number of patients in recent years. Clinical treatment of prostate cancer commonly used methods are surgical resection, radiation therapy and blocking androgen endocrine therapy. Androgen is closely related to the growth of prostate and the occurrence of prostate cancer. Therefore, endocrine therapy has become an effective way to treat prostate cancer. The method includes orchidectomy, estrogen therapy, gonadotropin-releasing hormone analog therapy, gonadotropin-releasing hormone antagonist therapy, androgen antagonistic therapy, etc., wherein androgen antagonist therapy can be both early treatment of prostate cancer can also be combined Surgery for adjuvant therapy is currently one of the main clinical treatment of prostate cancer. Androgen receptor as a biological target of androgen play an important role in the field of biomedical research.

Clinical trials have shown that exogenous androgen administration to patients with prostate cancer can lead to an exacerbation of the patient’s condition; conversely, if the testicles are removed and the level of androgens in the patient is reduced, the condition is relieved, indicating that androgens contribute to the development of prostate cancer Significant influence. According to receptor theory, androgen must bind with androgen receptor (AR) to cause subsequent physiological and pathological effects, which is the basis for the application of androgen receptor (AR) antagonist in the treatment of prostate cancer. In vitro experiments have shown that AR antagonists can inhibit prostate cell proliferation and promote apoptosis. Depending on the chemical structure of AR antagonists, they can be divided into steroidal AR antagonists and non-steroidal AR antagonists. Non-steroidal anti-androgen activity is better, there is no steroid-like hormone-like side effects, it is more suitable for the treatment of prostate cancer.

ODM-201 (BAY-1841788) is a non-steroidal oral androgen receptor (AR) antagonist used clinically to treat prostate cancer. The binding affinity of ODM-201 to AR was high, with Ki = 11nM and IC50 = 26nM. Ki was the dissociation constant between ODM-201 and AR complex. The smaller the value, the stronger the affinity. half maximal inhibitory concentration “refers to the half-inhibitory concentration measured, indicating that a certain drug or substance (inhibitor) inhibits half the amount of certain biological processes. The lower the value, the stronger the drug’s inhibitory ability. In addition, ODM-201 does not cross the blood-brain barrier and can reduce neurological related side effects such as epilepsy. Bayer Corporation has demonstrated in clinical trials the effectiveness and safety of ODM-201, demonstrating its potential for treating prostate cancer.

The chemical name of ODM-201 is: N – ((S) -l- (3- (3- chloro-4-cyanophenyl) -lH-pyrazol-l-yl) -propan- The chemical name contains the tautomer N – ((S) -1- (3- (3- 4-cyanophenyl) -1H-pyrazol- 1 -yl) -propan-2-yl) -5- (1 -hydroxyethyl) 1297538-32-9, the structural formula is shown in formula (I) :

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The different crystalline forms of solid chemical drugs can lead to differences in their solubility, stability, fluidity and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compounds (see K. Knapman, Modern Drug Discovery, 3, 53 -54,57,2000.), Resulting in differences in clinical efficacy. It has been found that new crystalline forms (including anhydrates, hydrates, solvates, etc.) of the active ingredients of the medicinal product may give rise to more processing advantages or provide substances with better physical and chemical properties such as better bioavailability, storage stability, ease Processed, purified or used as an intermediate to promote conversion to other crystalline forms. The new crystalline form of the pharmaceutical compound can help improve the performance of the drug and broaden the choice of starting material for the formulation.

Patent CN102596910B discloses the preparation of ODM-201, but does not disclose any crystal form information. Patent WO2016120530A1 discloses a crystalline form I represented by the formula (I) (CAS number: 1297538-32-9), a crystalline form I ‘represented by the formula (Ia) (CAS number: 1976022-48-6) and a compound represented by the formula (CAS No. 1976022-49-7). Document Expert Rev. Anticancer Ther. 15 (9), (2015) It has been reported that ODM-201 is composed of a 1: 1 ratio of (Ia) And (Ib), which is the structure shown in Formula (I), so the only existing crystal form I for ODM-201 is reported.

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However, the lower solubility of Form I and the high hygroscopicity, and the preparation of Form I requires the use of highly toxic acetonitrile solvents, which are carcinogenic in animals and are the second class of solvents that should be controlled during the process development stage. Form I preparation method is more complex, long preparation cycle, the process needs heating, increasing the cost of industrial preparation, is not conducive to industrial production. In order to overcome the above drawbacks, there is still a need in the art for a systematic and comprehensive development of other polymorphs of ODM-201 of formula (I), simplifying the preparation thereof, enabling its pharmacological development and releasing its potential, Preparation of a better formulation of the drug ingredients.

The inventors found through experiments that Form B and Form C of the present invention, and found that Form B and Form C of the present invention have more excellent properties than the prior art. Dissolution is a prerequisite for drug absorption, and increased solubility will help to increase the bioavailability of the drug and thereby improve the drug’s druggability. Compared with the prior art, the crystalline forms B and C of the invention have higher solubility and provide favorable conditions for drug development. Compared with the prior art, the crystalline forms B and C of the invention also have lower hygroscopicity. Hydroscopic drug crystal form due to adsorption of more water lead to weight changes, so that the raw material crystal component content is not easy to determine. In addition, the crystalline form of the drug substance absorbs water and lumps due to high hygroscopicity, which affects the particle size distribution of the sample in the formulation process and the homogeneity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample. The crystal form B and the crystal form C have the same moisture content under different humidity conditions, and overcome the disadvantages caused by high hygroscopicity, which is more conducive to the long-term storage of the medicine, reduces the material storage and the quality control cost.

In addition, the present invention provides Form B and Form C of ODM-201 represented by formula (I), which have good stability, excellent flowability, suitable particle size and uniform distribution. The solvent used in the preparation method of crystal form B and crystal form C of the invention has lower toxicity, is conducive to the green industrial production, avoids the pharmaceutical risk brought by the residue of the toxic solvent, and is more conducive to the preparation of the pharmaceutical preparation. The novel crystal type provided by the invention has the advantages of simple operation, no need of heating, short preparation period and cost control in industrialized production. Form B and Form C of the present invention provide new and better choices for the preparation of pharmaceutical formulations containing ODM-201, which are of great significance for drug development.

The problem to be solved by the invention

The main object of the present invention is to provide a crystal form of ODM-201 and a preparation method and use thereof.

//////////DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent, CRYSTAL

Drug Patents International


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SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd


Image result for PHARMARESOURCES (SHANGHAI) CO., LTD

SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

WO-2018032356, Pharmaresources (Shanghai) Co Ltd

CHEN, Ping; (CN).
PENG, Shaoping; (CN).
LI, Yinqiang; (CN).
LI, Dafeng; (CN).
DONG, Xuejun; (CN)

Process for the preparation of lactone derivatives and their intermediates are important precursors for the synthesis of anti-hepatitis C virus agents, including sofosbuvir . Represents a first filing from Pharmaresources (Shanghai) Co Ltd and the inventors on this API. Gilead Sciences , following its acquisition of Pharmasset , has developed and launched sofosbuvir, a pure chiral isomer of PSI-7851, a next-generation HCV uracil nucleotide analog polymerase inhibitor prodrug for once-daily oral use.

Hepatitis C virus (HCV) infection represents a global health thereat in need of more effective treatment options. The World Health Organization (WHO) estimates that 130-170 million of individuals worldwide have detectable antibodies to HCV and approximately 60-85%of this population develops into chronic disease, leading to liver cirrhosis (5-25%) and hepatocellular carcinoma (1-3%) and liver failure. While there were existing therapeutics including pegylated interferon- (Peg-IFN) and ribavirin (RBV) , they are suboptimal due to various adverse effects, intolerability, low efficacy and slow response in reducing the viral loads across the multiple genotypes (1-6) of HCV. Therefore, there is an urgent and enormous need to develop more effective and efficacious novel anti-HCV therapies.
During the past decade, there have been a variety of small molecule agents as direct-acting antivirals (DAAs) targeting HCV viral replication via action on both structural and nonstructural proteins (NS3-5) have been launched inmarket or in late-stage clinical development. Among the DAAs reported, Soforsbuvir (brand name Sovaldi) targeting NS5B protein from Gilead was approved by FDA in 2003 for HCV genotypes 2 and 3 (in combination with Ribavin) . In 2014, a combination of Sofosbuvir with viral NS5A inhibitor Ledipasvir (brand name Harvoni) was approved. This combination provides high cure rates in people infected with HCV genotype 1, the most common subtype in the US, Japan, and much of the Europe, without the use of interferon, and irrespective of prior treatment failure or the presence of cirrhosis. Compared to previous treatment, Sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a 2-4 fold reduced duration of therapy.
Sofosbuvir is a prodrug using the ProTide biotechnology strategy. It is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate. The triphosphate serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis.
Due to the tremendous success in Sorosbuvir-based oral therapy, there remains a need for a more efficient method for making sofosbuvir-like anti-hepatitis C virus agents, including sofosbuvir and intermediates thereof. A variety of methods describing different synthetic approaches for substituted lactone (VI) shown below, a key intermediate for Sofosbuvir and its like anti-viral drugs have been published.
WO2008045419 reported a seven-step synthesis (Scheme 1) for the γ-lactone intermediate. When chiral glyceraldehyde used as the starting material, two new chiral centers were generated following Witting reaction and dihydoxylation. After cyclic sulfonate formed, the fluoro subsititution was introduced stereospecifically by a SN2 reaction with HF-Et3N. Lactonization was achieved under the acid conditions followed by hydroxy protecting step to give the desired intermediate. The main disadvantage of this approach is that considerable quantities of both solid and acidic liquid wastes were produced during the process which is very difficult to handle with (e.x. filtration) and/or contributes to the enviroment pollution upon disposal.
Scheme 1
In a similar process reported in CN105418547A (Scheme 2) , the Witting product was epoxidized followed by ring-opening fluorolation by HF-Et3N or other fluoro-containing reagents, significant amount of regioisomer was observed which was difficult to remove from the oily mixture.
Scheme 2
US20080145901 reported an enzymetic approach to the γ-lactone intermediate (scheme 3) . Treatment of ethyl 2-fluoro-propinate with chiral glyceraldehyde to form the aldol adducts consisting the mixture of four disteroisomers. The disteroisomers were selectively hydrolyzed by enzyme and the major isomer was obtained. After lactonization and hydroxyl protecting, other two isomers were removed by recrystallization.
WO2008090046 reported a similar synthesis as described in Scheme 3.2-fluoro-propionic acid was converted to diffirent bulky ester or amide and reacted with chiral glyceraldehydes. The mixture of the disteroisomers were purified by recrystallization to obtain the pure isomer. By using the method described in Scheme 3, the γ-lactone can be scale up to kilogram quantities but the de value of the final product can not achieve desired level.
Scheme 3
In WO2014108525, WO2014056442 and CN105111169, diffirent auxiliaries were used in the Aldol Reaction to improve the disteroisomeric selectivity (Scheme 4) . The process was shortened to 3~4 steps and the de value was increase significantly.
Scheme 4
Examples
Example 1: preparation of 2-fluoropropanoyl chloride (3)
Chlorosulfonic acid (660 mL, 10 mol, 20 eq) was added to a solution of phthaloyl dichloride (1.4 L, 10 mol, 20 eq) and ethyl-2-fluoropropanoate (600 g, 5 mol) at room temperature. The solution was heated at 120 ℃ for 4 hs. 2- (R) -fluoropropanoyl chloride was distilled from the reaction mixture under reduced pressure and recovered as a colourless oil (320 g, 58.2%) . 1H-NMR (CDCl3, 400 MHz) : δ 5.08 (dq, J = 48.8, 6.8 Hz, 1 H) , 1.63 (dd, J =22.8, 6.8 Hz, 3 H) .
Example 2: preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (4)
n-Butyl lithium (2.5 M in hexane, 30 mL, 75 mmol, 1.1 eq) was added to a solution of 4-(R) -4-isopropyl-2-oxazolidinone (8.8 g, 68.2 mmol, 1 eq) in dry THF (80 mL) at -50 ℃ under N2 atomosphere. After 30 min, 2-fuoropropanoyl chloride (6.8 mL, 0.9 eq) was added, and the solution was stirred for 4 hs at -50 ℃. The reaction was then quenched with a saturated solution of NH4Cl (50 mL) , extracted with MTBE (80 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure. The product was purified over silica (Hexane/EtOAc= 10/1) and recovered as a brown oil (9 g, 74.8%) . 1H-NMR (CDCl3, 400 MHz) : δ 6.00 (dm, J = 49.2Hz, 1 H) , 4.27 -4.53 (m, 3 H) , 2.43 (dm, J = 52.6 Hz, 1 H) , 1.63 (td, J = 23.2Hz, 3 H) , 0.92 (dq, J = 17.8 Hz, 6 H) .

[0206]
Example 3: preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (5)

[0207]
n-Butyl lithium (2.5 M in hexane, 75 mL, 187 mmol, 1.1eq) was added to a solution of 4- (S) -4-isopropyl-2-oxazolidinone (22 g, 170 mmol, 1 eq) in dry THF (200 mL) at -50 ℃ under N2 atomosphere. After 30 min 2-fuoropropanoyl chloride (17 mL, 153 mmol, 0.9 eq) was added, and the solution was stirred for 1 h at -50 ℃. After the starting material was completely consumed, the reaction was then quenched with a saturated solution of NH4Cl (125 mL) , extracted with MTBE (200 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc= 10/1) and recovered as a brown oil (34 g, 83.3%) . 1H-NMR (CDCl3, 400 MHz) : δ 5.93 (dm, J = 48.8 Hz, 1 H) , 4.19 -4.17 (m, 3H) , 2.35 (dm, J = 52.8 Hz , 1 H) , 1.55 (td, J = 23.6 Hz, 3 H) , 0.85 (dq, J = 18 Hz, 6 H) .
Example 4: preparation of (4R) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (6)
n-Butyl lithium (2.5 M in hexane, 13.5 mL, 33.74 mmol, 1.1 eq) was added to a solution of (R) -4-phenyloxazolidin-2-one (5 g, 30.67 mmol, 1 eq) in dry THF (75 mL) at -50 ℃ under N2 atomosphere. After 30 minutes, 2-fuoropropanoyl chloride (3.75 g, 33.74 mmol) was added, and the solution was stirred for 1 h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH4Cl, extracted with EtOAc, washed with NaHCO3(sat) , brine and dried over MgSO4. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (4 g, 55%) . 1H-NMR (CDCl3, 400 MHz) : δ 7.35-7.21 (m, 5 H) , 5.99-5.84 (md, 1 H) , 5.42-5.33 (dd, 1 H) , 4.72 (dd, 1 H) , 4.31 (m, 1 H) , 1.50 (m, 3 H) .
Example 5: preparation of (4s) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7)
n-Butyl lithium (2.5 M in hexane, 67.5 mL, 169 mmol, 1.1 eq) was added to a solution of (s) -4-phenyloxazolidin-2-one (25 g, 153 mmol, 1 eq) in dry THF (375 mL) at -60 ℃ under N2 atomosphere. After 30 min, 2-fuoropropanoyl chloride (18.7 g, 169 mmol) was added, and the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH4Cl, extracted with EtOAc, washed with NaHCO3 (sat) , brine and dried over MgSO4. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (16.5 g, 45.4%) . 1H-NMR (CDCl3, 400 MHz) : δ 7.36-7.20 (m, 5 H) , 5.95-5.80 (md, 1 H) , 5.42-5.30 (dd, 1 H) , 4.71 (dd, 1 H) , 4.30 (m, 1 H) , 1.51 (m, 3 H) .
Example 6: preparation of (4S) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (8)
n-Butyl lithium (2.5 M in hexane, 54.7 mL, 137 mmol, 1.1eq) was added to a solution of (S) -4-benzyloxazolidin-2-one (22 g, 124 mmol, 1eq) in dry THF (220 mL) at -60 ℃ under N2 atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (15.2 g, 137 mmol) was added dropwisely below -50 ℃ , after adding the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH4Cl, extracted with EtOAc, washed with NaHCO3 (sat) , brine and dried over MgSO4. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc) and recovered as a brown oil (25.8 g, 82.7%) . 1H-NMR(400 MHz, CDCl3 ) : δ 7.29-7.13 (m, 5 H) , 6.01-5.81 (qd, 1 H) , 4.71-4.58 (md, 1 H) , 4.29-4.04 (m, 2 H) , 3.32-3.16 (dd, 1 H) , 2.79-2.74 (m, 1 H) , 1.51 (m, 3 H) .
Example 7: preparation of (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (9)
Use the procedure described in Example 6, (R) -4-benzyloxazolidin-2-one as the start material to give the desired compound (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (yield: 85%) . 1H-NMR (400 MHz, CDCl3 ) : δ 7.27 -7.12 (m, 5 H) , 6.00-5.83 (qd, 1 H) , 4.72-4.55 (md, 1 H) , 4.27-4.03 (m, 2 H) , 3.32 -3.16 (dd, 1 H) , 2.79 -2.72 (m, 1 H) , 1.53 (m, 3 H) .

[0221]
Example 8: preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (10)

[0222]

[0223]
n-Butyl lithium (2.5 M in hexane, 48 mL) was added to a solution of (R) -4-isopropyl-5,5-diphenyloxazolidin-2-one (28.1 g) in dry THF (150 mL) at -65 ℃ under N2 atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (16.4 g, 1.5 eq) was added dropwisely below -60 ℃. After adding the solution was stirred for 2 h at -60 ℃. The reaction was then quenched with a saturated solution of NH4Cl, extracted with EtOAc, washed with NaHCO3 (sat) , brine and dried over MgSO4. Solvents were removed under reduced pressure. The crude product was recrystalized in (DCM/PE) to give (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (30 g, 85%) . 1H-NMR (CDCl3, 400 MHz) : δ 7.50 -7.26 (m, 10 H) , 5.89 (ddq, J = 64.4, 49.3, 6.6 Hz, 1 H) , 5.37 (dd, J = 70.8, 3.4 Hz, 1 H) , 2.00 (dd, J = 7.3, 3.3 Hz, 1 H) , 1.70 (dd, J = 23.4, 6.7 Hz, 1.5 H) , 1.12 (dd, J = 23.8, 6.6 Hz, 1.5 H) , 0.83 (ddd, J = 28.0, 16.7, 6.9 Hz, 6 H) .

[0224]
Example 9: preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11)

[0225]

[0226]
Use the procedure described in Example 8 and (S) -4-isopropyl-5, 5-diphenyloxazolidin-2-one as the start material to give the desired compound (4S) -3- (2-fluoropropanoyl) -4-isopropyl- 5,5-diphenyl oxazolidin-2-one (yield: 82%) . 1H-NMR (CDCl3, 400 MHz) : δ 7.51 -7.27 (m, 10 H) , 5.90 (ddq, J = 64.4, 49.3, 6.6 Hz, 1 H) , 5.38 (dd, J = 70.8, 3.4 Hz, 1H) , 2.01 (dd, J = 7.3, 3.3 Hz, 1 H) , 1.71 (dd, J = 23.4, 6.7 Hz, 1.5 H) , 1.13 (dd, J = 23.8, 6.6 Hz, 1.5 H) , 0.84 (ddd, J = 28.0, 16.7, 6.9 Hz, 6 H) .

[0227]
Example 10: preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12)

[0228]

[0229]
Method A: TiCl4 (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N2 atomosphere. After 10 min, diisopropylethyl amine (10.3 mL, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl4 (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.2 g, yield: 80%, purity: 97.2%) . 1H-NMR (400 MHz, CDCl3) : δ 5.89 (dddd, J = 17.1, 10.5, 6.5, 0.8 Hz, 1 H) , 5.42 (d, J =17.2 Hz, 1 H) , 5.30 (d, J = 10.1 Hz, 1 H) , 4.68 (dd, J = 14.8, 6.5 Hz, 1 H) , 4.44 (d, J = 4.0 Hz, 1 H) , 4.32 (t, J = 8.5 Hz, 1 H) , 4.24 (dd, J = 9.1, 3.4 Hz, 1 H) , 3.61 (d, J = 6.5 Hz, 1 H) , 2.37 (dd, J = 7.0, 4.1 Hz, 1 H) , 1.73 (s, 1.5 H) , 1.67 (s, 1.5 H) , 0.92 (ddd, J = 7.8, 5.6, 2.4 Hz, 6 H) ; 19F-NMR (400 MHz, CDCl3) : -158.3 ppm.

[0230]
Method B: TiCl4 (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N2 atomosphere. After 10 min, (-) -spartein (14.5 g, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl4 (1 M in DCM, 50 mL, 50 mmol, 1.1eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with NH4Cl (sat 50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (9.4 g, yield: 75%, purity: 96.5%) .

[0231]
Example 11: preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (13)

[0232]

[0233]
TiCl4 (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N2 atomosphere. After 10 min, diisopropylethyl amine (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.4 g, yield: 83%, purity: 92.8%) . 1H-NMR (400 MHz, CDCl3) : δ 5.92 (d, J = 1.1 Hz, 1 H) , 5.44 (d, J = 17.2 Hz, 1 H) , 5.34 -5.28 (m, 1 H) , 4.73 (dd, J = 13.9, 6.2 Hz, 1 H) , 4.43 (m, 1 H) , 4.37 -4.30 (m, 1H) , 4.27 -4.21 (m, 1 H) , 2.43 -2.31 (m, 1H) , 1.77 (s, 1.5 H) , 1.71 (s, 1.5 H) , 0.91 (dd, J = 12.1, 7.0 Hz, 6 H) ; 19F-NMR (400 MHz, CDCl3) : δ -159.1ppm.

[0234]
Example 12: preparation of (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one

[0235]

[0236]
TiCl4 (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4S) -4-benzyl-3-(2-fluoro propanoyl) oxazolidin-2-one (8) (12.3 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N2 atomosphere. After 10 min, TMEDA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at -78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (50 mL) . The products were extracted into DCM (20 mL*2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (13 g, yield: 86%, purity: 91.5%) . 1H-NMR (400 MHz, CDCl3) : δ 7.38 -7.27 (m, 3 H) , 7.22 (d, J = 6.8 Hz, 2 H) , 5.96 (dddd, J = 17.0, 10.5, 6.2, 1.2 Hz, 1 H) , 5.47 (d, J = 17.2 Hz, 1 H) , 5.35 (d, J = 10.5 Hz, 1 H) , 4.75 (dd, J = 13.9, 6.2 Hz, 1 H) , 4.66 (td, J = 7.1, 3.6 Hz, 1 H) , 4.23 (dd, J = 16.3, 5.0 Hz, 2 H) , 3.33 (dd, J = 13.3, 3.3 Hz, 1 H) , 2.76 (dd, J =13.3, 10.0 Hz, 1 H) , 1.81 (s, 1.5 H) , 1.76 (s, 1.5 H) ; 19F-NMR (400 MHz, CDCl3) : δ -158.47 ppm.

[0237]
Example 13: preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0238]

[0239]
TiCl4 (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N2 atomosphere. After 10 min, Et3N (12.5 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (12 g, yield: 83%, purity: 90.5%) . 1H-NMR (400 MHz, CDCl3) : δ 7.43 -7.30 (m, 5 H) , 5.81 (dddd, J = 17.0, 10.5, 6.3, 1.1 Hz, 1 H) , 5.46 (dd, J = 8.4, 5.1 Hz, 1 H) , 5.37 (dt, J = 17.2, 1.2 Hz, 1 H) , 5.23 (d, J = 10.4 Hz, 1 H) , 4.74 (t, J = 8.7 Hz, 1 H) , 4.64 (dd, J = 13.5, 6.3 Hz, 1 H) , 4.31 (dd, J = 8.9, 5.2 Hz, 1 H) , 1.60 (s, 1.5H) , 1.55 (s, 1.5 H) ; 19F-NMR (400 MHz, CDCl3) : δ -158.47 ppm.

[0240]
Example 14: preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0241]

[0242]
TiCl4 (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoro propan oyl) -4-phenyloxazolidin-2-one (6) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N2 atomosphere. After 10 min, DIPEA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78℃. Then the reaction was quenched with a saturated solution of NH4Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (11.1 g, yield: 77%, purity: 91.5%) . 1H-NMR (400 MHz, CDCl3) : δ 7.44 -7.29 (m, 5 H) , 5.74 -5.63 (m, 1 H) , 5.48 (dd, J = 8.4, 5.3 Hz, 1 H) , 5.35 -5.26 (m, 1 H) , 5.15 (d, J = 10.5 Hz, 1 H) , 4.73 (t, 1 H) , 4.52 (dd, J = 14.8, 6.2 Hz, 1 H) , 4.28 (dd, J = 8.9, 5.3 Hz, 1 H) , 1.68 (s, 1.5 H) , 1.63 (s, 1.5 H) ; 19F-NMR (400 MHz, CDCl3) : δ -161.93 ppm.

[0243]
Example 15: preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one

[0244]

[0245]
Method 1: LiHMDS (1 M in THF, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry THF (100 mL) at -20 ℃ under N2 atomosphere. After 1.5 hs, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -20 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (50 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the crude product was used directly in the next step. m/z (ES+) : 412 [M+H] +.

[0246]
Method 2: (n-Bu) 2BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N2 atomosphere. After 15 min, 2, 6-lutidine (10.5g, 2eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (100 mL) . The products were extracted into DCM (40 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the crude product was used directly in the next step (17.82 g, yield: 88% (Internal standard yield) .

[0247]
Method 3: (n-Bu) 2BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N2 atomosphere. After 15 min, DIPEA (13 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (100 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the crude product was used directly in the next step (16.2 g, yield: 80% (Internal standard yield ) .

[0248]
Method 4: (C6H122BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N2 atomosphere. After 15 min, 2, 6-lutidine (10.5 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH4Cl (100 mL) . The products were extracted into DCM (50 mL *2) , washed with brine and dried over MgSO4. Solvents were removed under reduced pressure and the crude product was used directly in the next step (14.6 g, yield: 80% (Internal standard yield ) .

[0249]
Example 16: preparation of (3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydro furan-2 (3H) -one

[0250]
Method 1:

[0251]

[0252]
N-Bromosuccinimide (19.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in DME/H2O (4: 1, 130ml) at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO3 (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO4. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (bromomethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18a) . 1H-NMR (400 MHz, CDCl3) : δ 4.62 -4.53 (m, 1 H) , 4.37 (dd, J = 3.0, 1.9 Hz, 1 H) , 3.73 (dd, J = 10.1, 8.7 Hz, 1 H) , 3.60 (ddd, J = 10.1, 5.8, 1.9 Hz, 1 H) , 2.59 (dd, J = 2.5, 1.7 Hz, 1 H) , 1.67 (d, J = 22.7 Hz, 3 H) ; 19F-NMR (400 MHz, CDCl3) : δ -172.248 ppm.

[0253]
Alternative Method 1a: Br2 (17.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in MeCN/H2O (4: 1, 130 mL) between -5 ℃ to -10 ℃ and stirred for 2 hs . After the reaction was complete, Na2S2O3 (10%, 20 ml) was added and stirred for 0.5 h at rt then separated . The water phase was re-extracted by DCM (50 mL *2) , the combine organic phase was concentrated, dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to used in the next step.

[0254]
Alternative Method 1b: N-chlorosuccinimide (13.3 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in 100ml CH3CN at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO3 (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO4. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (chloromethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18b) , m/z (ES+) : 183 [M+H] +.

[0255]
The related lactone 18a or 18b (0.14eq) was dissolved in EtOH (104 mL) , then KOH (30%in H2O, 50 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into the mixture and reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (yield: 80~85%) . m/z (ES+) : 165 [M+H] +. 1H-NMR (400 MHz, MeOD) : δ 4.34 (ddd, J = 8.0, 4.2, 2.3 Hz, 1 H) , 4.02 (ddd, J = 17.6, 15.2, 5.1 Hz, 2 H) , 3.74 (dd, J = 13.0, 4.2 Hz, 1 H) , 1.60 (s, 1.5 H) , 1.54 (s, 1.5 H) ; 19F-NMR (400 MHz, MeOD) : -172.47 ppm.

[0256]
Method 2:

[0257]

[0258]
Osmium tetroxide (OsO4) (0.1 equiv) was added in one portion to a stirring solution of the (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in acetone/water (8: 1 ratio) under nitrogen. After 5 min, NMO (N-methylmorpholine N-oxide, 60%by weight in water, 1.1 equiv) was added in one portion and stirred for 24 h. The resulting reaction mixture was concentrated under reduced pressure and immediately purified via column chromatography to obtain the desired lactone (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (21) , yield: 87%, m/z (ES+) : 165 [M+H] +.

[0259]
15.1 g (92.3 mmol) (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydrofuran-2 (3H) -one (21) was dissolved in 25 mL pyridine and 11.1 g (96.9 mmol) methanesulfonyl chloride was slowly added dropwise at -25 degC. It was stirred for a day at -25 deg and a day at -10 deg. After adding 20 mL of ethyl acetate and 20 mL water, the solvent was removed on a rotary evaporator. After neutralization with dilute sodium hydrogen carbonate solution, the solvent was removed in vacuo again, the residue was digested with ethyl acetate, the eluate was dried with magnesium sulfate and concentrated in vacuo to dryness. Recrystallization from ethyl acetate/diethyl ether gave a colorless crystalline product ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate (18c) . Yield: 31 %.

[0260]
33.8g of ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate was disslolved in EtOH (104 mL) , then KOH (16.8 g , 3 eq) in H2O (52 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into, the mixture was reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (10.5 g, yield: 45%) .

[0261]
Alternative reagents and reactions to those disclosed above can also be employed. For example, 4-methylbenzene-1-sulfonyl chloride can be used instead of methanesulfonyl chloride. Moreover, primary alcohol can be converted to chloro or bromo by using Ph3P/CCl4, PPh3P/CBr4, PPh3/NCS, PPh3/NBS, or PPh3/C2Cl6 as a halogenation reagent. The desired product can be obtained in good yields using these reagents and reactions.

[0262]
Method 3: Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methyl pent-4-enoyl) -4-isopropyloxazolidin-2-one (13) as starting material provides the desired compound 19 (yield: 63.2%)

[0263]
Method 4: Using a method analogous to that described as hereinabove and (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one (14) as starting material provides the desired compound 19 (yield: 71.8%)

[0264]
Method 5: Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one (15) as the start material gives the desired compound 19 (yield: 65.7%)

[0265]
Method 6: Using a method analogous to that described as hereinabove and (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-oneas (16) starting material provides the desired compound 19 (yield: 59.5%)

[0266]
Method 7: Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (17) as starting material gives the desired compound 19 (yield: 66.7%)

[0267]
Example 17: preparation of ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetra hydro fur an-2-yl) methyl benzoate

[0268]

[0269]
(3R, 4R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (19) (25.4 g, 0.154 mol) obtained from example 3 was dissolved in 200 ml of THF. 4- (Dimethylamino) -pyridine (8.2 g, 0.066 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixture was cooled to 0 ℃. Benzoyl chloride (46.0 g, 0.33 mol) was added, and the mixture was warmed to 35-40 ℃ in the course of 2 hs. Upon completion of the reaction, water (100 mL) was charged and the mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tert-butyl ether (100 mL) was added and the mixture was stirred for 30 min. Phases were separated and the organic phase was washed with saturated NaCl solution (100 mL) . The combined organic phases were dried over Na2SO4 (20 g) filtered and the filtrate was evaporated to dryness. The residue was taken up in iso-propanol (250 mL) and the mixture was warmed to 50 ℃ and stirred for 60 min, then cooled down to 0 ℃ and further stirred for 60 min. The solid was filtered and the wet cake was washed with i-propanol (50 mL) and then dried under vacuum. The title compound ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methyl benzoate (47.5 g, 82.6 %yield) was obtained. ‘H-NMR (CDCl3, 400 MHz) : 8.10 (d, 7=7.6 Hz, 2H) , 8.00 (d, 7=7.6 Hz, 2H) , 7.66 (t, 7=7.6 Hz, IH) , 7.59 (t, 7=7.6 Hz, IH) , 7.50 (m, 2H) , 7.43 (m, 2H) , 5.53 (dd, 7=17.6, 5.6 Hz, IH) , 5.02 (m, IH) , 4.77 (dd, 7=12.8, 3.6 Hz, IH) , 4.62 (dd, 7=12.8, 5.2 Hz, IH) , 1.77 (d, 7=23.2 Hz, 3H) .

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BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA


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BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA

WO2018005328) DEUTERATED BICTEGRAVIR 

CONCERT PHARMACEUTICALS, INC.

TUNG, Roger, D.; (US)

How A Kidney Drug Almost Torpedoed Concert Pharma’s IPO

Concert CEO Roger Tung

Novel deuterated forms of bictegravir is claimed.  Gilead Sciences is developing the integrase inhibitor bictegravir as an oral tablet for the treatment of HIV-1 infection.

This invention relates to deuterated forms of bictegravir, and pharmaceutically acceptable salts thereof. In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11b is independently hydrogen or deuterium; provided that if each Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, and Y11 is hydrogen, then Y11b is deuterium.

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Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Exemplary Synthesis

[72] Deuterium-modified analogs of bictegravir can be synthesized by means known in the art of organic chemistry. For instance, using methods described in US Patent No.9,216,996 (Haolun J. et al., assigned to Gilead Sciences, Inc. and incorporated herein by reference), using deuterium-containing reagents provides the desired deuterated analogs.

[73] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

[74] A convenient method for synthesizing compounds of Formula I is depicted in the Schemes below.

 [75] A generic scheme for the synthesis of compounds of Formula I is shown in Scheme 1 above. In a manner analogous to the procedure described in Wang, H. et al. Org. Lett.2015, 17, 564-567, aldol condensation of compound 1 with appropriately deuterated compound 2 affords enamine 3. Enamine 3 is then reacted with primary amine 4 to afford enamine 5, which then undergoes cyclization with dimethyl oxalate followed by ester hydrolysis to provide carboxylic acid 7.

[76] In a manner analogous to the procedure described in US 9,216,996, acetal deprotection of carboxylic acid 7 followed by cyclization with appropriately deuterated aminocyclopentanol 9 provides carboxylic acid intermediate 10. Amide coupling with appropriately deuterated benzylamine 11 followed by deprotection of the methyl ether ultimately affords a compound of Formula I in eight overall steps from compound 1.

[77] Use of appropriately deuterated reagents allows deuterium incorporation at the Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11bpositions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and/or Y11b.

[78] Appropriately deuterated intermediates 2a and 2b, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 2 below.

S h 2 S th i f C d 2 d 2b

[79] Synthesis of compound 2a (wherein Y3=H) by acetal formation of N,N-dimethylformamide (DMF) with dimethylsulfate has been described in Mesnard, D. et. al. J. Organomet. Chem.1989, 373, 1-10. Replacing DMF with N,N-dimethylformamide-d1 (98-99 atom % D; commercially available from Cambridge Isotope Laboratories) in this reaction would thereby provide compound 2b (wherein Y3=D).

[80] Use of appropriately deuterated reagents allows deuterium incorporation at the Y3 position of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at Y3.

[81] Appropriately deuterated intermediates 4a-4d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 3 below.

[82] As described in Malik, M. S. et. al. Org. Prep. Proc. Int.1991, 26, 764-766, acetaldehyde is converted to alkylhalide 14a via reaction with chlorine gas and subsequent acetal protection with CaCl2 in methanol. As described in CN 103739506, reaction of 14a with aqueous ammonia and then sodium hydroxide provides primary amine 4a (wherein Y9=Y10a=Y10b=H). Replacing acetaldehyde with acetaldehyde-d1, acetaldehyde-2,2,2-d3, or acetaldehyde-d4 (all commercially available from CDN Isotopes with 98-99 atom % D) in the sequence then provides access to compounds 4b (Y9=D, Y10a=Y10b=H), 4c (Y9=H,

Y10a=Y10b=D) and 4d (Y9=Y10a=Y10b=D) respectively (Schemes 3b-d).

[83] Use of appropriately deuterated reagents allows deuterium incorporation at the Y9, Y10a, and Y10b positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y9, Y10a, and/or Y10b.

[84] Appropriately deuterated intermediates 9a-9d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 4 below.

 [85] Following the procedures described by Gurjar, M. et. al. Heterocycles, 2009, 77, 909-925, meso-diacetate 16a is prepared in 2 steps from cyclopentadiene. Desymmetrization of 16a is then achieved enzymatically by treatment with Lipase as described in Specklin, S. et. al. Tet. Lett.201455, 6987-6991, providing 17a which is subsequently converted to aminocyclopentanol 9a (wherein Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b=Y8=H) via a 3 step sequence as reported in WO 2015195656.

[86] As depicted in Scheme 4b, aminocyclopentanol 9b (Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b= Y8=D) is obtained through an analogous synthetic sequence using cyclopentadiene-d6 and performing the penultimate hydrogenation with D2 in place of H2. Cyclopentadiene-d6 is prepared according to the procedure described in Cangoenuel, A. et. al. Inorg. Chem.2013, 52, 11859-11866.

[87] Alternatively, as shown in Scheme 4c, the meso-diol obtained in Scheme 4a is oxidized to the diketone following the procedure reported by Rasmusson, G.H. et. al. Org. Syn.1962, 42, 36-38. Subsequent mono-reduction with sodium borodeuteride and CeCl3 then affords the D1-alcohol in analogy to the method described in WO 2001044254 for the all-protio analog using sodium borohydride. Reduction of the remaining ketone using similar conditions provides the meso-D2-diol in analogy to the method reported in Specklin, S. et. al. Tet. Lett.2014, 55, 6987-6991 for the all protio analog using sodium borohydride. The meso-D2-diol is then converted to 9c (Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=H, Y6=Y8=D) following the same procedures outlined in Scheme 4a.

[88] Likewise, the meso-diol obtained in Scheme 4b may be converted to 9d

(Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=D, Y6=Y8=H) in an analogous manner as depicted in Scheme 4d. The use of deuterated solvents such as D2O or MeOD may be considered to reduce the risk of D to H exchange for ketone containing intermediates.

[89] Use of appropriately deuterated reagents allows deuterium incorporation at the Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and Y8 positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and/or Y8.

[90] Appropriately deuterated intermediates 11a-11d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5 below.

Scheme 5. Synthesis of Benzylamines 11a-11d

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WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD


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WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

 (WO2018001353) METHOD FOR PREPARING APREMILAST

ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

DU, Xiaoqiu; (CN).
ZHOU, Lianchao; (CN).
LIU, Jiegen; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018001353&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

EN)Method one: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L-leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an aprotic solvent to produce the compound of formula I; method two: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L- leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an organic solvent in the presence of an organic alkaline or an alkali metal hydride to produce the compound of formula I. The method for preparing apremilast requires inexpensive raw materials and reagents , is suitable for industrialized production, and has great economic effects.

Apremilast is a PDE4 inhibitor developed by Celgene. Currently, there are clinical indications such as rheumatoid arthritis, psoriatic arthritis, Behcet’s disease and ulcerative colitis. March 21, 2014 FDA approves first indication – adult active psoriatic arthritis (PsA). Name of Product: (FDA, as a post-marketing requirement, will evaluate the effect of this drug on pregnant women through a pregnancy registry study.) Three clinical trials evaluated the safety and efficacy of Asprate in the treatment of PsA, The response rates to ACR20 in the prest and placebo groups were 32-41% and 18-19%, respectively.
Aspast’s oral anti-rheumatic drug, a new mechanism of action, distinguishes itself from currently available anti-TNF monoclonal antibodies. Thomson Pharma predicts rapid sales growth of 201.2 million U.S. dollars in 2015 with sales of US $ 516 million in 2015 . Upstall’s sales are expected to reach a maximum of 2 billion U.S. dollars. Compared with its counterparts, Actuate has the following advantages: It inhibits the production of various proinflammatory mediators (PDE-4, TNF-α, IL-2, interferon γ, leukotriene, NO synthase) Inflammation; selective inhibitor of phosphodiesterase 4 (PDE4), approved for use in psoriatic arthritis in September 2014 FDA approved mid-to-severe treatment of plaque psoriasis for phototherapy or systemic therapy Patient, the first and only PDE4 inhibitor approved for the treatment of plaque psoriasis; clinical trials have shown that OTEZLA reduces erythema, thickening and scaling in patients with moderate to severe plaque psoriasis; clinical trials have demonstrated Painstrept was well tolerated and had minimal adverse reactions. Patients in the Otezla-treated and placebo clinical trials showed signs and symptoms of PsA improvement including tenderness, joint swelling and physical function.
The original patent CN 101683334A reports the synthesis of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- ) And 3-acetylaminophthalic anhydride (3) Prepared with acetic acid as solvent (1), and the synthetic route is as follows:
The method has low yield, needs lower than 50 DEG C to distill the high-boiling acetic acid, and produces one deacetyl impurity (4) during the reflux reaction and the acetic acid distillation, which affects the product purity. Acetic acid will corrode the equipment at high temperatures. Distillation of high-boiling acetic acid will also increase plant production time. Acetic acid, which is not distilled away, consumes a large amount of lye to neutralize and increases the amount of wastes and production costs, which is not conducive to industrialized production.
Example one
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- 4.6g (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, then add 50mL of acetonitrile, heating 75 ~ 80 ℃, the reaction incubated for 18 hours and cooled to room temperature. After the reaction mixture was evaporated to dryness, 60 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 25 mL of water was added to the organic layer and stirred for 10-30 minutes. The layers were evaporated to dryness to give a light yellow solid, then add 30mL absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.4 g of a white powder in 91.2% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.
Example two
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- A solution of 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride in a 250 mL three-necked flask was charged with 80 mL of toluene and 10 mL of N, N-dimethylformamide. The mixture was heated to 100 ° C and the reaction was incubated for 12 hours and then cooled to room temperature. After the reaction solution was evaporated to dryness, 80 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 50 mL of water was added to the organic layer and stirred for 10 to 30 minutes. Evaporated to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. Cooled to 0 ~ 5 ℃ and stirred for 1 ~ 2 hours, filtered and drained, the filter cake was dried in vacuo to give 9.2g white powder, yield 89.2%, HPLC: 99.9%, wherein the deacetyl impurities (4 ) Has an HPLC area of 0.03%.
Example three:
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- To a 250 mL three-necked flask was added 4.6 g (0.0224 mol) of 3-acetamidophthalic anhydride followed by 50 mL of ethyl acetate and 1.81 g (0.8 eq) of triethylamine. The mixture was heated at 75-80 ° C and incubated for 18 hours. The reaction was stopped, 100 mL of ethyl acetate was further added and the mixture was cooled to 20-30 ° C. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was heated to 0-5 ° C for 1 to 2 hours, filtered and drained. The filter cake was vacuum dried to give 9.8 g of a white powder in 95.1% yield. HPLC: 99.9% ) Had an HPLC area of 0.04%.
Example 4:
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, followed by the addition of 120mL of isopropyl acetate and 30mL of acetonitrile and 1.81g (0.8eq) of triethylamine, heating 75 ~ 80 ℃, incubated reaction 16 hours. Stop the reaction, cooled to 20 ~ 30 ℃. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.6 g of a white powder in 93.1% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.
Comparative Example:
According to the preparation example of Compound A in original patent CN 101683334A, 10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4- methoxyphenyl) -2- (methylsulfonyl) N-acetyl-L-leucinate and 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride were placed in a 250 mL three-necked flask and 50 mL of acetic acid was added thereto. The mixture was heated at 75 to 80 ° C and the reaction was incubated for 18 hours. The reaction mixture was cooled to 40-50 ° C and the temperature of the water bath was controlled to 40-50 ° C. The reaction mixture was vortexed to glacial acetic acid without any significant fraction. 150 mL of ethyl acetate was added and the mixture was stirred to dissolve. 100 mL of water was added and the mixture was stirred 10 ~ 30 minutes, standing stratification, the organic layer was added 100mL water, stirred for 10 to 30 minutes, allowed to stand for stratification, the organic layer was added 100g 8% sodium bicarbonate solution, stirred for 10 to 30 minutes, The organic layer was added with 100g of 8% sodium bicarbonate solution and stirred for 10-30 minutes. The layers were separated and the organic layer was added with 100 mL of water. The mixture was stirred for 10-30 minutes, and the layers were separated. The organic layer was further added with 100 mL of water and stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. 68mL of anhydrous ethanol and 34mL of acetone were added to the solid, heated to 60-65 ° C, stirred to make it fully dissolved, and then cooled to 0-5 ° C and stirred for 1 to 2 hours, filtered and drained, and the filter cake was dried under vacuum to give 8.6 Class g white powder, yield 83.4%, HPLC: 99.7% with an HPLC area of deacetylated impurity (4) of 0.22%.

////////////WO 2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

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