INTRODUCTION

Tasimelteon has the chemical name: trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1yl]methyl]propanamide, has the structure of Formula I:

and is disclosed in U.S. Pat. No. 5,856,529 and in US 20090105333, both of which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about 78° C. (DSC) and is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG-400), and only slightly soluble in water. The native pH of a saturated solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times greater affinity for MT2R relative to MT1R. It’s affinity (K_i) for MT1R is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in the practice of this invention because it is a melatonin agonist that has been demonstrated, among other activities, to entrain patients suffering from Non-24.

SYNTHESIS

(1R-trans)-N-[[2 – (2,3-dihydro-4 benzofuranyl) cyclopropyl] methyl] propanamide PATENT: BRISTOL-MYERS SQUIBB PRIORITY DATE: 1996 HYPNOTIC

PREPARATION OF XV

XXIV D-camphorsulfonic acid IS REACTED WITH THIONYL CHLORIDE TO GIVE

…………XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

TREATED WITH

XXVI ammonium hydroxide

TO GIVE

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

TREATED WITH AMBERLYST15

….XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

TREATED WITH LAH, ie double bond is reduced to get

…..XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Intermediate

I 3-hydroxybenzoic acid methyl ester

II 3-bromo-1-propene

III 3 – (2-propenyloxy) benzoic acid methyl ester

IV 3-hydroxy-2-(2-propenyl) benzoic acid methyl ester

V 2,3-dihydro-4-hydroxy-2-benzofurancarboxylic acid methyl ester

VI benzofuran-4-carboxylic acid methyl ester

VII benzofuran-4-carboxylic acid

VIII 2,3-dihydro-4-benzofurancarboxylic acid

IX 2,3-dihydro-4-benzofuranmethanol

X 2,3-dihydro-4-benzofurancarboxaldehyde

XI Propanedioic acid

XII (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoic acid

XIII thionyl chloride

XIV (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoyl chloride

XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

XVI (3aS,6R,7aR)-1-[(E)-3-(2,3-dihydro-4-benzofuranyl)-1-oxo-2-propenyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVII (3aS,6R,7aR)-1-[[(1R,2R)-2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]carbonyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVIII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanol

XIX [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarboxaldehyde

XX hydroxylamine hydrochloride

XXI [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarbaldehyde oxime

XXII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanamine

XXIII propanoyl chloride

XXIV D-camphorsulfonic acid

XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

XXVI ammonium hydroxide

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Bibliography

– Patents: Benzofuran and dihydrobenzofuran melatonergic agents: US5856529 (1999)

Priority: US19960032689P, 10 Dec. 1996 (Bristol-Myers Squibb Company, U.S.)

– Preparation III (quinazolines): US2004044015 (2004) Priority: EP20000402845, 13 Oct. 2000

– Preparation of VII (aminoalkylindols): Structure-Activity Relationships of Novel Cannabinoid Mimetics Eissenstat et al, J.. Med. Chem. 1995, 38, 3094-3105

– Preparation XXVIII: Towson et al. Organic Syntheses, Coll. Vol. 8, p.104 (1993) Vol. 69, p.158 (1990)

– Preparation XV: Weismiller et al. Organic Syntheses, Coll. Vol. 8, p.110 (1993) Vol. 69, p.154 (1990).

– G. Birznieks et al. Melatonin agonist VEC-162 Improves sleep onset and maintenance in a model of transient insomnia. Sleep 2007, 30, 0773 Abstract.

-. Rajaratnam SM et al, The melatonin agonist VEC-162 Phase time immediately advances the human circadian system, Sleep 2006, 29, 0159 Abstract.

-. AK Singh et al, Evolution of a manufacturing route for a highly potent drug candidate, 229th ACS Natl Meet, March 13-17, 2005, San Diego, Abstract MEDI 576.

– Vachharajani NN et al, Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist, J Pharm Sci. 2003 Apr; 92 (4) :760-72.

. – JW Scott et al, Catalytic Asymmetric Synthesis of a melotonin antagonist; synthesis and process optimization. 223rd ACS Natl Meet, April 7-11, Orlando, 2002, Abstract ORGN 186.

SYNTHESIS CONSTRUCTION AS IN PATENT

WO1998025606A1

GENERAL SCHEMES

Reaction Scheme 1

The syntheses of the 4-aryl-propenoic acid derivatives, 2 and 3, are shown in Reaction Scheme 1. The starting aldehydes, 1 , can be prepared by methods well known to those skilled in the art. Condensation of malonic acid with the aldehydes, 1, in solvents such as pyridine with catalysts such as piperidine or pyrrolidine, gives the 4-aryl- propenoic acid, 2. Subsequent conversion of the acid to the acid chloride using reagents such as thionyl chloride, phosphoryl chloride, or the like, followed by reaction with N,0-dimethyl hydroxylamine gives the amide intermediate 3 in good yields. Alternatively, aldehyde 1 can be converted directly to amide 3 using reagents such as diethyl (N-methoxy- N-methyl-carbamoylmethyl)phosphonate with a strong base such as sodium hydride.

Reaction Scheme 2

The conversion of the amide intermediate 3 to the racemic, trans- cyclopropane carboxaldehyde intermediate, 4, is shown in Reaction Scheme 2. Intermediate 3 was allowed to react with cyclopropanating reagents such as trimethylsulfoxonium iodide and sodium hydride in solvents such as DMF, THF, or the like. Subsequent reduction using reagents such as LAH in solvents such as THF, ethyl ether, or the like, gives the racemic, trans-cyclopropane carboxaldehyde intermediates, 4.

Reaction Scheme 3

Racemic cyclopropane intermediate 5 (R = halogen) can be prepared from intermediate 2 as shown in Reaction Scheme 3. Intermediate 2 was converted to the corresponding allylic alcohol by treatment with reducing agents such as sodium borohydride plus iodine in solvents such as THF. Subsequent acylation using reagents such as acetic anhydride in pyridine or acetyl chloride gave the allylic acetate which was allowed to react with cyclopropanating reagents such as sodium chloro-difluoroacetate in diglyme to provide the racemic, trans- cyclopropane acetate intermediates, 5. Reaction Scheme 4

The conversion of the acid 2 to the chiral cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, is shown in Reaction Scheme 4. Intermediate 2 is condensed with (-)-2,10-camphorsultam under standard conditions, and then cyclopropanated in the presence of catalysts such as palladium acetate using diazomethane generated from reagents such as 1-methyl-3-nitro-1-nitrosoguanidine. Subsequent reduction using reagents such as LAH in solvents such as THF, followed by oxidation of the alcohol intermediates using reagents such as DMSO/oxalyl chloride, or PCC, gives the cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, in good yields. The enantiomer, (+)-(trans)-4, can also be obtained employing a similar procedure using (+)-2,10- camphorsultam in place of (-)-2,10-camphorsultam.

When it is desired to prepare compounds of Formula I wherein m = 2, the alcohol intermediate may be activated in the conventional manner such as with mesyl chloride and treated with sodium cyanide followed by reduction of the nitrile group with a reducing agent such as LAH to produce the amine intermediate 6.

Reaction Scheme 5

Reaction Scheme 5 shows the conversion of intermediates 4 and 5 to the amine intermediate, 7, and the subsequent conversion of 6. or 7 to compounds of Formula I. The carboxaldehyde intermediate, 4, is condensed with hydroxylamine and then reduced with reagents such as LAH to give the amine intermediate, 7. The acetate intermediate 5 is hydrolyzed with potassium hydroxide to the alcohol, converted to the mesylate with methane sulfonyl chloride and triethyl amine in CH₂CI₂and then converted to the azide by treatment with sodium azide in solvents such as DMF. Subsequent reduction of the azide group with a reducing agent such as LAH produced the amine intermediate 7. Further reaction of 6 or 7 with acylating reagents gives compounds of Formula I. Suitable acylating agents include carboxylic acid halides, anhydrides, acyl imidazoles, alkyl isocyanates, alkyl isothiocyanates, and carboxylic acids in the presence of condensing agents, such as carbonyl imidazole, carbodiimides, and the like. Reaction Scheme 6

Reaction Scheme 6 shows the alkylation of secondary amides of Formula I (R² = H) to give tertiary amides of Formula I (R² = alkyl). The secondary amide is reacted with a base such as sodium hydride, potassium tert-butoxide, or the like, and then reacted with an alkylating reagent such as alkyl halides, alkyl sulfonate esters, or the like to produce tertiary amides of Formula I.

Reaction Scheme 7

Reaction Scheme 7 shows the halogenation of compounds of Formula I. The carboxamides, i (Q¹ = Q² = H), are reacted with excess amounts of halogenating agents such as iodine, N-bromosuccinimide, or the like to give the dihalo-compounds of Formula I (Q¹ = Q² = halogen). Alternatively, a stoichiometric amount of these halogenating agents can be used to give the monohalo-compounds of Formula I (Q¹ = H, Q² = halogen; or Q¹ = halogen, Q² = H). In both cases, additives such as lead IV tetraacetate can be used to facilitate the reaction. Biological Activity of the Compounds

The compounds of the invention are melatonergic agents. They have been found to bind human melatonergic receptors expressed in a stable cell line with good affinity. Further, the compounds are agonists as determined by their ability, like melatonin, to block the forskolin- stimulated accumulation of cAMP in certain cells. Due to these properties, the compounds and compositions of the invention should be useful as sedatives, chronobiotic agents, anxiolytics, antipsychotics, analgesics, and the like. Specifically, these agents should find use in the treatment of stress, sleep disorders, seasonal depression, appetite regulation, shifts in circadian cycles, melancholia, benign prostatic hyperplasia and related conditions

EXPERIMENTAL PROCEDURES

SEE ORIGINAL PATENT FOR CORECTIONS

Preparation 1

Benzofuran-4-carboxaldehyde

Step 1 : N-Methoxy-N-methyl-benzofuran-4-carboxamide

A mixture of benzofuran-4-carboxylic acid [Eissenstat, et al.. J. Medicinal Chemistry, 38 (16) 3094-3105 (1995)] (2.8 g, 17.4 mmol) and thionyl chloride (25 mL) was heated to reflux for 2 h and then concentrated in vacuo. The solid residue was dissolved in ethyl acetate (50 mL) and a solution of N,O-dimethylhydroxylamine hydrochloride (2.8 g) in saturated NaHC0₃(60 mL) was added with stirring. After stirring for 1.5 h, the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated NaHCO₃ and concentrated in vacuo to give an oil (3.2 g, 95.4%).

Step 2: Benzofuran-4-carboxaldehyde

A solution of N-methoxy-N-methyl-benzofuran-4-carboxamide (3.2 g, 16.6 mmol) in THF (100 mL) was cooled to -45°C and then LAH (0.7 g, 18.7 mmol) was added. The mixture was stirred for 15 min, allowed to warm to -5°C, and then recooled to -45°C. Saturated KHS0₄ (25 mL) was added with vigorous stirring, and the mixture was allowed to warm to room temperature. The precipitate was filtered and washed with acetone. The filtrate was concentrated in vacuo to give an oil (2.3 g, 94%). Preparation 2

2,3-Dihydrobenzofuran-4-carboxaldehyde

Step 1 : 2,3-Dihydrobenzofuran-4-carboxylic acid

Benzofuran-4-carboxylic acid (10.0 g, 61 .7 mmol) was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd/C (2 g) for 12 hr. The mixture was filtered and the filtrate was diluted with water (500 mL) to give 2,3- dihydrobenzofuran-4-carboxylic acid as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-187.5°C).

Step 2: (2,3-Dihydrobenzofuran-4-yl)methanol

A solution of 2,3-dihydrobenzofuran-4-carboxylic acid (10 g, 61 mmol) in THF (100 mL) was stirred as LAH (4.64 g, 122 mmol) was slowly added. The mixture was heated to reflux for 30 min. The mixture was cooled and quenched cautiously with ethyl acetate and then with 1 N HCI (150 mL). The mixture was then made acidic with 12 N HCI until all the inorganic precipitate dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo. This oil was Kϋgelrohr distilled to a clear oil that crystallized upon cooling (8.53 g, 87.6%).

Step 3: 2.3-Dihydrobenzofuran-4-carboxaldehyde

DMSO (8.10 mL, 1 14 mmol) was added at -78°C to a stirred solution of oxalyl chloride in CH₂CI₂ (40 mL of a 2M solution). A solution of (2,3- dihydrobenzofuran-4-yl)methanol (8.53 g, 56.9 mmol) in CH₂CI₂ (35 mL) was added dropwise, and the solution stirred at -78°C for 30 min. Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min and diluted with CH₂CI₂ (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100%) that was used without purification.

Preparation 16

(±)-(trans)-2-(2,3-Dihyd robenzofuran-4-yl)cyclopropane- carboxaldehyde

Step 1 : (±Htrans)-N-Methoxy-N-methyl-2-(2.3-dihydrobenzofuran-4- yhcyclopropanecarboxamide

Trimethylsulfoxonium iodide (9.9 g, 45 mmol) was added in small portions to a suspension of sodium hydride (1 .8 g, 45 mmol) in DMF (120 mL). After the foaming had subsided (10 min), a solution of (trans)- N-methoxy-N-methyl-3-(2,3-dihydrobenzofuran-4-yl)propenamide (3.5 g, 15 mmol) in DMF (60 mL) was added dropwise, with the temperature maintained between 35-40°C. The mixture was stirred for 3 h at room temperature. Saturated NH₄CI (50 mL) was added dropwise and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with H₂O and brine, dried over K₂CO₃, and concentrated in vacuo to give a white wax (3.7 g, 100%).

Step 2: (±)-(trans)- 2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde

A solution of (±)-(trans)-N-methoxy-N-methyl-2-(2,3-dihydrobenzofuran- 4-yl)cyclopropanecarboxamide (3.7 g, 15 mmol) in THF (10 mL) was added dropwise to a rapidly stirred suspension of LAH (683 mg, 18 mmol) in THF (50 mL) at -45°C, maintaining the temperature below -40°C throughout. The cooling bath was removed, the reaction was allowed to warm to 5°C, and then the reaction was immediately recooled to -45°C. Potassium hydrogen sulfate (3.4 g, 25.5 mmol) in H₂0 (50 mL) was cautiously added dropwise, the temperature maintained below – 30°C throughout. The cooling bath was removed and the suspension was stirred at room temperature for 30 min. The mixture was filtered through Celite and the filter cake was washed with ether. The combined filtrates were then washed with cold 1 N HCI, 1 N NaOH, and brine. The filtrates were dried over MgSO4, and concentrated in vacuo to give a clear oil (2.6 g, 99%).

Preparation 18

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde

Step 1 : (-Htrans)-N-[3-(2.3-Dihvdrobenzofuran-4-yl)-propenoyll-2.10- camphorsultam

To a solution of (-)-2,10-camphorsultam (8.15 g, 37.9 mmol) in 50 mL toluene at 0°C was added sodium hydride (1.67 g, 41.7 mmol). After stirring for 0.33 h at 0°C and 0.5 h at 20°C and recooling to 0°C, a solution of 3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl chloride
(37.9 mmol), prepared in situ from the corresponding acid and thionyl chloride (75 mL), in toluene (50 mL), was added dropwise. After stirring for 18 h at 20°C, the mixture was diluted with ethyl acetate and washed with water, 1 N HCI, and 1 N NaOH. The organic solution was dried and concentrated in vacuo to give 15.8 g of crude product. Recrystallization form ethanol-methanol (600 mL, 1 :1) gave the product (13.5 g, 92%, mp 199.5-200°C).

Step 2: (-)-N-[[(trans)-2-(2,3-Dihydrobenzofuran-4-yl)-cyclopropylj- carbonylj-2, 10-camphorsultam

1 -Methyl-3-nitro-1 -nitrosoguanidine (23.88g 163 mmol) was added in portions to a mixture of 10 N sodium hydroxide (60 mL) and ether (200 mL) at 0°C. The mixture was shaken vigorously for 0.25 h and the ether layer carefully decanted into a solution of (-)-N-[3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl]-2,10-camphorsultam (9.67 g, 25 mmol) and palladium acetate (35 mg) in methylene chloride (200 mL). After stirring for 18 h, acetic acid (5 mL) was added to the reaction and the mixture stirred for 0.5 h. The mixture was washed with 1 N HCI, 1 N NaOH and brine. The solution was dried, concentrated in vacuo and the residue crystallized twice from ethanol to give the product (6.67 g, 66.5%, mp 157-159°C).

Step 3: (-)-(trans)-2-(2,3-Dihydrobenzofuran-4-yl)cyclopropane- methanol

A solution of (-)-N-[(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclo-propanecarbonylj-2,10-camphorsultam (4.3 g, 10.7 mmol) in THF (50 mL) was added dropwise to a mixture of LAH (0.81 g, 21.4 mmol) in THF (50 mL) at -45°C. The mixture was stirred for 2 hr while it warmed to 10°C. The mixture was recooled to -40°C and hydrolyzed by the addition of saturated KHS0 (20 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The precipitate was washed twice with acetone. The combined filtrate and acetone washes were concentrated in vacuo. The gummy residue was dissolved in ether, washed with 1 N NaOH and 1 N HCI, and then dried in vacuo to give the product (2.0 g, 98.4%).

Step 4: (-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde DMSO (1.6 g, 21 mmol) was added to oxalyl chloride in CH₂CI₂(7.4 mL of 2 M solution, 14.8 mmole) at -78°C. The (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropylmethanol (2.0 g, 10.5 mmol) in CH₂CI₂(15 mL) was added. The mixture was stirred for 20 min and then triethylamine (4.24 g, 42 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with CH₂CI₂ and washed with water, 1 N HCI, and then 1 N NaOH. The organic layer was dried and concentrated iι> vacuo to give the aldehyde product (1.98 g, 100%).

Preparation 24

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-methanamine A mixture of (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde (1.98 g, 10.5 mmol), hydroxylamine hydrochloride (2.29 g, 33 mmol), and 30% NaOH (3.5 mL, 35 mmol), in 5:1
ethanol/water (50 mL) was heated on a steam bath for 2 h. The solution was concentrated in vacuo. and the residue mixed with water. The mixture was extracted with CH₂CI₂. The organic extracts were dried and concentrated in vacuo to give a solid which NMR analysis showed to be a mixture of the cis and trans oximes. This material was dissolved in THF (20 mL) and added to solution of alane in THF [prepared from LAH (1.14 g, 30 mmol) and H₂S0₄ (1.47 g, 15 mmol) at 0°Cj. The reaction was stirred for 18 h, and quenched successively with water (1.15 mL), 15% NaOH (1.15 mL), and then water (3.45 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with ether and washed with water and then 1 N HCI. The acid washes were made basic and extracted with CH₂CI . The extracts were dried and concentrated in vacuo to give the amine product (1.4 g, 70.5%). The amine was converted to the fumarate salt in ethanol (mp: 197-198°C).
Anal. Calc’d for C₁₂H₁₅NO • C₄H₄0₄: C, 62.94; H, 6.27; N, 4.59.
Found: C, 62.87; H, 6.31 ; N, 4.52.

FINAL PRODUCT TASIMELTEON

Example 2

(-)-(trans)-N-[[2-(2,3-Dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl]propanamide

This compound was prepared similar to the above procedure using propionyl chloride and (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)- cyclopropanemethanamine to give an oil that solidified upon standing to an off-white solid (61 %, mp: 71-72°C). IR (NaCI Film): 3298, 1645, 1548, 1459, 1235 cm^“1.

Mo⁵ : -17.3°

Anal. Calc’d for C₁₅H₁₉N0₂: C, 73.44; H, 7.87; N, 5.71 . Found: C, 73.28; H, 7.68; N, 5.58

SYNTHESIS

SYN

Tasimelteon (Hetlioz)Tasimelteon, which is marketed by Vanda Pharmaceuticals as Hetlioz and developed in partnership with Bristol-Myers Squibb,is a drug that was approved by the US FDA in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD).234 Tasimelteon is a melatonin MT1
and MT2 receptor agonist; because it exhibits a greater affinity to the MT2 receptor than MT1, is also known as Dual Melatonin
Receptor Agonist.234 Two randomized controlled trials (phases II
and III) demonstrated that tasimelteon improved sleep latency
and maintenance of sleep with a shift in circadian rhythms, and
therefore has the potential to treat patients with transient insomnia
associated with circadian rhythm sleep disorders.235 Preclinical
studies showed that the drug has similar phase-shifting properties
to melatonin, but with less vasoconstrictive effects.236 The most
likely scale preparation of the drug, much of which has been published
in the chemical literature, is described below in Scheme 44.
Activation of commercial bis-ethanol 250 with 2.5 equivalents
of the Vilsmeier salt 251 followed by treatment with base resulted
an intramolecular cyclization reaction with the proximal phenol
and concomitant elimination of the remaining imidate to deliver
the vinylated dihydrobenzofuran 252 in 76% yield.237 Interestingly,
this reaction could be performed on multi-kilogram scale, required
no chromatographic purification, and generated environmentallyfriendly
DMF and HCl as byproducts.237 Sharpless asymmetric
dihydroxylation of olefin 252 delivered diol 253 in 86% yield and
impressive enantioselectivity (>99% ee). This diol was then activated
with trimethylsilyl chloride and then treated with base to generate epoxide 254.238 Next, a modified Horner–Wadsworth–
Emmons reaction involving triethylphosphonoacetate (TEPA, 255)
was employed to convert epoxide 254 to cyclopropane 256.239
The reaction presumably proceeds through removal of the acidic
TEPA proton followed by nucleophilic attack at the terminal epoxide
carbon. The resulting alkoxide undergoes an intramolecular
phosphoryl transfer reaction resulting in an enolate, which then attacked the newly formed phosphonate ester in an SN2 fashion
resulting in the trans-cyclopropane ester, which was ultimately
saponified and re-acidified to furnish cyclopropane acid 256.239
Conversion of this acid to the corresponding primary amide preceded
carbonyl reduction with sodium borohydride. The resulting
amine was acylated with propionyl chloride to furnish tasimelteon
(XXXI) as the final product in 86% yield across the four-step
sequence.

PATENTS

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extra info

Org. Synth.1990, 69, 154

(−)-D-2,10-CAMPHORSULTAM

[3H-3a,6-Methano-2,1-benzisothiazole, 4,5,6,7-tetrahydro-8,8-dimethyl-2,2-dioxide, (3aS)-]

Submitted by Michael C. Weismiller, James C. Towson, and Franklin A. Davis¹.

Checked by David I. Magee and Robert K. Boeckman, Jr..

1. Procedure

(−)-2,10-Camphorsultam. A dry, 2-L, three-necked, round-bottomed flask is equipped with a 1.5-in egg-shaped Teflon stirring bar, a 250-mL addition funnel, and a 300-mL Soxhlet extraction apparatus equipped with a mineral oil bubbler connected to an inert-gas source. The flask is charged with 600 mL of dry tetrahydrofuran (THF) (Note 1) and6.2 g (0.16 mol) of lithium aluminum hydride (Note 2). Into the 50-mL Soxhlet extraction thimble is placed 35.0 g (0.16 mol) of (−)-(camphorsulfonyl)imine (Note 3) and the reaction mixture is stirred and heated at reflux. After all of the(camphorsulfonyl)imine has been siphoned into the reaction flask (3–4 hr), the mixture is allowed to cool to room temperature. The unreacted lithium aluminum hydride is cautiously hydrolyzed by dropwise addition of 200 mL of 1 Nhydrochloric acid via the addition funnel (Note 4). After the hydrolysis is complete the contents of the flask are transferred to a 1-L separatory funnel, the lower, silver-colored aqueous layer is separated, and the upper layer placed in a 1-L Erlenmeyer flask. The aqueous phase is returned to the separatory funnel and washed with methylene chloride (3 × 100 mL). After the reaction flask is rinsed with methylene chloride (50 mL), the organic washings are combined with the THF phase and dried over anhydrous magnesium sulfate for 10–15 min. Filtration through a 300-mL sintered-glass funnel of coarse porosity into a 1-L round-bottomed flask followed by removal of the solvent on arotary evaporator gives 33.5 g (95%) of the crude (−)-2,10-camphorsultam. The crude sultam is placed in a 250-mL Erlenmeyer flask and crystallized from approximately 60 mL of absolute ethanol. The product is collected on a 150-mL sintered-glass funnel of coarse porosity and dried in a vacuum desiccator to give 31.1 g (88%) of the pure sultam. A second crop of crystals can be gained by evaporating approximately half the filtrate; the residue is crystallized as above to give 1.4 g (4%). The combined yield of white crystalline solid, mp 183–184°C, [α]_D −30.7° (CHCl₃, c 2.3) is92% (Note 5) and (Note 6).

2. Notes

1. Tetrahydrofuran (Aldrich Chemical Company, Inc.) was distilled from sodium benzophenone.

2. Lithium aluminum hydride was purchased from Aldrich Chemical Company, Inc.

3. (−)-(Camphorsulfonyl)imine, [(7S)-(−)-10,10-dimethyl-5-thia-4-azatricyclo[5.2.1.0^3,7]dec-3-ene 5,5-dioxide] was prepared by the procedure of Towson, Weismiller, Lal, Sheppard, and Davis, Org. Synth., Coll. Vol. VIII, 1993, 104.

4. The addition must be very slow at first (1 drop/5 sec) until the vigorous reaction has subsided.

5. The NMR spectrum of (−)-2,10-camphorsultam is as follows: ¹H NMR (CDCl₃) δ: 0.94 (s, 3 H, CH₃), 1.14 (s, 3 H, CH₃), 1.33 (m, 1 H), 1.47 (m,, 1 H), 1.80–2.05 (5 H), 3.09 (d, 1 H, J = 14), 3.14 (d, 1 H, J = 14), 3.43 (m, 1 H), 4.05 (br s, 1 H, NH); ¹³C NMR (CDCl₃) δ: 20.17 (q, CH₃), 26.51 (t), 31.55 (t), 35.72 (t), 44.44 (d), 47.15 (s), 50.08 (t), 54.46 (s), 62.48 (d).

6. Checkers obtained material having the same mp (183–184°C) and [α]_D − 31.8° (CHCl₃, c 2.3).

3. Discussion

(−)-2,10-Camphorsultam was first prepared by the catalytic hydrogenation of (−)-(camphorsulfonyl)imine overRaney nickel.² Lithium aluminum hydride reduction was used by Oppolzer and co-workers in their synthesis of the sultam.^3,4 However, because of the low solubility of the sultam in tetrahydrofuran, a large amount of solvent was required.⁴ In the procedure described here the amount of solvent is significantly reduced by using a Soxhlet extractor to convey the imine slowly into the reducing medium.⁵

Oppolzer’s chiral auxiliary,⁶ (−)-2,10-camphorsultam, is useful in the asymmetric Diels–Alder reaction,^3,4 and for the preparation of enantiomerically pure β-substituted carboxylic acids⁷ and diols,⁸ in the stereoselective synthesis of Δ²-isoxazolines,⁹ and in the preparation of N-fluoro-(−)-2,10-camphorsultam, an enantioselective fluorinating reagent.¹⁰

---

References and Notes

1. Department of Chemistry, Drexel University, Philadelphia, PA 19104.
2. Shriner, R. L.; Shotton, J. A.; Sutherland, H. J. Am. Chem. Soc.1938, 60, 2794.
3. Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta1984, 67, 1397.
4. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron1986, 42, 4035.
5. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, G.; Carroll,, P. J. J. Am. Chem. Soc.1988, 110, 8477.
6. Oppolzer, W. Tetrahedron1987, 43, 1969.
7. Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T. Helv. Chim. Acta1986, 69, 1542; Oppolzer, W.; Schneider, P. Helv. Chim. Acta1986, 69, 1817; Oppolzer, W.; Mills, R. J.; Réglier, M. Tetrahedron Lett.1986, 27, 183; Oppolzer, W.; Poli. G.Tetrahedron Lett.1986, 27, 4717; Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett.1988, 29, 3559.
8. Oppolzer, W.; Barras, J-P. Helv. Chim. Acta1987, 70, 1666.
9. Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett.1988, 29, 3555.
10. Differding, E.; Lang, R. W. Tetrahedron Lett.1988, 29, 6087.

---

Org. Synth.1990, 69, 158

(+)-(2R,8aS)-10-(CAMPHORYLSULFONYL)OXAZIRIDINE

[4H-4A,7-Methanooxazirino[3,2-i][2,1]benzisothiazole, tetrahydro-9,9-dimethyl-, 3,3-dioxide, [4aS-(4aα,7α,8aR^*)]]

Submitted by James C. Towson, Michael C. Weismiller, G. Sankar Lal, Aurelia C. Sheppard, Anil Kumar, and Franklin A. Davis¹.

Checked by David I. Magee and Robert K. Boeckman, Jr..

1. Procedure

A. (+)-(1S)-10-Camphorsulfonamide. Into a 2-L, two-necked, round-bottomed flask, equipped with a 250-mL dropping funnel, a magnetic stirring bar, and a reflux condenser fitted with an outlet connected to a disposable pipettedipped in 2 mL of chloroform in a test tube for monitoring gas evolution, were placed 116 g (0.5 mol) ofcamphorsulfonic acid (Note 1) and 750 mL of reagent-grade chloroform. The suspension of camphorsulfonic acid was heated to reflux and 71.4 g (43.77 mL, 0.6 mol, 1.2 equiv) of freshly distilled thionyl chloride was added dropwise over a 1-hr period. Heating was continued until gas evolution (sulfur dioxide and hydrogen chloride) had ceased (approximately 9–10 hr). The resultant solution of camphorsulfonyl chloride in chloroform was converted tocamphorsulfonamide without further purification.

In a 5-L, two-necked, round-bottomed flask fitted with a 250-mL dropping funnel and a mechanical stirrer was placed a solution of 1.6 L of reagent-grade ammonium hydroxide solution and the flask was cooled to 0°C in an ice bath. The solution of the crude camphorsulfonyl chloride, prepared in the preceding section, was added dropwise to the ammonium hydroxide solution at 0–10°C over a period of 1 hr. The reaction mixture was warmed to room temperature, stirred for 4 hr, the organic layer separated, and the aqueous layer was extracted with methylene chloride (3 × 250 mL). The combined organic layers were washed with brine (250 mL) and dried over anhydrousmagnesium sulfate. Removal of the solvent on the rotary evaporator gave 104.0 g (90%) of the crudecamphorsulfonamide (Note 2) and (Note 3).

B. (−)-(Camphorsulfonyl)imine. A 1-L, round-bottomed flask is equipped with a 2-in. egg-shaped magnetic stirring bar, a Dean–Stark water separator, and a double-walled condenser containing a mineral oil bubbler connected to an inert gas source. Into the flask are placed 5 g of Amberlyst 15 ion-exchange resin (Note 4) and 41.5 g of the crude(+)-(1S)-camphorsulfonamide in 500 mL of toluene. The reaction mixture is heated at reflux for 4 hr. After the reaction flask is cooled, but while it is still warm (40–50°C), 200 mL of methylene chloride is slowly added to dissolve any(camphorsulfonyl)imine that crystallizes. The solution is filtered through a 150-mL sintered glass funnel of coarse porosity an the reaction flask and filter funnel are washed with an additional 75 mL of methylene chloride.

Isolation of the (−)-(camphorsulfonyl)imine is accomplished by removal of the toluene on the rotary evaporator. The resulting solid is recrystallized from absolute ethanol (750 mL) to give white crystals, 34.5–36.4 g (90–95%), mp225–228°C; [α]_D −32.7° (CHCl₃, c 1.9) (Note 5).

C. (+)-(2R, 8aS)-10-Camphorylsulfonyloxaziridine. A 5-L, three-necked, round-bottomed Morton flask is equipped with an efficient mechanical stirrer, a 125-mm Teflon stirring blade, a Safe Lab stirring bearing (Note 6), and a 500-mL addition funnel. Into the flask are placed the toluene solution of (−)-(camphorsulfonyl)imine (39.9 g, 0.187 mol)prepared in Step B and a room-temperature solution of 543 g (3.93 mol, 7 equiv based on oxone) of anhydrouspotassium carbonate dissolved in 750 mL of water. The reaction mixture is stirred vigorously and a solution of 345 g (0.56 mol, 6 equiv of KHSO₅) of oxone dissolved in 1250 mL of water is added dropwise in three portions over 45 min(Note 7) and (Note 8). Completion of the oxidation is determined by TLC (Note 9) and the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity to remove solids. The filtrate is transferred to a 3-L separatory funnel, the toluene phase is separated and the aqueous phase is washed with methylene chloride (3 × 100 mL). The filtered solids and any solids remaining in the Morton flask are washed with an additional 200 mL of methylene chloride. The organic extracts are combined and washed with 100 mL of saturated sodium sulfite, dried over anhydrousmagnesium sulfate for 15–20 min, filtered, and concentrated on the rotary evaporator. The resulting white solid is crystallized from approximately 500 mL of hot 2-propanol to afford, after drying under vacuum in a desiccator, 35.9 g(84%) of white needles, mp 165–167°C, [α]_D +44.6° (CHCl₃, c 2.2) (Note 10) and (Note 11).

(−)-(2S,8aR)-10-(camphorylsulfonyl)oxaziridine is prepared in a similar manner starting from (−)-10-camphorsulfonic acid; mp 166–167°C, [α]_D +43.6° (CHCl₃, c 2.2).

2. Notes

1. (1S)-(+)-10-Camphorsulfonic acid was purchased from Aldrich Chemical Company, Inc.

2. The crude sulfonamide is contaminated with 5–10% of the (camphorsulfonyl)imine, the yield of which increases on standing.

3. The ¹H NMR spectrum of (+)-(1S)-10-camphorsulfonamide is as follows: (CDCl₃) δ: 0.93 (s, 3 H, CH₃), 1.07 (s, 3 H, CH₃), 1.40–2.50 (m, 7 H), 3.14 and 3.53 (AB quartet, 2 H, CH₂-SO₂, J = 15.1), 5.54 (br s, 2 H, NH₂).

4. Amberlyst 15 ion-exchange resin is a strongly acidic, macroreticular resin purchased from Aldrich Chemical Company, Inc.

5. The spectral properties of (−)-(camphorsulfonyl)imine are as follows: ¹H NMR (CDCl₃) δ: 1.03 (s, 3 H, CH₃), 1.18 (s, 3 H, CH₃), 1.45–2.18 (m, 6 H), 2.65 (m, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH₂-SO₂, J = 14.0); ¹³C NMR (CDCl₃) δ: 19.01 (q, CH₃), 19.45 (q, CH₃), 26.64 (t), 28.44 (t), 35.92 (t), 44.64 (d), 48.00 (s), 49.46 (t), 64.52 (s), 195.52 (s); IR (CHCl₃) cm⁻¹: 3030, 2967, 1366. Checkers obtained material having identical melting point and [α]_D−32.3° (CHCl₃, c 1.8).

6. The SafeLab Teflon bearing can be purchased from Aldrich Chemical Company, Inc. A glass stirring bearing lubricated with silicone grease is unsatisfactory because the dissolved salts solidify in the shaft, causing freezing.

7. Efficient stirring is important and indicated by a milky white appearance of the solution.

8. Occasionally batches of oxone purchased from Aldrich Chemical Company, Inc., have exhibited reduced reactivity in this oxidation. Oxone exposed to moisture prior to use also gives reduced reactivity in this oxidation. If this occurs, oxone is added until oxidation is complete as determined by TLC (Note 9). Potassium carbonate is added as needed to maintain the pH at approximately 9.0. Oxone stored in the refrigerator under an inert atmosphere has shown no loss in reactivity for up to 6 months.

9. Oxidation is generally complete after addition of the oxone solution. The oxidation is monitored by TLC as follows. Remove approximately 0.5 mL of the toluene solution from the nonstirring solution, spot a 250-μm TLC silica gel plate, elute with methylene chloride, and develop with 10% molybdophosphoric acid in ethanol and heating(camphorsulfonyl)imine R_f = 0.28 and (camphorylsulfonyl)oxaziridine R_f = 0.62. If (camphorsulfonyl)imine is detected, stirring is continued at room temperature until the reaction is complete (see (Note 8)). If the reaction mixture takes on a brownish color after addition of oxone and has not gone to completion after 30 min, the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity, and the solids are washed with 50 mL of methylene chloride. The aqueous/organic extracts are returned to the 5-L Morton flask and stirred vigorously and 52 g (0.08 mol, 1 equiv KHSO₅) of oxone is added over 5 min and stirring continued until oxidation is complete (approximately 10–15 min).

10. The submitters employed a toluene solution of crude imine prepared in Part B and obtained somewhat higher yields (90–95%). However, the checkers obtained yields in this range on one half the scale using isolatedsulfonylimine.

11. The spectral properties of (+)-(camphorsulfonyl)oxaziridine are as follows: ¹H NMR (CDCl₃) δ: 1.03 (s, 3 H, CH₃), 1.18 (s, 3 H, CH₃), 1.45–2.18 (m, 6 H), 2.65 (d, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH₂-SO₂, J = 14.0); ¹³C NMR (CDCl₃) δ: 19.45 (q, CH₃), 20.42 (q, CH₃), 26.55 (t), 28.39 (t), 33.64 (t), 45.78 (d), 48.16 (s), 48.32 (t), 54.07 (s), 98.76 (s). The checkers obtained material (mp 165–167°C) having [α]_D +44.7° (CHCl₃, c 2.2).

3. Discussion

Camphorsulfonamide, required for the preparation of the (camphorsulfonyl)imine, was previously prepared in two steps. The first step involved conversion of camphorsulfonic acid to the sulfonyl chloride with PCl₅ or SOCl₂. The isolated sulfonyl chloride was converted in a second step to the sulfonamide by reaction with ammonium hydroxide. This modified procedure is more efficient because it transforms camphorsulfonic acid directly to camphorsulfonamide, avoiding isolation of the camphorsulfonyl chloride.

(Camphorsulfonyl)imine has been reported as a by-product of reactions involving the camphorsulfonamide.^2,3,4,5Reychler in 1898 isolated two isomeric camphorsulfonamides,² one of which was shown to be the(camphorsulfonyl)imine by Armstrong and Lowry in 1902.³ Vandewalle, Van der Eycken, Oppolzer, and Vullioud described the preparation of (camphorsulfonyl)imine in 74% overall yield from 0.42 mol of the camphorsulfonyl chloride.⁶ The advantage of the procedure described here is that, by using ammonium hydroxide, the camphorsulfonyl chloride is converted to the sulfonamide in >95% yield.⁷ The sulfonamide is of sufficient purity that it can be used directly in the cyclization step, which, under acidic conditions, is quantitative in less than 4 hr. These modifications result in production of the (camphorsulfonyl)imine in 86% overall yield from the sulfonyl chloride.

In addition to the synthesis of enantiomerically pure (camphorylsulfonyl)oxaziridine⁷ and its derivatives,⁸ the(camphorsulfonyl)imine has been used in the preparation of (−)-2,10-camphorsultam (Oppolzers’ auxiliary),^6,9 (+)-(3-oxocamphorysulfonyl) oxaziridine,¹⁰ and the N-fluoro-2,10-camphorsultam, an enantioselective fluorinating reagent.¹¹

The N-sulfonyloxaziridines are an important class of selective, aprotic oxidizing reagents.¹²¹³¹⁴ Enantiomerically pure N-sulfonyloxaziridines have been used in the asymmetric oxidation of sulfides to sulfoxides (30–91% ee),¹⁵selenides to selenoxides (8–9% ee).¹⁶ disulfides to thiosulfinates (2–13% ee),⁵ and in the asymmetric epoxidation of alkenes (19–65% ee).^17,18 Oxidation of optically active sulfonimines (R^*SO₂N=CHAr) affords mixtures of N-sulfonyloxaziridine diastereoisomers requiring separation by crystallization and/or chromatography.³

(+)-(Camphorylsulfonyl)oxaziridine described here is prepared in four steps from inexpensive (1S)-(+)- or (1R)-(+)-10-camphorsulfonic acid in 77% overall yield.⁷ Separation of the oxaziridine diastereoisomers is not required because oxidation is sterically blocked from the exo face of the C-N double bond in the (camphorsulfonyl)imine. In general, (camphorsulfonyl)oxaziridine exhibits reduced reactivity compared to other N-sulfonyloxaziridines. For example, while sulfides are asymmetrically oxidized to sulfoxides (3–77% ee), this oxaziridine does not react with amines or alkenes.⁷ However, this oxaziridine is the reagent of choice for the hydroxylation of lithium and Grignard reagents to give alcohols and phenols because yields are good to excellent and side reactions are minimized.¹⁹ This reagent has also been used for the stereoselective oxidation of vinyllithiums to enolates.²⁰

The most important synthetic application of the (camphorylsulfonyl)oxaziridines is the asymmetric oxidation of enolates to optically active α-hydroxy carbonyl compounds.^{14,21,22,23,24} Chiral, nonracemic α-hydroxy carbonylcompounds have been used extensively in asymmetric synthesis, for example, as chiral synthons, chiral auxiliaries, and chiral ligands. This structural array is also featured in many biologically active natural products. This oxidizing reagent gives uniformly high chemical yields regardless of the counterion, and stereoselectivities are good to excellent (50–95% ee).^{9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24} Since the configuration of the oxaziridine three-membered ring controls the stereochemistry, both α-hydroxy carbonyl optical isomers are readily available. Representative examples of the asymmetric oxidation of prochiral enolates by (+)-(2R,8aS)-camphorylsulfonyl)oxaziridine are given in Tables I and II.

This preparation is referenced from:

• Org. Syn. Coll. Vol. 8, 110
• Org. Syn. Coll. Vol. 9, 212
• References and Notes
  1. Department of Chemistry, Drexel University, Philadelphia, PA 19104.
  2. Reychler, M. A. Bull. Soc. Chim. III1889, 19, 120.
  3. Armstrong, H. E.; Lowry, T. M. J. Chem. Soc., Trans.1902, 81, 1441.
  4. Dauphin, G.; Kergomard, A.; Scarset, A. Bull. Soc. Chim. Fr.1976, 862.
  5. Davis, F. A.; Jenkins, Jr., R. H.; Awad, S. B.; Stringer, O. D.; Watson, W. H.; Galloy, J. J. Am. Chem. Soc.1982, 104, 5412.
  6. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron, 1986, 42, 4035.
  7. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carroll, P. J. J. Am. Chem. Soc.1988, 110, 8477.
  8. Davis, F. A.; Weismiller, M. C.; Lal, G. S.; Chen, B. C.; Przeslawski, R. M. Tetrahedron Lett., 1989, 30, 1613.
  9. Oppolzer, W. Tetrahedron1987, 43, 1969.
  10. Glahsl, G.; Herrmann, R. J. Chem. Soc., Perkin Trans. I1988, 1753.
  11. Differding, E.; Lang, R. W. Tetrahedron Lett.1988, 29, 6087.
  12. For recent reviews on the chemistry of N-sulfonyloxaziridines, see: (a) Davis, F. A.; Jenkins, Jr., R. H. in “Asymmetric Synthesis,” Morrison, J. D., Ed.; Academic Press: Orlando, FL, 1984, Vol. 4, Chapter 4;
  13. Davis, F. A.; Haque, S. M. in “Advances in Oxygenated Processes,” Baumstark, A. L., Ed.; JAI Press: London, Vol. 2;
  14. Davis, F. A.; Sheppard, A. C. Tetrahedron1989, 45, 5703.
  15. Davis, F. A.; McCauley, Jr., J. P.; Chattopadhyay, S.; Harakal, M. E.; Towson, J. C.; Watson, W. H.; Tavanaiepour, I. J. Am. Chem. Soc.1987, 109, 3370.
  16. Davis, F. A.; Stringer, O. D.; McCauley, Jr., J. M. Tetrahedron1985, 41, 4747.
  17. Davis, F. A.; Chattopadhyay, S. Tetrahedron Lett.1986, 27, 5079.
  18. Davis, F. A.; Harakal, M. E.; Awad, S. B. J. Am. Chem. Soc.1983, 105, 3123.
  19. Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick S. Tetrahedron Lett.1987, 28, 5115.
  20. Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett.1988, 29, 4269.
  21. Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem.1986, 51, 2402.
  22. Davis, F. A.; Haque, M. S. J. Org. Chem.1986, 51, 4083; Davis, F. A.; Haque, M. S.; Przeslawski, R. M. J. Org. Chem.1989, 54, 2021.
  23. Davis, F. A.; Ulatowski, T. G.; Haque, M. S. J. Org. Chem.1987, 52, 5288.
  24. Davis, F. A.; Sheppard, A. C., Lal, G. S. Tetrahedron Lett.1989, 30, 779.
  25. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am. Chem. Soc.1990, 112, 6679.

a US 5 856 529 (Bristol-Myers Squibb; 5.1.1999; appl. 9.12.1997; USA-prior. 10.12.1996).

• • b US 7 754 902 (Vanda Pharms.; 13.7.2010; appl. 18.5.2006).

• treatment of circadian rhythm disorders:

  • US 8 785 492 (Vanda Pharms.; 22.7.2014; appl. 25.1.2013; USA-prior. 26.1.2012).

• synthesis cis-isomer:

  • US 6 214 869 (Bristol-Myers Squibb; 10.4.2001; appl. 25.5.1999; USA-prior. 5.6.1998).

Patents

References

Tasimelteon

Clinical data
Trade names	Hetlioz
License data	EUEMA: by INN
Pregnancy category	US:C (Risk not ruled out)
Routes of administration	Oral
ATC code	N05CH03 (WHO)
Legal status
Legal status	US:℞-only
Pharmacokinetic data
Bioavailability	not determined in humans[1]
Protein binding	89–90%
Metabolism	extensive hepatic, primarily CYP1A2 and CYP3A4-mediated
Elimination half-life	0.9–1.7 h / 0.8–5.9 h (terminal)
Excretion	80% in urine, 4% in feces
Identifiers
IUPAC name[show]
CAS Number	609799-22-6
PubChemCID	10220503
IUPHAR/BPS	7393
ChemSpider	8395995
UNII	SHS4PU80D9
ChEBI	CHEBI:79042
ECHA InfoCard	100.114.889
Chemical and physical data
Formula	C15H19NO2
Molar mass	245.32 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] CCC(=O)NC[C@@H]1C[C@H]1C2=C3CCOC3=CC=C2
InChI[hide] InChI=1S/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1  Key:PTOIAAWZLUQTIO-GXFFZTMASA-N

DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

Chemical and physical properties 

Tasimelteon has two stereogenic centers. Besides the medically used trans-1 R , 2 R isomer (in the picture above left), there are thus three further stereoisomers that do not arise in the synthesis.

Tasimelteon is a white to off-white crystalline non-hygroscopic substance, soluble in water at physiologically relevant pH levels and readily soluble in alcohols, cyclohexane and acetonitrile. The compound occurs in two crystal forms. It is an anhydrate melting at 74 ° C and a hemihydrate . ^[4] The hemihydrate is from about 35 ° C the water of hydration and converts thereby in the anhydrate form to. ^[4] The anhydrate crystallizes in a monoclinic lattice with the space group P 2 ₁ , and the hemihydrate crystallizes in a tetragonal lattice with the space group P 4 ₃ 2₁ 2. ^[4]

4  Kaihang Liu, Zhou Xinbo, Zhejing Xu, Bai Hongzhen, Jianrong Zhu Jianming Gu, Guping Tang, Liu Xingang, Hu Xiurong: anhydrate and hemihydrate of Tasimelteon: Synthesis, structure, and pharmacokinetic study in J. Pharm. Biomed. Anal. 151 (2018) 235-243, doi : 10.1016 / j.jpba.2017.12.035 .