WO2009111004A1 - Processes for the preparation of intermediates related to the 5-ht2c agonist (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine - Google Patents

Processes for the preparation of intermediates related to the 5-ht2c agonist (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine Download PDF

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Publication number
WO2009111004A1
WO2009111004A1 PCT/US2009/001340 US2009001340W WO2009111004A1 WO 2009111004 A1 WO2009111004 A1 WO 2009111004A1 US 2009001340 W US2009001340 W US 2009001340W WO 2009111004 A1 WO2009111004 A1 WO 2009111004A1
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chlorophenyl
process according
conducted
ethanol
reacting
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PCT/US2009/001340
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English (en)
French (fr)
Inventor
Marlon V. Carlos
Ryan O. Castro
Tawfik Gharbaoui
Xiao-Xiong Lu
You-An Ma
Nicholas D. San Martin
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Arena Pharmaceuticals Inc
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Arena Pharmaceuticals Inc
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Priority to US12/921,101 priority Critical patent/US8822727B2/en
Priority to CN200980116092.7A priority patent/CN102015591B/zh
Priority to JP2010549649A priority patent/JP5491421B2/ja
Priority to EP09717615A priority patent/EP2288585A1/en
Publication of WO2009111004A1 publication Critical patent/WO2009111004A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/38—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

Definitions

  • the present invention provides processes and intermediates useful in the preparation of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, a serotonin (5- ⁇ T) receptor agonist that is useful in the treatment or prophylaxis of, for example, central nervous system disorders, such as obesity.
  • Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in neurological and in psychiatric disorders.
  • 5-HT has been implicated in the regulation of feeding behavior. 5-HT is believed to work by inducing a feeling of fullness or satiety so eating stops earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT on the 5HT 2 c receptor plays an important role in the control of eating. Furthermore, stimulation of the 5HT 2 c receptor has also been shown to play an important role in the anti-obesity effect of d-fenfluramine.
  • the 5-HT 2 c receptor As the 5-HT 2 c receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus specifically in the PVN and DMH, and predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral tissues, a selective 5-HT 2 c receptor agonist can be a more effective and safe anti-obesity agent. Also, 5-HT 2C knockout mice are overweight with cognitive impairment and susceptibility to seizure. Thus, the 5HT 2 c receptor is recognized as a well-accepted receptor target for the treatment of obesity, psychiatric disorders, and other disorders.
  • This compound is useful in the treatment of 5-HT 2 c receptor associated disorders, such as, obesity, and is disclosed in PCT patent publication, WO2003/086303.
  • Some embodiments of the present invention disclose processes for preparing 2-(4- chlorophenyl)ethyl bromide comprising the steps: reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol to form a reaction mixture comprising the 2-(4-chlorophenyl)ethyl bromide; and isolating the 2-(4-chlorophenyl)ethyl bromide from the reaction mixture.
  • Some embodiments of the present invention disclose processes for preparing 2-chloro- N-(4-chlorophenethyl)propan-l -amine hydrochloride comprising the steps: a) reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol to form 2-(4- chlorophenyl)ethyl bromide; b) reacting said 2-(4-chlorophenyl)ethyl bromide with l-aminopropan-2-ol to form 1 -(4-chlorophenethylamino)propan-2-ol; and c) reacting said l-(4-chlorophenethylamino)propan-2-ol with thionyl chloride to form 2-chloro-N-(4-chlorophenethyl)propan-l -amine hydrochloride.
  • the processes and intermediates of the present invention are useful in the preparation of the therapeutic agent (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, including, salts and crystal forms thereof.
  • the compound (/?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine, including, salts and crystal forms are disclosed in PCT patent publications, WO2003/086306 and WO2006/069363.
  • 2-(4-chlorophenyl)-ethyl bromide can be prepared from the commercially available compound, 2-(4-chlorophenyl)ethanol, according to the process depicted in Synthetic Scheme 1.
  • the invention discloses processes for preparing 2-(4- chlorophenyl)ethyl bromide comprising reacting hydrogen bromide with 2-(4- chlorophenyl)ethanol to form 2-(4-chlorophenyl)ethyl bromide.
  • the present invention discloses processes for preparing 2-(4- chlorophenyl)ethyl bromide comprising the steps: reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol to form a reaction mixture comprising the 2-(4-chlorophenyl)ethyl bromide; and isolating the 2-(4-chlorophenyl)ethyl bromide from the reaction mixture.
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted in the absence of an added solvent.
  • absence of an added solvent is intended to mean that none or no substantial amount of solvent is added to the reaction (e.g. the reaction can be conducted "neat” in the absence of solvent). It is understood that during the reaction an equivalent amount of water is formed together with 2-(4- chlorophenyl)ethyl bromide and that this water so formed is not considered as a solvent but merely as a co-product for purposes of this definition.
  • any impurity present in 2-(4-chlorophenyl)ethanol in an amount of about 5% or less as determined by HPLC does not constitute "an added solvent" for the purposes of this definition.
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted by adding the hydrogen bromide to the 2-(4- chlorophenyl)ethanol .
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted by adding the hydrogen bromide as a gas to the 2-(4- chlorophenyl)ethanol .
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted by adding the hydrogen bromide as a gas above the surface of the 2-(4-chlorophenyl)ethanol.
  • the presure above the surface of the 2- (4-chlorophenyl)ethanol is about +2 bar to about ambient presure. In some embodiments, the presure above the surface of the 2-(4-chlorophenyl)ethanol is about +1.65 bar to about +0.5 bar.
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted by adding the hydrogen bromide as a gas below the surface of the 2-(4-chlorophenyl)ethanol. In some embodiments, the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted at a temperature from about 25 0 C to about 110 0 C.
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted at a temperature from about 60 0 C to about 100 0 C.
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted at a temperature from about 70 0 C to about 90 0 C.
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar to about +2.00 bar.
  • the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar to about +0.50 bar. In some embodiments, the reacting of hydrogen bromide with 2-(4- chlorophenyl)ethanol is conducted at a pressure from about -0.85 bar to about +0.37 bar.
  • isolating comprises separating the water co-product from the 2- (4-chlorophenyl)ethyl bromide.
  • 2-(4-chlorophenyl)ethyl bromide has a purity of about 95% or greater as determined by HPLC. In some embodiments, after the isolating step, 2-(4-chlorophenyl)ethyl bromide has a purity of about 97% or greater as determined by HPLC.
  • HPLC refers to High Performance Liquid Chromatography. In some embodiments, “HPLC” refers to Reversed-Phase High Performance Liquid Chromatography. In some embodiments, “HPLC” refers to Normal-Phase High Performance Liquid Chromatography.
  • 2-chloro-N-(4-chlorophenethyl)propan-l -amine hydrochloride can be prepared from 2-(4-chlorophenyl)ethanol according to the process depicted in Synthetic Scheme 2.
  • the present invention discloses processes for preparing 2-chloro-
  • N-(4-chlorophenethyl)propan-l -amine hydrochloride comprising the steps: a) reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol to form 2-(4- chlorophenyl)ethyl bromide; b) reacting the 2-(4-chlorophenyl)ethyl bromide with 1 -aminopropan-2-ol to form l-(4-chlorophenethylamino)propan-2-ol; and c) reacting the l-(4-chlorophenethylamino)propan-2-ol with thionyl chloride to form 2-chloro-N-(4-chlorophenethyl)propan-l -amine hydrochloride.
  • reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted in the absence of an added solvent. In some embodiments, reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted by adding the hydrogen bromide to the 2-(4-chlorophenyl)ethanol.
  • reacting hydrogen bromide with said 2-(4-chlorophenyl)ethanol is conducted by adding said hydrogen bromide as a gas to said 2-(4-chlorophenyl)ethanol.
  • reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from about 25 0 C to about 110 °C. In some embodiments, reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from about 60 0 C to about 100 0 C.
  • reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from about 70 0 C to about 90 0 C. In some embodiments, reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar to about +2.00 bar.
  • reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar to about +0.50 bar.
  • reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from about -0.85 bar to about +0.37 bar.
  • reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol produces 2-(4-chlorophenyl)ethyl bromide with a purity of about 95% or greater as determined by HPLC. In some embodiments, reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol, produces 2-(4-chlorophenyl)ethyl bromide with a purity of about 97% or greater as determined by HPLC.
  • HPLC refers to Reversed-Phase High Performance Liquid Chromatography. In some embodiments, “HPLC” refers to Normal-Phase High Performance Liquid Chromatography.
  • reacting 2-(4-chlorophenyl)ethyl bromide with 1-aminopropan- 2-ol is conducted by the addition of 2-(4-chlorophenyl)ethyl bromide to l-aminopropan-2-ol. In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with l-aminopropan-
  • 2-ol is conducted by the addition of 2-(4-chlorophenyl)ethyl bromide to l-aminopropan-2-ol at a rate such that l-(bis(4-chlorophenethyl)amino)propan-2-ol is formed in an amount less than about 10% compared to l-(4-chlorophenethylamino)propan-2-ol as determined by HPLC.
  • reacting 2-(4-chlorophenyl)ethyl bromide with 1-aminopropan- 2-ol is conducted by the addition of 2-(4-chlorophenyl)ethyl bromide to l-aminopropan-2-ol at a rate such that l-(bis(4-chlorophenethyl)amino)propan-2-ol is formed in an amount less than about 5% compared to l-(4-chlorophenethylamino)propan-2-ol as determined by HPLC.
  • the chemcial structure for l-(bis(4-chlorophenethyl)amino)propan-2-ol is shown below:
  • reacting 2-(4-chlorophenyl)ethyl bromide with 1-aminopropan- 2-ol is conducted in the presence of a molar excess of l-aminopropan-2-ol compared to 2-(4- chlorophenyl)ethyl bromide.
  • reacting 2-(4-chlorophenyl)ethyl bromide with 1-aminopropan- 2-ol is conducted in the presence of about 5 molar excess of l-aminopropan-2-ol compared to 2- (4-chlorophenyl)ethyl bromide.
  • reacting 2-(4-chlorophenyl)ethyl bromide with l-aminopropan- 2-ol is conducted at a temperature from about 60 0 C to about 95 0 C.
  • reacting 2-(4-chlorophenyl)ethyl bromide with 1-aminopropan- 2-ol is conducted at a temperature from about 75 0 C to about 90 0 C.
  • reacting l-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted in the presence of a solvent.
  • the solvent is an aromatic hydrocarbon.
  • the solvent comprises toluene.
  • the solvent is toluene.
  • reacting l-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted in the presence of dimethylacetamide (also referred to as DMA).
  • DMA dimethylacetamide
  • reacting l-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted in the presence of dimethylformamide (also referred to as DMF).
  • dimethylformamide also referred to as DMF
  • reacting l-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted at a temperature from about 55 0 C to about 70 0 C.
  • reacting l-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted at a temperature from about 60 0 C to about 65 0 C.
  • the process further comprises a step of separating a water co- product from the 2-(4-chlorophenyl)ethyl bromide after step a) and prior to step b). In some embodiments, wherein after step a) the resulting mixture is used in step b) without substantial purification.
  • the process further comprises a step of removing 1- aminopropan-2-ol from the mixture after step b) and prior to step c).
  • the removing of l-aminopropan-2-ol from the mixture after after step b) is conducted by the steps comprising: adding water and an immiscible organic solvent to the mixture after step b) to form a biphasic mixture comprising an aqueous phase and an organic phase; mixing the biphasic mixture and subsequently allowing to separate into the aqueous phase and the organic phase; and removing the aqueous phase from the organic phase.
  • the immiscible organic solvent comprises toluene.
  • the immiscible organic solvent is toluene.
  • the process further comprises a step of crystallizing the 2-chloro- N-(4-chlorophenethyl)propan-l -amine hydrochloride after step c).
  • crystallizing the 2-chloro-N-(4-chlorophenethyl)propan-l -amine hydrochloride is conducted in the presence of a mixture comprising a Ci-C 6 alcohol.
  • crystallizing the 2-chloro-N-(4-chlorophenethyl)propan- 1 -amine hydrochloride is conducted in the presence of a mixture comprising isopropanol.
  • steps a), b) and c) are conducted without substantial purification and in doing so steps a), b) and c) are considered to be “telescoped” steps.
  • the phrase "without substantial purification” is intended to mean that little or no substantial purification is utilized, such as, chromatography (reverse-phase chromatography, normal -phase chromatography, flash, HPLC, MPLC, etc.), distillation (vacuum or atmospheric) of product, etc. It is understood that, 1) the mere removal of water by phase separation, where the water was either a co-product of the reaction or physically added; 2) the removal of a volatile solvent (i.e. a liquid with a boiling point of about 150 0 C or less at atmospheric pressure); and 3) recrystallization and crystallization, are not considered substantial purification steps for purposes of this definition.
  • Example 1 Preparation of 2-(4-chlorophenyI)ethyl bromide from 2-(4- chlorophenyl)ethanol.
  • the vessel was gradually filled with hydrogen bromide gas and stirred at an internal pressure between +1.38 and +1.65 bar for 2 h. Conversion to the bromide was found to be 92.67 % by HPLC. The reaction was held at a bath temperature of 96 0 C at atmospheric pressure for 45 min. The vessel was then evacuated and slowly backfilled with hydrogen bromide gas over 15 min to +1.38 bar. After stirring for a further 2.5 h at +1.24 to +1.38 bar, the vessel was vented to the caustic scrubber and held at a bath temperature of 96 0 C in closed system at atmospheric pressure. Conversion to the bromide was found to be 99.49% by HPLC with a peak area purity of 98.71%.
  • the pressure vessel was then evacuated and gradually back filled with hydrogen bromide gas to an internal pressure of +1.03 bar.
  • the dark brown suspension was allowed to stir at +1.03 bar at a bath temperature of 96 0 C.
  • the internal pressure had risen to +2.41 bar and the vessel was vented to the caustic scrubber, purged with nitrogen, and allowed to cool to ambient temperature.
  • the peak area purity was found to be 96.06%.
  • the reaction mixture was transferred to a seperatory funnel and allowed to separate at room temp.
  • the upper product phase was washed with water (412 mL) in 2 portions to leave a milky beige suspension (563.4 g) with an HPLC peak area purity of 99.29%.
  • Example 2 Preparation of 2-(4-chlorophenyl)ethyl bromide from 2-(4- chlorophenyl)ethanol.
  • 2-(4-Chlorophenyl)ethanol (1600 kg, 10.22 mol) was heated with stirring in a jacketed reactor to 70 0 C. After the reactor had been evacuated to -0.85 bar and sealed, hydrogen bromide gas was bubbled into the liquid 2-(4-chlorophenyl)ethanol while allowing the heat of reaction to warm the stirred reaction mixture to 90 0 C. The hydrogen bromide gas addition was continued sufficiently slowly to maintain the stirred reactor contents at 90 0 C with reactor jacket cooling.
  • the stirred upper product phase was sparged with nitrogen at atmospheric pressure for 77 minutes at 30 0 C, evacuated to -0.85 bar, sparged with nitrogen again and maintained under reduced pressure for one hour at 30 0 C.
  • Water (445 kg) was then added, and the resulting stirred mixture was sparged with nitrogen at 30 °C for 2 h.
  • the reactor contents were then allowed to stand for 3 h to permit phase separation.
  • the milky lower product phase was drained from the clear upper aqueous phase.
  • the upper aqueous phase weighed 465 kg.
  • the lower product phase weighed 2190 kg (97.7% yield not corrected for assay) and was found to have an HPLC peak area purity of 98.0%.
  • Example 4 Representative HPLC conditions.
  • Solvents Acetonitrile/Water/o-Phosphoric acid (50/50/1 v/v/w). Sample Size: 5 ⁇ L, Injection with needle-wash (solvent). Column: MZ-Aqua Perfect C 18, 3 pm, 250 x 4.0 mm (Supplier: EGT-Chemie AG, Art. No:
  • Detection wavelength UV, 195 nm.
  • Detection wavelength UV, 220 ran.
  • Example 5 Preparation of 2-(4-chlorophenyI)ethyl bromide from 2-(4- chlorophenyl)ethanol.
  • the quantities in the following procedure are normalized to 1.00 kg of the starting material 2-(4-chlorophenyl)ethanol.
  • the yield shown below is the average from four separate production runs using 1600-2400 kg of the starting material 2-(4-chlorophenyl)ethanol, the following quantities and volume ratios.
  • the resulting crude product was sparged with nitrogen gas at 30° C and atmospheric pressure for about 75 minutes to remove as much residual hydrogen bromide as possible before the final water wash.
  • the reactor was evacuated and the nitrogen sparging of nitrogen was continued through the stirred crude product at 30° C for about an hour while continuing to pull full vacuum.
  • To the resulting crude product was charged with water (0.278 kg) the contents stirred at 30° C for 15 minutes. The stirring was stopped and the phases were allowed to separate at 30 °C over 2 to 3 hours.

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/US2009/001340 2008-03-04 2009-03-03 Processes for the preparation of intermediates related to the 5-ht2c agonist (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine Ceased WO2009111004A1 (en)

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US12/921,101 US8822727B2 (en) 2008-03-04 2009-03-03 Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
CN200980116092.7A CN102015591B (zh) 2008-03-04 2009-03-03 制备与5-ht2c激动剂(r)-8-氯-1-甲基-2，3，4，5-四氢-1h-3-苯并氮杂卓相关的中间体的方法
JP2010549649A JP5491421B2 (ja) 2008-03-04 2009-03-03 ５−ｈｔ２ｃアゴニストである（ｒ）−８−クロロ−１−メチル−２，３，４，５−テトラヒドロ−１ｈ−３−ベンゾアゼピンに関連する中間体の調製のためのプロセス
EP09717615A EP2288585A1 (en) 2008-03-04 2009-03-03 Processes for the preparation of intermediates related to the 5-ht2c agonist (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine

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US6810208P 2008-03-04 2008-03-04
US61/068,102 2008-03-04

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WO2010148207A2 (en) 2009-06-18 2010-12-23 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-ht2c receptor agonists
WO2011153206A1 (en) 2010-06-02 2011-12-08 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-ht2c receptor agonists
WO2012030951A1 (en) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Fast-dissolve dosage forms of 5-ht2c agonists
WO2012030927A2 (en) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-ht2c agonists useful for weight management
WO2012030957A2 (en) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Non-hygroscopic salts of 5-ht2c agonists
WO2012030938A1 (en) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Salts of lorcaserin with optically active acids
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US8153621B2 (en) 2004-12-23 2012-04-10 Arena Pharmaceuticals, Inc. 5ht2C receptor modulator compositions
US8168782B2 (en) 2006-04-03 2012-05-01 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8367657B2 (en) 2003-06-17 2013-02-05 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
WO2014058441A1 (en) 2012-10-09 2014-04-17 Arena Pharmaceuticals, Inc. Method of weight management
CN103901151A (zh) * 2014-04-23 2014-07-02 湖北朗昕生化药业有限公司 一种hplc法检测氯卡色林盐酸盐含量的方法
US8822727B2 (en) 2008-03-04 2014-09-02 Arena Pharmaceuticals, Inc. Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
WO2014187768A1 (en) 2013-05-20 2014-11-27 Lek Pharmaceuticals D.D. Novel synthetic processes to 8-chloro-3-benzo[d]azepine via friedel-crafts alkylation of olefin
WO2014202765A1 (en) 2013-06-21 2014-12-24 Lek Pharmaceuticals D.D. Preparation of chiral 1-methyl-2,3,4,5-1h-benzodiazepines via asymmetric reduction of alpha-substituted styrenes
WO2016069875A1 (en) 2014-10-30 2016-05-06 Arena Pharmaceuticals, Inc. Compositions and methods for ceasing tobacco smoking
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