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US20140303382A1 - Process for the preparation of 6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide and intermediates thereof - Google Patents

Process for the preparation of 6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide and intermediates thereof Download PDF

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Publication number
US20140303382A1
US20140303382A1 US14/352,623 US201214352623A US2014303382A1 US 20140303382 A1 US20140303382 A1 US 20140303382A1 US 201214352623 A US201214352623 A US 201214352623A US 2014303382 A1 US2014303382 A1 US 2014303382A1
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Prior art keywords
compound
process according
solvent
reaction
water
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Abandoned
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US14/352,623
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English (en)
Inventor
Enrica Diodato
Katia Marcucci
Russell Thomas
Paul Wiedenau
Martin Rettig
Huw Roberts
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Siena Biotech SpA
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Siena Biotech SpA
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Assigned to SIENA BIOTECH S.P.A. reassignment SIENA BIOTECH S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DIODATO, Enrica, MARCUCCI, KATIA, RETTIG, MARTIN, ROBERTS, HUW, THOMAS, RUSSELL, WIEDENAU, Paul
Publication of US20140303382A1 publication Critical patent/US20140303382A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • the present invention relates to a novel process for the preparation of rac-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (I) in pharmaceutically acceptable polymorphic form and to intermediates thereof.
  • the compound 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (I) is known from WO2005026112 to possess anti Sirt1 activity, and as such useful in the preparation of medicaments for any condition which may benefit from the inhibition of Sirt1.
  • metabolic diseases such as metabolic syndrome, type I diabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerative conditions that are caused at least in part by polyglutamine aggregation, such as Huntington's disease, spinalbulbar muscular atrophy (SBMA or Kennedy's disease) dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Joseph disease (MJD;SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCAT), and spinocerebellar ataxia 12 (SCA12).
  • metabolic diseases such as metabolic syndrome, type I diabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,
  • Compound (I) can be isolated, depending on the method of preparation, in crystalline form A or B or in amorphous form.
  • Form A is a solvent-free ( FIG. 1 ), non hygroscopic ( FIG. 2 ) form that can be obtained by crystallisation from isopropanol or by concentration at room temperature from various polar protic solvents such as methanol, ethanol, isopropanol or water, as well as from ethyl acetate.
  • Form A is characterised by
  • a Raman spectrum shown in FIG. 5 having characteristic peaks expressed in cm ⁇ 1 at approximately 3450, 3050, 1649, 1616, 1476, 1307, 1194, 901, 831, 323 and 197.
  • Form B is a non hygroscopic form ( FIG. 7 ) that can be obtained by evaporation at room temperature from acetone or MEK (methyl ethyl ketone), or a mixture of solvents which contain acetone or MEK.
  • acetone or MEK methyl ethyl ketone
  • a Raman spectrum shown in FIG. 10 having characteristic peaks expressed in cm ⁇ 1 at approximately 1712, 1623, 1485, 1313, 1163, 843, 339 and 212.
  • the amorphous form of (I) is characterised by the lack of sharp X-ray diffraction peaks in its XRPD pattern ( FIG. 11 ) and can be obtained by cryogrinding.
  • the amorphous form can easily be converted into form A or into form B. This can be achieved by slurrying in ethanol or acetone, towards forms A or B, respectively. In turn, form B can be easily converted into form A. This can be achieved by slurrying form B in water at various temperatures.
  • Form A is non hygroscopic ( FIG. 2 ), stable over time (Tables 3 and 4) and it is suitable for use in pharmaceutical compositions.
  • Form A can be suitably formulated into various pharmaceutically acceptable preparations, which are preferably for oral administration.
  • the present invention provides a process for obtaining compound (I) which avoids the drawbacks in the prior art and which is conveniently applicable on a technical scale.
  • the invention provides a process for the preparation of intermediate (I′-b) according to the following scheme:
  • R is C 1 -C 6 linear, branched or cyclic alkyl chain and preferably ethyl
  • the process for the preparation of compound (I′-b) as above defined further comprises removing water from the reaction mixture by azeotropic distillation.
  • the crude mixture containing compound (I′-b) obtained by the invention process is crystallized from an apolar solvent, preferably from cyclohexane (see examples 3 and 4).
  • Compound (I) may be further processed by:
  • Step a) may be performed by evaporation under reduced pressure and/or heating and/or sparging the reaction mixture with an inert gas.
  • Step b) may be performed by addition of water to the reaction mixture.
  • Exemplary suitable solvents in step c) are ethyl acetate, water, methanol, ethanol and isopropanol, with isopropanol being preferred.
  • GMP-grade form A it may be preferable to perform two or more subsequent crystallizations.
  • GMP-grade material can be obtained after only two re-crystallisations if the crude precipitate ensuing from step b) is crystallised from MEK/cyclohexane before performing step c) (example 7).
  • the process of the invention does not require chromatographic purification of the final product and allows to obtain (I) in crystalline form A.
  • the starting compound (I′-a) can be obtained by reacting equimolar amounts of bromine and a compound of formula I′-c, at 0-5° C. in DCM:
  • the compound (I-a′) is obtained by slow addition, under stirring, of gaseous bromine to a solvent-free equimolar amount of compound (I′-c), at 0-10° C.
  • FIG. 1 DSC (upper) and TGA (lower) curves of form A
  • FIG. 2 Absorption-Desorption spectrum of form A
  • FIG. 3 XPRD spectrum of form A
  • FIG. 4 IR spectrum of form A
  • FIG. 5 Raman spectrum of form A
  • FIG. 6 DSC (upper) and TGA (lower) curves of form B isolated from acetone.
  • FIG. 7 Absorption-desorption spectrum of form B
  • FIG. 8 XPRD spectrum of Form B
  • FIG. 9 IR spectrum of form B
  • FIG. 10 Raman spectrum of form B
  • FIG. 11 XPRD spectrum of the amorphous form
  • the reaction was quenched with water (5 L) allowing the exotherm to take the temperature to 20-25° C.
  • the organic layer (bottom, hazy yellow, 10.78 kg) was separated form the clear colourless aqueous layer (5.97 kg).
  • the organic layer was washed with sat. sodium bicarbonate solution (4 kg) and then separated (organic (10.43 kg) and aqueous (4.2 kg)).
  • the organic layer was stripped to an oil under reduced pressure and ethanol (2 L) charged. The ethanol was then removed by distillation at reduced pressure to give a orange oil (2950.9 g).
  • Ethyl-2-cyclohexanone-carboxylate (497 kg) is cooled down to 0° C. and bromine is added over 9 h while stirring, keeping the temperature at 0° ⁇ 10° C. After complete addition, the mixture is stirred at 0° C. for 4 h (content of starting material 2.8% by GC), then it is warmed up to 20° C. and nitrogen is bubbled through the reaction mixture to drive off the HBr gas. Then the reaction mixture is stirred for another 25 h at 5° C. (content of HBr 0.8% by titration). 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid ethyl ester is drummed off and stored at 0° C. prior to use as such in the subsequent step.
  • 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid ethyl ester and ammonia in methanol (7N) were charged to the 3 litre autoclave and heated to 60-65° C. (a pressure of 2.3 bar was reached). The reaction mixture was then held at this temperature for 48 hours then cooled to 20-25° C. and sampled for completion.
  • the reaction solution was transferred to a 3 L flange reactor and nitrogen was bubbled through the solution via a sparge tube for 3 hours. During this process the product precipitated out of solution.
  • the mixture was then heated to reflux and methanol (505 ml) was removed by distillation at atmospheric pressure (distillation started at 42° C. head T/46° C. pot T and was terminated at 60° C. head T/63° C. pot T). Water (270 ml) was then added slowly over 15 minutes maintaining the reaction temperature at reflux (the product precipitated during the addition). The mixture was cooled to 0-5° C. and held at this temperature for 1 hour. The product was isolated by filtration and the damp filter cake washed with cold (5° C.) methanol/water 1:1 (120 ml). The crude 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid amide was isolated as a damp grey crystalline solid (305.59 g).
  • the solid is suspended in 2-propanol heated to reflux within 2 h 20 min (complete dissolution), then cooled to 0 ⁇ 5° C. over 2.5 h and kept at to 0 ⁇ 5° C. for 1 h.
  • the solid is centrifuged and then dried for 18 in a paddle dryer (to 20-49° C., 28-86 mbar) to give the final product (88.3 kg).
  • Tables 3 and 4 Form A stability data: Compound (I) in the form of Form A was packed in double bagged polythene bags (fastened with cable/security ties) and placed inside 3.6 L Curtec kegs (HDPE) to simulate typical drug substance storage conditions. Stability tests were performed at 40° C./75% RH (table 3) and 25° C./60% RH (table 4).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
US14/352,623 2011-10-20 2012-10-19 Process for the preparation of 6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide and intermediates thereof Abandoned US20140303382A1 (en)

Applications Claiming Priority (3)

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EP11185959 2011-10-20
EP11185959.1 2011-10-20
PCT/EP2012/070769 WO2013057258A1 (fr) 2011-10-20 2012-10-19 Procédés pour la préparation de 6-chloro-2,3,4,9-tétrahydro-1h-carbazole-1-carboxamide et de ses précurseurs

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US15/134,028 Active US10329254B2 (en) 2011-10-20 2016-04-20 Process for the preparation of 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and intermediates thereof

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US (2) US20140303382A1 (fr)
EP (1) EP2768807B1 (fr)
JP (1) JP6142459B2 (fr)
CN (1) CN103958467B (fr)
AR (1) AR088377A1 (fr)
AU (1) AU2012324824B2 (fr)
BR (1) BR112014009297A2 (fr)
CA (1) CA2852797C (fr)
ES (1) ES2585077T3 (fr)
HR (1) HRP20160918T1 (fr)
HU (1) HUE029282T2 (fr)
IL (1) IL232058A (fr)
PL (1) PL2768807T3 (fr)
PT (1) PT2768807T (fr)
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JP3248174B2 (ja) 1992-10-02 2002-01-21 日本電信電話株式会社 光通信方式
JP3252303B2 (ja) 1993-03-11 2002-02-04 日本電信電話株式会社 光通信方式
GB201312768D0 (en) * 2013-07-17 2013-08-28 Ge Healthcare Ltd Work-up procedure
CN121127455A (zh) 2023-05-16 2025-12-12 Aop奥尔芬知识产权公司 晶体形式的(s)-6-氯-2,3,4,9-四氢-1h-咔唑-1-甲酰胺的新型多晶型物
AR132691A1 (es) 2023-05-16 2025-07-23 Aop Orphan Ip Ag Preparación de (s)-6-cloro-2,3,4,9-tetrahidro-1h-carbazol-1-carboxamida en forma enantioméricamente enriquecida mediante proceso de resolución
CN120118019A (zh) * 2023-12-08 2025-06-10 苏州湃芮生物科技有限公司 一种RNA m6A调控剂的共晶形式及其制备方法与应用
CN120136769A (zh) * 2023-12-11 2025-06-13 苏州湃芮生物科技有限公司 一种RNA m6A调控剂的结晶形式及其制备方法与应用

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US20080081910A1 (en) * 2005-02-17 2008-04-03 Wyeth Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives
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CN103958467B (zh) 2016-10-12
AU2012324824B2 (en) 2016-08-11
ES2585077T3 (es) 2016-10-03
AU2012324824A1 (en) 2014-05-08
US10329254B2 (en) 2019-06-25
JP6142459B2 (ja) 2017-06-07
JP2014530839A (ja) 2014-11-20
BR112014009297A2 (pt) 2017-04-11
IL232058A (en) 2016-02-29
HRP20160918T1 (hr) 2016-09-23
HK1200452A1 (en) 2015-08-07
AR088377A1 (es) 2014-05-28
HUE029282T2 (en) 2017-02-28
PL2768807T3 (pl) 2017-03-31
EP2768807A1 (fr) 2014-08-27
CA2852797C (fr) 2020-02-04
WO2013057258A1 (fr) 2013-04-25
CA2852797A1 (fr) 2013-04-25
US20160304455A1 (en) 2016-10-20
IL232058A0 (en) 2014-05-28
PT2768807T (pt) 2016-08-08
CN103958467A (zh) 2014-07-30
EP2768807B1 (fr) 2016-05-04
SI2768807T1 (sl) 2016-09-30

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