EP2989082A1 - Neuartiges synthetisches verfahren für 8-chlor-1-methyl-benzo[d]azepin, neuartige zwischenprodukte und herstellung davon - Google Patents

Neuartiges synthetisches verfahren für 8-chlor-1-methyl-benzo[d]azepin, neuartige zwischenprodukte und herstellung davon

Info

Publication number
EP2989082A1
EP2989082A1 EP14719726.3A EP14719726A EP2989082A1 EP 2989082 A1 EP2989082 A1 EP 2989082A1 EP 14719726 A EP14719726 A EP 14719726A EP 2989082 A1 EP2989082 A1 EP 2989082A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound according
enantiopure
represented
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14719726.3A
Other languages
English (en)
French (fr)
Inventor
Gaj STAVBER
Jerome Cluzeau
Frank Richter
Gerhard Laus
Ivana Gazic Smilovic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lek Pharmaceuticals dd filed Critical Lek Pharmaceuticals dd
Priority to EP14719726.3A priority Critical patent/EP2989082A1/de
Publication of EP2989082A1 publication Critical patent/EP2989082A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
    • C07C209/58—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions from or via amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/40—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the same carbon atom of the carbon skeleton, e.g. amino-ketals, ortho esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the first route starts from the same 2-(4-chlorophenyl)ethanamine 19 as used in WO03086306 but further transformations enabled a more simple and efficient process.
  • the amino intermediate is then acylated with chloropropionyl chloride to form the amide precursor 25 which is cyclized in presence of aluminum chloride as Lewis acid activator.
  • the amide 26 is reduced to racemic lorcaserin 9.
  • the optically active lorcaserin 18 has been obtained by using classical optical resolution of the racemic mixture with tartaric acid .
  • the second route is using the amide precursor 25 which is reduced directly to the secondary amine 27 and then cyclized using aluminum chloride in 1,2-dichlorobenzene, which is known to be toxic, to yield racemic lorcaserin 9.
  • the third route starts from 2-(4-chlorophenyl)ethanol 28 which is first brominated using phosphorous tribromide, which is known to be expensive.
  • the bromide 29 is transformed to the alcohol precursor 30 with an excess of l-amino-2-propanol .
  • the alcohol is substituted with thionyl chloride in the presence of a catalytic amount of DMA to give the same solid hydrochloride precursor 27 as obtained also in the second route.
  • the chloride precursor is closed via Friedel-Crafts alkylation in the presence of AICI 3 to the desired lorcaserin.
  • the resulting amide 32 or its mixture with the minor dihydrooxazole compound 33 are then reduced using various reducing agents (borane in THF or DMS, sodium borohydride in the presence of iodine) to afford the similar alcohol precursor 30 which has already been presented in the previously cited patent applications (WO05019179 and WO07120517).
  • reducing agents borane in THF or DMS, sodium borohydride in the presence of iodine
  • This invention has the object to provide a new, simple and economical process for the preparation of 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[c/]azepine or related compound, especially lorcaserin, via novel intermediates.
  • the invention has the further object to provide novel intermediates to be useful in the preparation of 8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-benzo[c/]azepine or related compound, especially lorcaserin.
  • the invention has the further object to provide a process for producing these novel intermediates.
  • the present invention provides a novel racemic synthetic route for synthesizing 8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine (compound A), or its salt, as illustrated in Scheme 6.
  • the present invention further provides for the first time a highly selective asymmetric synthetic route for synthesizing (R)- 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine ((R)-A), or its salt, or (S)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine ((S)-A), or its salt, as illustrated in Scheme 7.
  • the synthetic route is simple, industrial friendly and enables transformations with no racemization of chiral intermediates. Further, the synthesic route requires only simple and commercially available reagents and catalysts.
  • the present invention provides the possibility of an efficient and highly selective asymmetric approach. This is more advantageous in comparison with a low efficiency of chemical optical resolution of the racemic mixture of the final lorcaserin used in the prior art.
  • the highly selective asymmetric synthesis uses optically active starting material which is simple, reliable and suitably cost-beneficial. Thus, the chirality is already present in the molecule in early steps (first synthetic step). There is no need for using special asymmetric methodologies based on expensive and hazardous transition metal chiral catalysts or specific enzymes in order to induce enantioselectivity.
  • the present invention performs the final ring closing in the para-position relative to the CI substituent so that the chirality of the methyl substituent in the present invention is not prone to racemization compared to the prior art final ring closing performed in the mefa-position relative to the CI substituent as illustrated by the above Schemes 1 to 3.
  • R in the formula II is an amino protecting group which is preferably selected from -Boc (terf-butyloxycarbonyl), -Cbz (carbo- benzyloxy), -Bz (benzoyl), -Bn (benzyl), -Ac (acetyl), or -CH 2 CH(OR 2 ) 2 (wherein R 2 is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R 2 may bond together to constitute a C2- or C3- alkylene chain for forming a 5- or 6-membered ring);
  • R in the formula III is the same as defined for the formula II above;
  • X in the formula Ilia is a leaving group suitable for a cyclizing intramolecular Friedel-Crafts alkylation reaction or a group which can suitably be converted to a such a leaving group, and wherein X is preferably -OH, tosylate, mesylate, triflate, or a halogen selected from CI, Br, I, and wherein X is most preferably CI or Br; or
  • R 2 is the same as defined for the formula II above, wherein R* is an amino protecting group
  • (d-1) performing a cyclizing intramolecular reaction, which is preferably a cyclizing intramolecular Friedel-Crafts or a
  • step (a) comprises the steps of:
  • step (a-2) optionally includes
  • R in the formula VI is the same as defined for the formula V above; and (a-2-2) subsequently oxidizing the compound according to the formula VI to obtain the compound according to the formula II, preferably without isolating the intermediate compound VI.
  • step (a-2-2) comprises the oxidation of the compound according to the formula VI by using an oxidizing agent selected from Ru0 2 , NaI0 4 , H 2 0 2 , urea-H 2 0 2 , cumene H 2 0 2 , m-CPBA (mefa-chloroperoxybenzoic acid), NaB0 3 -xH 2 0, Mn0 2 , and Oxone, preferably NaI0 4 and Ru0 2 .
  • an oxidizing agent selected from Ru0 2 , NaI0 4 , H 2 0 2 , urea-H 2 0 2 , cumene H 2 0 2 , m-CPBA (mefa-chloroperoxybenzoic acid), NaB0 3 -xH 2 0, Mn0 2 , and Oxone, preferably NaI0 4 and Ru0 2 .
  • X 1 is selected from OH, F, CI, and Br, preferably CI
  • X 2 is selected from OH, CI, and Br, and is preferably CI or Br
  • R in the compound according to the above formula III is already represented by the above defined -CH 2 CH(OR 2 ) 2 , protecting the amino group with a protecting group, preferably selected from unsubstituted benzyl (Bn) or substituted, preferably a-methyl, p- nitro, p-methyl or p-methoxy substituted benzyl (PMB), polyphenyl substituted methyl preferably trityl (Tr), unsubstituted or fluorinated Ci-C 4 -alkanesulfonyl, preferably methanesulfonyl (mesyl, Ms) or trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl, unsubstituted or substituted Ci-C 6 -alkanoyl, preferably
  • a Lewis acids selected from AICI 3 , FeCI 3 , InCI 3 , InBr 3 , Bi(OTf) 3 , BiCI 3 , Sc(OTf) 3 , TeCI 4 , BF 3 xOEt 2 , preferably anhydrous AICI 3 , or a Br0nsted acid selected from HOTf, pTsOH, TFA, CH 3 S0 3 H, H 3 P0 4 / P 2 0 5 , H 2 S0 4 / AcOH mixture, cone. H 2 S0 4 or polyphosphoric acid (PPA), and preferably H 2 S0 4 or PPA, or
  • R 3 is H, methyl or ethyl, and R* is the same as defined in c-3-2 or c-3-3 of item 6 and and wherein the reduction in the step (d-2), required only for the
  • a suitable reducing agent which is preferably selected from BH 3 complexes, H ⁇ metal cat. (preferably Rh, Ru, Pd), NaBH 4 / H 2 S0 4 , LiAIH 4 , Et 3 N / HCOOH, RED-AI, DIBAL-H, Hz/Pd/C/HCI or Zn/HCI, and most preferably BH 3 -THF complex or hydrides for the reduction of the compound according to the formulae IVa, and H ⁇ Pd/C/HCI, H ⁇ PtO, or Zn/HCI for the reduction of the compound according to the formula IVc, and H ⁇ PtO for the reduction of the compound according to the formula IVd or IVe,
  • a suitable reducing agent which is preferably selected from BH 3 complexes, H ⁇ metal cat. (preferably Rh, Ru, Pd), NaBH 4 / H 2 S0 4 , LiAIH 4 , Et 3 N / HCOOH, RED-AI, DIBAL-H, Hz/
  • a suitable reducing agent preferably selected from LiAIH 4 , RED-AI, DIBAL-H, diborane, BH 3 -THF complex or hydrides, most preferably BH 3 -THF complex;
  • R 2 is preferably methyl or ethyl) or OHC-CH(OR 2 ) 2 (wherein
  • R 2 is preferably methyl or ethyl
  • step (b) wherein the compound according to the formula (R)-II is converted in step (b) to the essentially enantiopure or enantiopure R-enantiomer of the compound according to the formula III represented by the following formula (R)-III :
  • step (c) wherein the racemic compound according to the formula Hid in the step (c) is transformed to the essentially enantiopure or enantiopure S- enantiomer of the compound according to the formula (S)-IIId ((S)-IIId) by removing the opposite enantiomer by additional steps of one
  • R' in formula III' is represented (i) by the above defined R, which is an amino protection group, which is preferably selected from -Boc (tert- butyloxycarbonyl), -Cbz (carbobenzyloxy), -Bz (benzoyl), -Bn (benzyl), -Ac (acetyl), or -CH 2 CH(OR 2 ) 2 (wherein R 2 is alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R 2 may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring) or is represented by (ii) -H, -COCH 2 X or -CH 2 CH 2 -X (wherein X is defined as above and is preferably -OH, tosylate, mesylate, triflate or a halogen, preferably CI, Br or I, and wherein X is most preferably CI or
  • the compound according to the formula III', or its salt is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • X being represented by CI, Br or I, more preferably CI or Br.
  • R' in the compound (R)-III' is the same as defined in any one of items 14 to 17.
  • the compound according to the formula (R)-III', or its salt is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl- benzo[c/]azepine derivatives, or its salts.
  • a compound according to any one of items 18 to 21 which is the essentially enantiopure or enantiopure S-enantiomer of the compound according to the formula III', represented by the following formula (S)- III', or its salt:
  • a method for producing a compound according to any one of items 22 to 27 wherein the method comprises the reaction step (b) as defined by any one of items 1, 5, 8, 9, 12 or 13, the method optionally further comprising one or more of the reaction steps (c), (c-1), (c-2), (c-3), (c-1-1), (c-1-2), (c-2-1), (c-2-2), and (c-3-1) as defined by any of items 1, 6, 8, 9, 11, 12 or
  • the compound according to the formula IVa is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • the compound according to the formula (R)-IVa is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.
  • the compound according to the formula IVc is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • the compound according to the formula (R)-IVc is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro- l-methyl-benzo[c/]azepine derivatives, or its salts.
  • the compound according to the formula IVd is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • the compound according to the formula (R)-IVd is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.
  • the compound according to the formula IVe is a useful novel intermediate for the synthesis of the compound A or related 8-chloro-l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • the compound according to the formula (R)-IVe is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.
  • R * is defined as above and is preferably p-toluenesulfonyl.
  • the compound according to the formula X is a useful novel intermediate for the synthesis of the compound A or related 8-chloro-l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • the compound according to the formula (R)-X is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.
  • R 2 is methyl or ethyl or both R 2 may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring
  • R 2 is methyl or ethyl or both R 2 may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring
  • R 2 is methyl or ethyl or both R 2 may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring
  • R 2 is methyl or ethyl or both R 2 may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring
  • the compound according to the formula II is a useful novel intermediate for the synthesis of the compound A or related 8-chloro-l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • the compound according to the formula (R)-II' is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.
  • the present invention provides an industrially applicable, economical and simple asymmetric process for the preparation of serotonin antagonizing 8-chloro-l-methyl-benzo[c/]azepine or related compounds, or its salts, particularly lorcaserin, as well as key intermediates for the synthesis thereof.
  • Lorcaserin is a selective 5-HT 2c receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT 2c over other related targets.
  • the activation of 5-HT 2c receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety.
  • POMC proopiomelanocortin
  • essentially enantiopure as used herein means an enantiomeric excess (ee) of 70 % ee or more, preferably 80 % ee or more, more preferably 90 % ee or more, most preferably 97 % ee or more.
  • salt refers to any suitable salt form of the respective compound.
  • the salt is pharmaceutically acceptable.
  • racemic, essentially enantiopure or enantiopure l-aminopropan-2-ol may be converted in step (a-1) to a compound according to the formula V, wherein R in the formula V is an amino protecting group, or -CH 2 CH(OR 2 ) 2 (wherein R 2 is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R 2 may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring).
  • amino protecting group means a group that protects an amine in particular transformations of the process of the invention and can be selected from known “amino protecting groups” as recited in "Greene's Protective Groups in Organic Synthesis", 4th Edition (Peter G. M . Wuts, Theodora W. Greene; ISBN : 978-0-471-69754-1).
  • the "amino protecting group” in the present invention is selected from -Boc (tert-butyloxycarbonyl), -Cbz (carbobenzyloxy), -Bz (benzoyl), - Bn (benzyl), -Ac (acetyl).
  • -Boc group Specific conditions for protecting the amino group by means of these groups can be found in the above referenced "Greene's Protective Groups in Organic Synthesis".
  • the invention uses
  • the protecting group is selected for use in cyclisation of the compound according to the formula III to the compound of formula IV, wherein besides the groups as disclosed above some others which are less suitable for formation of the cyclic sulfonamide according to the formula II can be used.
  • Such preferable additional “amino protecting groups” are introduced by conditions using
  • the invention uses (vi) a compound represented by the above defined X 3 CH 2 CH(OR 2 ) 2 (wherein X 3 is tosylate, mesylate, triflate or a halogen, preferably CI or Br, and R 2 is the same as defined above, preferably methyl or ethyl) or the above defined OHC-CH(OR 2 ) 2 , wherein X 3 is tosylate, mesylate, triflate or a halogen, preferably CI or Br, and R 2 is the same as defined above, for introducing the above defined -CH 2 CH(OR 2 ) 2 (wherein R 2 is the same as defined above).
  • the present invention takes advantage of a one-pot reaction using a suitable reducing agent, preferably H ⁇ Pd/C/HCI, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy- borohydride, most preferably H ⁇ Pd/C/HCI .
  • a suitable reducing agent preferably H ⁇ Pd/C/HCI, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy- borohydride, most preferably H ⁇ Pd/C/HCI .
  • the synthesis route may proceed with the step (a- 2).
  • This step (a-2) may be accomplished in a one-step procedure or in a two-step procedure.
  • the compound according to the formula II may directly be formed from the compound according to the formula V by protocols as reviewed by Melendez et al. (Tetrahedron, Volume 59, Issue 15, pages 2581-2616) by making use of sulfuryl chloride or preferably 1,1'- sulfonyl diimidazole.
  • the compound according to the formula II may be formed from the compound according to the formula V via the step (a-2-1) of forming of an intermediate compound according to the formula VI which is subsequently oxidized in the step (a-2-2) to yield the compound according to the formula II.
  • the intermediate compound according to the formula VI needs not to be isolated, but may be oxidized immediately following a simple liquid extraction protocol, such as washing the organic reaction phase with an aqueous phase for removing salts, etc.
  • the formation of the intermediate compound according to the formula VI in the step (a-2-1) is preferably accomplished by the use of thionyl chloride under the conditions, such as reviewed by Melendez et al.
  • Suitable oxidizing agents may be selected from Ru0 2 , NaI0 4 , H 2 0 2 , urea-H 2 0 2 , cumene H 2 0 2 , m-CPBA (meta-chloroperoxybenzoic acid), NaB0 3 -xH 2 0, Mn0 2 , and Oxone (Potassium peroxysulfate), which may be used in combination with a catalyst.
  • the invention uses NaI0 4 catalyzed with a Ruthenium catalyst (such as Ru0 2 or RuCI 3 ).
  • R" in the formula II" is the above defined -CH 2 CH(OR 2 ) 2 represents a novel and suitable intermediate for the synthesis of compound A or related 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • This compound may be racemic or essentially enantiopure or even enantiopure in the R- or S-form, preferably in the R- form.
  • This novel intermediate is suitably produced according to the above described reaction steps (a) and/or (a-1) and/or (a-2) and/or (a-2-1) and/or (a-2-2) as defined by any one of the above items 1, 2, 3 (vi), 4, 10, 12 or 13.
  • the synthesis route may proceed with the step (b) in order to yield the compound according to the formula III.
  • the compound according to the formula II may be ring opened in the step (b) with an organometallic compound accordin to the formula VII :
  • M in the formula VII is a suitable metal for said ring opening, which is preferably selected from Li, MgBr and MgCI, most preferably MgCI.
  • M MgCI catalyzed with Cul is particularly preferred. Suitable reaction conditions are reviewed by Melendez et al. (Tetrahedron, Volume 59, Issue 15, pages 2581-2616) or described by Hebeisen et al. (Tetrahedron Lett. 2011, 52, 5229).
  • the present invention takes advantage of a Knochel type halogen metal exchange of l-chloro-3-iodo-benzene with isopropyl- magnesium chloride, preferably upon the addition of a catalytic copper(I) salt such as Cul.
  • the ring opening reaction in the step (b) proceeds with an inversion of configuration (see Scheme 7 above). Therefore, the synthesis may be performed in a highly selective asymmetric manner by suitably selecting an essentially enantiopure or even enantiopure starting material I which, as being illustrated in the above items 12 and 13, subsequently leads to the essentially enantiopure or even enantiopure final product according to the formula (R)-A or (S)-A, or its salt, respectively.
  • the synthesis leads to the essentially enantiopure or even enantiopure compound according to the formula (R)-A by using the essentially enantiopure or even enantiopure compound according to the formula (R)-I as a starting material.
  • R is an amino protection group which is preferably selected from -Boc (terf-butyloxycarbonyl), -Cbz (carbobenzyloxy), -Bz (benzoyl), -Bn (benzyl), -Ac (acetyl) or -CH 2 CH(OR 2 ) 2 (wherein R 2 is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R 2 may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring) or is represented by
  • the residue X is most preferably represented by CI or Br.
  • the residue X is most preferably represented by CI or Br.
  • the residue R 2 is most preferably represented by methyl or ethyl .
  • this intermediate compound is suitably produced according to the above described reaction step (b) as defined by any one of the above items 1, 5, 8, 9, 12 or 13.
  • the method optionally further comprises one or more of the reaction steps (c), (c- 1 ), (c-2), (c-3), (c- 1- 1 ), (c- 1-2), (c-2- 1), (c-2-2), and (c-3- 1) as defined by any of the above items 1, 6, 8, 9, 11, 12 or 13.
  • step (c) After the step (b) is accomplished to give the compound according to the formula III, the synthesis route may proceed with the step (c) .
  • This step (c) may split into three alternatives given by the above described steps (c- 1), (c-2) and (c-3), respectively.
  • step (c- 1) the compound according to the formula III is converted to a compound according to the formula Ilia:
  • X in the formula Ilia is a leaving group suitable for an cyclizing intramolecular Friedel-Crafts alkylation reaction or a group which can suitably be converted to a such a leaving group wherein X is preferably -OH, tosylate, mesylate, triflate or a halogen, preferably selected from CI, Br, I, more preferably CI or Br. Most preferably, X is represented by CI or Br.
  • leaving group suitable for a cyclizing intramolecular Friedel-Crafts alkylation reaction and "a group which can suitably be converted to such a leaving group” used in this invention mean a group which forms an electrophilic species suitably reacting with aromatics in a Friedel-Crafts reaction upon the presence of a Lewis acid or Br0nsted acid or by a photochemical reaction .
  • a "group which can suitably be converted to such a leaving group” has the capability of being conventionally converted to a desired leaving group which preferably takes place in situ.
  • the respective leaving group of a precursor group thereof can be protected by usual and known protecting groups. The respective meanings of these terms become further apparent from the more specific definitions provided herein in the disclosure of preferred embodiments.
  • the step (c-1) may further comprise the step (c-1-1) of removing the group R from the compound according to the formula III, if R is a group other than the above defined -CH 2 CH(OR 2 ) 2 , to obtain the compound according to the formula Hid :
  • R in the compound according to the formula III is represented by the above defined -CH 2 CH(OR 2 ) 2
  • the step (c-1) may further comprise the step (c-1-2) of reacting the compound according to the formula Hid with a compound represented by the above formula VIII :
  • X 1 is selected from OH, F, CI, and Br, preferably CI
  • a conversion of the alcoholic hydroxyl group i.e.
  • X 2 OH
  • the compound represented by the formula VIII is one selected from chloroacetyl chloride or bromoacetyl chloride.
  • step (c-1) the compound according to the formula Ilia of the first alternative is converted in the step (d) according to above item 1 to give a compound according to the formula A, or its salt, or its R- or S-enantiomer if following the above described asymmetric protocol .
  • the step (d) may be divided in the above defined first step (d-1) and (d-1-1), respectively, and the above defined second step (d-2).
  • the compound according to the formula Ilia is converted in a Friedel-Crafts alkylation reaction or photochemically induced ring closing reaction to give the compound according to the formula IVa.
  • a Friedel-Crafts alkylation reaction may be accomplished in the presence of a Lewis acids selected from AICIs, FeCIs, InCI 3 , InBr 3 , Bi(OTf) 3 , BiCI 3 , Sc(OTf) 3 , TeCI 4 , BF 3 xOEt 2 , preferably anhydrous AICI 3 , or a Br0nsted acid selected from HOTf, pTsOH, TFA, CH 3 S0 3 H, H 3 P0 4 / P 2 0 5 , H 2 S0 4 / AcOH mixture, cone.
  • a Lewis acids selected from AICIs, FeCIs, InCI 3 , InBr 3 , Bi(OTf) 3 , BiCI 3 , Sc(OTf) 3 , TeCI 4 , BF 3 xOE
  • PPA polyphosphoric acid
  • the Friedel-Crafts alkylation takes advantage of the anhydrous AICI 3 .
  • reaction conditions without excess of Lewis acid or Br0nsted acid are reviewed by Magnus Rueping et al. (Beilstein Journal of Organic Chemistry 2010, 6, No. 6).
  • the ring closing may be accomplished by a photochemical reaction. Such a photochemical ring closing reaction may be performed in a photochemical reactor by using solar-light or UV irradiation.
  • the photochemical ring closing reaction may use for instance a 100 W lamp to irradiate the compound according to the formula Ilia dissolved in a suitable solvent such as aqueous MeCN or aqueous EtOH .
  • Photochemical reactions can preferably be conducted in an immersion-type reactor consisting of a reactor body made from borosilicate glass with inserted double-walled borosilicate immersion well.
  • This Hg-lamp can be inserted into a vertically arranged double-walled, water cooled immersion well.
  • the reacting time is not specifically limited and the efficiency and selectivity of the reaction may be monitored by e.g.
  • reaction time for the Friedel-Crafts reaction 2 to 36 hours is sufficient while irradiation time of 0.25 to 4 hours may be sufficient.
  • Common reaction conditions may be applied while the conditions according to one of the examples 15 to 18 are particularly preferred.
  • the compound according to the formula IVa is reduced by a suitable reducing agent to yield the compound according to the formula A, or its salt, or its R- or S- enantiomer if following the above described asymmetric protocol.
  • the reducing agent is not specifically limited but it is preferably selected from BH 3 complexes, Hz/metal cat. (preferably Rh, Ru, Pd), NaBH 4 / H 2 S0 4 , LiAIH 4 , Et 3 N / HCOOH, RED-AI, DIBAL-H, and most preferably BH 3 -THF complex or hydrides. Common reaction conditions may be applied while the conditions according to example 14 are particularly preferred.
  • compound A represents a novel and suitable intermediate for the synthesis of compound A or related 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • This compound may be racemic or essentially enantiopure or even enantiopure in the R- or S-form, preferably in the R- form.
  • This compound is suitably produced according to the above described reaction steps (d-1) and/or (d-1-1) as defined by any one of items 1, 7, 8, 13 or 14, the method preferably using anhydrous AICI 3 or hv.
  • step (c-2) the compound according to the formula III is converted to a compound according to the formula Illb:
  • the step (c-2) may be accomplished by means of the above step (c-2-1) or alternatively by means of the above step (c-2-2).
  • step (c-2-1) the group R from the compound according to the formula III is removed according to the above described deprotection step (c-1-1), if R is a group other than the above defined -CH 2 CH(OR 2 ) 2 , to obtain the compound according to the following formula Hid :
  • R in the compound according to the formula III is represented by the above defined -CH 2 CH(OR 2 ) 2 , such a compound is already represented by the compound according to formula IIIc and the subsequent synthesis would then proceed via the alternative (c-3) so that no deprotection is required .
  • the compound according to the formula Hid may first be converted to the compound according to the formula Ilia following the above reaction step (c-1-2).
  • step (c-2-1) the compound according to formula Ilia is subsequently reduced according to step (c-2-1) to give the compound according to formula Illb by use of a suitable reducing agent, preferably selected from LiAIH 4 , RED-AI, DIBAL-H, diborane, BH 3 -THF complex or hydrides, most preferably BH 3 -THF complex.
  • a suitable reducing agent preferably selected from LiAIH 4 , RED-AI, DIBAL-H, diborane, BH 3 -THF complex or hydrides, most preferably BH 3 -THF complex.
  • the compound according to the formula Hid may be converted to the compound according to the formula Illb according to the step (c-2-2) by means of a reductive amination reaction with use of a compound represented by the above formula IX:
  • the compound according to the formula IX may be bromoacetaldehyde (The Journal of Organic Chemistry, 48, p. 2111, 1983) and more preferably readily available chloroacetaldehyde. Common reaction conditions may be applied during the reductive amination reaction.
  • step (c-2) is accomplished by means of the above step (c-2- 1) or alternatively by means of the above step (c-2-2)
  • the compound according to the formula Illb of the second alternative is converted in the step (d) of item 1 to give a compound according to the formula A, or its salt, or its R- or S- enantiomer if following the above described asymmetric protocol.
  • This step (d) corresponds to the above defined first step (d-1) and (d-1-2), respectively.
  • the Friedel-Crafts alkylation reaction or the photochemically induced ring closing reaction may be accomplished in the same way as described for the step (d-1-1) with respect to first alternative described for the compound according to the formula Ilia above.
  • step (c-3) the compound according to the formula III is converted to a compound according to the formula IIIc:
  • R 2 is as defined above.
  • the formation of the compound according to the formulas IIIc may be omitted for the event that R in the compound according to the above formulae II and III is already represented by the above defined -CH 2 CH(OR 2 ) 2 .
  • step (c-3) may be represented by the above step (c-3-1) according to the above item 6 which comprises the above deprotection step (c-1-1) for removing the group R from the compound according to the formula III, if R is a group other than the above defined -CH 2 CH(OR 2 ) 2 , to obtain the compound according to the formula Hid :
  • the compound according to the formula Hid is reacted with the compound represented by the above defined formula X 3 CH 2 CH(OR 2 ) 2 (wherein X 3 is preferably CI or Br, and R 2 is preferably methyl or ethyl), most preferably bromoacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal, or with the compound represented by the above defined formula OHC-CH(OR 2 ) 2 (wherein R 2 is preferably methyl or ethyl), to obtain the compound according to the formula IIIc.
  • X 3 is preferably CI or Br
  • R 2 is preferably methyl or ethyl
  • OHC-CH(OR 2 ) 2 wherein R 2 is preferably methyl or ethyl
  • step (c-3-1) the compound according to the formula IIIc in the third alternative is converted in the step (d) of item 1 to give a compound according to the formula A, or its salt, or its R- or S-enantiomer if following the above described asymmetric protocol .
  • This step (d) may be divided into the above defined first step (d-1) and (d-1-3), respectively, and the above defined second step (d-2.
  • the compound according to the formula IIIc is converted in a Friedel-Crafts reaction under essentially the same conditions as described for the step (d-1-1) with respect to the compound according to the formula Ilia above. That is to say, the acetal (which represents a group that can be suitably converted to a Friedel-Crafts leaving group in situ) in the compound according to the formula IIIc is activated by a Lewis acid, preferably anhydrous AICI 3 or BF 3 xOEt 2 , or a Br0nsted acid, preferably cone. H 2 S0 4 , PPA or MeS0 3 H, to react with the aromatic ring upon the formation of a compound according to the formula IVc ' wherein R 2 derives from the acetal group being not limited to methyl or ethyl.
  • a Lewis acid preferably anhydrous AICI 3 or BF 3 xOEt 2
  • Br0nsted acid preferably cone.
  • H 2 S0 4 , PPA or MeS0 3 H to react with
  • the compound according to the above defined formula IIIc (where R 2 is preferably selected but not limited to methyl or ethyl) is intramoleculary cyclized under Friedel-Crafts reaction conditions to give products depending on the reaction conditions. If the Friedel-Crafts reaction is performed without solvents in molten phase (neat conditions), the reaction yields the compound according to the below formula IVd, which can be isolated in the form of hydrochloride by partitioning between brine and dichloromethane.
  • the intermediate compounds according to the below formulae IVc' and/or its hydrolytic derivative IVc" wherein R 2 is defined as above, preferably represented by methyl or ethyl, can also be isolated, under some conditions as predominate products. In some cases all three compounds are detected in the mixture.
  • reaction should be forced to yield the final product with a double bond according to the formula IVd.
  • Such a Friedel-Crafts alkylation reaction applied in the present invention are preferably accomplished in the presence of a Lewis acids, preferably selected from AICI 3 , FeCI 3 , InCI 3 , InBr 3 , Bi(OTf) 3 , BiCI 3 , Sc(OTf) 3 , TeCI 4 , most preferably from anhydrous AICI 3 .
  • the Friedel-Crafts reaction is carried out without solvent (neat conditions) or in a solvent, selected from nitromethane, aromatic hydrocarbons, preferably nitrobenzene, chlorinated hydrocarbons, preferably dichloromethane for 10 min to 36 hours.
  • the Friedel-Crafts reaction is preferably carried out without solvent (neat conditions) for cyclizing the compound according to the formula IVd, where the secondary amine is unprotected.
  • the amino protecting group R* as used herein means a group that protects the secondary amine of the compound according to the formula IIIc such that this group is applicable to the Friedel-Crafts reaction conditions applied in step (d-1), and (d-1-3), respectively.
  • Such an amino protecting group R* is thus limited only by its suitability to perform under the reaction conditions of said reactions step (d) and can be selected from known "amino protecting groups” as recited in "Greene's Protective Groups in Organic Synthesis", 4th Edition (Peter G. M . Wuts, Theodora W. Greene; ISBN : 978-0-471-69754-1).
  • the amino protecting group R* used in the present invention is selected from unsubstituted benzyl (Bn) or substituted, preferably a-methyl, p-nitro, p-methyl or p-methoxy substituted benzyl (PMB), polyphenyl substituted methyl, preferably trityl (Tr), unsubstituted or fluorinated Ci-C 4 -alkanesulfonyl, preferably methanesulfonyl (mesyl, Ms) or trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl, unsubstituted or substituted Ci-C 6 -alkanoyl, preferably acetyl (Ac) or arylcarbonyl, preferably benzoyl (Bz), to obtain the compound according to the formula
  • the media of the protection reactions are preferably selected from aprotic solvents, preferably dichloromethane.
  • Step (c-3-2) the compound according to the formula III, wherein R is a group other than the above defined -CH 2 CH(OR 2 ) 2 , is reacted with the compound represented by the above defined formula X 3 CH 2 CH(OR 2 ) 2 (wherein X 3 is preferably CI or Br, and R 2 is preferably methyl or ethyl), most preferably bromoacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal, or with the compound represented by the above defined formula OHC-CH(OR 2 ) 2 (wherein R 2 is preferably methyl or ethyl), not applying previous removing to obtain the compound according to the formula Hie, wherein R* is limited to the substituents R.
  • the compound according to the formula Hie is prepared from the compound according to the formula IIIc by a reaction of introduction of a protecting group by methods such as:
  • - unsubstituted benzyl or substituted preferably a-methyl, p-nitro, p- methyl or p-methoxy substituted benzyl, or polyphenyl substituted methyl by a reaction with the corresponding halogenide, selected from chloride, bromide or iodide in basic conditions; - unsubstituted or fluorinated Ci-C 4 -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl by a reaction with the corresponding sulfonyl halogenide, preferably chloride, such as tosyl chloride (TsCI), or sulfonyl anhydrides, such as triflic anhydride (Tf 2 0) in basic conditions; or
  • Ci-C 6 -alkanoyl preferably acetyl or arylcarbonyl, preferably benzoyl by a reaction with corresponding acyl halogenide, preferably chloride, or acyl anhydride, such as acetic anhydride (Ac 2 0) or benzoyl chloride in basic conditions.
  • acyl halogenide preferably chloride
  • acyl anhydride such as acetic anhydride (Ac 2 0) or benzoyl chloride in basic conditions.
  • step (c-3-3) some protected groups, which are not possible in the method according to the step (c-3-2), can be introduced.
  • Such type of groups is represented by sulfonyl protecting groups, which are preferable in the Fridel-Crafts transformation in view of yields and purity.
  • the media of the protection reactions are preferably selected from aprotic solvents, most preferably from dichloromethane.
  • the compound of formula IIIc, used in the step (c-3-3) can be prepared from the compound according to the formula II in the step (b) if R is -CH 2 -CH(OR 2 ) 2 , or from the compound according to the formula III in the step (c-3-1) if R is not a group other than the above defined - CH 2 CH(OR 2 ) 2 .
  • the compounds according to the formula IVc', IVc", IVd, and IVe are usually isolated by quenching the reaction mixture with water, neutralizing the mixture with a base, such as sodium hydroxide, and extracting the product with a water immiscible solvent, followed by removal of the solvent.
  • a base such as sodium hydroxide
  • the compounds according to the formulae IVc', IVc", IVd or mixtures thereof are reduced with a suitable reducing agent to yield the compound according to the formula A, or its salt, or its R- or S-enantiomer if following the above described asymmetric protocol.
  • the reducing agent is not specifically limited but it is preferably selected from Hz/Pd/C/HCI or Zn/HCI .
  • the compound according to the formula IVe is reduced to a compound according to the formula X:
  • reducing agents preferably selected from boron hydrides, such as alkali metal borohydrides, preferably NaBH 4 or borane complexes, preferably BH 3 -THF, aluminum hydrides, preferably LiAIH 4 , DIBALH, RedAI, by NEt 3 /HC0 2 H, Zn in acidic conditions, or by catalytic hydrogenation using metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by catalytic hydrogenation using metal transition catalysts.
  • the preferred method for reduction of the compounds of the formulae IVd or IVe is the catalytic hydrogenation on platinum oxide.
  • the amino protection group R* of the compound according to the formula X is deprotected using standard protocols, known to a skilled person, which may be selected from acid or alkali hydrolysis or hydrogenation, to give the final product according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof.
  • This compound represents a novel and suitable intermediate for the synthesis of the compound A or related 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.
  • This compound may be racemic or essentially enantiopure or even enantiopure in the R- or S-form, preferably in the R-form.
  • This compound is suitably produced according to the above described reaction step (d-1) and/or (d-1-3) as defined by any one of items 1, 7, 10, 11, 12 or 13, the method preferably using anhydrous AICI 3 , cone. H 2 S0 4 or PPA.
  • the present invention for the first time provides the possibility for an asymmetric synthesis of 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts, by using essentially enantiopure or enantiopure starting material.
  • the present invention provides a facile, economically and selective synthesis.
  • the invention provides an insight about new key intermediates for the synthesis of such compounds and their respective production way.
  • optical resolution of the non-chlorinated analogue 2-phenyl-l-propaneamine with L-malic acid in EtOH at 70 °C is disclosed in the following patent applications: WO008073789, WO01090057, WO01089530. It was surprisingly found, that optical resolution of the chlorinated derivative Hid with L-malic acid is completely useless due to precipitation of malate with racemic Hid .
  • a chiral organic acid preferably selected from phenyl substituted alkanoic acids in an organic solvent, from which one enantiomer precipitates in a highly enriched or essentially enantiopure form.
  • the most preferred chiral acids are 2- phenylpropanoic acid and 3-phenyl lactic acid .
  • Enantiomeric purity can be further improved by one or more crystallisations to obtain enantiopure material.
  • the crystallization is performed by mixing both components with the solvent, heating above 50 degrees to dissolve all or most of solid material, optionally filtering impurities and cooling down the solution to crystallise the salt.
  • the precipitated material is isolated by filtration or centrifugation and dried .
  • the obtained compound according to the formula (7? IIId is recovered in a form a base by alkalizing, for example by aqueous NaOH followed by extraction with a water unmixable solvent and evaporation.
  • Such compound can be further used in the steps (c) and (d) to obtain the compound of formula A in essentially enantiopure or enantiopure form, preferably lorcaserin in the (R) form, or its salts.
  • the racemic compound of formula Hid may be synthesised by a newly disclosed alternative way from 2-(3-chlorophenyl)acetonitrile via 2- (3-chlorophenyl)propanenitrile followed by reduction to 2-(3- chlorophenyl)propan-l-amine, which was reported in J. Med. Chem. 2013, 56, 4786-4797) and in J. Am. Chem. Soc. 2013, 135, 2100-2103 (Scheme 8).
  • Example 2 Synthesis of optically active teri " -butyl-2-(hydroxypropyl)- carbamate ((R)-V-Boc or (S)-V-Boc from chiral l-aminopropan-2-ol ((R)- I or (S)-I) :
  • reaction mixture was first diluted with deionized water.
  • the organic phase was separated, washed with aqueous solution of citric acid (50 ml_) and brine (50 ml_) and the solvent was than evaporated under reduced pressure.
  • a solid material (mixture of isomers) was obtained (VI-Boc, 1.99g, 90% yield) and characterized with 13 C NMR spectroscopy.
  • Example 4 Direct synthesis of tert-butyl-5-methyl-l,2,3-oxathiazolidine-3- carboxylate-2,2-dioxide (II-Boc) from teri " -butyl-2-(hydroxypropyl)- carbamate (V-Boc)
  • the reaction mixture was first diluted with deionized water, the organic phase was separated, washed with aqueous solution of citric acid (50 mL) and brine (50 mL). The organic phase was then used for further oxidation process where the aqueous solution of NaI0 4 (5.8 g in 50 mL of water) was slowly added into the system at 0°C followed by the addition of Ru0 2 -H 2 0 catalyst (90 mg). The reaction system was then vigorously stirred for an hour at 0°C and then 2-3 hours at room temperature. The reaction mixture was first diluted with aqueous solution of ascorbic acid, the organic phase was separated, washed with brine (50 mL) and solvent was evaporated under reduced pressure. The crude material (yellowish oil) was dried under vacuum to afford the final crystalline product (II-Boc, 1.91 g, 80% yield) which was characterized with 1 H and 13 C NMR spectroscopy.
  • Example 5 Direct synthesis of optical active teri " -butyl-5-methyl-l,2,3- oxathiazolidine-3-carboxylate-2,2-dioxide ((R)-II-Boc or (S)-II-Boc)
  • reaction system was than vigorously stirred for an hour at 0°C and then 3 hours at room temperature.
  • the reaction mixture was first diluted with aqueous solution of citric acid, the organic phase was separated, washed with brine (50 mL) and solvent was than evaporated under reduced pressure.
  • the crude material (yellowish oil) was dried under vacuum to afford a crystalline yellow product ((R)-II-Boc or (S)-II-Boc, 2.32 g, 86% yield).
  • Analytical data were in accordance to previous example 4 (HPLC analysis (single enantiomer) and 1 H, 13 C NMR spectroscopy).
  • Example 7 Synthesis of optical active teri " -butyl-(2-(3- chlorophenyl)propyl)carbamate ((R)-III-Boc or (S)-III-Boc) from chiral i " eri " -butyl-5-methyl-l,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide ((R)- II-Boc or (S)-II-Boc)
  • Example 8 Deprotection of teri " -butyl-(2-(3- chlorophenyl)propyl)carbamate (III-Boc) to 2-(3-chlorophenyl)propan-l- amine (Hid)
  • Example 15 Transformation of A/-(2-chloroethyl)-2-(3- chlorophenyl)propan-l-amine (IHb) to 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[c/]azepine (A)
  • Example 22 Optical resolution of 2-(3-chlorophenyl)propan-l-amine with L-(-)-3-phenyllactic acid
  • the lactic salt was optionally transformed to the base by washing ethyl acetate solution with aqueous Na 2 C0 3 followed by removal of the solvent by evaporation.
  • Example 25 Synthesis of 8-chloro-l-methyl-3-tosyl-2,3-dihydro-lH- benzo[d]azepine from N-(2-(3-chlorophenyl)propyl)-N-(2,2- dimethoxyethyl)-4-methyl benzene sulfonamide
  • Example 26 Synthesis of 8-chloro-l-methyl-3-tosyl-2,3,4,5-tetrahydro- lH-benzo[d]azepine from 8-chloro-l-methyl-3-tosyl-2,3-dihydro-lH- benzo[d]azepine
  • Example 27 Synthesis of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine from 8-chloro-l-methyl-3-tosyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP14719726.3A 2013-04-23 2014-04-23 Neuartiges synthetisches verfahren für 8-chlor-1-methyl-benzo[d]azepin, neuartige zwischenprodukte und herstellung davon Withdrawn EP2989082A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14719726.3A EP2989082A1 (de) 2013-04-23 2014-04-23 Neuartiges synthetisches verfahren für 8-chlor-1-methyl-benzo[d]azepin, neuartige zwischenprodukte und herstellung davon

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP13164994 2013-04-23
EP14719726.3A EP2989082A1 (de) 2013-04-23 2014-04-23 Neuartiges synthetisches verfahren für 8-chlor-1-methyl-benzo[d]azepin, neuartige zwischenprodukte und herstellung davon
PCT/EP2014/058194 WO2014173928A1 (en) 2013-04-23 2014-04-23 Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof

Publications (1)

Publication Number Publication Date
EP2989082A1 true EP2989082A1 (de) 2016-03-02

Family

ID=48141864

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14719726.3A Withdrawn EP2989082A1 (de) 2013-04-23 2014-04-23 Neuartiges synthetisches verfahren für 8-chlor-1-methyl-benzo[d]azepin, neuartige zwischenprodukte und herstellung davon

Country Status (3)

Country Link
EP (1) EP2989082A1 (de)
CN (1) CN105358534A (de)
WO (1) WO2014173928A1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2015209239C1 (en) 2014-01-24 2026-05-07 Turning Point Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
MX2017017097A (es) 2015-07-02 2018-05-23 Tp Therapeutics Inc Macrociclos diarílicos quirales como moduladores de proteínas quinasas.
PL3319969T3 (pl) 2015-07-06 2024-06-24 Turning Point Therapeutics, Inc. Diarylowe polimorfy makrocykliczne
CN109574859A (zh) * 2018-11-26 2019-04-05 山东省科学院新材料研究所 一种贝蒂碱衍生物的合成方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082205A2 (en) * 2002-03-27 2003-10-09 Smithkline Beecham Corporation Compounds and methods
MXPA05013364A (es) * 2003-06-17 2006-03-17 Arena Pharm Inc Procedimiento para preparar 3-benzazepinas.
ES2533026T3 (es) * 2010-06-03 2015-04-07 Bayer Intellectual Property Gmbh N-[(het)arilalquil)]pirazol (tio)carboxamidas y sus análogos heterosustituidos
LT2785695T (lt) * 2011-11-30 2020-08-25 F. Hoffmann-La Roche Ag Nauji dviciklio dihidroizochinolin-1-ono dariniai

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PAUL HEBEISEN ET AL: "Ring opening of cyclic sulfamidates with bromophenyl metal reagents: complementarity of sulfamidates and aziridines", TETRAHEDRON LETTERS, vol. 52, no. 41, 1 October 2011 (2011-10-01), AMSTERDAM, NL, pages 5229 - 5233, XP055318635, ISSN: 0040-4039, DOI: 10.1016/j.tetlet.2011.07.123 *

Also Published As

Publication number Publication date
WO2014173928A1 (en) 2014-10-30
CN105358534A (zh) 2016-02-24

Similar Documents

Publication Publication Date Title
TWI464165B (zh) 用於製備藥劑之方法及中間物
CN101959870B (zh) 吗啉衍生物的制备
CA2373920A1 (en) Substituted heterocycle fused gamma-carbolines
JP2014514292A (ja) アミン中間体化合物を使用してドロネダロンを製造するための還元アミノ化方法
WO2008035381A2 (en) Process for the preparation of amine derivatives as calcimimetics
CN114206847B (zh) 杂环亚基乙酰胺衍生物的制造方法
WO2014173928A1 (en) Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof
EP3022183A1 (de) Verfahren zur racemisierung unerwünschter enantiomere
CN102399166B (zh) 光学异构的千金藤啶碱及其衍生物的制备方法
JPH09110811A (ja) Ｎ−（ヒドロキシ）アラルキルフェニルエタノールアミン類のｏ−アルキル化された化合物
EP2349976B1 (de) Verfahren zur herstellung von (s)-3-[(1-dimethylamino)ethyl]phenyl-n-ethyl-n- methylcarbamat über neue zwischenprodukte
AU2017200463A1 (en) The process for the preparation of metaraminol
TW200918532A (en) Chiral synthesis of diazepinoquinolines
JP6235560B2 (ja) （３，４−ジクロロ−フェニル）−（（ｓ）−３−プロピル−ピロリジン−３−イル）−メタノン塩酸塩及び製造方法
WO2014202765A1 (en) Preparation of chiral 1-methyl-2,3,4,5-1h-benzodiazepines via asymmetric reduction of alpha-substituted styrenes
CN104837817B (zh) 制备3‑氨基‑哌啶化合物的合成路线
HK1225388A1 (zh) 通过环化2-(氨基乙氧基)苯甲酸衍生物制备3，4-二氢-1，4-苯并氧氮杂环庚三烯-5(2h)-酮衍生物
BRPI0614154A2 (pt) sìntese e intermediários de diazepinoquinolinas
AU2020270992B2 (en) D3 receptor agonist compounds; methods of preparation; intermediates thereof; and methods of use thereof
IE61811B1 (en) 2-amino-7-hydroxytetralin carboxyalkyl ethers
WO2020171073A1 (ja) ベンゾアゼピン誘導体の製造方法及びその中間体
CN107935866A (zh) 盐酸达泊西汀杂质的制备方法
WO2014187768A1 (en) Novel synthetic processes to 8-chloro-3-benzo[d]azepine via friedel-crafts alkylation of olefin
JP5130212B2 (ja) 光学活性３−アミノ−２，５−ジオキソピロリジン−３−カルボキシレート類およびその製造方法ならびに該化合物の使用
CN104955803B (zh) 通过硝基‑四氢吡啶前体制备3‑氨基‑哌啶化合物

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20151118

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20161129

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20170411