EP3010887A1 - Préparation de 1-méthyl-2,3,4,5-1h-benzodiazépines chirales par réduction asymétrique de styrènes alpha-subst itués - Google Patents

Préparation de 1-méthyl-2,3,4,5-1h-benzodiazépines chirales par réduction asymétrique de styrènes alpha-subst itués

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Publication number
EP3010887A1
EP3010887A1 EP14731300.1A EP14731300A EP3010887A1 EP 3010887 A1 EP3010887 A1 EP 3010887A1 EP 14731300 A EP14731300 A EP 14731300A EP 3010887 A1 EP3010887 A1 EP 3010887A1
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Prior art keywords
formula
compound according
asymmetric
compound
methyl
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English (en)
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Gaj STAVBER
Ivana Gazic Smilovic
Jerome Cluzeau
Frank Richter
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Lek Pharmaceuticals dd
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Lek Pharmaceuticals dd
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    • 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
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
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    • C07C233/16—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 singly-bound oxygen atoms
    • C07C233/17—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 singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—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 singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C255/35—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a 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
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C12P13/00—Preparation of nitrogen-containing organic compounds
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    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
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    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of organic synthesis, in particular to the synthesis of benzodiazepines with stimulating activity on serotonin receptors, especially lorcaserin.
  • the third route starts from 2-(4-chlorophenyl)ethanol (formula 7) which is first brominated using expensive phosphorous tribromide.
  • the bromide according to the formula 3 is transformed to the alcohol precursor (formula 8) with an excess of 1 - amino-2-propanol.
  • the alcohol is substituted with thionyl chloride in the presence of catalytic amount of dimethylacetamide to give the same solid hydrochloride precursor according to the formula 12 obtained in the second route.
  • the resulting amide (formula 14), optionally in a mixture with the minor dihydrooxazole compound (formula 15), is then reduced using various reducing agents (borane in tetrahydrofuran or dimethylsulfide, sodium boronhydride in presence of iodine) to afford the alcohol precursor according to the formula 8 which is further transformed to lorcaserin (formula 1 ) as described in the previous publications.
  • various reducing agents borane in tetrahydrofuran or dimethylsulfide, sodium boronhydride in presence of iodine
  • the publication WO 09/1 1 1004 describes a further improvement of the process of Scheme 2 using a new bromination methodology including HBr gas instead of expensive PBr 3 (Scheme 4).
  • the publication also discloses a problem dialkylation of 1 - amino-2-propanol with the bromide according to the formula 3 to produce the impurity represented by the formula 16, which is reduced to the content of less than 10% in the desired product according to the formula 8.
  • This invention has the object to provide a new, simple, economical and environmentally benign highly enantioselective synthesis to optically active 8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 /-/-benzo[c ]-azepine from a new starting point proceeding via novel intermediates.
  • the present invention has the object to provide novel asymmetric, efficient chemical catalytic systems.
  • Such asymmetric methodologies are also developed with an emphasis on green and sustainable development, where pure water instead of toxic, expensive and pollutant solvents is used as green solvent. Attention is also focused on the important last stages, where improved closing reactions of final intermediates to lorcaserin are presented. Summary of the invention
  • the present invention provides a novel asymmetric synthetic route for synthesizing 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/- benzo[c/]azepine (compound A), or a salt thereof, preferably lorcaserin, or a salt thereof. This approach is illustrated in Scheme 6.
  • the synthetic route is simple, industrial friendly and enables transformations with no racemization of chiral intermediates. Further, the synthesis route requires simple and/or commercially available reagents and catalysts. The efficient and highly selective asymmetric approach is advantageous in comparison with low efficiency of chemical optical resolution of racemic mixture of final lorcaserin used in the prior art.
  • 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 for racemization compared to the prior art final ring closing performed in the meta-position relative to the CI substituent as illustrate by the above Schemes 1 to 3.
  • substituents A and B represent groups, which are convertible to the aminomethyl group -CH 2 -NHR', wherein R' is H or CH 2 CH(OR)2 (wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C 2 - or C 3 -alkylene chain for forming a 5- or 6-membered ring), by an asymmetric enzymatic, biomimetic or catalytic reduction to give the compound according to the formula II:
  • R is defined as above, and * represents the same configuration as for the compound according to the formula II; by
  • PG is an amino protection group, which is preferably selected from unsubstituted or substituted benzyl, unsubstituted or fluorinated CrC 4 -alkanesulfonyl, or unsubstituted or para-substituted benzenesulfonyl, or CrC 6 -alkanoyl, or arylcarbonyl and wherein * represents the same configuration as for the compound according to the formula II;
  • R-i is hydrogen or PG, wherein PG is defined as above, and * represents the same configuration as for the compound according to the formula II;
  • step (e1 ) reducing the compound according to the formula VI; and (e2) if R- ⁇ is PG, deprotecting the group PG, wherein PG is defined as above, wherein the step (e1 ) is preferably applied prior to the step (e2);
  • Asymmetric method according to item 1 wherein the compounds are produced with the asymmetric carbon atom indicated by * being enantiomerically enriched, essentially enantiopure or enantiopure in the (R) configuration, preferably with an ee of at least 60 % ee, more preferably of at least 90 % ee or more, still more preferably of at least 98 % ee.
  • a in the compound according to the formula la is selected from -CN, -COY (with Y being OH, C C 6 -alkoxy, NH 2 , or NH-CH 2 CH(OR) 2 , wherein R is defined as above), -CH 2 -N0 2 , -CH 2 -NO, -CH 2 N 3 , and wherein A is preferably -CN, -COOH, -COOMe, -COOEt, -CONH 2 or -CONH-CH 2 CH(OR) 2 , most preferably -CN; and
  • step (a) Asymmetric method according to any one of items 1 to 3, wherein an asymmetric enzymatic reduction is applied in step (a) with the enzymes being selected from reductases of natural or recombinant sources, and wherein the natural reductases are preferably used as isolated enzymes, in mixtures or in a fermentation process with reductases rich microorganisms.
  • a microorganism friendly water miscible solvent preferably selected from alcohols or acetone, most preferably ethanol.
  • asymmetric enzymatic method is preferably applied for the compound Ib- N0 2 being dissolved in a microorganism friendly water miscible solvent, preferably ethanol, using baker's yeast containing fungi of the species Saccharomyces cerevisiae in a water medium and for the compound la-CN added undissolved using baker's yeast containing fungi of the species Saccharomyces cerevisiae in a water medium in a mixture with a water immiscible solvent, preferably petroleum ether.
  • a microorganism friendly water miscible solvent preferably ethanol
  • step (a) Asymmetric method according to any one of items 1 to 3, wherein an asymmetric biomimetic reduction is applied in step (a) in the presence of a hydrogen donor and an organocatalyst, wherein 1 ,4-dihydropyridines are preferably used as proton donors, which are more preferably selected from diethyl 1 ,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate or di-i-butyl 1 ,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate, and wherein the organocatalyst is selected from chiral derivatives of thioureas, urea sulfinamides and imidazolones, which are preferably selected from enantiopure ⁇ /-[2- (3-(3,5-bis(trifluoromethyl)phenyl)ureido)cyclohexyl]-ie f-butyl-s
  • Asymmetric method according to item 7, wherein the asymmetric biomimetic reduction is applied for the compound lb with B being represented by CH-N0 2 (lb-N0 2 ), preferably by using 2-[[3,5-bis(trifluoromethyl)phenyl]thioureido]-/V-benzyl- /V,3,3-tri methylbutanamide as an organocatalyst.
  • step (a) an asymmetric catalytic reduction is applied in step (a) in the presence of hydrogen or a hydride donor and of a catalyst, selected from a transition metal, which is preferably selected from ruthenium, rhodium, iridium and copper, in a combination with a chiral ligand preferably selected from phosphine and diphosphine ligands.
  • a catalyst selected from a transition metal, which is preferably selected from ruthenium, rhodium, iridium and copper, in a combination with a chiral ligand preferably selected from phosphine and diphosphine ligands.
  • Asymmetric method according to item 9 wherein the asymmetric catalytic reduction is performed with hydrogen under the pressure of 1 to 50 bar, preferably 1 to 5 bar.
  • a hydride donor is used for the asymmetric catalytic reduction, which is preferably selected from mono-, di- or tri- d- C 6 -alkyl or aryl substituted silanes, most preferably from phenylsilane or triethylsilane and/or alkyl substituted polyhydrosiloxanes, preferably polymethylhydrosiloxane (PMHS).
  • a hydride donor is used for the asymmetric catalytic reduction, which is preferably selected from mono-, di- or tri- d- C 6 -alkyl or aryl substituted silanes, most preferably from phenylsilane or triethylsilane and/or alkyl substituted polyhydrosiloxanes, preferably polymethylhydrosiloxane (PMHS).
  • PMHS polymethylhydrosiloxane
  • transition metal is copper, which is used in the form of copper (I) salts, preferably in the form of copper (I) chloride, or in the form of copper (II) compounds, preferably selected from copper (II) halogenide, nitrate, sulfate, hydroxide or carbonate, more preferably from hydroxide or basic carbonate (Cu(OH) 2 -CuC0 3 ).
  • the chiral diphosphine ligands are selected from ferrocene containing ligands, preferably selected from the Josiphos group, Mandyphos or Walphos group of ligands and wherein the chiral phosphine ligands are preferably selected from oxazoline type ligands (PHOX).
  • Asymmetric method according to any one of items 9 and 1 1 to 13, wherein the asymmetric catalytic reduction uses a combination selected from the group consisting of Cu(OH) 2 /Walphos, Cu(OH) 2 /PHOX, Cu(OH) 2 CuC0 3 /Walphos, Cu(OH) 2 CaC0 3 /PHOX or CuCI/PHOX preferably in the presence of phenylsilane and polymethylhydrosiloxane (PMHS).
  • a combination selected from the group consisting of Cu(OH) 2 /Walphos, Cu(OH) 2 /PHOX, Cu(OH) 2 CuC0 3 /Walphos, Cu(OH) 2 CaC0 3 /PHOX or CuCI/PHOX preferably in the presence of phenylsilane and polymethylhydrosiloxane (PMHS).
  • step (b1 ') Asymmetric method according to any one of items 1 to 16, wherein the compound according to the formula ll-N0 2 is reduced in step (b1 ') to give the compound according to the formula III by inorganic reducing agents selected from inorganic sulfides, selected from sodium hydrogensulfide, sulfide or polysulfide, from sodium dithionite or thiourea dioxide in basic conditions, or by catalytic hydrogenation, preferably using platinum, palladium or vanadium catalysts, or low-valent metal salts, preferably selected from iron (II) or tin (II) salts or elemental metal in the presence of acids, preferably zinc or iron in hydrochloric acid or acetic acid, optionally diluted by a water miscible solvent selected from CrC 4 -alcohol and tetrahydrofuran, wherein the reduction most preferably uses zinc in methanolic HCI.
  • inorganic reducing agents selected from inorganic sulfides, selected
  • step (b1 ') Asymmetric method according to any one of items 1 to 7 and 9 to 15, wherein the compound according to the formula II with A being represented by -CONH 2 or -CN is reduced in step (b1 ') to give the compound according to the formula III by catalytic hydrogenation on Raney® Ni or by using a hydride, selected from boron hydrides, preferably selected from borane complexes, such as BH 3 .THF, aluminum hydrides, such as lithium aluminum hydride or DIBALH, the reduction most preferably using BH 3 .THF.
  • a hydride selected from boron hydrides, preferably selected from borane complexes, such as BH 3 .THF, aluminum hydrides, such as lithium aluminum hydride or DIBALH, the reduction most preferably using BH 3 .THF.
  • step (b1 ) Asymmetric method according to any one of items 1 to 7 and 9 to 16, wherein the compound according to the formula II with A being represented by -CONHCH 2 C(OR) 2 is reduced in step (b1 ") to give the compound according to the formula IV by a hydride, selected from borohydrides, preferably lithium borohydride, boron hydrides, preferably selected from borane complexes, such as BH 3 .THF, or aluminum hydrides, such as lithium aluminum hydride or DIBALH, to give the compound according to the formula IV.
  • a hydride selected from borohydrides, preferably lithium borohydride, boron hydrides, preferably selected from borane complexes, such as BH 3 .THF, or aluminum hydrides, such as lithium aluminum hydride or DIBALH, to give the compound according to the formula IV.
  • step (b1 ") further comprises a step of converting the residue A, which may be represented by -COY (Y is CrC 6 -alkoxy or NH 2 ), to give the compound according to the formula II with A being represented by -CONHCH 2 C(OR) 2 .
  • step (d) is accomplished in the presence of a Lewis acid, preferably selected from AICI 3 , FeCI 3 , InCIs, lnBr 3 , Bi(OTf) 3 , BiCI 3 , Sc(OTf) 3 , TeCI 4 , most preferably from anhydrous AICI 3 .
  • a Lewis acid preferably selected from AICI 3 , FeCI 3 , InCIs, lnBr 3 , Bi(OTf) 3 , BiCI 3 , Sc(OTf) 3 , TeCI 4 , most preferably from anhydrous AICI 3 .
  • Asymmetric method according to any one of items 1 to 24, wherein the reduction in the step (e1 ) is accomplished by using reducing agents selected from boron hydrides, such as alkali metal borohydrides, preferably NaBH 4 , or borane complexes, preferably BHs-THF, aluminum hydrides, preferably LiAIH 4 , DIBALH, RedAI, by NEt 3 /HC0 2 H, or by catalytic hydrogenation using metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by catalytic hydrogenation using metal transition catalysts.
  • boron hydrides such as alkali metal borohydrides, preferably NaBH 4 , or borane complexes, preferably BHs-THF
  • aluminum hydrides preferably LiAIH 4 , DIBALH, RedAI, by NEt 3 /HC0 2 H
  • metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by
  • substituents A and B represent groups, which are convertible to the aminomethyl group -CH 2 -NHR', wherein R' is H or CH 2 CH(OR) 2 (wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C 2 - or C 3 -alkylene chain for forming a 5- or 6-membered ring), wherein the asymmetric catalytic reduction is applied in an aqueous medium in the presence of a hydride donor and of a copper catalyst, which is used in the form of copper (I) salts, preferably in the form of copper (I) chloride, or in the form of copper (II) compounds, preferably selected from copper (II) halogenide, nitrate, sulfate, hydroxide or carbonate, more preferably from hydroxide or basic carbonate (Cu(OH) 2 -CuC0 3 ), in a combination with a chiral lig
  • aqueous medium is water not containing organic solvents or a biphasic system with a water immiscible solvent, preferably toluene, wherein the aqueous medium is preferably water not containing organic solvents.
  • hydride donor is selected from mono-, di- or tri- CrC 6 -alkyl or aryl substituted silanes, most preferably from phenylsilane or triethylsilane and/or alkyl substituted polyhydrosiloxanes, preferably polymethylhydrosiloxane (PMHS).
  • PMHS polymethylhydrosiloxane
  • a in the compound according to the formula la is selected from -CN, -COY (with Y being OH, C C 6 -alkoxy, NH 2 , or NH-CH 2 CH(OR) 2 , wherein R is defined as above), -CH 2 -N0 2 , -CH 2 -NO, -CH 2 N 3 , and wherein A is preferably -CN, -COOH, -COOMe, -COOEt, -CONH 2 or -CONH-CH 2 CH(OR) 2 , most preferably -CN; and
  • Y is CrC 6 -alkoxy, preferably methoxy.
  • Asymmetric method for producing one of the compounds according to item 35 or 36 the method at least comprising the step (a) of an asymmetrical enzymatic, biomimetic or catalytic reduction as defined according to any one of items 1 to 16 and 26 to 30.
  • R 1 is selected from hydrogen, unsubstituted benzyl or substituted benzyl, preferably ⁇ -methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated CrC 4 -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or d-C 6 -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl.
  • PG is selected from unsubstituted benzyl or substituted benzyl, preferably ct- methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated Ci-C 4 - alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or CrC 6 -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl.
  • the compound according to item 42 which is enantiomerically enriched, essentially enantiopure or enantiopure in the (R) configuration.
  • the present invention provides an industrially applicable, economical and simple enantioselective process for the preparation of serotonin antagonizing chiral 8-chloro-1 - methyl-benzo[c/]azepine or related compounds, or its salts, particularly lorcaserin, as well as key intermediates for the synthesis thereof.
  • 8-chloro-1 -methyl- benzo[c/]azepine and related compounds, or its salts, particularly lorcaserin the synthetic route described herein benefits from simple reactions, mild reaction conditions and readily available and cheap chemicals.
  • the starting styrenes for the overall synthesis are readily available by simple processes known to a skilled person.
  • the chiral reduction of styrenes according to the invention applies enzymatic, biomimetic or catalytic approaches with easy available and cheap enzymes, reagents, catalysts and ligands leading to corresponding chiral 2-propyl substituted benzenes with high ee.
  • Such intermediates are easily converted to chiral 1 -methyl-2,3,4,5-1 /-/- benzodiazepines with retention of chirality.
  • enantiomerically enriched means that one enantiomer predominates over the other expressing 10 to 70 % ee, preferably 30 to 70 % ee, more preferably 60 to 70 % ee.
  • 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.
  • enantiopure as used herein means an enantiomeric excess (ee) of 98 % ee or more, preferably 99 % ee or more.
  • salt refers to any suitable salt form of the respective compound.
  • the salt is pharmaceutically acceptable.
  • the present invention provides a method for asymmetrically synthesizing 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo[c/]azepine being illustrated by the following formula A, or a salt thereof: wherein * in the formulae denotes an asymmetric carbon atom in (R) or (S) configuration being enantiomerically enriched, essentially enantiopure or enantiopure, the method comprising the steps:
  • substituents A and B represent groups, which are convertible to the aminomethyl group -CH 2 -NHR', wherein R' is H or CH 2 CH(OR) 2 (wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C 2 - or C 3 -alkylene chain for forming a 5- or 6-membered ring), by an asymmetric enzymatic, biomimetic or catalytic reduction to give the compound according to the formula II:
  • R is defined as above, and * represents the same configuration as for the compound according to the formula II; by
  • PG is an amino protection group, which is preferably selected from unsubstituted or substituted benzyl, unsubstituted or fluorinated CrC 4 -alkanesulfonyl, or unsubstituted or para-substituted benzenesulfonyl, or CrC 6 -alkanoyl, or arylcarbonyl and wherein * represents the same configuration as for the compound according to the formula II;
  • R-i is hydrogen or PG, wherein PG is defined as above, and * represents the same configuration as for the compound according to the formula II;
  • step (e2) if R-i is PG, deprotecting the group PG, wherein PG is defined as above, wherein the step (e1 ) is preferably applied prior to the step (e2);
  • the configuration (R) or (S) of the enantiopure compound according to the formula A or the predominant enantiomer in the enantiomerically enriched mixture thereof is determined in the step (a) depending on the selection of an enzyme or enzymatic method in the enzymatic approach or on the selection of a catalyst in the biomimetic or the catalytic approach. For illustration only, a skilled person may simply take a ligand of reverse chirality in a catalytic system to obtain a product of reverse chirality.
  • the initial configuration, created in the step (a) is retained through the step (b) to (f) to the final compound according to the formula A, or a salt thereof, without substantial racemization or inversion.
  • an enzymatic or a catalytic system is selected to produce compounds of configuration (R), which are suitable intermediates for preparation of the obesity drug lorcaserin.
  • R compounds of configuration
  • Such compounds are illustrated as formulae (R)-W, (R)- ⁇ , (R)- IV, (R)M, (R)M ⁇ , (R)-V ⁇ as shown in Scheme 8.
  • the starting compound can exist in structures la and/or lb. Generally they are different compounds which can lead in conditions of the reaction of the step (a) to the same product of the formula II, using same or different approaches in view of reagents, enzymes or process conditions. In some cases one of the structures is preferred. For instance, if the substituent A or B, respectively, contains an electron withdrawing group, such as nitro, the structure lb is preferred. Furthermore, in some cases the structures may be transformable in conditions of the reaction of the step (a) behaving like tautomers.
  • the most preferred starting compounds according to the general formula la according to the embodiment are selected from acrylonitrile according to the formula la-CN or acrylic esters of the formula la-Y, wherein Y is CrC 6 -alkoxy, preferably methoxy (la-Me) being illustrated by Scheme 9.
  • Such a-aryl substituted acrylic derivatives can be easily prepared according to state of the art from corresponding aryl substituted acetates or acetonitrile by formaldehyde derivatives in various reaction conditions, preferably by ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethylaminomethane (TDAM) in acetic anhydride (Scheme 10).
  • TDAM ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethylaminomethane
  • Y is CrC 6 -alkoxy, preferably methoxy, represents a novel and suitable intermediate for use in the synthesis of compound A, preferably lorcaserin, or its salts.
  • the most preferred starting compound according to the general formula lb according to the embodiment is selected from a ⁇ -styrene according to the formula lb-N0 2 :
  • Such ⁇ -styrene can be easily prepared according to state of the art from corresponding acetophenone and nitro methane or from a-styrene and sodium nitrite in the presence of ammonium cerium nitrate in acidic medium (Scheme 1 1 ).
  • the enzymes are preferably selected from reductases of natural or recombinant sources, wherein the natural reductases are used as isolated enzymes, in mixtures or in a fermentation process with reductases rich microorganisms.
  • the most preferred approach according to the invention uses baker's yeast, which contains various reductases.
  • the baker's yeast is not a selective source of reductases, the transformation with the baker's yeast according to the step (a) gives the compounds according to the formula II in high yield and enantiomeric excess, Furthermore, this reduction is comprehensive for the compounds la and lb with most of substituents A or B, respectively.
  • the enzymatic reduction according to the step (a) is most preferably carried out using baker's yeast containing fungi of the species Saccharomyces cerevisiae in a water medium, preferably containing a buffer of pH 7-9, most preferably the phosphate buffer of pH 8, optionally in a mixture with a water immiscible solvent, preferably selected from hydrocarbons.
  • the mixture is optionally pre-prepared by adding a feed, preferably selected from glucose tempering it at the temperature from 15 to 40 °C, preferably at 35 °C.
  • a substrate selected from a compound according to the formula la or lb is added undissolved or dissolved in a microorganism friendly water miscible solvent, preferably selected from alcohols or acetone, most preferably ethanol.
  • the bioreaction mixture is usually stirred for 3 hours to 5 days, preferably 1 day, at the temperature from 15 to 40 °C, preferably at 35 °C.
  • the product can be isolated by removal of biomaterial followed by extraction and can be purified by the methods of state of the art.
  • the nitro compound lb-N0 2 is reduced to the compound according to the formula ll-N0 2 with high ee, the acrylic ester la -Me to the compound according to the formula ll-Me and the acrylonitrile la-CN to the compound according to the formula ll-CN with very high ee (Scheme 12).
  • the favored configuration of the products according to the formula II prepared by the bioreaction with the baker's yeast is (R).
  • this biomimetic reduction is preferably performed in the presence of a hydrogen donor and an organocatalyst.
  • the biomimetic reaction represents a reaction, which mimics a bioreaction by using unnatural reagents.
  • the reduction mimics a bioreduction, such as a transfer hydrogenation which is usually performed with NADH dehydrogenases in nature.
  • 1 ,4-dihydropyridines, also named Hantzsch esters are preferably used as proton donors in the biomimetic reactions.
  • any Hantzsch ester can be used, but the simplest and the cheapest representatives such as diethyl 1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate or di-i-butyl 1 ,4-dihydro- 2,6-dimethyl-3,5-pyridine dicarboxylate are most preferred.
  • Organocatalysts for the biomimetic transfer hydrogenation reaction are selected from chiral derivatives of thioureas, urea sulfinamides and imidazolones, which are preferably selected from enantiopure ⁇ /-[2-(3-(3,5- bis(trifluoromethyl)phenyl)ureido)cyclohexyl]-ie f-butyl-sulfinamide, 2-[[3,5- bis(trifluoromethyl)phenyl]thioureido]-/V-benzyl-/V,3,3-trimethylbutanamide,
  • organocatalysts play a role of chiral inductors for the generation of a particular configuration at the chiral carbon atom in the position 2 of the resulting 2-arylpropane (indicated by * ), which is dependent on configuration of the organocatalyst.
  • the transfer hydrogenation reaction is preferably applied on nitrostyrenes (compound according to the formula lb-N0 2 ).
  • the reactions are usually performed in an organic solvent, preferably selected from aromatic or aliphatic hydrocarbons, most preferably toluene, at the temperature from 10 to 100 °C, preferably from 30 to 45 °C, for 6 hours to 5 days, preferably from 12 hours to 2 days.
  • organic solvent preferably selected from aromatic or aliphatic hydrocarbons, most preferably toluene, at the temperature from 10 to 100 °C, preferably from 30 to 45 °C, for 6 hours to 5 days, preferably from 12 hours to 2 days.
  • Such biomimetic approach gives moderate to high ee of at least 60 % ee, preferably at least of 90 % ee and at least 90 % conversion, in most cases a full conversion to the compound according to the formula ll-N0 2 .
  • this catalytic reduction is performed by use of hydrogen or a hydride donor in the presence of a catalyst, preferably selected from a transition metal, which is preferably selected from ruthenium, rhodium, iridium and copper, in a combination with a chiral ligand preferably selected from phosphine and diphosphine ligands.
  • a catalyst preferably selected from a transition metal, which is preferably selected from ruthenium, rhodium, iridium and copper, in a combination with a chiral ligand preferably selected from phosphine and diphosphine ligands.
  • the reaction with hydrogen is usually performed under the pressure of 1 to 50 bar, preferably 1 to 5 bar.
  • hydride donors preferably selected from mono-, di- or tri- CrC 6 -alkyl or aryl substituted silanes, most preferably from phenylsilane or triethylsilane and/or alkyl substituted polyhydrosiloxanes, preferably polymethylhydrosiloxane (PMHS).
  • PMHS polymethylhydrosiloxane
  • the transition metal can be introduced into the reaction system in the form of a complex with the corresponding ligand or in the form of a salt, oxide, hydroxide in particular valence states with separate addition of a ligand or its predecessor.
  • copper catalysts show high efficiency in reduction of a-substituted styrene and, furthermore, in the combination with particular phosphine ligands, also high enantioselectivity.
  • Copper is preferably introduced in the form of Cu(l) salts, preferably in the form of copper (I) chloride, or in the form of copper (II) compounds, selected from copper (II) halogenides, nitrate, sulfate, hydroxide or carbonate, preferably from hydroxide or basic carbonate.
  • copper (II) basic carbonate (“basic CuC0 3 ”) as used herein, refers to malachite (Cu(OH) 2 .CuC0 3 ) or the azurite (Cu 3 (OH) 2 (C0 3 )2) form of copper (II) carbonate.
  • the malachite form of copper (II) basic carbonate Cu(OH) 2 .CuC0 3 represents a readily available and surprisingly effective catalytic system for reductions, acting as a metal and a base activator in one molecule.
  • Diphosphine ligands are preferably selected from commercially available ferrocene containing ligands, selected from the Josiphos, Mandyphos or Walphos group of ligands. Phosphine ligands are preferably selected from oxazoline type ligands (PHOX).
  • the reduction which is first used in this invention, can be successfully preformed in water media, which is highly advantageous for industrial use, while the prior art methodology based on copper fluoride or ie f-butylate with Josiphos or BINAP ligands does not work in aqueous medium.
  • Such a catalytic reduction represents a novel key synthesis step to be preferably applied in the synthesis of the compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, and can therefore also suitably be used for producing the novel and suitable intermediates according to the formulae III, IV and V:
  • a copper based asymmetric catalytic reduction of the compound according to the formula lb-N0 2 is performed in an aqueous medium, such as water not containing organic solvents or optionally in a biphasic system with a water immiscible solvent, preferably toluene.
  • the copper compound is preferably mixed with the ligand creating compound after which the catalyst is created in 15 to 60 minutes.
  • the procedure is usually followed by the addition of reducing agent, such as phenylsilane and the additive PMHS.
  • the nitrostyrene is added, followed by a second portion of silane.
  • the reaction is normally performed at a temperature from 10 - 50 °C, preferably from 20 to 30 °C in 6 hours to 2 days, preferably in one day.
  • the product can be extracted from the aqueous medium and can then be isolated and purified by the methods of the state of the art.
  • the group A in the compound according to the formula II is converted to the aminomethyl group in a reaction or in a set of reactions, wherein at least one consists of a reduction.
  • the group A in the compound according to the formula II is represented by -CN, -COY (with Y being OH, C C 6 -alkoxy, NH 2 , or NH- CH 2 CH(OR) 2 , wherein R is defined as above), -CH 2 -N0 2 , -CH 2 -NO, -CH 2 N 3 , and wherein A in the compound according to the formula II is most preferably selected from -CN (ll-CN), -COOMe (ll-Me), and -CH 2 -N0 2 (ll-N0 2 )
  • the compound according to the formula ll-N0 2 is reduced to the compound according to the formula III by inorganic reducing agents selected from inorganic sulfides, selected from sodium hydrogensulfide, sulfide or polysulfide, from sodium dithionite or thiourea dioxide in basic conditions, or by catalytic hydrogenation, preferably using platinum, palladium or vanadium catalysts, or low-valent metal salts, preferably selected from iron (II) or tin (II) salts or elemental metal in the presence of acids, preferably zinc or iron in hydrochloric acid or acetic acid, optionally diluted by a water miscible solvent selected from CrC 4 -alcohol and tetrahydrofuran.
  • inorganic reducing agents selected from inorganic sulfides, selected from sodium hydrogensulfide, sulfide or polysulfide, from sodium dithionite or thiourea dioxide in basic conditions, or by catalytic hydrogenation, preferably
  • the compound according to the formula II, wherein A is represented by -CO-NH 2 or CN (ll-CN) is catalytically hydrogenated on Raney® Ni or is reduced by a hydride, selected from boron hydrides, preferably selected from borane complexes, such as BH 3 .THF, aluminum hydrides, such as lithium aluminum hydride or DIBALH to give the compound according to the formula III.
  • a hydride selected from boron hydrides, preferably selected from borane complexes, such as BH 3 .THF, aluminum hydrides, such as lithium aluminum hydride or DIBALH to give the compound according to the formula III.
  • XI by means of coupling reagents selected from activated isoureas, or carbodiimides, preferably N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 0 - 50 %, preferably 5 - 20 % molar excess, optionally in the presence of bases, which are preferably selected from tertiary amines, such as triethylamine, ethyldiisopropylamine or N-methylmorpholine, or via preparation of reactive acid derivatives, such as halogenides, by reacting the acid with e.g.
  • bases which are preferably selected from tertiary amines, such as triethylamine, ethyldiisopropylamine or N-methylmorpholine, or via preparation of reactive acid derivatives, such as halogenides, by reacting the acid with e.g.
  • a hydride selected from borohydrides, preferably lithium borohydride, boron hydrides, preferably selected from borane complexes, such as BH 3 .THF, or aluminum hydrides, such as lithium aluminum hydride or DIBALH, to give the compound according to the formula IV.
  • the compound according to the formula III is preferably reacted with the compound represented by the above defined formula XCH 2 CH(OR)2 (wherein X is preferably CI or Br, and R is preferably methyl or ethyl), most preferably chloroacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal, optionally in the presence of a base, or with the compound represented by the above defined formula OHC-CH(OR) 2 (wherein R is preferably methyl or ethyl) under conditions of reductive amination by using alkali metal borohydrides, preferably selected from sodium borohydride or sodium triacetoxyborohydride, or by catalytic hydrogenation on palladium on supporter, preferably 10 % palladium on charcoal, to obtain the compound according to the formula IV.
  • alkali metal borohydrides preferably selected from sodium borohydride or sodium triacetoxyborohydride, or by catalytic hydrogenation on palladium on supporter
  • the compounds according to the formula III or IV are optionally isolated as solid salts, preferably hydrochlorides.
  • the compounds are first isolated as oils in a crude state or in a purified state following purification by e.g. column chromatography. Then, the crude or purified oil is diluted by an organic solvent, preferably selected from tetrahydrofuran, followed by addition of an acid, such as hydrochloric acid or gaseous hydrogen chloride. The salt, such as hydrochloride, is then precipitated and filtered off.
  • the compounds according to the formula III or IV can be extracted by partitioning the reaction mixture between concentrated aqueous sodium chloride solution (brine), which is acidified by an acid, such as hydrochloric acid, and an organic solvent, preferably dichloromethane, wherein the salt is forced to the organic phase which is afterwards separated off and concentrated to give the compound according to the formula III or IV in the form of a salt, preferably as hydrochloride salt.
  • brine concentrated aqueous sodium chloride solution
  • an organic solvent preferably dichloromethane
  • the compound according to the above defined formula IV (where R 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 V , which can be isolated in the form of hydrochloride by partitioning between brine and dichloromethane.
  • the intermediate compounds according to the below formulae XII and/or XIII, wherein R is defined as above, preferably represented by methyl or ethyl, can also be isolated, under some conditions as predominate products.
  • reaction should be forced to yield the final product with a double bond according to the formula V .
  • 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 , InCIs, lnBr 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 IV, where the secondary amine is unprotected.
  • the compound according to the formula IV may preferably be transformed in step (c) to the compound according to the formula V:
  • the amino protecting group PG as used herein means a group that protects the secondary amine of the compound according to the formula IV such that this group is applicable to the Friedel-Crafts reaction conditions applied in step (d).
  • Such an amino protecting group PG 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 PG used in the present invention is selected from
  • acyl halogenide preferably chloride
  • acyl anhydride such as acetic anhydride (Ac 2 0) or benzoyl chloride in basic conditions.
  • the media of the protection reactions are preferably selected from aprotic solvents, preferably dichloromethane.
  • step (d) The resultant compound according to the formula V is converted in step (d) under the same Friedel-Crafts reaction conditions as described for the compound according to the formula IV above, to give the compound according to the formula Vl 2 :
  • the compound according to the formula Vl 2 is 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
  • step (e) the compound according to the formula Vl 2 is reduced in the sub-step (e1 ) to a compound according to the formula VII:
  • 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, or by catalytic hydrogenation using metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by catalytic hydrogenation using metal transition catalysts.
  • 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, or by catalytic hydrogenation using metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by catalytic hydrogenation using metal transition catalysts.
  • step (e2) of step (e) the amino protection group PG of the compound according to the formula VII 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.
  • the compound according to the formula V is reduced in the sub-step (e1 ) of step (e) by using the reducing agents as described for the reduction of the compound according to the formula Vl 2 above, thereby yielding the final compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof.
  • step (d) the synthetic route, wherein the protection-(c)/de-protection-(e2) protocol is used, is more robust in easier achieving better yields and purity. Therefore, it is preferred to introduce an amino protection group PG by means of the step (c) prior to the Friedel-Crafts alkylation applied in step (d).
  • the compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, being prepared according to the steps (a) to (e) of the invention is enantiomerically enriched, essentially enantiopure or enantiopure in the enantiomer, which is created in excess in the key step (a).
  • the catalytic system used for the reduction of the compounds according to the formula la and lb prefers one of the enantiomers, either (R) or (S), preferably (R).
  • the initial configuration, created in the key step (a) is retained through the step (b) to (f) to give the final compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, without substantial changes.
  • the enantiomeric excess may be only slightly diminished by minor racemization or even improved by optional crystallizations or purifications of intermediates.
  • the preferred (R) enantiomer of the compound according to the formula II leads through steps from (b) to (e) to antiobesity drug lorcaserin, or a salt thereof.
  • a preferred but non-limiting embodiment of an advantageous method for the preparation of the (R) isomer of the compound according to the formula II, preferably II-NO 2 , which leads to lorcaserin, or a salt thereof, is making use of the baker's yeast, which gives the preferred enantiomer in high ee and yield.
  • the preferential configuration of the chiral carbon atom is defined by selection of the catalytic system, wherein the configuration of the organic catalyst or the ligand of metal catalyst determines the predominate configuration.
  • the enantiomerically excess is preferably improved by performing a chiral resolution via selective crystallization of diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange to yield a product with at least 90 % ee or more, most preferably 97 % ee or more.
  • a resolving agent preferably tartaric acid
  • the final steps optionally include purification in order to remove chemical impurities and transformation into a pharmaceutical salt.
  • the compound according to the formula (R)-A (lorcaserin) is transformed into the hydrochloride salt (lorcaserin hydrochloride, compound according to the above formula 1 ), by treating it with HCI in a solvent such as acetone or ether, and wherein the residue is optionally re-suspended or recrystallized from a solvent to obtain a crystalline and purified product.
  • a solvent such as acetone or ether
  • the compound represented by the formula VI in the form of the enantiomerically enriched, essentially enantiopure or enantiopure (R) or (S) enantiomer:
  • R 1 is selected from hydrogen, unsubstituted benzyl or substituted benzyl, preferably ⁇ -methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated CrC 4 -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or CrC 6 -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl, represents a novel and suitable intermediate for the synthesis of compound A, or a salt thereof, with the (RJ-enantiomer being suitable for the synthesis of lorcaserin, or a salt thereof.
  • PG is selected from unsubstituted benzyl or substituted benzyl, preferably a- methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated C1-C4- alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or CrC 6 -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl, represents a novel and suitable intermediate for the synthesis of compound A, or a salt thereof, with the (RJ-enantiomer being suitable for the synthesis of lorcaserin, or a salt thereof.
  • the present invention for the first time provides an asymmetric synthesis of 8-chloro-1 -methyl-benzo[c ]azepine derivatives, preferably lorcaserin, or its salts.
  • Various asymmetric methodologies can be used on the intermediates in order to selectively and efficiently establish asymmetric step, using simple and commercially available reagents and catalysts or baker's yeast as a cheapest way of enzymatic approach.
  • One approach uses novel, simple and highly enantioselective catalytic systems based on simple Cu(ll) and Cu(l) catalysts (copper (II) hydroxide, basic copper (II) carbonate and copper (I) chloride) and readily available chiral ligands, used for reduction of unsaturated intermediates in pure aqueous medium under mild reaction conditions. There is no need for hazardous high hydrogen pressures (asymmetric catalytic hydrogenation) and toxic, pollutant and expensive organic solvents as usual.
  • the present invention provides a facile, economically and selective synthesis. Moreover, the invention provides an insight about new key intermediates for the synthesis of such compounds and their respective production way.
  • the present invention presents efficient, simple and highly selective asymmetric approach to final lorcaserin, or a salt thereof. This is more advantageous and much more efficient in comparison with chiral resolution of enantiomers using chiral chromatography or classical optical resolution via diastereoisomeric salts what are well known approaches used in prior art.
  • Example 1 Preparation of (£)-1 -chloro-3-(1 -nitroprop-1 -en-2-yl)benzene from 1 - chloro-3-(prop-1 -en-2-yl)benzene
  • Example 2 Enzymatic synthesis of (R)-1 -chloro-3-(1 -nitropropan-2-yl)benzene in aqueous medium using baker ' s yeast
  • D-Glucose (5 g) was totally dissolved in aqueous phosphate buffer (100 mL) at pH 8 in a 500 mL flask equipped with magnetic stir followed by addition of dry Baker ' s yeast (type Saccharomyces Carevisiae; 10 g) and the reaction mixture was stirred at 35 °C. Afterwards, the nitro alkene starting material lb-N0 2 in EtOH solution (100 g/L) was slowly added drop wise and the reaction system was vigorously stirred (900 rpm) under nitrogen for 24 hours at 35 °C.
  • aqueous phosphate buffer 100 mL
  • EtOH solution 100 g/L
  • the reaction system was diluted with CH 2 CI 2 , filtered through Celite ® , the phases were separated and the aqueous phase was again extracted with CH 2 CI 2 .
  • Example 4 Asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic biomimetic transfer hydrogenation using urea- sulfinamide type chiral catalyst
  • Example 5 Asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic biomimetic transfer hydrogenation using thiourea-/V- benzyl-trimethylbutanamide type chiral catalyst
  • the reducing agent diethyl 1 ,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate (Hantzsch ester; 1 .1 eq. according to substrate; 0.5 mmol; 140 mg) was added in two portions and the reaction mixture was vigorously stirred at 40 °C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, the organic residue was extracted with two portions of MTBE (100 ml_), the combined organic phases were washed with brine and purified with flash chromatography (Si0 2 ; n-pentane : MTBE).
  • Example 6 Asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic biomimetic transfer hydrogenation using thiourea- cyclohexyl-imino type chiral catalyst
  • the reducing agent diethyl-1 ,4-dihydro- 2,6-dimethyl-3,5-pyridinedicarboxylate (Hantzsch ester; 1 .1 equv. according to substrate; 0.5 mmol; 140 mg) was added in two portions and the reaction mixture was vigorously stirred at 40 °C for 48 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the organic residue was extracted with two portions of MTBE (100 mL), the combined organic phases were washed with brine and purified with flash chromatography (Si0 2 ; n-pentane : MTBE).
  • Example 7 Asymmetric synthesis of optical active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic transfer hydrogenation using imidazolidinone type chiral catalyst
  • the reducing agent diethyl-1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (Hantzsch ester; 1 .1 equv. according to substrate; 0.5 mmol; 140 mg) was added in two portions and reaction mixture was vigorously stirred at 40 °C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, the organic residue was extracted with two portions of MTBE (100 mL), the combined organic phases were washed with brine and purified with flash chromatography (Si0 2 ; n-pentane : MTBE).
  • Example 8 Copper(ll) hydroxide/chiral phosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in pure water
  • Example 9 Copper(ll) hydroxide/chiral diphosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in pure water
  • the starting material ⁇ , ⁇ -disubstituted nitroalkene lb-N0 2 (7.5 mmol) was then added followed by a second portion of PhSiH 3 (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 48 h.
  • the reaction system was diluted with water, extracted with two portions of EtOAc (100 mL), the organic phases were washed with NaHC0 3 and brine, dried under anhydrous Na 2 S0 4 and the solvent was evaporated under reduced pressure.
  • Example 10 Basic copper(ll) carbonate/chiral phosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in aqueous toluene
  • Catalyst basic CuC0 3 (0.05 mmol) and chiral ligand 4-ie/f-butyl-2-[(S p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.025 mmol) were added to toluene (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N 2 for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH 3 (0.75 equiv. according to starting material) were added and reaction system stirred for 30.
  • the starting material ⁇ , ⁇ -disubstituted nitroalkene lb-N0 2 (0.5 mmol) was then added followed by a second portion of PhSiH 3 (0.75 equiv.) and water.
  • the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 h.
  • the reaction system was diluted with water, the phases were separated in separating funnel, the organic phase were washed with NaHC0 3 and brine, dried over anhydrous Na 2 S0 4 and the solvent was evaporated under reduced pressure.
  • Example 11 Basic copper(ll) carbonate/chiral diphosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in aqueous toluene
  • Catalyst basic CuC0 3 (0.05 mmol) and chiral ligand diphenylphosphino-phenyl- ferrocenyl-ethylbis[3,5-bis-trifluoromethyl)phenyl]phosphine (0.025 mmol) were added to toluene (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N 2 for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH 3 (0.75 equiv. according to starting material) and water were added and the reaction system stirred for 30 min.
  • PMHS 0.05 mmol
  • PhSiH 3 (0.75 equiv. according to starting material
  • the starting material ⁇ , ⁇ -disubstituted nitroalkene lb-N0 2 (0.5 mmol) was then added followed by a second portion of PhSiH 3 (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 hours.
  • the reaction system was diluted with water, the phases were separated in a separating funnel, the organic phase were washed with NaHC0 3 and brine, dried over anhydrous Na 2 S0 4 and the solvent was evaporated under reduced pressure.
  • Vlll-Me la-Me ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyldiaminomethane (TMDAM, 48.9 mmol; 6.9 ml.) was added to the solution of the starting material methyl 2-(3-chlorophenyl)acetate Vlll-Me (16.3 mmol; 3 g) in Ac 2 0 (48.9 mmol; 4.7 mL) and the reaction mixture was stirred at 70 °C overnight. After cooling to room temperature, the reaction mixture was neutralized by addition of saturated aqueous solution of NaHC0 3 (15 mL) followed by addition of water (15 mL) and extraction with EtOAc (2 x 50 mL).
  • Example 14 Enzymatic synthesis of optically active methyl 2-(3- chlorophenyl)propanoate from methyl 2-(3-chlorophenyl)acrylate using Baker ' s yeast
  • reaction mixture which contained 2-(3-chlorophenyl)acrylate la -Me (2.7 mmol; 0.53 g), enzyme (yeast from Saccharomyces cerevisiae, 26.5 g), petroleum ether (26.5 mL) and water (79.5 mL), was stirred overnight at room temperature.
  • the reaction mixture was filtered through Celite ® pad. The filter pad was washed with CH 2 CI 2 and the solvent was removed under reduced pressure. Final product was characterized with 1 H NMR spectroscopy and HPLC chiral analysis (60 % ee).
  • Example 15 Basic copper(ll) carbonate/chiral phosphine ligand catalysed asymmetric synthesis of optically active ethyl-2-(3-chlorophenyl)propanoate via conjugate reduction in aqueous toluene
  • Catalyst basic CuC0 3 (0.05 mmol) and chiral ligand 4-ie/f-butyl-2-[(S p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.025 mmol) were added to toluene (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N 2 for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH 3 (0.75 equiv. according to starting material) were added and the reaction system stirred for 30 min.
  • PMHS 0.05 mmol
  • PhSiH 3 (0.75 equiv. according to starting material
  • the starting material methyl-2-(3-chlorophennyl)acrylate la-Me (0.5 mmol) was then added followed by a second portion of PhSiH 3 (0.75 equiv.) and water.
  • the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 h.
  • the reaction system was diluted with water, phases were separated in a separating funnel, the organic phase was washed with NaHC0 3 and brine, dried over anhydrous Na 2 S0 4 and the solvent was evaporated under reduced pressure.
  • TDAM ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyldiaminomethane
  • Example 17 Enzymatic synthesis of optically active (R)-2-(3- chlorophenyl)propanenitrile from 2-(3-chlorophenyl)acrylonitrile using Baker ' s yeast
  • a reaction mixture which contained 2-(3-chlorophenyl)acrylonitrile la-CN (3.1 mmol; 0.5 g), yeast (yeast from Saccharomyces cerevisiae, 30 g), petroleum ether (25 mL) and water (50 mL), was stirred overnight at room temperature. After completion, the reaction mixture was filtered through Celite ® pad. The filter pad was washed with CH 2 CI 2 . After removal of solvent by evaporation, the residue was purified by flash chromatography (eluent: EtOAc/n-heptane, EtOAc gradient 2 - 20 %. Colorless oily product (0.27 g; 54 % yield; 98.8 % ee) was obtained and characterized with 1 H and 13 C NMR.
  • Example 18 Copper(ll) hydroxide/chiral diphosphine ligand catalysed asymmetric synthesis of optically active 2-(3-chlorophenyl)acrylonitrile II-CN via conjugate reduction in pure water
  • Example 20 Copper(l) chloride/chiral phosphine ligand catalysed asymmetric synthesis of optically active 2-(3-chlorophenyl)acrylonitrile II-CN via conjugate reduction in pure water
  • the CH 2 CI 2 phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in toluene (40 mL) and the solution was extracted three times with water (3 * 30 mL). The combined water phase was saturated with NaCI and the solution was extracted twice with CH 2 CI 2 (2 ⁇ 30 mL). The combined CH 2 CI 2 phases were dried over sodium sulfate, filtered and concentrated to give clean product IV-Me.HCI characterized by 1 H NMR.
  • the starting material (R)-IV-Me.HCI (50 mg; 0.25 mmol) was mixed with anhydrous aluminum chloride (69 mg; 3 equiv.). The fine mixture was heated to 90 °C to obtain a molten phase and stirred overnight. The solution was diluted with CH 2 CI 2 (20 mL) and washed brine (20 mL). The phases were separated and the water phase was re- extracted with CH 2 CI 2 (10 mL). The combined CH 2 CI 2 was dried over sodium sulfate, filtered and concentrated. The obtained crude mixture was analyzed and the obtained final product was characterized / detected with GC-MS analysis (m/z : 193) and 1 H NMR.
  • Example 28 Synthesis of N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4- methylbenzenesulfonamide from 2-(3-chlorophenyl)-N-(2,2-dimethoxyethyl)propan-1 - amine
  • Example 30 Synthesis of 8-chloro-1 -methyl-3-tosyl-2,3-dihydro-1 H-benzo[d]azepine from N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4-methylbenzene sulfonamide
  • Example 33 Synthesis of 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[d]azepin- 3(2H)ethanone from 1 -(8-chloro-1 -methyl-1 H-benzo[d]azepin-3(2H)-yl)ethanone
  • Example 34 Synthesis of 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine from 8-chloro-1 -methyl-3-tosyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine
  • Example 35 Synthesis of 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine from 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[d]azepin-3(2H)ethanone

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Abstract

La présente invention concerne une synthèse asymétrique et économique de 8-chloro-1-méthyl-2,3,4,5-tétrahydro-1H-benzo[d]azépine par de nouveaux intermédiaires appliquant une réduction enzymatique, biomimétique ou catalytique asymétrique. La présente invention concerne également une nouvelle réduction catalytique asymétrique verte adaptée pour un milieu aqueux devant être appliqué dans la synthèse de 8-chloro-1-méthyl-2,3,4,5-tétrahydro-1H-benzo[d]azépine ou de nouveaux intermédiaires.
EP14731300.1A 2013-06-21 2014-06-20 Préparation de 1-méthyl-2,3,4,5-1h-benzodiazépines chirales par réduction asymétrique de styrènes alpha-subst itués Withdrawn EP3010887A1 (fr)

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EP14731300.1A EP3010887A1 (fr) 2013-06-21 2014-06-20 Préparation de 1-méthyl-2,3,4,5-1h-benzodiazépines chirales par réduction asymétrique de styrènes alpha-subst itués

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EP14731300.1A EP3010887A1 (fr) 2013-06-21 2014-06-20 Préparation de 1-méthyl-2,3,4,5-1h-benzodiazépines chirales par réduction asymétrique de styrènes alpha-subst itués
PCT/EP2014/063048 WO2014202765A1 (fr) 2013-06-21 2014-06-20 Préparation de 1-méthyl-2,3,4,5-1h-benzodiazépines chirales par réduction asymétrique de styrènes alpha-subst itués

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EP2332919A3 (fr) 2003-06-17 2011-10-19 Arena Pharmaceuticals, Inc. Procédés de préparation de 3-benzazepines
CA2646044A1 (fr) 2006-04-03 2007-10-25 Arena Pharmaceuticals, Inc. Procedes de preparation de 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine et produits intermediaires associes
WO2008070111A2 (fr) 2006-12-05 2008-06-12 Arena Pharmaceuticals, Inc. Procédés de préparation de (r)-8-chloro-1-méthyl-2,3,4,5-tétrahydro-1h-3-benzazépine et intermédiaires de celle-ci
EP2288585A1 (fr) 2008-03-04 2011-03-02 Arena Pharmaceuticals, Inc. Procédés de préparation d'intermédiaires se rapportant à l'agoniste 5-ht2c (r)-8-chloro-1-méthyl-2,3,4,5-tétrahydro-1h-3-benzazepine
WO2010148207A2 (fr) 2009-06-18 2010-12-23 Arena Pharmaceuticals, Inc. Procédés pour la préparation d'agonistes du récepteur 5-ht2c
JP2013539470A (ja) 2010-09-01 2013-10-24 アリーナ ファーマシューティカルズ， インコーポレイテッド ロルカセリンと光学活性な酸との塩

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