WO2017016960A1 - Process for the preparation of (6s)-6-alkyl-10-alkoxy-9-(substituted alkoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid analogues - Google Patents

Process for the preparation of (6s)-6-alkyl-10-alkoxy-9-(substituted alkoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid analogues Download PDF

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WO2017016960A1
WO2017016960A1 PCT/EP2016/067351 EP2016067351W WO2017016960A1 WO 2017016960 A1 WO2017016960 A1 WO 2017016960A1 EP 2016067351 W EP2016067351 W EP 2016067351W WO 2017016960 A1 WO2017016960 A1 WO 2017016960A1
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formula
compound
process according
organic solvent
acid
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French (fr)
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Zhengming Du
Lin Wang
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • 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 present invention relates to a process for the preparation of a compound of formula
  • R 1 is or haloCi 2
  • R is C 1-6 alkyl, or Ci- 6 alkyl substituted by Ci_
  • R is Ci- 6 alkyl, or pharmaceutically acceptable salts thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
  • Another aspect of the present invention relates to a novel process for the preparation of a compound of formula (X),
  • R 1 , R2 and R 3 are defined above, which is an important intermediate in the synthesis and manufacture of pharmaceutically active compound of formula (I).
  • Another aspect of the present invention relates to a novel process for the preparation of a compound of formula (XII), wherein R 1 , R2 and R 3 are defined as above, which is an important intermediate in the synthesis and manufacture of pharmaceutically active compound of formula (I).
  • One object of this invention is to develop a safe, effective and scalable synthetic process to synthesize compounds of formula (I). Another object is to simplify purification of the compound of formula (I) by avoiding racemization during reactions and improving reaction yield.
  • a further object of this invention is to provide synthetic approach which can be applied on technical scale and allows obtaining the product in good yield, desired purity and stable form without using genotoxic reagent.
  • Ci_ 6 alkyl signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ie/ -butyl and the like.
  • Particular “Ci_ 6 alkyl” group is propyl or isopropyl.
  • Ci_6alkoxy denotes a group of the formula -O-R', wherein R' is a Ci_6alkyl group.
  • Ci- 6 alkoxy moieties include methoxy, ethoxy, isopropoxy, and ie/t-butoxy.
  • Particular "Ci_6alkoxy” group is methoxy.
  • haloCi_ 6 alkoxy denotes a Ci- 6 alkoxy group wherein at least one of the hydrogen atoms of the group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloCi_ 6 alkoxyl examples include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxy or -propoxy, for example fluoropropoxy, difluoropropoxy, trifluoropropoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, fluoromethoxy,
  • haloCi_6alkoxy is 3 -fluoropropoxy, 3,3- difluoropropoxy, 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as /7-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
  • the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et ah, Organic Process Research & Development 2000, 4, 427-435.
  • R is Ci- 6 alkoxy or haloCi_6alkoxy
  • R is Ci- 6 alkyl or Ci- 6 alkyl substituted by Ci- 6 alkoxy or R 3 is Chalky!.
  • R 1 , R2 and R 3 are defined as above; X is bromo, iodo or OTf; Y is chloro, bromo, iodo OMs, or OTs; R 4 is C ⁇ alkyl; R 5 is C ⁇ alkyl.
  • R 1 , R 2 and R 3 are defined as above;
  • R 1 , R 2 and R 3 are defined as above;
  • Step c) Formylation of a compound of formula (X) to form a compound of formula (XI),
  • R 1 , R 2 and R 3 are defined as above;
  • Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII),
  • R 1 , R 2 , R 3 , R 4 and R 5 are defined as above;
  • R 1 , R 2 , R 3 and R 4 are defined as above;
  • Step g Hydrolysis of a compound of formula (XV) to form a compound of formula (I), wherein R 1 , R 2 and R 3 are defined as above.
  • Another embodiment of the present invention is a process comprises the following steps: Step 1) O-alkylation of a compound of formula (II) to form a compound of formula (IV),
  • R 1 , R 2 and X are defined as above;
  • Step 2 C-alkylation of a compound of formula (IV) to form a compound of formula (VI),
  • R 1 , R 2 and R 3 are defined as above;
  • R 1 , R 2 and R 3 are defined as above;
  • Step c) Formylation of a compound of formula (X) to form a compound of formula (XI),
  • R 1 , R 2 and R 3 are defined as above;
  • Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII),
  • R 1 , R 2 and R 3 are defined as above;
  • R 1 , R 2 , R 3 , R 4 and R 5 are defined as above;
  • R 1 , R 2 , R 3 and R 4 are defined as above;
  • Step 1) O-alkylation of a compound of formula (II) to form a compound of formula (IV)
  • the O-alkylation of a compound of formula (II) is usually performed in the presence of a suitable base and a suitable organic solvent.
  • the conversion as a rule is performed under a heating condition.
  • the suitable base is selected from TEA, DIPEA, K 2 CO 3 and Na 2 C0 3 , particularly the base
  • the suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH, DMF, ACN and acetone, particularly the organic solvent is EtOH or ACN.
  • the O-alkylation reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between75 °C and 80 °C.
  • Step 2 C-alkylation of a compound of formula (IV) to form a compound of formula (VI)
  • the C-alkylation of a compound of formula (IV) is usually performed in the presence of a suitable catalyst, a suitable ligand and a suitable base in a suitable organic solvent.
  • the conversion as a rule is performed under a heating condition.
  • the suitable catalyst is selected from Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , PdCl 2 (dppf) 2 and PdCl 2 , particularly the catalyst is Pd 2 (dba) 3 .
  • the suitable ligand is selected from Xphos, Duphos and Xantphos, particularly the ligand is Xantphos.
  • the suitable base is selected from i-BuONa, NaOMe, i-BuOK and CS 2 CO 3 , particularly the base is i-BuONa.
  • the suitable organic solvent is selected from TBME, THF, Et 2 0 and MeTHF, particularly the organic solvent is MeTHF.
  • the reductive amination of a compound of formula (VI) is usually performed in the presence of a suitable amine provider and a suitable reductive reagent in a suitable organic solvent.
  • the conversion as a rule is performed under a heating condition.
  • the suitable amine provider is selected from NH 4 OAc, NH 4 C1 and ammonia, particularly the amine provider is NH 4 OAc.
  • the suitable reductive reagent is selected from NaBH 3 CN, NaBH(OAc)3 and NaBH 4 , particularly the reductive reagent is NaBH 3 CN.
  • the suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH and toluene, particularly the organic solvent is MeOH.
  • the reductive amination reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 45 °C and 50 °C.
  • the formation of the enantiomeric salt of formula (IX) is usually performed in the presence of a suitable organic acid (VIII) in a suitable organic solvent.
  • the conversion as a rule is performed under a heating condition.
  • the suitable organic acid (VIII) used in salt formation is selected from L-(+) -tartaric acid, L-(-)-DTTA, L-(-)-DBTA and (R)-mandelic acid, particularly the organic acid is (R)-mandelic acid.
  • the suitable organic solvent used in salt formation is selected from MeOH, EtOH, IPA,
  • the suitable amount of organic acid (VIII) is 0.5 eq - 1.0 eq, particularly the amount is 1.0 eq.
  • the salt formation as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 55 °C and 60 °C.
  • the recrystallization of the crude enantiomeric salt of formula (IX) is achieved by selective crystallization in a suitable solvent.
  • the other enantiomeric salt as a rule remains in the mother liquor.
  • the suitable solvent used in recrystallization is selected from MeOH, EtOH, IPA, IP Ac, MIBK, EA, and MTBE, particularly the organic solvent is a mixture of EtOH and MTBE.
  • the recovery of enantiomeric compound of formula (X) can be achieved by reacting desired enantiomeric salt of formula (IX) with a suitable amount of base in a suitable solvent.
  • the suitable base is selected from TEA, DIPEA, NaOH, Na 2 C0 3 , NaHC0 3 and a mixture thereof, particularly the base is Na 2 C0 3 .
  • the suitable amount of the base is selected from 1.0 eq - 1.5 eq, particularly the amount of the base is 1.1 eq.
  • the suitable solvent is selected from DCM, IP Ac and MeTHF, particularly the solvent is DCM.
  • the formylation of a compound of formula (X) is usually performed in the presence of a suitable formylation reagent and a suitable organic solvent.
  • the conversion as a rule is performed under a heating condition.
  • the suitable formylation reagent is selected from formic acid, methyl formate and formic anhydride, particularly the reagent is formic acid.
  • the suitable organic solvent is selected from IP Ac, dioxane, MeTHF and toluene, particularly the organic solvent is MeTHF.
  • Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII).
  • the intramolecular cyclization of a compound of formula (XI) is usually performed in the presence of a suitable acid in a suitable organic solvent.
  • the conversion as a rule is performed under a heating condition.
  • the suitable acid is selected from HC1, H 2 S0 4 , H 3 P0 4 , MeS0 3 H and POCl 3 , particularly the base is POCl 3 .
  • the suitable organic solvent is selected from ACN, MeTHF and IP Ac, particularly the organic solvent is MeTHF.
  • the intramolecular cyclization reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 20 °C and 30 °C.
  • Step e) Intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) to form a compound of formula (XIV).
  • the intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) is usually performed in a suitable solvent.
  • the conversion as a rule is performed under a heating condition.
  • the intermolecular cyclization reaction is usually performed in the absence or in the presence of a suitable catalyst.
  • the suitable catalyst is selected from NH 4 C1, LiCl, MgCl 2 , phenylboronic acid and (5)- ⁇ . Particularly the intermolecular cyclization reaction is performed in the absence of catalyst.
  • the suitable solvent is selected from MeOH, EtOH, IPA, MeTHF, CF 3 CH 2 OH, i-butyl alcohol, i-amyl alcohol, H 2 0, 95 EtOH and toluene, particularly the solvent is H 2 0.
  • the intermolecular cyclization reaction as a rule is performed at a temperature range between 50 °C and 100 °C, particularly at a temperature range between 75 °C and 85 °C.
  • Step f) Oxidation of a compound of formula (XIV) to form a compound of formula (XV).
  • the oxidation of a compound of formula (XIV) is usually performed in the presence of a suitable oxidative reagent and a suitable solvent.
  • the conversion as a rule is performed under a heating condition.
  • the suitable oxidative reagent is selected from DDQ, CuCl 2 , Cul 2 , Cul, CuCl, oxone, bleach, 30% H 2 0 2 , CuBr 2 and I 2 , particularly the oxidative reagent is I 2 .
  • the suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH, DME, MeTHF and IP Ac, particularly the organic solvent is MeTHF.
  • the oxidation reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 45 °C and 55 °C.
  • Step g Hydrolysis of a compound of formula (XV) to form a compound of formula (I).
  • the hydrolysis of a compound of formula (XV) is usually performed in the presence of a suitable base and a suitable organic solvent.
  • the conversion as a rule is performed under a room temperature condition.
  • the suitable base is selected from LiOH, NaOH and KOH, particularly the base is LiOH or NaOH.
  • the suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH and THF, particularly the organic solvent is THF.
  • the hydrolysis reaction as a rule is performed at a temperature range between 10 °C and 30 °C, particularly at a temperature range between 25 °C and 30 °C.
  • the invention further relates to a compound of formula (X):
  • R , R and R are defined as above.
  • the invention is also related to a compound of formula (XII):
  • R , R and R are defined as above.
  • Acidic condition A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • LC/MS spectra were also obtained using a SHIMADZU, LCMS-2020 and SHIMADZU LC20AB with UV DAD or Agilent G 1956 A and Agilent 1200 Series LC; UV DAD.
  • Standard LC/MS conditions were as follows (running time 20 minutes):
  • Acidic condition A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • Mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H) + .
  • the filter cake was washed with MTBE (8 L) and dried at room temperature for 16 hours to give 840 g of (25 , )- l-[4-methoxy-3-(3- methoxypropoxy)phenyl]-3-methyl-butan-2-amine mono (2R)-2-hydroxy-2-phenyl- acetic acid salt as an off-white solid.
  • the recovery was 85 %, the chiral purity was 99.1 %, and MS obsd.
  • Example 8A Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
  • Example 8B Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
  • Example 8C Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
  • Example 9A Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methox ropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
  • the aqueous layer was separated and discarded, and to the organic layer was added 10% brine (5 L). The resulting mixture was stirred at room temperature for another 20 minutes. The aqueous layer was separated and discarded, and then to the organic layer was added 2N HC1 (4 L). The resulting mixture was stirred at room temperature for another 30 minutes. The organic layer was separated and discarded, and to the aqueous layer was added 2N NaOH (4.2 L) and DCM (10 L) successively. The resulting mixture was stirred at room temperature for another 30 minutes.
  • Example 9B Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
  • Example 9A The title compound was also prepared in analogy to Example 9A starting from Example 8C by using CuBr 2 instead of tetrachlorobenzoquinone.
  • the yield was 60 % for 2 steps, the purity was 99.1 %, the chiral purity was 99.2%, and MS obsd. (ESI + ) [(M+H) + ]: 429.5.
  • Example 9C Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
  • Example 9A The title compound was also prepared in analogy to Example 9A starting from Example 8C by using I 2 instead of tetrachlorobenzoquinone.
  • the yield was 80 % for 2 steps, the purity was 99.3 %, the chiral purity was 99.2%, and MS obsd. (ESI + ) [(M+H) + ]: 429.5.

Abstract

The present invention relates to a process for synthesizing a compound of formula (I), wherein R1 is C1-6alkoxy or haloC1-6alkoxy, R2 is C1-6alkyl unsubstituted or substituted by a substituent selected from C1-6alkoxy and haloC1-6alkoxy, R3 is C1-6alkyl,or pharmaceutically acceptable salts thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

Description

Process for the preparation of (6S)-6-alkyl-10-alkoxy-9-(substituted alkoxy)-2-oxo- 6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid analogues
Field of the invention
The present invention relates to a process for the preparation of a compound of formula
(I),
Figure imgf000002_0001
wherein R 1 is or haloCi 2
_6alkoxy, R is C1-6alkyl, or Ci-6alkyl substituted by Ci_
6alkoxy or haloCi_6alkoxy, R is Ci-6alkyl, or pharmaceutically acceptable salts thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
Another aspect of the present invention relates to a novel process for the preparation of a compound of formula (X),
Figure imgf000002_0002
wherein R 1 , R2 and R 3 are defined above, which is an important intermediate in the synthesis and manufacture of pharmaceutically active compound of formula (I).
Another aspect of the present invention relates to a novel process for the preparation of a compound of formula (XII),
Figure imgf000003_0001
wherein R 1 , R2 and R 3 are defined as above, which is an important intermediate in the synthesis and manufacture of pharmaceutically active compound of formula (I).
BACKGROUND OF THE INVENTION The earlier work, Robert A. Fecik reported a synthetic approach (Journal of Medicinal
Chemistry (2005), 48(4), 1229-1236), which can be used to prepare compounds of formula (I). However, its low yield, racemization during intermolecular cyclization with tedious column purifications and using a genotoxic oxidant reagent (tetrachloro-l,4-benzoquinone) make it not suitable for process chemistry. One object of this invention is to develop a safe, effective and scalable synthetic process to synthesize compounds of formula (I). Another object is to simplify purification of the compound of formula (I) by avoiding racemization during reactions and improving reaction yield. A further object of this invention is to provide synthetic approach which can be applied on technical scale and allows obtaining the product in good yield, desired purity and stable form without using genotoxic reagent.
DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS
As used herein, the term "Ci_6alkyl" signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ie/ -butyl and the like. Particular "Ci_6alkyl" group is propyl or isopropyl.
The term "Ci_6alkoxy" denotes a group of the formula -O-R', wherein R' is a Ci_6alkyl group. Examples of Ci-6alkoxy moieties include methoxy, ethoxy, isopropoxy, and ie/t-butoxy. Particular "Ci_6alkoxy" group is methoxy. The term "haloCi_6alkoxy" denotes a Ci-6alkoxy group wherein at least one of the hydrogen atoms of the
Figure imgf000004_0001
group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloCi_6alkoxyl include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxy or -propoxy, for example fluoropropoxy, difluoropropoxy, trifluoropropoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, fluoromethoxy,
difluoromethoxy or trifluoromethoxy. Particular "haloCi_6alkoxy" group is 3 -fluoropropoxy, 3,3- difluoropropoxy, 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy.
The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as /7-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et ah, Organic Process Research & Development 2000, 4, 427-435.
"(6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid" and "(65,)-10-methoxy-6-isopropyl-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid)" refer to the same compound with the structure shown as:
Figure imgf000004_0002
ABBREVIATION eq Equivalent
DTTA Di-p-toluoyl-tartaric acid
DBTA Dibenzoyl-tartaric acid
DIPEA N,N-Diisopropylethylamine
ACN Acetonitrile
IPA Isopropanol
IP Ac Isopropyl acetate
MIBK Methyl isobutyl ketone
MSA Methanesulfonic acid
MTBE Methyl tert-butyl ether
CPME Cyclopentyl methyl ether
DIPE Diisopropyl ether
TEA Triethylamine
TFA Trifluoro acetic acid
(S)-BINAP (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate
DDQ 2,3-Dicyano-5,6-dichlorobenzoquinone
DME 1 ,2-Dimethoxyethane
i-BuOH /t-Butanol
THF Tetrahydrofuran
MeTHF 2-Methyl tetrahydrofuran
V volume
wt% weight percent
Pd2(dba)3 Trisi dibenz v I ideneaceto ne id ipalladiu m
PdCl2(dppf)2 [ 1 , 1 '-Bisf diphenylphosphino )fenocene|dichloropalladium( II I
Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Bleach Sodium hypochlorite
Oxone Potassium peroxymonosulfate
SYNTHESIS The present invention provides a process for preparing the compounds of formula (I) as
1 2 outlined in Scheme 1 exemplified for the compound with R is Ci-6alkoxy or haloCi_6alkoxy, R is Ci-6alkyl or Ci-6alkyl substituted by Ci-6alkoxy or
Figure imgf000005_0001
R3 is Chalky!.
Figure imgf000006_0001
Figure imgf000006_0002
wherein R 1 , R2 and R 3 are defined as above; X is bromo, iodo or OTf; Y is chloro, bromo, iodo OMs, or OTs; R4 is C^alkyl; R5 is C^alkyl. One embodiment of the present invention is a process comprising one or more of the following steps:
Step a) Formation and recrystallization of the salt of formula (IX),
Figure imgf000007_0001
wherein R1, R2 and R3 are defined as above;
Step b) Recovery of compound of formula (X) from its salt of formula (IX),
Figure imgf000007_0002
wherein R1, R2 and R3 are defined as above;
Step c) Formylation of a compound of formula (X) to form a compound of formula (XI),
Figure imgf000007_0003
wherein R1, R2 and R3 are defined as above;
Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII),
Figure imgf000007_0004
(XII), wherein R 1 , R2 and R 3 are defined as above;
Step e) Intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) to form a compound of formula (XIV),
Figure imgf000008_0001
(xiii),
Figure imgf000008_0002
wherein R1, R2, R3, R4 and R5 are defined as above;
Step f) Oxidation of a compound of formula (XIV) to form a compound of formula (XV),
Figure imgf000008_0003
wherein R1, R2, R3 and R4 are defined as above;
Step g) Hydrolysis of a compound of formula (XV) to form a compound of formula (I),
Figure imgf000009_0001
wherein R1, R2 and R3 are defined as above.
Another embodiment of the present invention is a process comprises the following steps: Step 1) O-alkylation of a compound of formula (II) to form a compound of formula (IV),
Figure imgf000009_0002
wherein R1, R2 and X are defined as above;
Step 2) C-alkylation of a compound of formula (IV) to form a compound of formula (VI),
Figure imgf000009_0003
wherein R1, R2 and R3 are defined as above; Step 3) Reductive amination of a compound of formula (VI) to form a compound of formula (VII),
Figure imgf000009_0004
wherein R1, R2 and R3 are defined as above;
Step a) Formation and recrystallization of the enantiomeric salt of formula (IX),
Figure imgf000010_0001
wherein R1, R2 and R3 are defined as above;
Step b) Recovery of enantiomeric compound of formula (X) from its enantiomeric salt of formula (IX),
Figure imgf000010_0002
wherein R1, R2 and R3 are defined as above;
Step c) Formylation of a compound of formula (X) to form a compound of formula (XI),
Figure imgf000010_0003
wherein R1, R2 and R3 are defined as above;
Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII),
Figure imgf000010_0004
wherein R1, R2 and R3 are defined as above;
Step e) Intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) to form a compound of formula (XIV),
Figure imgf000011_0001
wherein R1, R2, R3, R4 and R5 are defined as above;
Step f) Oxidation of a compound of formula (XIV) to form a compound of formula (XV),
Figure imgf000011_0002
wherein R1, R2, R3 and R4 are defined as above;
Step g) Hydrolysis of a compound of formula (XV) to form a compound of formula (I),
Figure imgf000011_0003
wherein R 1 , R2 and R 3 are defined as above. Synthesis of a compound of formula (X) by Step (a) and (b) is another aspect of the present invention.
Synthesis of a compound of formula (XII) by step (a), (b), (c) and (d) is another aspect of the present invention. A detailed description of the present invention of process steps is as following:
Step 1) O-alkylation of a compound of formula (II) to form a compound of formula (IV)
The O-alkylation of a compound of formula (II) is usually performed in the presence of a suitable base and a suitable organic solvent. The conversion as a rule is performed under a heating condition. The suitable base is selected from TEA, DIPEA, K2CO3 and Na2C03, particularly the base
The suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH, DMF, ACN and acetone, particularly the organic solvent is EtOH or ACN.
The O-alkylation reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between75 °C and 80 °C.
Step 2) C-alkylation of a compound of formula (IV) to form a compound of formula (VI)
The C-alkylation of a compound of formula (IV) is usually performed in the presence of a suitable catalyst, a suitable ligand and a suitable base in a suitable organic solvent. The conversion as a rule is performed under a heating condition. The suitable catalyst is selected from Pd2(dba)3, Pd(PPh3)4, PdCl2(dppf)2 and PdCl2, particularly the catalyst is Pd2(dba)3.
The suitable ligand is selected from Xphos, Duphos and Xantphos, particularly the ligand is Xantphos.
The suitable base is selected from i-BuONa, NaOMe, i-BuOK and CS2CO3, particularly the base is i-BuONa. The suitable organic solvent is selected from TBME, THF, Et20 and MeTHF, particularly the organic solvent is MeTHF.
The C-alkylation reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 55 °C and 60 °C. Step 3) Reductive amination of a compound of formula (VI) to form a compound of formula (VII)
The reductive amination of a compound of formula (VI) is usually performed in the presence of a suitable amine provider and a suitable reductive reagent in a suitable organic solvent. The conversion as a rule is performed under a heating condition. The suitable amine provider is selected from NH4OAc, NH4C1 and ammonia, particularly the amine provider is NH4OAc.
The suitable reductive reagent is selected from NaBH3CN, NaBH(OAc)3 and NaBH4, particularly the reductive reagent is NaBH3CN.
The suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH and toluene, particularly the organic solvent is MeOH.
The reductive amination reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 45 °C and 50 °C.
Step a) Formation and recrystallization of the enantiomeric salt of formula (IX).
The formation of the enantiomeric salt of formula (IX) is usually performed in the presence of a suitable organic acid (VIII) in a suitable organic solvent. The conversion as a rule is performed under a heating condition.
The suitable organic acid (VIII) used in salt formation is selected from L-(+) -tartaric acid, L-(-)-DTTA, L-(-)-DBTA and (R)-mandelic acid, particularly the organic acid is (R)-mandelic acid. The suitable organic solvent used in salt formation is selected from MeOH, EtOH, IPA,
IP Ac, MIBK, EA, MTBE, DIPE, CPME and toluene, particularly the organic solvent is MTBE. The suitable amount of organic acid (VIII) is 0.5 eq - 1.0 eq, particularly the amount is 1.0 eq.
The salt formation as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 55 °C and 60 °C. The recrystallization of the crude enantiomeric salt of formula (IX) is achieved by selective crystallization in a suitable solvent. The other enantiomeric salt as a rule remains in the mother liquor.
The suitable solvent used in recrystallization is selected from MeOH, EtOH, IPA, IP Ac, MIBK, EA, and MTBE, particularly the organic solvent is a mixture of EtOH and MTBE. Step b) Recovery of enantiomeric compound of formula (X) from its enantiomeric salt of formula (IX).
The recovery of enantiomeric compound of formula (X) can be achieved by reacting desired enantiomeric salt of formula (IX) with a suitable amount of base in a suitable solvent.
The suitable base is selected from TEA, DIPEA, NaOH, Na2C03, NaHC03 and a mixture thereof, particularly the base is Na2C03.
The suitable amount of the base is selected from 1.0 eq - 1.5 eq, particularly the amount of the base is 1.1 eq.
The suitable solvent is selected from DCM, IP Ac and MeTHF, particularly the solvent is DCM. Step c) Formylation of a compound of formula (X) to form a compound of formula (XI).
The formylation of a compound of formula (X) is usually performed in the presence of a suitable formylation reagent and a suitable organic solvent. The conversion as a rule is performed under a heating condition.
The suitable formylation reagent is selected from formic acid, methyl formate and formic anhydride, particularly the reagent is formic acid. The suitable organic solvent is selected from IP Ac, dioxane, MeTHF and toluene, particularly the organic solvent is MeTHF.
The formylation reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 75 °C and 80 °C. Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII).
The intramolecular cyclization of a compound of formula (XI) is usually performed in the presence of a suitable acid in a suitable organic solvent. The conversion as a rule is performed under a heating condition. The suitable acid is selected from HC1, H2S04, H3P04, MeS03H and POCl3, particularly the base is POCl3.
The suitable organic solvent is selected from ACN, MeTHF and IP Ac, particularly the organic solvent is MeTHF.
The intramolecular cyclization reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 20 °C and 30 °C.
Step e) Intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) to form a compound of formula (XIV).
The intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) is usually performed in a suitable solvent. The conversion as a rule is performed under a heating condition.
The intermolecular cyclization reaction is usually performed in the absence or in the presence of a suitable catalyst. The suitable catalyst is selected from NH4C1, LiCl, MgCl2, phenylboronic acid and (5)-ΒΙΝΑΡ. Particularly the intermolecular cyclization reaction is performed in the absence of catalyst.
The suitable solvent is selected from MeOH, EtOH, IPA, MeTHF, CF3CH2OH, i-butyl alcohol, i-amyl alcohol, H20, 95 EtOH and toluene, particularly the solvent is H20. The intermolecular cyclization reaction as a rule is performed at a temperature range between 50 °C and 100 °C, particularly at a temperature range between 75 °C and 85 °C.
Step f) Oxidation of a compound of formula (XIV) to form a compound of formula (XV).
The oxidation of a compound of formula (XIV) is usually performed in the presence of a suitable oxidative reagent and a suitable solvent. The conversion as a rule is performed under a heating condition.
The suitable oxidative reagent is selected from DDQ, CuCl2, Cul2, Cul, CuCl, oxone, bleach, 30% H202, CuBr2 and I2, particularly the oxidative reagent is I2.
The suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH, DME, MeTHF and IP Ac, particularly the organic solvent is MeTHF.
The oxidation reaction as a rule is performed at a temperature range between 0 °C and 80 °C, particularly at a temperature range between 45 °C and 55 °C.
Step g) Hydrolysis of a compound of formula (XV) to form a compound of formula (I).
The hydrolysis of a compound of formula (XV) is usually performed in the presence of a suitable base and a suitable organic solvent. The conversion as a rule is performed under a room temperature condition.
The suitable base is selected from LiOH, NaOH and KOH, particularly the base is LiOH or NaOH.
The suitable organic solvent is selected from MeOH, EtOH, IPA, i-BuOH and THF, particularly the organic solvent is THF.
The hydrolysis reaction as a rule is performed at a temperature range between 10 °C and 30 °C, particularly at a temperature range between 25 °C and 30 °C.
The invention further relates to a compound of formula (X):
Figure imgf000016_0001
1 2 3
wherein R , R and R are defined as above.
The invention is also related to a compound of formula (XII):
Figure imgf000017_0001
1 2 3
wherein R , R and R are defined as above.
BRIEF DESCRIPTION OF THE FIGURE Figure 1. X-ray structure of Example 10A
EXAMPLES The invention is illustrated further by the following examples. They should not, however, be construed as limiting the scope of the invention.
GENERAL EXPERIMENTAL CONDITIONS
LC/MS spectra were obtained using an Acquity Ultra Performance LC - 3100 Mass
Detector or Acquity Ultra Performance LC - SQ Detector. Standard LC/MS conditions were as follows (running time 3 minutes):
Acidic condition: A: 0.1% formic acid in H20; B: 0.1% formic acid in acetonitrile;
Basic condition: A: 0.05% NH3 H20 in H20; B: acetonitrile;
Neutral condition: A: FLO; B: acetonitrile.
LC/MS spectra were also obtained using a SHIMADZU, LCMS-2020 and SHIMADZU LC20AB with UV DAD or Agilent G 1956 A and Agilent 1200 Series LC; UV DAD. Standard LC/MS conditions were as follows (running time 20 minutes):
Acidic condition: A: 0.1% TFA in water (V/V); B: 0.1% TFA in acetonitrile (V/V)
Basic condition: A: 0.05% NH3H20 in water (V/V); B: acetonitrile
Neutral condition: A: water; B: acetonitrile
Chiral. spectra were obtained using an Agilent 1200 Series HPLC with DAD detector. Standard conditions were as follows (running time 20 minutes):
Acidic condition: A: 0.1% formic acid in H20; B: 0.1% formic acid in acetonitrile;
Basic condition: 0.1%DEA in EtOH;
Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H)+.
NMR Spectra were obtained using Bruker Avance 400 MHz or 300MHz.
Al l reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted. PREPARATIVE EXAMPLES
Exam le 1A: Preparation of 4-bromo-l-methoxy-2-(3-methoxypropoxy)benzene
Figure imgf000018_0001
To a 50 L jacket reactor containing 5-bromo-2-methoxy-phenol (1.185 kg, 5.78mol), 1- bromo-3-methoxy-propane (1.028 kg, 6.52 mol) and acetonitrile (12 L) was added anhydrous K2C03 (1.212 kg, 8.68 mol) in one portion at room temperature. The resulting mixture was heated to 75 °C and the agitation was maintained for 16 hours. The reaction mixture was slowly cooled to room temperature, and to the mixture was added water (6 L) and EA (8 L). The organic phase was separated and washed with 5% brine (6 L) again. The organic layer was filtered through a Na2S04 pad, and concentrated under reduced pressure to give 1.6 Kg of 4-bromo- l- methoxy-2-(3-methoxypropoxy)benzene as a light brown solid, which was used directly in the next step without further purification. The yield was 98 %, the purity was 99.3 %, and MS obsd. (ESI+) [(M+H)+] : 275.1. 1H NMR (400 MHz, DMSO- ) δ ppm 1.84 - 2.04 (m, 2 H) 3.25 (s, 3 H) 3.33 (s, 1 H) 3.46 (t, 7=6.27 Hz, 2 H) 4.01 (t, 7=6.27 Hz, 2 H) 5.58 - 9.80 (m, 3 H) 5.58 - 9.80 (m, 3 H) 6.92 (d, 7=8.53 Hz, 1 H) 7.04 - 7.13 (m, 2 H). Example IB: Preparation of_4-bromo-l-methoxy-2-(3-methoxypropoxy)benzene
I I
Figure imgf000018_0002
The title compound was also prepared in analogy to Example 1A by using EtOH instead of acetonitrile. The yield was 98%, the purity was 99.2% and MS obsd. (ESI+) [(M+H)+]: 275.1. 1H NMR (400 MHz, DMSO- ) δ ppm 1.84 - 2.04 (m, 2 H) 3.25 (s, 3 H) 3.33 (s, 1 H) 3.46 (t, 7=6.27 Hz, 2 H) 4.01 (t, 7=6.27 Hz, 2 H) 5.58 - 9.80 (m, 3 H) 5.58 - 9.80 (m, 3 H) 6.92 (d, 7=8.53 Hz, 1 H) 7.04 - 7.13 (m, 2 H).
Example 2A: Preparation of l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl- butan-2-one
Figure imgf000019_0001
f-BuONa, THF
To a 50 L jacket reactor containing 4-bromo-l-methoxy-2-(3-methoxypropoxy)benzene (1.6 kg, 5.69 mol), methyl isopropyl ketone (1.5 kg, 17.24 mol), Pd2(dba)3 (0.133 kg, 0.14 mol), Xantphos (0.1 kg ,0.17 mol) and THF (13 L) was added i-BuONa (1.9 kg, 19.57 mol) portionwise with agitation at room temperature. After being blown with N2 for 1 hour at room temperature, the resulting mixture was heated to 55 °C and the agitation was maintained for 3 hours. The resulting reaction mixture was then cooled to room temperature, stirred at room temperature for 16 hours and then filtered. The solid was washed with THF (2 L) and transferred to a 50 L jacket reactor. Then to the reactor was added water (4 L) and IP Ac (5.5 L). After the resulting mixture was stirred at room temperature for 30 minutes, the organic layer was separated, washed with 5% brine (6 L), filtered through a Na2S04 pad, and concentrated under reduced pressure to give 1.4 Kg of l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl-butan-2-one as a light brown oil, which was used directly into the next step without further purification. The yield was 87 %, the purity was 86.3 %, and MS m/e = 280.4 [M+H]+. 1H NMR (400 MHz, DMSO- ) δ ppm 1.01 (d, 7=6.78 Hz, 6 H) 1.88 - 2.02 (m, 2 H) 2.57 - 2.77 (m, 1 H) 3.27 - 3.35 (m, 1 H) 3.47 (t, 7=6.15 Hz, 2 H) 3.70 - 3.76 (m, 5 H) 3.96 (t, 7=6.53 Hz, 2 H) 6.70 (dd, 7=8.03, 2.01 Hz, 1 H) 6.79 (d, 7=2.01 Hz, 1 H) 6.88 (d, 7=8.28 Hz, 1 H). Example 2B: Preparation of l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl- butan-2-one
Figure imgf000020_0001
r-BuONa, MeTHF
The title compound was also prepared in analogy to Example 2A by using MeTHF instead of THF. The yield was 81%, the purity was 70% and MS obsd. (ESI+) [(M+H)+]: 280.4. 1H NMR (400 MHz, DMSO- ) δ ppm 1.01 (d, 7=6.78 Hz, 6 H), 1.88 - 2.02 (m, 2 H), 2.57 - 2.77 (m, 1 H), 3.27 - 3.35 (m, 1 H), 3.47 (t, 7=6.15 Hz, 2 H), 3.70 - 3.76 (m, 5 H), 3.96 (t, 7=6.53 Hz, 2 H), 6.70 (dd, 7=8.03, 2.01 Hz, 1 H), 6.79 (d, 7=2.01 Hz, 1 H), 6.88 (d, 7=8.28 Hz, 1 H).
Example 3: Preparation of l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl- butan-2-amine
Figure imgf000020_0002
To a 50 L jacket reactor containing l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3- methyl-butan-2-one (1.4 kg, 5.0 mol), NH4OAc (3.85 kg, 49.0 mol) and MeOH (11 L) was added NaBH3CN (0.25 kg, 4.0 mol) with agitation at room temperature in 10 minutes. The resulting reaction mixture was heated to 50 °C and the agitation was maintained for 21 hours. The resulting mixture was slowly cooled to room temperature, and concentrated under reduced pressure. To the reactor was added water (4 L), 10 N NaOH(l L) and DCM (6 L). After the resulting mixture was stirred at room temperature for 60 minutes, the organic layer was separated, washed with 10% brine (5 L) twice, then filtered through a Na2S04pad, and concentrated under reduced pressure to give 1.4 Kg of l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl-butan- 2-amine as a light yellow solid, which was used directly in the next step without further purification. The yield was 93 %, the purity was 92.6 %, and MS obsd. (ESI+) [(M+H)+]: 281.4. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.78 - 0.98 (m, 6 H), 1.00 - 1.18 (m, 2 H), 1.42 - 1.67 (m, 1 H), 1.94 (quin, 7=6.34 Hz, 2 H), 2.28 (dd, 7=12.92, 8.66 Hz, 1 H), 2.57 - 2.69 (m, 2 H), 3.30 - 3.50 (m, 2 H), 3.61 - 3.82 (m, 3 H), 3.98 (t, 7=6.53 Hz, 2 H), 6.70 (dd, 7=8.16, 1.88 Hz, 1 H), 6.80 (s, 1 H), 6.85 (d, 7=7.70 Hz, 1 H).
Example 4A: Preparation of (2S)-l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3- methyl-butan-2-amine mono (2R)-2-hydroxy-2-phenyl-acetic acid salt
Figure imgf000021_0001
To a 50 L jacket reactor was charged with l-[4-methoxy-3-(3-methoxypropoxy)phenyl]- 3-methyl-butan-2-amine (1.38 kg, 4.57 mol) and MTBE (42 L) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. With agitation, to the solution was added (R)-mandelic acid (0.67 kg, 4.37 mol) at room temperature in 10 minutes. The reaction mixture was heated to 55 °C and the agitation was maintained for 16 hours. After being cooled to 25 °C slowly, the resulting reaction mixture was stirred at room temperature for another 2 hours, and then filtered. The filter cake was washed with MTBE (8 L) and dried at room temperature for 16 hours to give 840 g of (25,)- l-[4-methoxy-3-(3- methoxypropoxy)phenyl]-3-methyl-butan-2-amine mono (2R)-2-hydroxy-2-phenyl- acetic acid salt as an off-white solid. The recovery was 85 %, the chiral purity was 99.1 %, and MS obsd.
(ESI+) [(M+H)+] : 281.4. 1H NMR (400 MHz, DMSO- ) δ ppm 0.92 (br d, 7=6.78 Hz, 3 H), 0.94 (br d, 7=7.03 Hz, 3 H), 1.77 (dq, 7=10.95, 7.06 Hz, 1 H), 1.91 - 1.99 (m, 2 H), 2.55 - 2.63 (m, 1 H), 2.66 - 2.77 (m, 1 H), 3.07 - 3.24 (m, 1 H), 3.28 - 3.53 (m, 4 H), 3.74 (s, 3 H), 3.99 (t, 7=6.53 Hz, 2 H), 4.52 (s, 1 H), 6.76 (dd, 7=8.28, 1.76 Hz, 2 H), 6.82 - 6.97 (m, 3 H), 7.13 - 7.29 (m, 3 H), 7.35 - 7.43 (m, 2 H).
Example 4B: Preparation of (2S)-l-[4-methoxy-3-(3-methoxypropoxy)phi
methyl-butan-2-amine mono (2R)-2-hydroxy-2-phenyl-acetic acid salt
Figure imgf000021_0002
The title compound was also prepared in analogy to Example 4A by using IP Ac instead of MTBE. The recovery was 80%, the chiral purity was 99.2%, and MS obsd. (ESI+) [(M+H)+] : 281.4. 1H NMR (400 MHz, DMSO- ) δ ppm 0.92 (br d, 7=6.78 Hz, 3 H), 0.94 (br d, 7=7.03 Hz, 3 H), 1.77 (dq, 7=10.95, 7.06 Hz, 1 H), 1.91 - 1.99 (m, 2 H), 2.55 - 2.63 (m, 1 H), 2.66 - 2.77 (m, 1 H), 3.07 - 3.24 (m, 1 H), 3.28 - 3.53 (m, 4 H), 3.74 (s, 3 H), 3.99 (t, 7=6.53 Hz, 2 H), 4.52 (s, 1 H), 6.76 (dd, 7=8.28, 1.76 Hz, 2 H), 6.82 - 6.97 (m, 3 H), 7.13 - 7.29 (m, 3 H), 7.35 - 7.43 (m, 2 H).
Example 5: Preparation of (2S)-l-[4-methoxy-3-(3-methoxypropoxy)phi
meth l-butan-2-amine
Figure imgf000022_0001
To a 50 L jacket reactor containing (2S)-l-[4-methoxy-3-(3-methoxypropoxy) phenyl]-3- methyl-butan-2-amine mono (2R)-2-hydroxy-2-phenyl-acetic acid salt (0.7 kg, 1.62 mol) and water (4 L) was added an aqueous solution (3 L) containing Na2C03 (0.223 kg, 2.1 mol) at room temperature. The resulting mixture was stirred at room temperature and the agitation was maintained for 2 hours until the mixture turned into a clear solution. To the resulting mixture was added DCM (8 L) and NaCl (0.2 kg). The resulting mixture was stirred at room temperature for another 30 minutes. The organic layer was separated, washed with 15% brine (5 L), filtered through a Na2S04pad, and concentrated under reduced pressure to give 0.5 Kg of (25)-1-[4- methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl-butan-2-amine as light yellow oil, which was used directly in the next step without further purification. The yield was 99 %, the chiral purity was 99.1%, and MS obsd. (ESI+) [(M+H)+]: 281.4. 1H NMR (400 MHz, DMSO- ) δ ppm 0.78 - 0.98 (m, 6 H), 1.00 - 1.18 (m, 2 H), 1.42 - 1.67 (m, 1 H), 1.94 (quin, 7=6.34 Hz, 2 H), 2.28 (dd, 7=12.92, 8.66 Hz, 1 H), 2.57 - 2.69 (m, 2 H), 3.30 - 3.50 (m, 2 H), 3.61 - 3.82 (m, 3 H), 3.98 (t, 7=6.53 Hz, 2 H), 6.70 (dd, 7=8.16, 1.88 Hz, 1 H), 6.80 (s, 1 H), 6.85 (d, 7=7.70 Hz, 1 H).
Example 6A: Preparation of N-[(lS)-l-[[4-methoxy-3-(3- methoxypropoxy)phenyl]methyl]-2-methyl-propyl]formamide
Figure imgf000022_0002
To a 12 L jacket reactor was charged with (25 - l-[4-methoxy-3-(3- methoxypropoxy)phenyl]-3-methyl-butan-2-amine (0.455 kg, 1.62 mol) and MeTHF (4 L) at room temperature. To the reaction was added formic acid (0.42 kg, 8. Imol) at room temperature. The reaction mixture was heated to 80°C and the agitation was maintained for 23 hours. The mixture was cooled to room temperature, and to the mixture was charged with 10% brine (4 L). Then the mixture was stirred at room temperature for another 30 minutes. The organic layer was separated and washed with 10% brine (2.5 L). The organic layer was filtered through a Na2S04 pad, and concentrated under reduced pressure to give 0.7 Kg of N-[(lS)- l-[[4-methoxy-3-(3- methoxypropoxy)phenyl]methyl]-2-methyl-propyl]formamide as a light pink solid, which was used directly in the next step without further purification. The yield was 99%, the purity was
99.7 %, the chiral purity was 99.1%, and MS obsd. (ESI+) [(M+H)+] : 309.4 . 1H NMR (400 MHz, DMSO- ) δ ppm 0.84 - 0.92 (m, 8 H), 1.11 - 1.36 (m, 2 H), 1.66 - 2.01 (m, 5 H), 2.42 - 2.49 (m, 1 H), 2.63 - 2.75 (m, 1 H), 3.29 - 3.40 (m, 1 H), 3.42 - 3.59 (m, 3 H), 3.70 - 3.78 (m, 4 H), 3.80 - 4.08 (m, 4 H), 6.68 - 6.73 (m, 1 H), 6.78 - 6.86 (m, 3 H), 7.52 - 7.63 (m, 1 H), 7.82 (br d, 7=9.29 Hz, 1 H), 7.94 (d, 7=1.51 Hz, 1 H), 8.14 (s, 1 H), 12.77 (br s, 1 H) .
Example 6B: Preparation of N-[(lS)-l-[[4-methoxy-3-(3- methoxypropoxy)phenyl]methyl]-2-methyl-propyl]formamide
Figure imgf000023_0001
The title compound was also prepared in analogy to Example 6A by using IPAc instead of MeTHF. The yield was 70%, the purity was 99.7%, the chiral purity was 99.1%, and MS obsd. (ESI+) [(M+H)+] : 309.4. 1H NMR (400 MHz, DMSO- ) δ ppm 0.84 - 0.92 (m, 8 H), 1.11 - 1.36 (m, 2 H), 1.66 - 2.01 (m, 5 H), 2.42 - 2.49 (m, 1 H), 2.63 - 2.75 (m, 1 H), 3.29 - 3.40 (m, 1 H), 3.42 - 3.59 (m, 3 H), 3.70 - 3.78 (m, 4 H), 3.80 - 4.08 (m, 4 H), 6.68 - 6.73 (m, 1 H), 6.78 - 6.86 (m, 3 H), 7.52 - 7.63 (m, 1 H), 7.82 (br d, 7=9.29 Hz, 1 H), 7.94 (d, 7=1.51 Hz, 1 H), 8.14 (s, 1 H), 12.77 (br s, 1 H).
Example 7A: Preparation of (3S)-3-isopropyl-7-methoxy-6-(3-methoxypropoxy)-3,4- dihydroisoquinoline
Figure imgf000024_0001
To a 12 L jacket reactor was charged with N-[(lS)-l-[[4-methoxy-3-(3- methoxypropoxy)phenyl]methyl]-2-methyl-propyl]formamide (0.5 kg, 1.62 mol) and acetonitrile (4 L) at room temperature. To the mixture was added phosphorous oxychloride (0.3 kg, 1.94 mol) at room temperature. The mixture was stirred at room temperature and the agitation was maintained for 18hrs. Then the resulting mixture was added to another flask contained water (2.5 L). After the addition, the organic solvent was removed by concentration under reduced pressure. To the mixture was added ammonia (1 L) dropwise. The resulting mixture was diluted with DCM (3 L), and then stirred at room temperature for another 30 minutes. The organic layer was separated, washed with 15% brine (2.5 L) twice, then filtered through a Na2S04pad, and concentrated under reduced pressure to give 0.46 kg of (3S)-3-isopropyl-7-methoxy-6-(3- methoxypropoxy)-3,4-dihydroiso-quinoline as a light yellow solid, which was used directly in the next step without further purification. The yield was 95 %, the purity was 99.3 %, the chiral purity was 99.1%, and MS obsd. (ESI+) [(M+H)+]: 291.4. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.81 - 1.02 (m, 6 H), 1.78 - 1.99 (m, 3 H), 2.29 - 2.48 (m, 1 H), 2.52 - 2.67 (m, 1 H), 3.00 - 3.21 (m, 1 H), 3.26 - 3.34 (m, 1 H), 3.46 (t, 7=6.24 Hz, 2 H), 3.70 - 3.78 (m, 3 H), 4.04 (t, 7=6.48 Hz, 2 H), 6.86 (s, 1 H), 7.03 (s, 1 H), 8.21 (d, 7=2.93 Hz, 1 H).
Example 7B: Preparation of (3S)-3-isopropyl-7-methoxy-6-(3-methoxypropoxy)-3,4- dihydroisoquinoline
Figure imgf000024_0002
The title compound was prepared in analogy to Example 7A by using MeTHF instead of acetonitrile. The yield was 82%, the purity was 99.5%, the chiral purity was 99.1%, and MS obsd. (ESI+) [(M+H)+]: 291.4. 1H NMR (400 MHz, DMSO- ) δ ppm 0.81 - 1.02 (m, 6 H), 1.78 - 1.99 (m, 3 H), 2.29 - 2.48 (m, 1 H), 2.52 - 2.67 (m, 1 H), 3.00 - 3.21 (m, 1 H), 3.26 - 3.34 (m, 1 H), 3.46 (t, 7=6.24 Hz, 2 H), 3.70 - 3.78 (m, 3 H), 4.04 (t, 7=6.48 Hz, 2 H), 6.86 (s, 1 H),
1 H), 8.21 (d, 7=2.93 Hz, 1 H).
Example 8A: Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
Figure imgf000025_0001
To a 50 L jacket reactor was charged with (35,)-3-isopropyl-7-methoxy-6-(3- methoxypropoxy)-3,4-dihydroiso-quinoline (1.92 kg, 6.42 mol) and EtOH (19 L) at room temperature. To the mixture was added ethyl 2-(ethoxymethylene)acetoacetate (3.6 kg, 19.3 mol) at room temperature. The mixture was stirred at 80 °C and the agitation was maintained for 28hrs. The mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure to give 5.6 Kg of crude ethyl (6S)-6-isopropyl- 10-methoxy-9-(3- methoxypropoxy)-2-oxo- l,6,7, l lb-tetrahydrobenzo[a]quinolizine-3-carboxylate as a light brown solid, which was used directly in the next step without further purification. The purity was 61.4%, the chiral purity was 99.2%, and MS obsd. (ESI+) [(M+H)+] : 431.5. 1H NMR (400 MHz, DMSO- de) δ ppm 0.70 (d, 7=6.78 Hz, 3 H), 0.88 (d, 7=6.78 Hz, 3 H), 1.56 - 1.71 (m, 1 H), 1.99 (quin, 7=6.34 Hz, 2 H), 3.08 - 3.23 (m, 1 H), 3.27 - 3.37 (m, 2 H), 3.48 (t, 7=6.27 Hz, 2 H), 3.88 (s, 3 H), 4.01 - 4.19 (m, 2 H), 4.44 (br dd, 7=9.41, 4.14 Hz, 1 H), 7.09 (s, 1 H), 7.46 (s, 1 H), 7.52 (s, 1 H), 8.78 (s, 1 H). Example 8B: Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
Figure imgf000025_0002
To a 100 mL jacket reactor was charged with (35,)-3-isopropyl-7-methoxy-6-(3- methoxypropoxy)-3,4-dihydroiso-quinoline (1.92 g, 6.42 mmol), EtOH (15 mL) and water (15 mL) at room temperature. To the mixture was added ethyl 2-(ethoxymethylene)acetoacetate (3.6 g, 19.3 mmol) at room temperature. The resulting mixture was stirred at 80 °C and the agitation was maintained for 28hrs. The mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure to give 6.2 g of crude ethyl (6S)-6-isopropyl-10-methoxy-9- (3-methoxypropoxy)-2-oxo-l,6,7,l lb-tetrahydrobenzo[a]quinolizine-3-carboxylate as a light brown solid, which was used directly in the next step without further purification. The purity was 62%, the chiral purity was 99.1%, and MS obsd. (ESI+) [(M+H)+]: 431.5. 1H NMR (400 MHz, DMSO- ) δ ppm 0.70 (d, 7=6.78 Hz, 3 H), 0.88 (d, 7=6.78 Hz, 3 H), 1.56 - 1.71 (m, 1 H), 1.99 (quin, 7=6.34 Hz, 2 H), 3.08 - 3.23 (m, 1 H), 3.27 - 3.37 (m, 2 H), 3.48 (t, 7=6.27 Hz, 2 H), 3.88 (s, 3 H), 4.01 - 4.19 (m, 2 H), 4.44 (br dd, 7=9.41, 4.14 Hz, 1 H), 7.09 (s, 1 H), 7.46 (s, 1 H), 7.52 (s, 1 H), 8.78 (s, 1 H).
Example 8C: Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
Figure imgf000026_0001
To a 300 L jacket reactor was charged with (35,)-3-isopropyl-7-methoxy-6-(3- methoxypropoxy)-3,4-dihydroiso-quinoline (11.8 kg, 40.5 mol) and purified water (118.4 kg) at room temperature. To the mixture was added ethyl 2-(ethoxymethylene)acetoacetate (22.7 kg, 121.7 mol) at room temperature. The mixture was stirred at 85 °C and the agitation was maintained for 29hrs. The mixture was cooled to room temperature, and the reaction mixture was extracted with IP Ac (55 kg). The organic layer was separated, washed with 15% brine (40 kg), then filtered through a Na2S04pad, and concentrated under reduced pressure to give 24.2 Kg of crude ethyl (6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-l, 6,7,1 lb- tetrahydrobenzo[a]quinolizine-3-carboxylate as a light brown solid, which was used directly in the next step without further purification. The purity was 93.3%, the chiral purity was 99.2%, and MS obsd. (ESI+) [(M+H)+]: 431.5. 1H NMR (400 MHz, DMSO- ), δ ppm 0.70 (d, 7=6.78 Hz, 3 H), 0.88 (d, 7=6.78 Hz, 3 H), 1.56 - 1.71 (m, 1 H), 1.99 (quin, 7=6.34 Hz, 2 H), 3.08 - 3.23 (m, 1 H), 3.27 - 3.37 (m, 2 H), 3.48 (t, 7=6.27 Hz, 2 H), 3.88 (s, 3 H), 4.01 - 4.19 (m, 2 H), 4.44 (br dd, 7=9.41, 4.14 Hz, 1 H), 7.09 (s, 1 H), 7.46 (s, 1 H), 7.52 (s, 1 H), 8.78 (s, 1 H).
Example 9A: Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methox ropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
Figure imgf000027_0001
To a 50 L jacket reactor containing ethyl (65,)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,l lb-tetrahydrobenzo[a]quinolizine-3-carboxylate (2.77 kg, 4.5 mol, Example 8A) and MeTHF (12 L) was added tetrachlorobenzoquinone (1.1 kg, 4.5 mol) at room temperature. The resulting mixture was stirred at 55 °C and the agitation was maintained for 2 hours. The resulting reaction mixture was cooled to room temperature, and to the mixture was added 15% aqueous solution of Na2C03 (6 L). The aqueous layer was separated and discarded, and to the organic layer was added 10% brine (5 L). The resulting mixture was stirred at room temperature for another 20 minutes. The aqueous layer was separated and discarded, and then to the organic layer was added 2N HC1 (4 L). The resulting mixture was stirred at room temperature for another 30 minutes. The organic layer was separated and discarded, and to the aqueous layer was added 2N NaOH (4.2 L) and DCM (10 L) successively. The resulting mixture was stirred at room temperature for another 30 minutes. The organic layer was separated, washed with 15% brine (6.5 L), filtered through a Na2S04pad, and concentrated under reduced pressure to give 1.5 Kg of ethyl (6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylate as a light brown oil, which was used directly into the next step without further purification. The yield was 50 % for 2 steps, the purity was 99.3 %, the chiral purity was 99.2%, and MS obsd. (ESI+) [(M+H)+]: 429.5. 1H NMR (400 MHz, DMSO- ) δ ppm 0.72 (d, 7=6.78 Hz, 3 H), 0.86 (d, 7=6.53 Hz, 3 H), 1.04 - 1.23 (m, 2 H), 1.27 (t, 7=7.15 Hz, 3 H), 1.58 (br d, 7=9.79 Hz, 1 H), 1.80 - 2.03 (m, 3 H), 2.98 - 3.14 (m, 1 H), 3.17 - 3.31 (m, 5 H), 3.35 - 3.58 (m, 3 H), 3.86 (s, 4 H), 4.01 - 4.26 (m, 6 H), 6.91 (s, 1 H), 7.03 (s, 1 H), 7.37 (s, 1 H), 8.35 (s, 1 H). Example 9B: Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
Figure imgf000028_0001
The title compound was also prepared in analogy to Example 9A starting from Example 8C by using CuBr2 instead of tetrachlorobenzoquinone. The yield was 60 % for 2 steps, the purity was 99.1 %, the chiral purity was 99.2%, and MS obsd. (ESI+) [(M+H)+]: 429.5. 1H NMR (400 MHz, DMSO- ) δ ppm 0.72 (d, 7=6.78 Hz, 3 H), 0.86 (d, 7=6.53 Hz, 3 H), 1.04 - 1.23 (m, 2 H), 1.27 (t, 7=7.15 Hz, 3 H), 1.58 (br d, 7=9.79 Hz, 1 H), 1.80 - 2.03 (m, 3 H), 2.98 - 3.14 (m, 1 H), 3.17 - 3.31 (m, 5 H), 3.35 - 3.58 (m, 3 H), 3.86 (s, 4 H), 4.01 - 4.26 (m, 6 H), 6.91 (s, 1 H), 7.03 (s, 1 H), 7.37 (s, 1 H), 8.35 (s, 1 H).
Example 9C: Preparation of ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
Figure imgf000028_0002
The title compound was also prepared in analogy to Example 9A starting from Example 8C by using I2 instead of tetrachlorobenzoquinone.The yield was 80 % for 2 steps, the purity was 99.3 %, the chiral purity was 99.2%, and MS obsd. (ESI+) [(M+H)+]: 429.5. 1H NMR (400 MHz, DMSO- ) δ ppm 0.72 (d, 7=6.78 Hz, 3 H), 0.86 (d, 7=6.53 Hz, 3 H), 1.04 - 1.23 (m, 2 H), 1.27 (t, 7=7.15 Hz, 3 H), 1.58 (br d, 7=9.79 Hz, 1 H), 1.80 - 2.03 (m, 3 H), 2.98 - 3.14 (m, 1 H), 3.17 - 3.31 (m, 5 H), 3.35 - 3.58 (m, 3 H), 3.86 (s, 4 H), 4.01 - 4.26 (m, 6 H), 6.91 (s, 1 H), 7.03 (s, 1 H), 7.37 (s, 1 H), 8.35 (s, 1 H). Example 10A: Preparation of (6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2- oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid
Figure imgf000029_0001
To a 50 L jacket reactor containing ethyl (6S)-6-isopropyl-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate (1.45 kg, 3.38 mol), THF (4.5 L) and deionized water (5 L) was added a solution of LiOH.H20 (0.21 kg, 5.1 mol) in deionized water (2.5 L) at room temperature in 40 minutes. The resulting mixture was stirred at room temperature and the agitation was maintained for 1.5 hours. To the resulting reaction mixture was added 4N HC1 (1.3 L). The resulting mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate (8 L). The resulting mixture was stirred at room temperature for 20 minutes. The aqueous layer was separated and extracted with ethyl acetate (4 L) again. The organic layers were combined, washed with 15% brine (5 L), filtered through a Na2S04pad, and concentrated under reduced pressure to give the crude product as black oil. The black oil was dissolved with MTBE (8 L). The solvent was concentrated under reduced pressure again to almost dryness, solid appeared during the concentration. The solid was filtered, washed with MTBE (3 L) and dried in an oven at 50 °C under reduced pressure to constant weight to afford 910 g of (6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo- 6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid as a light yellow solid. The yield was 80 %, the purity was 99.2 %, the chiral purity was 99.3%, and MS obsd. (ESI+) [(M+H)+]: 401.4. The absolute stereochemistry was confirmed by X-ray diffraction study (Figure 1). 1H NMR (400
MHz, DMSO- ) δ ppm 0.70 (d, 7=6.53 Hz, 3 H), 0.88 (d, 7=6.78 Hz, 3 H), 1.57 - 1.69 (m, 1 H), 1.99 (quin, 7=6.34 Hz, 2 H), 3.08 - 3.22 (m, 1 H), 3.24 - 3.32 (m, 4 H), 3.48 (t, 7=6.27 Hz, 2 H), 3.88 (s, 3 H), 4.04 - 4.16 (m, 2 H), 4.44 (br dd, 7=9.66, 4.14 Hz, 1 H), 7.09 (s, 1 H), 7.45 (s, 1 H), 7.52 (s, 1 H), 8.78 (s, 1 H).
Example 10B: Preparation of (6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2- -6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid
Figure imgf000030_0001
The title compound was prepared in analogy to Example 10A by using NaOH instead of LiOH.H20. The yield was 82 %, the purity was 99.1 %, the chiral purity was 99.2%, and MS obsd. (ESI+) [(M+H)+]: 401.4. 1H NMR (400 MHz, DMSO- ) δ ppm 0.70 (d, 7=6.53 Hz, 3 H), 0.88 (d, 7=6.78 Hz, 3 H), 1.57 - 1.69 (m, 1 H), 1.99 (quin, 7=6.34 Hz, 2 H), 3.08 - 3.22 (m, 1 H), 3.24 - 3.32 (m, 4 H), 3.48 (t, 7=6.27 Hz, 2 H), 3.88 (s, 3 H), 4.04 - 4.16 (m, 2 H), 4.44 (br dd, 7=9.66, 4.14 Hz, 1 H), 7.09 (s, 1 H), 7.45 (s, 1 H), 7.52 (s, 1 H), 8.78 (s, 1 H).

Claims

Claims
1. Process for the preparation of a compound of the formula (I),
Figure imgf000031_0001
_6alkoxy , R is or Ci_6alkyl substituted by or haloCi_6alkoxy, R is C1-6alkyl, or pharmaceutically acceptable salts thereof; comprising one or more of the following steps:
Step a) Formation and recrystallization of the enantiomeric salt of formula (IX),
Figure imgf000031_0002
wherein R 1 , R2 and R 3 are defined as above;
Step b) Recovery of enantiomeric compound of formula (X) from its enantiomeric salt of formula (IX),
Figure imgf000031_0003
wherein R 1 , R2 and R 3 are defined as above;
Step c) Formylation of a compound of formula (X) to form a compound of formula (XI),
Figure imgf000032_0001
wherein R1, R2 and R3 are defined as above;
Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII),
Figure imgf000032_0002
wherein R1, R2 and R3 are defined as above;
Step e) Intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) to form a compound of formula (XIV),
Figure imgf000032_0003
wherein R1, R2 and R3 are defined as above, R4 is Chalky!, R5 is Ci_6alkyl;
Step f) Oxidation of a compound of formula (XIV) to form a compound of formula (XV),
Figure imgf000033_0001
wherein R1, R2, R3 and R4 are defined as above;
Step g) Hydrolysis of a compound of formula (XV) to form a compound of formula (I),
Figure imgf000033_0002
wherein R1, R2 and R3 are defined as above.
2. A process according to claim 1, comprising the following steps:
Step a) Formation and recrystallization of the enantiomeric salt of formula (IX),
Figure imgf000033_0003
wherein R1, R2 and RJ are defined as in claim 1 ;
Step b) Recovery of enantiomeric compound of formula (X) from its enantiomeric salt of formula (IX),
Figure imgf000033_0004
(X), wherein R1, R2 and R3 are defined as in claim 1 ;
Step c) Formylation of a compound of formula (X) to form a compound of formula (XI),
Figure imgf000034_0001
wherein R1, R2 and R3 are defined as in claim 1 ; Step d) Intramolecular cyclization of a compound of formula (XI) to form a compound of formula (XII),
Figure imgf000034_0002
wherein R1, R2 and RJ are defined as in claim 1 ;
Step e) Intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) to form a compound of formula (XIV),
Figure imgf000034_0003
wherein R1, R2, R3, R4 and R5 are defined as in claim 1 ; Step f) Oxidation of a compound of formula (XIV) to form a compound of formula (XV),
Figure imgf000035_0001
wherein R1, R2, R3 and R4 are defined as in claim 1 ;
Step g) Hydrolysis of a compound of formula (XV) to form a compound of formula (I),
Figure imgf000035_0002
1 2 3
wherein R , R and R are defined as in claim 1.
1 2 3
3. A process according to claim 1 or 2, wherein R is methoxy; R is methoxypropoxy; R is isopropyl, R4 is ethyl, R5 is ethyl.
4. A process according to any one of claims 1, 2 and 3, wherein the formation of the enantiomeric salt of formula (IX) in step a) is performed in the presence of an organic acid in an organic solvent, wherein the organic acid is selected from L-(+) -tartaric acid, L-(-)-DTTA, L-(-)- DBTA and (R)-mandelic acid, particularly the organic acid is (R)-mandelic acid; the suitable amount of organic acid (VIII) is 0.5 eq - 1.0 eq, particularly the amount is 1.0 eq.
5. A process according to claim 4, wherein the organic solvent used in the formation of enantiomeric salt of formula (IX) in step a) is selected from MeOH, EtOH, IPA, IP Ac, MIBK, EA, MTBE, IPE, CME and toluene, particularly the organic solvent is MTBE.
6. A process according to claim 4 or 5, wherein the formation of enantiomeric salt of formula
(IX) in step a) is performed at a temperature range of 0 °C to 80 °C, particularly at a temperature range of 55 °C to 60 °C.
7. A process according to any one of claims 1 to 6, wherein the recrystallization in step a) is performed in an organic solvent or a mixture of organic solvents, wherein the organic solvent is selected from MeOH, EtOH, IPA, IP Ac, MIBK, EA, and MTBE, particularly the organic solvent is a mixture of EtOH and MTBE.
8. A process according to any one of claims 1 to 7, wherein the recovery of enantiomeric compound of formula (X) from its enantiomeric salt of formula (IX) in step b) is performed in the presence of a base in an organic solvent, wherein the base is selected from TEA, DIPEA, NaOH, Na2C03, NaHC03 and a mixture thereof, particularly the base is Na2C03; the suitable amount of the base is selected from 1.0 eq - 1.5 eq, particularly the amount of the base is 1.1 eq.
9. A process according to claim 8, wherein the organic solvent used in step b) is selected from DCM, IP Ac and MeTHF, particularly the solvent is DCM. 10. A process according to any one of claims 1 to 9, wherein the formylation of a compound of formula (X) in step c) is performed in the presence of a formylation reagent in an organic solvent, wherein the formylation reagent is selected from formic acid, methyl formate and formic anhydride, particularly the formylation reagent is formic acid.
11. A process according to claim 10, wherein the organic solvent used in step c) is selected from IP Ac, dioxane, MeTHF and toluene, particularly the organic solvent is MeTHF.
12. A process according to claim 10 or 11, wherein the formylation of a compound of formula
(X) in step c) is performed at a temperature range of 0 °C to 80 °C, particularly at a temperature range of 75 °C to 80 °C.
13. A process according to any one of claims 1 to 12, wherein the intramolecular cyclization of a compound of formula (XI) in step d) is performed in the presence of an acid in an organic solvent, wherein the acid is selected from HCl, H2S04, H3P04, MeS03H and POCl3, particularly the acid is POCl3.
14. A process according to claim 13, wherein the organic solvent used in step d) is selected from ACN, MeTHF and IP Ac, particularly the organic solvent is MeTHF.
15. A process according to any one of claims 1 to 14, wherein the intermolecular cyclization of a compound of formula (XII) with a compound of formula (XIII) in step e) is performed in the absence or in the presence of a catalyst in a solvent, wherein the catalyst is selected from NH4C1, LiCl, MgCl2, phenylboronic acid and (5)-ΒΙΝΑΡ; particularly the intermolecular cyclization reaction is performed in the absence of catalyst.
16. A process according to claim 15, wherein the solvent used in the intermolecular cyclization in step e) is selected from MeOH, EtOH, IPA, MeTHF, CF3CH2OH, ί-butyl alcohol, i-amyl alcohol, H20, 95 EtOH and toluene, particularly the solvent is H20.
17. A process according to claim 15 or 16, wherein the intermolecular cyclization is performed at a temperature range of 50 °C to 100 °C, particularly a temperature range of 75 °C to 85 °C.
18. A process according to any one of claims 1 to 17, wherein the oxidation of a compound of formula (XIV) in step f) is performed in the presence of an oxidative reagent in an organic solvent, wherein the oxidative reagent is selected from DDQ, CuCl2, Cul2, Cul, CuCl, oxone, Bleach, 30% H202, CuBr2 and I2, particularly the oxidative reagent is I2. 19. A process according to claim 18, wherein the organic solvent used in the oxidation in step f) is selected from MeOH, EtOH, IPA, i-BuOH, DME, MeTHF and IP Ac, particularly the organic solvent is MeTHF.
20. A process according to claim 18 or 19, wherein the oxidation is performed at a temperature range of 0 °C to 80 °C, particularly a temperature range of 45 °C to 55 °C. 21. A process according to any one of claims 1 to 20, wherein the hydrolysis of a compound of formula (XV) in step g) is performed in the presence of a base and an organic solvent at a temperature range of 10 °C to 30 °C, particularly at a temperature range of 25 °C to 30 °C.
22. A process according to claim 21, wherein the base used in the hydrolysis in step g) is selected from LiOH, NaOH and KOH, particularly the base is LiOH or NaOH. 23. A process according to claim 21 or 22, wherein the organic solvent is selected from MeOH, EtOH, IPA, i-BuOH and THF, particularly the organic solvent is THF.
A compound of formula (X)
Figure imgf000038_0001
wherein R 1 is
Figure imgf000038_0002
or haloCi_6alkoxy, R 2 is or Ci_6alkyl substituted by Ci or haloCi_6alkoxy, R is Ci_6alkyl.
25. A compound of formula (XII):
Figure imgf000038_0003
(xii) wherein R 1 is
Figure imgf000038_0004
or haloCi_6alkoxy, R 2 is or Ci-6alkyl substituted by or haloCi_6alkoxy, R is Ci-6alkyl.
26. The invention as herein before described.
PCT/EP2016/067351 2015-07-24 2016-07-21 Process for the preparation of (6s)-6-alkyl-10-alkoxy-9-(substituted alkoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid analogues WO2017016960A1 (en)

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