WO2017016960A1 - Procédé de préparation d'analogues de l'acide (6s)-6-alkyl-10-alcoxy-9-(alcoxy substitué)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylique - Google Patents

Procédé de préparation d'analogues de l'acide (6s)-6-alkyl-10-alcoxy-9-(alcoxy substitué)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylique 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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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

La présente invention concerne un procédé de synthèse de composé de formule (I), dans laquelle R1 est un groupe alcoxy en C1-6 ou halogénoalcoxy en C1-6, R2 est un groupe alkyle en C1-6 non substitué ou substitué par un substituant choisi parmi les groupes alcoxy en C1-6 et halogénoalcoxy en C1-6, R3 est un groupe alkyle en C1-6, ou ses sels pharmaceutiquement acceptables, qui est utile pour la prophylaxie et le traitement d'une maladie virale chez un patient se rapportant à une infection due au virus de l'hépatite B ou une maladie provoquée par une infection due au virus de l'hépatite B.
PCT/EP2016/067351 2015-07-24 2016-07-21 Procédé de préparation d'analogues de l'acide (6s)-6-alkyl-10-alcoxy-9-(alcoxy substitué)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylique WO2017016960A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2015085049 2015-07-24
CNPCT/CN2015/085049 2015-07-24
CNPCT/CN2016/082772 2016-05-20
CN2016082772 2016-05-20

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US10093673B2 (en) 2016-02-19 2018-10-09 Novartis Ag Tetracyclic pyridone compounds as antivirals
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