[go: up one dir, main page]

WO2018193463A1 - Procédé amélioré de préparation de composés tétrahydroisoquinoléines - Google Patents

Procédé amélioré de préparation de composés tétrahydroisoquinoléines Download PDF

Info

Publication number
WO2018193463A1
WO2018193463A1 PCT/IN2018/050153 IN2018050153W WO2018193463A1 WO 2018193463 A1 WO2018193463 A1 WO 2018193463A1 IN 2018050153 W IN2018050153 W IN 2018050153W WO 2018193463 A1 WO2018193463 A1 WO 2018193463A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
alkylphenyl
process according
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2018/050153
Other languages
English (en)
Inventor
Mahesh Bhagoji Dalvi
Rajesh Shashikant Kenny
Ajit Aappa PATIL
Tushar Tanaji PALKAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NEON LABORATORIES Ltd
Original Assignee
NEON LABORATORIES Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NEON LABORATORIES Ltd filed Critical NEON LABORATORIES Ltd
Publication of WO2018193463A1 publication Critical patent/WO2018193463A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms

Definitions

  • the present invention relates to an improved process for preparation of tetrahydroisoquinoline compounds and its acid addition salts in good yields which are possible intermediates for the synthesis of neuromuscular-blocking drug.
  • One of the important intermediates is pentamethylene bis(l-(3,4-dimethoxybenzyl)- 3,4-dihydro-6,7-dimethoxy-lH-isoquinoline-2-propionate) and its acid addition salts.
  • This tetrahydroisoquinoline compound and its acid addition salts can be used as an intermediates for manufacture of neuromuscular-blocking drugs or skeletal muscle relaxants.
  • the tetrahydroisoquinoline moiety has been found in variety of natural products such as those obtained from cactus alkaloids, mammalian alkaloids, the esteinascidine family and spiro-benzoisoquinoline alkaloids.
  • Various substituted 1,2,3,4-tetrahydroisoquinolines are found to possess varied activity such as potent bronchodilators, anti-convulsant, peripheral vasodilators, analgesic, potent dopamine D2 receptor-blocking activity and specific bradycardic agents.
  • N- alkylated tetrahydroisoquinolines and their quartemary ammonium salts are kind of drugs which are used for the treatment of muscle relaxant during surgery, tracheal intubation, controlled ventilation and other conditions. They are also known to interfere with the anaesthetic drugs and other components in body which relaxes skeletal muscle.
  • US 4, 179,507 disclose the preparation of pentamethylene bis(l-(3,4- dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-lH-isoquinoline-2-propionate) first by reacting 1,5-pentanediol with acryloyl chloride in presence of triethylamine and pyrogallol as stabilizer to give 1,5-pentamethylene diacrylate.
  • pentamethylene diacrylate With tetrahydropapaverine gives pentamethylene bis(l-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-lH- isoquinoline-2-propionate), which is further converted in to its dioxalate salt.
  • the process involves the use of acryloyl chloride which is light sensitive and results in to formation of polymerized products.
  • the intermediate compound 1,5- pentamethylene diacrylate is sensitive to light and undergoes polymerization leading to concerns about storage and handling. The material thus obtained is impure and in low yields.
  • PCT int. application WO2010128518 A2 discloses a similar method for the preparation of pentamethylene bis(lR-l-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7- dimethoxy-lH-isoquinoline-2-propionate).
  • pentamethylene diacrylate is prepared by reacting 1,5-pentanediol with methyl acrylate in presence of p-toluenesulfonic acid.
  • the process involves the use of methyl acrylate which is a light sensitive compound and results in to formation of polymerized products.
  • the intermediate compound 1,5 -pentamethylene diacrylate is sensitive to light and undergoes polymerization leading to concerns about storage and handling. Also the material thus obtained is impure and in low yields.
  • US patents 5,453,510 and 5,556,987 disclose the preparation of pentamethylene bis(lR-l-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-lH-isoquinoline-2- propionate). The process involves reacting 3-bromopropionic acid with 1,5- pentanediol in presence of p-toluenesulfonic acid to give pentamethylene diacrylate.
  • EP0219616 Al discloses preparation of pentamethylene bis(l-(3,4- dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-lH-isoquinoline-2-propionate) first by reacting tetrahydropapaverine with beta-propiolactone to give N-(2- carboxy ethyl)- 1 -(3 ,4-dimethoxybenzyl)-6,7-dimethoxy- 1,2,3,4- tetrahydroisoquinoline.
  • Beta-propiolactone can react with nucluophile in two ways i.e. alkylation or acylation thus resulting in to poor yields due to formation of amide undesired product and other undesired products.
  • Indian patent application number 02725/ MUM/2008 A discloses the process for the preparation of pentamethylene bis(lR-l-(3,4-dimethoxybenzyl)-3,4-dihydro- 6,7-dimethoxy-lH-isoquinoline-2-propionate) by the reaction of N-(2- carboxy ethyl)- 1 -(3 ,4-dimethoxybenzyl)-6,7-dimethoxy- 1,2,3,4- tetrahydroisoquinoline with dihalopentane in presence of organic base to give bis(lR-l-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-lH-isoquinoline-2- propionate).
  • Another object of the invention is to provide the process for manufacture of such isoquinoline compounds and its acid addition salts by use of cheaper and easily available raw materials that can be stored for longer period of time and are easy to handle during manufacturing process.
  • the present invention provides a simple and mild process for condensation of (un) substituted tetrahydroisoquinoline with various esters of 3-chloropropionic acid to give tetrahydroisoquinoline compounds of formula I and IV.
  • the present invention also describes novel reactions which can easily be utilized in the synthesis of large number of active aromatic amino derivatives or salts of biological and physiological importance or can be used as intermediates in the development of active compounds.
  • one aspect of the present invention provides an improved process for the synthesis of tetrahydroisoquinoline compounds of formula I,
  • R is selected from optionally substituted Ci-io alkylene groups
  • Rl, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen, optionally substituted -Ci-io alkyl, -C2-10 alkenyl, -C2-10 alkynyl, or form an optionally substituted 3 to 7 member cyclic ring which optionally includes at least one heteroatom selected from O, N and S in the cyclic ring; -C1-7 alkylphenyl, -phenyl, -phenylCi-7 alkyl, -OCi-10 alkyl, -OC1-7 alkylphenyl, - Ophenyl, -OphenylCi-7 alkyl, -SCi-7alkyl, -SC1-7 alkylphenyl, -Sphenyl, - SphenylCi-7 alkyl, - H2, - H(Ci- 7 alkyl), - H(Ci- 7 alkylphenyl), - H(phenyl),
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above;
  • R is as defined above, in presence of a base or a solvent.
  • the invention provides an improved process for the synthesis of tetrahydroisoquinoline compounds of formula IV or their acid addition salts.
  • RIO is selected from ORl l, NHRl l, NR12R13 where Rl l, R12 and R13 are independently hydrogen, optionally substituted -Ci-io alkyl, -C2-10 alkenyl, -C2-10 alkynyl, -C3-10 cycloalkyl, -C3-10 cycloalkenyl, -C5-10 cycloalkynyl, -C1-7 alkylphenyl, -phenyl, -phenylCi-7 alkyl, aryl, heteroaryl, heterocyclic or R12 and R13 along with N form an optionally substituted 3 to 7 member cyclic or benzocyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring;
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above;
  • the compound of formula II as used herein in the process of the present invention is a chiral molecule and thus the compounds of formula I and IV will have chirality in its structure and thus encompasses all the enantiomers and stereoisomers thereof.
  • tetrahydroisoquinoline compounds of formula I and formula IV or its acid addition salts can be used as drugs or as intermediates for the synthesis of drugs such as but not limited to neuromuscular-blocking drugs or skeletal muscle relaxants.
  • a dash (“-") that is not between two letters or symbols is used to indicate point of attachment of a substituent.
  • -C(0)OH is attached through carbon atom.
  • optionally substituted alkyl encompasses both “alkyl” and “substituted alkyl” such as but not limited to methyl, ethyl, isopropyl, 2-methylpropyl, neopentyl, 2-chloroethyl, 2-methoxy ethyl, 2-nitropropyl, 3-acetyloxypropyl, 2- cyclobutylmethyl, etc.
  • optionally substituted -Ci-io alkyl, -C2-10 alkenyl, -C2- 10 alkynyl includes optionally substituted -Ci-10 alkyl, optionally substituted -C2- 10 alkenyl, optionally substituted -C2-10 alkynyl. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.
  • Alkylene encompasses: linear or branched bivalent saturated aliphatic radical of carbon atoms such as a methylene, 1,1- or 1,2- ethylene, 1,1- 1,2- or 1,3- propylene, 1, 1- 1,2- 2,2- 1,3- or 1,4- butylene, methyl- 1,3 -propylene, 2,3- 2,4- or 1,5-pentylene, 1,6-hexylene or 1,6-heptylene group
  • Alkyl encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms.
  • Ci-6 alkyl encompasses both straight and branched chain alkyl or from 1 to 6 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3- methylpentyl, and the like.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl.
  • “Lower alkyl” refers to alkyl groups having one to four carbons. Alkenyl is yet another subset of alkyl, referring to the same residues as alkyl, but having at least one carbon-carbon double bond. For example, ethenyl, 2-propenyl,
  • Alkynyl is yet another subset of alkyl, referring to the same residues as alkyl, but having at least one carbon-carbon triple bond. For example,
  • alkylphenyl is meant an group of formula (alkyl)(phenyl) attached through the alkyl carbon wherein the alkyl group has the indicated number of carbon atoms.
  • a C1-7 alkylphenyl is straight or branched alkyl group with 1 to 7 carbon atoms with a phenyl group substituted over it.
  • benzyl 1- phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and the like.
  • phenylalkyl is meant an group of formula (phenyl)(alkyl) attached through the phenyl ring carbon wherein the alkyl group has the indicated number of carbon atoms.
  • a phenylCi-7 alkyl is phenyl group with straight or branched alkyl group with 1 to 7 carbon atoms substituted over it.
  • Cycloalkyl encompasses a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, as well as bridged and caged saturated ring groups such as norbornane.
  • Cycloalkenyl encompasses a non-aromatic carbocyclic ring, usually having from 4 to 7 ring carbon atoms and one or more carbon-carbon double bonds.
  • Examples of cycloalkenyl groups include cyclopentenyl, cyclohexenyl, etc.
  • Cycloalkynyl encompasses a non-aromatic carbocyclic ring, usually having from 5 to 7 ring carbon atoms and one or more carbon-carbon triple bonds.
  • Examples of cycloalkynyl groups include cyclohexynyl, cycloheptynyl, etc.
  • Cyclic ring encompasses: a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms which optionally includes at least one carbon-carbon double bonds or carbon-carbon triple bonds in the ring. For example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cyclohexynyl, cycloheptynyl, etc.
  • Cyclic ring includes non-aromatic carbocyclic ring fused to a aryl ring, heteroaryl ring or 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O and S.
  • Cyclic ring does not encompass or overlap in any way with heterocyclic ring, separately defined below. Hence, if one or more heteroatom is included in the cyclic ring, the resulting ring system is heterocyclic ring, not cyclic, as defined herein.
  • Aryl encompasses: carbocyclic aromatic ring for example benzene; bicyclic ring systems such as carbocyclic and aromatic ring systems, for example, naphthalene, and azulene; tricyclic ring systems such as carbocyclic and aromatic ring systems, for example, anthracene, phenanthrene, etc.
  • aryl includes carbocyclic aromatic ring fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O and S. For such fused ring systems where in only one of the ring is carbocyclic aromatic ring the point of attachment is at the carbocyclic aromatic ring.
  • Aryl however does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic ring is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • Heteroaryl encompasses: 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon;
  • bicyclic heteroaryl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and
  • heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring.
  • bicyclic heteroaryl ring systems wherein only one of the aromatic rings contains one or more heteroatoms, the point of attachment is at aryl or heteroaryl ring.
  • fused rings encompasses: bicyclic, tricyclic or polycyclic, aryl or heteroaryl rings where in two rings share a common C-C or C-N connecting bonds, for example, Naphthalene, Anthracene, Phenanthrene, benzofuran, benzothiophene, dibenzofuran, dibenzothiophene, and the like.
  • Heterocyclic ring encompasses: a non-aromatic carbocyclic ring, usually having from 3 to 7 ring atoms which includes one or more heteroatom included in the cyclic ring selected from N, O and S.
  • -Salkyl is meant an alkyl group of the indicated number of carbon atoms attached through a sulfur bridge such as, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, 2-pentylthio, isopentylthio, neopentylthio, hexylthio, 2-hexylthio, 3-hexylthio, 3- methylpentylthio, and the like.
  • -SC1-7 alkyl groups will usually have from 1 to 7 carbon atoms attached through the sulfur bridge.
  • “Lower -Salkyl” refers to alkylthio groups having one to four carbons.
  • -Salkylphenyl is meant an alkylphenyl group of the indicated number of carbon atoms attached through a sulfur bridge such as, for example, benzylthio, 2- phenyl ethylthio, 2-phenylpropylthio, and the like.
  • -SCi-7alkylphenyl groups are alkylthio groups which will usually have from 1 to 7 carbon atoms attached through the oxygen bridge and a phenyl ring substituted over it. For example, phenylmethylthio, 2-phenylethylthio, 1- phenyl ethylthio, and the like.
  • -SPhenyl is meant a phenyl group is attached through a sulfur bridge, example, phenylthio.
  • -Sphenylalkyl is meant a phenylalkyl group of the indicated number of carbon atoms in the alkyl group attached through a sulfur bridge such as, for example, 2-methylphenylthio, 2-ethylphenylthio, 4-ethylphenylthio, and the like.
  • the -SphenylCi-7 alkyl groups are phenylthio groups attached through the sulfur bridge and which will usually have alkyl group from 1 to 7 carbon atoms substituted over phenyl.
  • phenylthio 2-methylphenylthio, 2-ethylphenylthio, 4- ethylphenylthio, and the like.
  • the present invention describes a convenient synthesis for preparation of tetrahydroisoquinoline compound of formula I or its acid addition salt and tetrahydroisoquinoline compound of formula IV or its acid addition salt with better yields and purity.
  • the compound of formula II and compound of formula III may be employed in the ratio of 2: 1 to 3.5: 1, more preferably in the ratio of 2.2: 1 to 3 : 1 and most preferably in the ratio of 2.4: 1 to 2.75: 1.
  • solvents with different constitution may be used which are process specific and product specific.
  • the process of condensation of compound of formula II and compound of formula III may be facilitated by the use of diverse group of solvents with or without heteroatom present in the molecular formula.
  • the solvents used for the above process are selected from but not limited to dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane and tetrahydrofuran either alone or a mixture thereof.
  • the present invention provides use of a base in condensation of compound of formula II with compound of formula III.
  • the base may be optionally used to enhance process of condensation thereby reducing the time required for the completion of the process or eliminate the formation of undesired products.
  • the base used in the present invention is selected from organic or inorganic base.
  • the organic bases are selected from but not limited to N-methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N- methylpyrrolidine either alone or a mixture thereof.
  • the most preferred organic bases which can be advantageously used are selected from N-methylmorpholine, triethylamine and diisopropylethylamine either alone or a mixture thereof.
  • the inorganic bases are selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof.
  • the most preferred inorganic bases which can be advantageously used are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof.
  • the tetrahydroisoquinoline compound of formula I can be optionally purified.
  • the purification of tetrahydroisoquinoline compound of formula I may involve dissolving the compound in a solvent in which it possess high solubility and then precipitating using a solvent in which it possess low or no solubility.
  • the generally used solvents with high solubility of tetrahydroisoquinoline compound of formula I are selected from but are not limited to methylene chloride, chloroform, ethyl acetate, dichloroethane, methanol, isopropyl alcohol, acetonitrile, acetone, 2-butanone and tetrahydrofuran either alone or a mixture thereof.
  • the generally used solvents with low or no solubility of tetrahydroisoquinoline compound of formula I are selected from but are not limited to n-hexane, cyclohexane, heptane, isopropylether, benzene and toluene either alone or a mixture thereof.
  • Yet another and most preferred method for purification of tetrahydroisoquinoline compound of formula I which comprises contacting the base with a suitable acid in presence of solvent to give its acid addition salt.
  • the acid used for the process is selected from the group of organic or inorganic acid.
  • the organic acids are selected from but are not limited to oxalic acid, succinic acid, adipic acid, acetic acid, benzoic acid, citric acid, p-toluenesulfonic acid and trifluoroacetic acid either alone or a mixture thereof.
  • the preferred organic acids are oxalic acid, succinic acid, citric acid and p-toluenesulfonic acid either alone or a mixture thereof.
  • the inorganic acids are selected from but are not limited to hydrochloric acid, sulphuric acid, phosphoric acid, phosphinic acid and nitric acid either alone or a mixture thereof.
  • the preferred inorganic acids are hydrochloric acid and sulphuric acid either alone or a mixture thereof.
  • the most preferred acids are oxalic acid and citric acid.
  • the solvents used for the preparation of acid addition salt are selected from polar or non-polar solvent either alone or a mixture thereof.
  • the polar solvents are selected from but are not limited to acetone, 2-butanone, acetonitrile, methanol, ethanol, dimethylformamide, dimethylsulfoxide, sulfolane, hexamethylphosphoramide and isopropanol either alone or a mixture thereof.
  • the non-polar solvents are selected from but are not limited to toluene, benzene, diethyl ether, tetrahydrofuran, heptanes, hexane and cyclohexane either alone or a mixture thereof.
  • the most preferred solvent is selected from polar solvent.
  • the most preferred solvents are acetone and acetonitrile.
  • the acid addition salt of tetrahydroisoquinoline compound of formula I thus obtained can be optionally purified to give the pure acid addition salt. Purification of such addition salt is carried out by converting it into its free base using an organic or inorganic base and further contacting it with an acid in a suitable solvent to give pure desired acid addition salt.
  • the organic base is selected from but not limited to methylamine, diethylamine, N-methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N- methylpyrrolidine either alone or a mixture thereof.
  • the most preferred organic base which can be advantageously used is selected from methylamine, diethylamine, and triethylamine either alone or a mixture thereof.
  • the inorganic base is selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof.
  • the most preferred inorganic base which can be advantageously used is selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof.
  • the solvents and acids used for re-conversion of tetrahydroisoquinoline compound of formula I into desired acid addition salts are as mentioned above. Acid addition salt can also be purified by crystallization from suitable solvents or mixtures thereof.
  • the solvents used for the crystallization of such acid addition salts are selected from but not limited to dimethylformamide, acetonitrile, acetone, 2-butanone methanol, ethanol and isopropanol either alone or a mixture thereof.
  • These salts are also purified by stirring or repulping in any solvent preferably polar protic or aprotic solvent either alone or a mixture thereof.
  • One of the methods involve dissolving acid addition salts in known quantity of dimethylformamide, adding known quantity of acetone to the mixture at elevated temperature and cooling the mixture at lower temperatures to give pure acid addition salts.
  • the compound of formula II and compound of formula V may be employed in the ratio of 1 : 1 to 1 :5, more preferably in the ratio of 1 : 1.5 to 1 :4 and most preferably in the ratio of 1 : 1.75 to 1 :2.5.
  • solvents with different constitution may be used which are process specific and product specific.
  • the process of condensation of compound of formula II with compound of formula V may be facilitated by the use of diverse group of solvents with or without heteroatom present in the molecular formula.
  • the solvents used for the above process are selected from but not limited to dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane and tetrahydrofuran either alone or a mixture thereof.
  • the present invention provides use of base in condensation of compound of formula II with compound of formula III.
  • the base may be optionally used to enhance process of condensation thereby reducing the time required for the completion of the process or eliminate the formation of undesired products.
  • the base used in the present invention is selected from organic or inorganic base.
  • the organic bases are selected from but not limited to N-methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N- methylpyrrolidine either alone or a mixture thereof.
  • the most preferred organic bases which can be advantageously used are selected from N-methylmorpholine, triethylamine and diisopropylethylamine either alone or a mixture thereof.
  • the inorganic bases are selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof.
  • the most preferred inorganic bases which can be advantageously used are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof.
  • the tetrahydroisoquinoline compounds of formula IV can be optionally purified to give the pure tetrahydroisoquinoline compounds of formula IV or can be used directly for further steps involved for the formation of neuromuscular-blocking drug or skeletal muscle relaxant.
  • the purification of tetrahydroisoquinoline compounds of formula IV may involve dissolving the base in solvent in which it possess high solubility and then precipitating using solvent in which it possess low or no solubility.
  • the solvents with high solubility of tetrahydroisoquinoline compounds of formula IV are selected from but are not limited to methylene chloride, chloroform, ethyl acetate, dichloroethane, methanol, isopropyl alcohol, acetonitrile, acetone, 2-butanone and tetrahydrofuran either alone or a mixture thereof.
  • the solvent with low or no solubility of tetrahydroisoquinoline compounds of formula IV are selected from but are not limited to n-hexane, cyclohexane, heptane, isopropyl ether, benzene and toluene used either alone or a mixture thereof.
  • Yet another and most preferred method for purification of tetrahydroisoquinoline compounds of formula IV is by contacting the free base of tetrahydroisoquinoline compounds of formula IV with a suitable acid in presence of solvent to give its acid addition salt.
  • the acid used for the process is selected from the group of organic or inorganic acid.
  • the organic acids are selected from but are not limited to oxalic acid, succinic acid, adipic acid, acetic acid, benzoic acid, citric acid, p- toluenesulfonic acid and trifluoroacetic acid either alone or a mixture thereof.
  • the preferred organic acids are oxalic acid, succinic acid, citric acid and p- toluenesulfonic acid used either alone or a mixture thereof.
  • the inorganic acids are selected from but are not limited to hydrochloric acid, sulphuric acid, phosphoric acid, phosphinic acid and nitric acid used either alone or a mixture thereof.
  • the preferred inorganic acids are hydrochloric acid and sulphuric acid either alone or a mixture thereof.
  • the most preferred acids are oxalic acid and citric acid.
  • the solvent used for the preparation of acid addition salt of tetrahydroisoquinoline compounds of formula IV are selected from polar or non- polar solvent either alone or a mixture thereof.
  • the polar solvents are selected from but are not limited to acetone, 2-butanone, acetonitrile, methanol, ethanol, dimethylformamide, dimethylsulfoxide, sulfolane, hexamethylphosphoramide and isopropanol either alone or a mixture thereof.
  • the non-polar solvents are selected from but are not limited to toluene, benzene, diethyl ether, tetrahydrofuran, heptanes, hexane and cyclohexane either alone or a mixture thereof.
  • the most preferred solvent is selected from polar solvent.
  • the most preferred solvents are acetone and acetonitrile.
  • the acid addition salt of tetrahydroisoquinoline compounds of formula IV can be optionally purified to give the pure acid addition salt of tetrahydroisoquinoline compounds of formula IV.
  • Purification of acid addition salt of tetrahydroisoquinoline compounds of formula IV is carried out by converting it into tetrahydroisoquinoline compounds of formula IV using a base and further contacting it with an acid in a suitable solvent to give the corresponding pure acid addition salt of tetrahydroisoquinoline compounds of formula IV.
  • the base used in the present invention is selected from organic or inorganic base.
  • the organic bases are selected from but not limited to methylamine, diethylamine, N- methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N-methylpyrrolidine either alone or a mixture thereof.
  • the most preferred organic bases which can be advantageously used are selected from methylamine, diethylamine, and triethylamine either alone or a mixture thereof.
  • the inorganic bases are selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof.
  • the most preferred inorganic bases which can be advantageously used are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof.
  • the solvents and acids used for re-conversion of tetrahydroisoquinoline compounds of formula IV into acid addition salt are as mentioned above.
  • the acid addition salt of tetrahydroisoquinoline compounds of formula IV can also be purified by crystallization from suitable solvents or mixtures thereof.
  • the solvents used for the crystallization of acid addition salts of tetrahydroisoquinoline compounds of formula IV are selected from but not limited to dimethylformamide, acetonitrile, acetone, 2-butanone, methanol, ethanol and isopropanol either alone or a mixture thereof.
  • the acid addition salts of tetrahydroisoquinoline compounds of formula IV can also be purified by stirring or repulping in any solvent preferably polar protic or aprotic solvent either alone or a mixture thereof.
  • One of the methods involve dissolving acid addition salts in known quantity of dimethylformamide, adding known quantity of acetone to the mixture at elevated temperature and cooling the mixture at lower temperatures to give pure acid addition salts of tetrahydroisoquinoline compounds of formula IV.
  • Example 5 N,N-diethyl-3-[l-(3,4- Dimethoxybenzyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-2- yl]propanamide from tetrahydropapaverine (9.0 gms, 0.026 mol) and 3-chloro- N,N-diethylpropanamide (8.5 gm, 0.052 mol) in acetonitrile (50 ml) and triethylamine (5.05 gm, 0.05 mol).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation de pentaméthylène bis(1-(3,4-diméthoxybenzyl)-3,4-dihydro-6,7- diméthoxy-1H-isoquinoléine-2-propionate) sensiblement pur, un composé de formule I et ses sels d'addition d'acide avec de bons rendements. Le pentaméthylène bis(1-(3,4-diméthoxybenzyl)-3,4- dihydro-6,7-diméthoxy-1H-isoquinoléine-2-propionate) ou ses sels d'addition d'acide est l'intermédiaire clé pour la synthèse d'un médicament de blocage neuromusculaire non dépolarisant. Le procédé de l'invention peut également être utilisé pour la synthèse de divers dérivés de tétrahydroisoquinoléine.
PCT/IN2018/050153 2017-04-21 2018-03-16 Procédé amélioré de préparation de composés tétrahydroisoquinoléines Ceased WO2018193463A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201721014267 2017-04-21
IN201721014267 2017-04-21

Publications (1)

Publication Number Publication Date
WO2018193463A1 true WO2018193463A1 (fr) 2018-10-25

Family

ID=63855629

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2018/050153 Ceased WO2018193463A1 (fr) 2017-04-21 2018-03-16 Procédé amélioré de préparation de composés tétrahydroisoquinoléines

Country Status (1)

Country Link
WO (1) WO2018193463A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112778200A (zh) * 2021-01-20 2021-05-11 江苏诚信药业有限公司 一种苯磺顺阿曲库铵的制备方法及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179507A (en) * 1975-12-10 1979-12-18 Burroughs Wellcome Co. Quarternary ammonium compounds
WO2008132746A1 (fr) * 2007-05-01 2008-11-06 Chemagis Ltd. Nouveaux composés d'isoquinolinium utiles dans la préparation de cisatracurium et intermédiaires associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179507A (en) * 1975-12-10 1979-12-18 Burroughs Wellcome Co. Quarternary ammonium compounds
WO2008132746A1 (fr) * 2007-05-01 2008-11-06 Chemagis Ltd. Nouveaux composés d'isoquinolinium utiles dans la préparation de cisatracurium et intermédiaires associés

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112778200A (zh) * 2021-01-20 2021-05-11 江苏诚信药业有限公司 一种苯磺顺阿曲库铵的制备方法及其应用

Similar Documents

Publication Publication Date Title
IL95480A (en) Process for the preparation of cyclic amino acids and intermediates
KR20020057949A (ko) 신규한 페닐피페라진
JPWO2003097632A1 (ja) プロパノールアミン誘導体、及び３−ｎ−メチルアミノ−１−（２−チエニル）−１−プロパノールの製造方法、並びにプロパノールアミン誘導体の製造方法
WO2015007897A1 (fr) Procédé de racémisation d'énantiomères indésirables
CA2221375A1 (fr) Procede permettant le dedoublement d'acides chiraux a l'aide de 1-aminoindan-2-ols
WO2014012495A1 (fr) Composé chiral d'α-méthylène-β-lactame, et procédé de préparation et application de ce dernier
WO2000062782A1 (fr) Nouvelle synthese et cristallisation de composes contenant de la piperazine
WO2018193463A1 (fr) Procédé amélioré de préparation de composés tétrahydroisoquinoléines
CN113816855B (zh) 合成手性烯丙基羧酸酯的方法
CN103012350B (zh) 苯并吡喃类手性化合物的合成方法
CN103183673A (zh) (s，s)-2，8-二氮杂双环[4，3，0]壬烷的合成方法
CN114409585A (zh) 2-氧吡咯烷衍生物、其制备方法及中间体的制备方法
US6545149B2 (en) Synthesis and crystallization of piperazine ring-containing compounds
TWI628181B (zh) 一種ｄｐｐ－ｉｖ抑制劑的中間體、其製備方法和藉由其製備ｄｐｐ－ｉｖ抑制劑的方法
FR2795071A1 (fr) Nouveaux derives de carboxylate de 7-oxo-2,3,7,14- tetrahydro-1h-benzo[b]pyrano[3,2,h] acridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
SK13592001A3 (sk) Syntéza 3-amino-3-arylpropanoátov
TWI430996B (zh) 製備富含鏡像異構物之ｎ－羧酸酐之方法
CN103420962B (zh) 3-芳基戊二酸单酯类化合物、其制备方法和用途
CN100341850C (zh) 去甲基苯环壬酯光学异构体与n－对甲基苯磺酰谷氨酸光学异构体的盐及其制备方法和用途
CN110590641B (zh) 一种3-羟基异吲哚-1-酮系列化合物的绿色制备方法
US20040176591A1 (en) Novel synthesis and crystallization of peperazine ring-containing compounds
US2644010A (en) Salts of d-amidone with an optically active acid and process for resolving dl-amid-one
CN101454290A (zh) 2-烷氧基-3,4,5-三羟基-烷基酰胺-苯并吖庚因，它们的制备，含有它们的组合物和用途
KR20120001763A (ko) 치치바빈 폐환 반응에 의한 디아자인돌의 개선된 화학적 합성
HUP0003433A2 (hu) Kristályos 10,10-bisz((2-fluor-4-piridinil)-metil)-9(10H)-antracenon és eljárás annak előállítására

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18787955

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18787955

Country of ref document: EP

Kind code of ref document: A1