[go: up one dir, main page]

US20010016669A1 - Novel process and intermediates - Google Patents

Novel process and intermediates Download PDF

Info

Publication number
US20010016669A1
US20010016669A1 US09/748,042 US74804200A US2001016669A1 US 20010016669 A1 US20010016669 A1 US 20010016669A1 US 74804200 A US74804200 A US 74804200A US 2001016669 A1 US2001016669 A1 US 2001016669A1
Authority
US
United States
Prior art keywords
compound
formula
defined above
enantiomerically enriched
salt
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.)
Granted
Application number
US09/748,042
Other versions
US6310248B2 (en
Inventor
Pher Andersson
Christian Hedberg
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.)
Pfizer Health AB
Original Assignee
Pharmacia AB
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 Pharmacia AB filed Critical Pharmacia AB
Priority to US09/748,042 priority Critical patent/US6310248B2/en
Assigned to PHARMACIA AB reassignment PHARMACIA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANDERSSON, PHER G., HEDBERG, CHRISTIAN
Priority to US09/919,401 priority patent/US6566537B2/en
Publication of US20010016669A1 publication Critical patent/US20010016669A1/en
Application granted granted Critical
Publication of US6310248B2 publication Critical patent/US6310248B2/en
Priority to US10/401,361 priority patent/US6689916B2/en
Priority to US10/402,671 priority patent/US6790998B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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 hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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 hydroxy groups linked by carbon chains having at least three 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
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
    • C07C35/32—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system being a (4.3.0) system, e.g. indenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to a novel process of preparing tolterodine and analogues thereof, as well as to novel intermediates prepared in the process.
  • Tolterodine i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine
  • the major, active metabolite of tolterodine i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine
  • Tolterodine and analogues thereof including the corresponding (S)-enantiomer, as well as processes for the preparation thereof are disclosed in U.S. Pat. No. 5,382,600.
  • the active metabolite and analogues are disclosed in U.S. Pat. No. 5,559,269.
  • the (S)-enantiomer and its use in the treatment of urinary and gastrointestinal disorders is further described in WO 98/03067.
  • One of the processes described in U.S. Pat. No. 5,382,600 comprises the steps of preparing the lactone 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, reductively ring-opening the lactone to prepare the corresponding alcohol, reacting the alcohol with isopropylamine, and resolving the racemate formed to isolate tolterodine.
  • U.S. Pat. No. 5,922,914 discloses a modified process for preparing tolterodine by reducing the above-mentioned lactone to the corresponding alcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol, reductively aminating the alcohol, and resolving the racemate formed to isolate tolterodine.
  • This method comprises a copper bromide catalyzed asymmetric addition of 2-methoxy-5-methylphenylmagnesium bromide to a 3-phenyl-prop-2-enoyl-oxazolidinone to produce the (5S)-phenyl-(3R)-(2-benzyloxy-5-methylphenyl)-3-phenylpropanoyl-2-oxazolidinone, hydrolyzation of the oxazolidinone to the corresponding propanoic acid, reaction with diisopropylamine to form the amide, and reduction of the amide to tolterodine.
  • the present invention provides an alternate enantioselective synthesis of tolterodine which is more convenient to perform than the prior art method outlined above and which gives a final product of high enantiomeric purity.
  • a key step of the present method is the preparation of the above-mentioned lactone, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (also referred to as 6-methyl-4-phenyl-chroman-2-one), in an enantiomerically enriched form by enantioselective reactions.
  • the present invention provides a process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib):
  • R 1 , R 2 and R 3 independently of each other are hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and R 4 and R 5 independently of each other are C 1-6 -alkyl, or a salt thereof, which process comprises the steps of:
  • R 1 , R 2 and R 3 are as defined above, or a salt thereof,
  • R 1 , R 2 and R 3 are as defined above, or a salt thereof;
  • R 1 , R 2 and R 3 are as defined above or a salt thereof;
  • step d) comprises:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • steps d1) and d2) are performed simultaneously in a single step.
  • step d) comprises:
  • R 1 , R 2 and R 3 are as defined in claim 1;
  • the present invention provides a process for the enantioselective preparation of a compound of the general formula (Va) or (Vb):
  • R 1 , R 2 and R 3 are as defined above, or a salt thereof, which process comprises the steps of:
  • R 1 , R 2 and R 3 are as defined above, or a salt thereof, to form an enantiomerically enriched compound of formula (IIIA) or (IIIb):
  • R 1 , R 2 and R 3 are as defined above, or a salt thereof,
  • R 1 , R 2 and R 3 are as defined above, or a salt thereof;
  • the compound of formula (II) may be prepared by subjecting a compound of the general formula (IX):
  • R 1 , R 2 , and R 3 are as defined in claim 1, and Hal is halogen (preferably bromine), or a salt thereof, to a reductive ring closure reaction.
  • the compound of formula (IX) may be prepared by reacting a compound of the general formula (X):
  • R 2 and R 3 are as defined above.
  • compounds of formula Ia or Ib are prepared in which R 1 is methyl or hydroxymethyl in 5-position, R 2 and R 3 are hydrogen, and R 4 and R 5 are both iso-propyl.
  • the present invention provides novel compounds of the above f of the formulae (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb), and (IX) as defined above and wherein R 1 is methyl or hydroxymethyl in 5-position and R 2 and R 3 are hydrogen and compounds of the formulae (IX) wherein R 1 is hydroxymethyl in 5-position, R 2 and R 3 are hydrogen and halogen is Br, J or F.
  • a basic concept behind the present invention is the enantioselective reduction of the compound of formula (II) to a compound of formula (IIIa) or (IIIb) in enantiomerically enriched form, which is then rearranged to form the lactone (Va) or (Vb).
  • the respective lactone enantiomers may then be reacted further to tolterodine by methods known per se in the art, e.g. as described in the above-mentioned U.S. Pat. No. 5,382,600 and U.S. Pat. No. 5,922,914.
  • the enantioselective reduction of the compound (II) to a compound of formula (IIIa) or (IIIb) may be performed in an organic solvent with a variety of reducing agents and reaction conditions as are known per se in the art for enantioselective reduction of carbonyl groups.
  • reducing agents and reaction conditions as are known per se in the art for enantioselective reduction of carbonyl groups.
  • Such methods are described in, for example, Houben-Weyl, Stereoselective Synthesis, Ed: Günter Helmchen et al., Vol. 7, Chapter 2.3, Thime, Stuttgart-New York 1996.
  • the reaction is carried out at from about 0° C. to about room temperature.
  • An exemplary method includes the use of a chiral catalyst, such as (R)- or (S)-MeCBS (3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[ 1,2-c][1.3.2]oxazaborole) which is commercially available, a borane complex and a base.
  • a chiral catalyst such as (R)- or (S)-MeCBS (3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[ 1,2-c][1.3.2]oxazaborole) which is commercially available, a borane complex and a base.
  • the stereochemistry can be directed by using either the R or S enantiomer of the MeCBS oxazaborolidine catalyst in the asymmetric borane reduction of the compound (II).
  • the reduction of a similar substrate is described in, for example, WO 97/17341.
  • the sigmatropic 1,3-rearrangement (hydride shift) of the compound (IIIa) or (IIIb) to a compound of formula (IVa) or (IVb) may be carried out by treatment with a base, such as triethylamine, and a palladium catalyst, such as Pd(dppe)Cl 2 ([1,2-bis(diphenylphosphino)ethane] palladium (II) chloride) in an organic solvent (see e.g. the above WO 97/17341).
  • a base such as triethylamine
  • a palladium catalyst such as Pd(dppe)Cl 2 ([1,2-bis(diphenylphosphino)ethane] palladium (II) chloride
  • the rearrangement reaction may be carried out by treatment with DABCO (1,4-diazabicyclo[2.2.2]octane) and a base, such as triethylamine, in an organic solvent (see Example 1 below).
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • a base such as triethylamine
  • the indanone (IVa) or (IVb) obtained is generally a highly crystalline solid which makes it possible to raise the enantiomeric purity, if desired, by recrystallization from a suitable solvent (for example, an enantiomeric excess (as defined below) of 99% or more may be obtained).
  • the Baeyer-Villiger oxidation of compounds (IVa) and (IVb) may be performed by a variety of oxidizing agents as is well known in the art, e.g. hydrogen peroxide or a peroxy acid, such as 3-chloro-peroxybenzoic acid, preferably in the presence of an acid catalyst, such as p-tolylsulphonic acid (TsOH).
  • oxidizing agents e.g. hydrogen peroxide or a peroxy acid, such as 3-chloro-peroxybenzoic acid, preferably in the presence of an acid catalyst, such as p-tolylsulphonic acid (TsOH).
  • TsOH p-tolylsulphonic acid
  • Enantiomeric purity is usually expressed as “enantiomeric excess”, below abbreviated as “ee”, and defined as (R ⁇ S)/(R+S), where R and S are the amounts of the R- and S-enantiomers, respectively.
  • enantiomeric excess below abbreviated as “ee”, and defined as (R ⁇ S)/(R+S), where R and S are the amounts of the R- and S-enantiomers, respectively.
  • the enantiomeric purity in the enantioselective process steps is usually at least about 50%, preferably at least about 85%.
  • tolterodine is an amine, it may form salts with both organic and inorganic acids.
  • the pharmaceutically acceptable salts may, depending on the pharmaceutical formulation, be preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline.
  • Exemplary pharmaceutically acceptable salts include salts with acids such as methane sulphonic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, and maleic acids.
  • TLC refers to thin-layer chromatography
  • MeCBS refers to 3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[ 1,2-c][1.3.2]oxazaborole.
  • DABCO refers to 1,4-diazabicyclo[2.2.2]octane.
  • ChiralCel OD-H refers to a chiral stationary phase for liquid chromatography consisting of cellulose tris(3,5-dimethylphenyl carbamate) on a silica gel substrate (Daicel Chemical Industries, Ltd).
  • mCPBA refers to 3-chloroperoxybenzoic acid.
  • (R)-MeCBS catalyst (0.22 ml, 1 M, 0.22 mmol) was mixed in 5 ml of dry THF, and stirred for 1 h at room temperature. After cooling to 0° C., 2.5 ml of 2 M BH 3 :Me 2 S (4.99 mmol) in THF were added. 5-Methyl-3-phenyl-inden-1-one (1.00 g, 4.54 mmol) was added as a solution in toulene (2 ml) over 2 h via a syringe pump. The reaction was followed by TLC. After completeness, methanol (0.6 ml, 17 mmol) was added at 0° C. and the mixture was evaporated to dryness.
  • Tolterodine may be prepared from 6-methyl-4-(S)-phenyl-chroman-2-one as obtained above by method steps corresponding to Examples 3 and 4 of the above-mentioned U.S. Pat. No. 5,922,914 (the full disclosure of which is incorporated by reference herein), i.e. by (i) reducing the lactone 6-methyl-4-(S)-phenyl-chroman-2-one with diisobutylaluminiumhydride in toluene solution at ⁇ 20 to ⁇ 25° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Urology & Nephrology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The invention relates to a process for the enantioselective preparation of tolterodine and analogues and salts thereof comprises the steps of:
a) enantioselectively reducing the carbonyl function in a compound of formula (II):
Figure US20010016669A1-20010823-C00001
 wherein R1, R2 and R3 independently of each other are hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):
Figure US20010016669A1-20010823-C00002
 wherein R1, R2 and R3 are as defined above;
b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb):
Figure US20010016669A1-20010823-C00003
 wherein R1, R2 and R3 are as defined above;
c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form a corresponding enantiomerically enriched compound of the general formula (Va) or (Vb):
Figure US20010016669A1-20010823-C00004
 wherein R1, R2 and R3 are as defined above;
d) converting the compound of formula (Va) or (Vb) to form the corresponding enantiometrically enriched compound of tolterodine or analogue, and
e) optionally converting a compound obtained in base form to a salt thereof, or converting a salt form to the free base.
The invention also relates to novel starting materials and intermediates used in the process.

Description

    FIELD OF THE INVENTION
  • The present invention relates to a novel process of preparing tolterodine and analogues thereof, as well as to novel intermediates prepared in the process. [0001]
    • BACKGROUND OF THE INVENTION
  • Tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, is useful for treating urinary incontinence. The major, active metabolite of tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine, contributes significantly to the therapeutic effect of tolterodine. Tolterodine and analogues thereof, including the corresponding (S)-enantiomer, as well as processes for the preparation thereof are disclosed in U.S. Pat. No. 5,382,600. The active metabolite and analogues are disclosed in U.S. Pat. No. 5,559,269. The (S)-enantiomer and its use in the treatment of urinary and gastrointestinal disorders is further described in WO 98/03067. [0002]
  • One of the processes described in U.S. Pat. No. 5,382,600 comprises the steps of preparing the lactone 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, reductively ring-opening the lactone to prepare the corresponding alcohol, reacting the alcohol with isopropylamine, and resolving the racemate formed to isolate tolterodine. [0003]
  • U.S. Pat. No. 5,922,914 discloses a modified process for preparing tolterodine by reducing the above-mentioned lactone to the corresponding alcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol, reductively aminating the alcohol, and resolving the racemate formed to isolate tolterodine. [0004]
  • While the above prior art methods thus produce a racemate which has to be resolved to obtain the desired tolterodine enantiomer, Andersson, Pher G. et al., J. Org. Chem. 1998, 63, 8067-8070 discloses an enantioselective synthesis of tolterodine which obviates the need of the enantiomer separation step. This method comprises a copper bromide catalyzed asymmetric addition of 2-methoxy-5-methylphenylmagnesium bromide to a 3-phenyl-prop-2-enoyl-oxazolidinone to produce the (5S)-phenyl-(3R)-(2-benzyloxy-5-methylphenyl)-3-phenylpropanoyl-2-oxazolidinone, hydrolyzation of the oxazolidinone to the corresponding propanoic acid, reaction with diisopropylamine to form the amide, and reduction of the amide to tolterodine. [0005]
    • SUMMARY OF THE INVENTION
  • The present invention provides an alternate enantioselective synthesis of tolterodine which is more convenient to perform than the prior art method outlined above and which gives a final product of high enantiomeric purity. A key step of the present method is the preparation of the above-mentioned lactone, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (also referred to as 6-methyl-4-phenyl-chroman-2-one), in an enantiomerically enriched form by enantioselective reactions. [0006]
  • Thus, in a first aspect the present invention provides a process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib): [0007]
    Figure US20010016669A1-20010823-C00005
  • wherein R[0008] 1, R2 and R3 independently of each other are hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and R4 and R5 independently of each other are C1-6-alkyl, or a salt thereof, which process comprises the steps of:
  • a) enantioselectively reducing the carbonyl function in a compound of formula (II): [0009]
    Figure US20010016669A1-20010823-C00006
  • wherein R[0010] 1, R2 and R3 are as defined above, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):
    Figure US20010016669A1-20010823-C00007
  • wherein R[0011] 1, R2 and R3 are as defined above, or a salt thereof,
  • b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb): [0012]
    Figure US20010016669A1-20010823-C00008
  • wherein R[0013] 1, R2 and R3 are as defined above, or a salt thereof;
  • c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form a corresponding enantiomerically enriched compound of the general formula (Va) or (Vb): [0014]
    Figure US20010016669A1-20010823-C00009
  • wherein R[0015] 1, R2 and R3 are as defined above or a salt thereof;
  • d) converting the compound of formula (Va) or (Vb) to form the corresponding enantiometrically enriched compound of formula (Ia) or (Ib), or a salt thereof; and [0016]
  • e) optionally converting a compound of formula (Ia) or (Ib) in base form to a salt thereof, or converting a salt form to the free base. [0017]
  • In one embodiment of the first aspect of the invention, step d) comprises: [0018]
  • d1) reacting the compound of formula (Va) or (Vb) with an amine of the general formula (VI): [0019]
    Figure US20010016669A1-20010823-C00010
  • wherein R[0020] 4 and R5 are as defined above, to form a corresponding enantiomerically enriched compound of the general formula (VIIa) or (VIIb):
    Figure US20010016669A1-20010823-C00011
  • wherein R[0021] 1, R2, R3, R4 and R5 are as defined above; and
  • d2) reducing the carbonyl function in the compound of formula (VIIa) or (VIIb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib). [0022]
  • Optionally, steps d1) and d2) are performed simultaneously in a single step. [0023]
  • In an alternative embodiment, step d) comprises: [0024]
  • d1′) reducing the compound of formula (Va) or (Vb) to form a corresponding enantiomerically enriched hydroxy compound of the general formula (VIIIa) or (VIIIb): [0025]
    Figure US20010016669A1-20010823-C00012
  • wherein R[0026] 1, R2 and R3 are as defined in claim 1; and
  • d2′) reductively aminating the hydroxy compound of formula (VIIIa) or (VIIIb) with the amine of formula (VI) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib). [0027]
  • In second aspect, the present invention provides a process for the enantioselective preparation of a compound of the general formula (Va) or (Vb): [0028]
    Figure US20010016669A1-20010823-C00013
  • wherein R[0029] 1, R2 and R3 are as defined above, or a salt thereof, which process comprises the steps of:
  • a) enantioselectively reducing the carbonyl function in a compound of formula (II): [0030]
    Figure US20010016669A1-20010823-C00014
  • wherein R[0031] 1, R2 and R3 are as defined above, or a salt thereof, to form an enantiomerically enriched compound of formula (IIIA) or (IIIb):
    Figure US20010016669A1-20010823-C00015
  • wherein R[0032] 1, R2 and R3 are as defined above, or a salt thereof,
  • b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb): [0033]
    Figure US20010016669A1-20010823-C00016
  • wherein R[0034] 1, R2 and R3 are as defined above, or a salt thereof; and
  • c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form the corresponding enantiomerically enriched compound of the general formula (Va) or (Vb), or salt thereof. [0035]
  • The compound of formula (II) may be prepared by subjecting a compound of the general formula (IX): [0036]
    Figure US20010016669A1-20010823-C00017
  • wherein R[0037] 1, R2, and R3 are as defined in claim 1, and Hal is halogen (preferably bromine), or a salt thereof, to a reductive ring closure reaction.
  • The compound of formula (IX) may be prepared by reacting a compound of the general formula (X): [0038]
    Figure US20010016669A1-20010823-C00018
  • wherein R[0039] 1 and Hal are as defined above, with a compound of the general formula (XI):
    Figure US20010016669A1-20010823-C00019
  • wherein R[0040] 2 and R3 are as defined above.
  • Preferably, compounds of formula Ia or Ib are prepared in which R[0041] 1 is methyl or hydroxymethyl in 5-position, R2 and R3 are hydrogen, and R4 and R5 are both iso-propyl.
  • In a third aspect, the present invention provides novel compounds of the above f of the formulae (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb), and (IX) as defined above and wherein R[0042] 1 is methyl or hydroxymethyl in 5-position and R2 and R3 are hydrogen and compounds of the formulae (IX) wherein R1 is hydroxymethyl in 5-position, R2 and R3 are hydrogen and halogen is Br, J or F.
    • DETAILED DESCRIPTION OF THE INVENTION
  • A basic concept behind the present invention is the enantioselective reduction of the compound of formula (II) to a compound of formula (IIIa) or (IIIb) in enantiomerically enriched form, which is then rearranged to form the lactone (Va) or (Vb). The respective lactone enantiomers may then be reacted further to tolterodine by methods known per se in the art, e.g. as described in the above-mentioned U.S. Pat. No. 5,382,600 and U.S. Pat. No. 5,922,914. [0043]
  • The enantioselective reduction of the compound (II) to a compound of formula (IIIa) or (IIIb) may be performed in an organic solvent with a variety of reducing agents and reaction conditions as are known per se in the art for enantioselective reduction of carbonyl groups. Such methods are described in, for example, Houben-Weyl, Stereoselective Synthesis, Ed: Günter Helmchen et al., Vol. 7, Chapter 2.3, Thime, Stuttgart-New York 1996. Preferably, the reaction is carried out at from about 0° C. to about room temperature. An exemplary method includes the use of a chiral catalyst, such as (R)- or (S)-MeCBS (3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[ 1,2-c][1.3.2]oxazaborole) which is commercially available, a borane complex and a base. The stereochemistry can be directed by using either the R or S enantiomer of the MeCBS oxazaborolidine catalyst in the asymmetric borane reduction of the compound (II). The reduction of a similar substrate is described in, for example, WO 97/17341. The enantioselectivity of asymmetric borane reductions is not very sensitive to stereoelectronic effects. [0044]
  • The sigmatropic 1,3-rearrangement (hydride shift) of the compound (IIIa) or (IIIb) to a compound of formula (IVa) or (IVb) may be carried out by treatment with a base, such as triethylamine, and a palladium catalyst, such as Pd(dppe)Cl[0045] 2 ([1,2-bis(diphenylphosphino)ethane] palladium (II) chloride) in an organic solvent (see e.g. the above WO 97/17341). Alternatively, the rearrangement reaction may be carried out by treatment with DABCO (1,4-diazabicyclo[2.2.2]octane) and a base, such as triethylamine, in an organic solvent (see Example 1 below). The indanone (IVa) or (IVb) obtained is generally a highly crystalline solid which makes it possible to raise the enantiomeric purity, if desired, by recrystallization from a suitable solvent (for example, an enantiomeric excess (as defined below) of 99% or more may be obtained).
  • The Baeyer-Villiger oxidation of compounds (IVa) and (IVb) may be performed by a variety of oxidizing agents as is well known in the art, e.g. hydrogen peroxide or a peroxy acid, such as 3-chloro-peroxybenzoic acid, preferably in the presence of an acid catalyst, such as p-tolylsulphonic acid (TsOH). The reaction is preferably carried out in an organic solvent and at e.g. from about 0° C. to about room temperature. [0046]
  • Enantiomeric purity, or enantiomeric enrichment, is usually expressed as “enantiomeric excess”, below abbreviated as “ee”, and defined as (R−S)/(R+S), where R and S are the amounts of the R- and S-enantiomers, respectively. For the purposes of the present invention, the enantiomeric purity in the enantioselective process steps is usually at least about 50%, preferably at least about 85%. [0047]
  • Since tolterodine is an amine, it may form salts with both organic and inorganic acids. The pharmaceutically acceptable salts may, depending on the pharmaceutical formulation, be preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline. Exemplary pharmaceutically acceptable salts include salts with acids such as methane sulphonic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, and maleic acids. [0048]
  • The invention will now be illustrated further by the following non-limiting Example. [0049]
  • In the Example: [0050]
  • TLC refers to thin-layer chromatography. [0051]
  • MeCBS refers to 3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[ 1,2-c][1.3.2]oxazaborole. [0052]
  • DABCO refers to 1,4-diazabicyclo[2.2.2]octane. [0053]
  • ChiralCel OD-H (trademark) refers to a chiral stationary phase for liquid chromatography consisting of cellulose tris(3,5-dimethylphenyl carbamate) on a silica gel substrate (Daicel Chemical Industries, Ltd). [0054]
  • mCPBA refers to 3-chloroperoxybenzoic acid. [0055]
  • “ee” refers to enantiomeric excess as defined above. [0056]
    • EXAMPLE 1 1-(2-Bromo-4-methyl-phenyl)-3-phenyl-propenone
  • To a solution of 2-bromo-4-methylacetophenone (7.20 g, 34.0 mmol) and benzaldehyde (3.65 g, 34.0 mmol) in dry methanol (50 ml) was added freshly prepared sodium methoxide (35.7 mmol) in dry methanol (30 ml) at 0° C. The resulting mixture was stirred at 0° C. for 5 h and raised to room temperature over night. 10 ml of HCl (10%) were added slowly and the mixture was evaporated to near dryness under reduced pressure. The residue was suspended in saturated NaHCO[0057] 3 (50 ml) and extracted with 3×50 ml diethyl ether, washed with brine and dried over MgSO4. Purification by flash chromatography eluting with diethyl ether:pentane 5:95, gave 10.1 g (95%) of the title compound. Rf 0.66 (diethyl ether:pentane 20:80). 1H NMR δ: 2.25 (s, 3H), 6.96 (d, J=10.2 Hz, 1H), 7.15 (d, J=10.2 Hz, 1H), 7.05 (dd, J=7.6 Hz, 2.6 Hz, 1H), 7.24 (m, 3H), 7.34 (m, 2H), 7.40 (m, 3H). 13C NMR δ: 21.4, 112.5, 117.3, 122.5, 122.8, 123.7, 124.9, 128.4, 132.2, 133.6, 133.9, 143.6, 145.3, 186.6.
    • 5-Methyl-3-phenyl-inden-1-one
  • To a suspension of anhydrous K[0058] 2CO3 (9.76 g, 70.6 mmol) in dry DMF (100 ml) was added 1-(2-bromo-4-methyl-phenyl)-3-phenyl-propenone (8.40 g, 28.3 mmol), and the mixture was deaerated with dry argon for 15 min. Triphenylphosphine (0.73 g, 2.83 mmol) was added followed by PdCl2 (0.20 g, 1.13 mmol). The mixture was heated at 80° C. until NMR sample indicated disappearance of starting material (5 h). The mixture was reduced to half volume under reduced pressure and poured on ice:water (200 ml). Extractive work-up with CH2Cl2 followed by flash chromatography eluting with diethyl ether:pentane 5:95 gave 4.2 g (72%) of the title compound. Rf 0.62 (diethyl ether:pentane 20:80). IR (neat cm−1): 1704, 1606, 1355, 1101, 815, 743. 1H NMR δ: 2.40 (s, 3H), 5.99 (s, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.18 (s, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.53 (m, 3H), 7.66 (m, 2H). 13C NMR δ: 22.1, 122.7, 122.9, 123.5, 127.4, 128.6, 128.9, 129.2, 129.9, 130.3, 133.2, 143.7, 144.4, 162.4. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 205 (75), 191 (51), 177 (10), 165 (15).
    • 5-Methyl-3-phenyl-(S)-1H-inden-1-ol
  • (R)-MeCBS catalyst (0.22 ml, 1 M, 0.22 mmol) was mixed in 5 ml of dry THF, and stirred for 1 h at room temperature. After cooling to 0° C., 2.5 ml of 2 M BH[0059] 3:Me2S (4.99 mmol) in THF were added. 5-Methyl-3-phenyl-inden-1-one (1.00 g, 4.54 mmol) was added as a solution in toulene (2 ml) over 2 h via a syringe pump. The reaction was followed by TLC. After completeness, methanol (0.6 ml, 17 mmol) was added at 0° C. and the mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate:pentane 10:90 gave 0.96 g (95%) of the title compound. Rf 0.35 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 24.53 min, (R)-isomer 27.22 min, 93% ee. IR (neat cm−1): 3300, 1605, 1446, 949, 813. 1H NMR δ: 1.40 (s, 1H), 2.40 (s, 3H), 5.27 (d, J=8 Hz, 1H), 6.43 (d J=2 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.27 (s, 1H), 7.47 (m, 4H), 7.59 (m, 2H). 13C NMR δ: 21.6, 76.2, 121.6, 123.6, 126.9, 127.6, 128.2, 128.6, 134.1, 134.9, 138.2, 142.1, 143.7, 145.6. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 207 (71), 178 (66), 144 (42), 116 (23).
    • 5-Methyl-3-(S)-phenyl-indan-1-one
  • 5-Methyl-3-phenyl-(S)-1H-inden-1-ol (750 mg, 3.41 mmol) and DABCO (190 mg, 1.71 mmol) were dissolved in dry THF:triethylamine 20:1 (15 ml) and refluxed for 3 h. The reaction mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate:pentane 5:95 gave 690 mg (92%) of the title compound. R[0060] f 0.62 (ethyl actetate:pentane 20:80) (ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 19.12 min, (R)-isomer 22.33 min, 89% ee. IR (neat cm−1): 3027, 2361, 1710, 1605, 1280, 1238, 1040. 1H NMR δ: 2.39 (s, 3H), 2.69 (dd, J=3.0, 19.2 Hz, 1H), 3.23 (dd, J=8.0, 19.2 Hz, 1H), 4.53 (q, J=4 Hz, 1H), 7.07 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.26 (m, 2H), 7.33 (m, 2H), 7.72 (d, J 7.6 Hz, 1H). 13C NMR δ: 22.1, 44.3, 46.9, 123.2, 126.9, 127.0, 127.6, 128.9, 134.5, 143.8, 146.3, 158.4, 205.5. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 207 (55), 194 (19), 178 (60), 144 (10).
    • 6-Methyl-4-(S)-phenyl-chroman-2-one
  • 5-Methyl-3-(S)-phenyl-indan-1-one (400 mg, 1.8 mmol) and mCPBA (98%, 485 mg, 2.8 mmol) were suspended in dry CH[0061] 2Cl2 (6 ml) at 0° C. followed by TsOH:H2O (20 mg). The reaction was kept at 4° C. for 48 h. The mixture was diluted with 10 ml of CH2Cl2 and washed with 2×10 ml of saturated Na2SO3, saturated NaHCO3 and brine. Flash chromatography eluting with ethyl acetate:pentane 10:90 gave 390 mg (90%) of the title compound. Rf 0.83 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 mL/min of hexane/isopropanol 95/5 (S)-isomer 15.18 min, (R)-isomer 17.42 min, 89% ee. IR (neat cm−1): 2900, 2360, 1769, 1495, 1208, 1145. 1H NMR δ: 2.28 (s, 3H), 3.05 (m, 1H), 4.32 (t, J=6.8 Hz, 1H), 6.98 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.11 (dd, J=2.0, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.33 (m, 3H) 13C NMR δ: 20.7, 37.1, 40.7, 116.8, 125.3, 127.5, 127.6, 128.6, 129.1, 129.3, 134.3, 140.5, 149.6, 167.8. MS (EI 70 eV) m/z (rel. intensity): 238 (55) [M+], 220 (57), 195 (100), 181(10), 165 (12), 152 (9).
    • (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine (tolterodine)
  • Tolterodine may be prepared from 6-methyl-4-(S)-phenyl-chroman-2-one as obtained above by method steps corresponding to Examples 3 and 4 of the above-mentioned U.S. Pat. No. 5,922,914 (the full disclosure of which is incorporated by reference herein), i.e. by (i) reducing the lactone 6-methyl-4-(S)-phenyl-chroman-2-one with diisobutylaluminiumhydride in toluene solution at −20 to −25° C. to the corresponding hydroxy compound, 6-methyl-4-(S)-phenyl-chroman-2-ol; (ii) reductively aminating the 6-methyl-4-(S)-phenyl-chroman-2-ol in methanol by reaction with diisopropylamine and hydrogenation with palladium on carbon at 45-50 psi and 48° C., and subsequent filtration (solka floc) to obtain the title compound (tolterodine) in substantially enantiomerically pure form. [0062]

Claims (10)

1. A process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib):
Figure US20010016669A1-20010823-C00020
wherein R1, R2 and R3 independently of each other are hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and R4 and R5 independently of each other are C1-6-alkyl, or a salt thereof, which process comprises the steps of:
a) enantioselectively reducing the carbonyl function in a compound of formula (II):
Figure US20010016669A1-20010823-C00021
 wherein R1, R2 and R3 are as defined above, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):
Figure US20010016669A1-20010823-C00022
 wherein R1, R2 and R3 are as defined above;
b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb):
Figure US20010016669A1-20010823-C00023
 wherein R1, R2 and R3 are as defined above;
c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form a corresponding enantiomerically enriched compound of the general formula (Va) or (Vb):
Figure US20010016669A1-20010823-C00024
 wherein R1, R2 and R3 are as defined above;
d) converting the compound of formula (Va) or (Vb) to form the corresponding enantiometrically enriched compound of formula (Ia) or (Ib); and
e) optionally converting the compound of formula (Ia) or (Ib) to a salt thereof.
2. The process according to
claim 1
, wherein step d) comprises:
d1) reacting the compound of formula (Va) or (Vb) with an amine of the general formula (VI):
Figure US20010016669A1-20010823-C00025
 wherein R4 and R5 are as defined in
claim 1
, to form a corresponding enantiomerically enriched compound of the general formula (VIIa) or (VIIb):
Figure US20010016669A1-20010823-C00026
 wherein R1, R2, R3, R4 and R5 are as defined above; and
d2) reducing the carbonyl function in the compound of formula (VIIa) or (VIIb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).
3. The process according to
claim 2
, wherein steps d1) and d2) are performed simultaneously in a single step.
4. The process according to
claim 1
, wherein step d) comprises:
d1′) reducing the compound of formula (Va) or (Vb) to form a corresponding enantiomerically enriched hydroxy compound of the general formula (VIIIa) or (VIIIb):
Figure US20010016669A1-20010823-C00027
 wherein R1, R2 and R3 are as defined in
claim 1
; and
d2′) reductively aminating the hydroxy compound of formula (VIIIa) or (VIIIb) with the amine of formula (VI) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).
5. A process for the enantioselective preparation of a compound of the general formula (Va) or (Vb):
Figure US20010016669A1-20010823-C00028
wherein R1, R2 and R3 are as defined in
claim 1
, or a salt thereof, which process comprises the steps of:
a) enantioselectively reducing the carbonyl function in a compound of formula (II):
Figure US20010016669A1-20010823-C00029
 wherein R1, R2 and R3 are as defined above, or a salt thereof, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):
Figure US20010016669A1-20010823-C00030
 wherein R1, R2 and R3 are as defined above, or a salt thereof;
b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb):
Figure US20010016669A1-20010823-C00031
 wherein R1, R2 and R3 are as defined above, or a salt thereof, and
c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form the corresponding enantiomerically enriched compound of the general formula (Va) or (Vb), or salt thereof.
6. The process according to any one of
claims 1
 to
5
, which further comprises preparing the compound of formula (II) by subjecting a compound of the general formula (IX):
Figure US20010016669A1-20010823-C00032
wherein R1, R2, and R3 are as defined in
claim 1
, and Hal is halogen, or a salt thereof, to a reductive ring closure reaction.
7. The process according to
claim 6
, further comprising preparing the compound of formula (IX) by reacting a compound of the general formula (X):
Figure US20010016669A1-20010823-C00033
wherein R1 and Hal are as defined above, with a compound of the general formula (XI):
Figure US20010016669A1-20010823-C00034
wherein R2 and R3 are as defined in
claim 1
.
8. The process according to any one of
claims 1
 to
7
, wherein R1 is methyl or hydroxymethyl in 5-position, R2 and R3 are hydrogen, and R4 and R5 are both iso-propyl.
9. The process according to any one of
claims 1
 to
4
 and
6
 to 8, wherein tolterodine is prepared.
10. Compounds of the formulae (II), (IIIa), (IIIb), (IVa), (IVb), (Va) and (Vb) as defined in
claims 1
 to
8
 and wherein R1 is methyl or hydroxymethyl in 5-position and R2 and R3 are hydrogen and compounds of the formulae (IX) wherein R1 is hydroxymethyl in 5-position, R2 and R3 are hydrogen and halogen is Br, J or F.
US09/748,042 1999-12-30 2000-12-22 Process and intermediates Expired - Fee Related US6310248B2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US09/748,042 US6310248B2 (en) 1999-12-30 2000-12-22 Process and intermediates
US09/919,401 US6566537B2 (en) 1999-12-30 2001-07-31 Process and intermediates
US10/401,361 US6689916B2 (en) 1999-12-30 2003-03-28 Phenyl propenone compounds
US10/402,671 US6790998B2 (en) 1999-12-30 2003-03-28 Phenyl inden-1-one compounds

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
SE9904850-6 1999-12-30
SE9904850 1999-12-30
SE9904850A SE9904850D0 (en) 1999-12-30 1999-12-30 Novel process and intermediates
US17743900P 2000-01-21 2000-01-21
US09/748,042 US6310248B2 (en) 1999-12-30 2000-12-22 Process and intermediates

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/919,401 Division US6566537B2 (en) 1999-12-30 2001-07-31 Process and intermediates

Publications (2)

Publication Number Publication Date
US20010016669A1 true US20010016669A1 (en) 2001-08-23
US6310248B2 US6310248B2 (en) 2001-10-30

Family

ID=20418365

Family Applications (1)

Application Number Title Priority Date Filing Date
US09/748,042 Expired - Fee Related US6310248B2 (en) 1999-12-30 2000-12-22 Process and intermediates

Country Status (29)

Country Link
US (1) US6310248B2 (en)
EP (2) EP1496045A3 (en)
JP (1) JP2003519207A (en)
KR (1) KR20020062669A (en)
CN (1) CN1209342C (en)
AR (1) AR027138A1 (en)
AT (1) ATE282019T1 (en)
AU (1) AU782796B2 (en)
BR (1) BR0016785A (en)
CA (1) CA2392832A1 (en)
CZ (1) CZ20022255A3 (en)
DE (1) DE60015799T2 (en)
DK (1) DK1242361T3 (en)
EE (1) EE200200325A (en)
ES (1) ES2228658T3 (en)
HU (1) HUP0203816A3 (en)
IL (1) IL150275A0 (en)
MX (1) MXPA02006415A (en)
MY (1) MY118906A (en)
NO (1) NO20023189L (en)
NZ (1) NZ519079A (en)
PE (1) PE20011123A1 (en)
PL (1) PL355947A1 (en)
PT (1) PT1242361E (en)
SE (1) SE9904850D0 (en)
SK (1) SK9392002A3 (en)
TW (1) TWI225476B (en)
WO (1) WO2001049649A1 (en)
ZA (1) ZA200204066B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871275B2 (en) 2007-08-08 2014-10-28 Inventia Healthcare Private Limited Extended release compositions comprising tolterodine

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0957073A1 (en) 1998-05-12 1999-11-17 Schwarz Pharma Ag Novel derivatives of 3,3-diphenylpropylamines
WO2003064501A1 (en) * 2002-01-31 2003-08-07 Clarke Slemon Conformationally restricted compounds as dendrimer cores
US6703504B2 (en) 2002-02-11 2004-03-09 Clarke Slemon Conformationally constrained compounds as dendrimer cores
EP1424079A1 (en) * 2002-11-27 2004-06-02 Boehringer Ingelheim International GmbH Combination of a beta-3-receptor agonist and of a reuptake inhibitor of serotonin and/or norepinephrine
DE10315917A1 (en) * 2003-04-08 2004-11-18 Schwarz Pharma Ag Highly pure bases of 3,3-diphenylpropylamine monoesters
ITMI20031354A1 (en) * 2003-07-02 2005-01-03 Istituto Di Chimica Biomolecolare D El Cnr Sezione ENANTIOSELECTIVE SYNTHESIS OF ENANTIOMERICALLY ENRICHED COMPOUNDS.
ES2235648B1 (en) * 2003-12-22 2006-11-01 Ragactives, S.L. PROCEDURE FOR OBTAINING TOLTERODINE.
ITMI20040616A1 (en) * 2004-03-30 2004-06-30 Dinamite Dipharma S P A In For PROCESS FOR THE PREPARATION OF TOLTERODINE AND ITS INTERMEDIATES
EP1629834A1 (en) 2004-08-27 2006-03-01 KRKA, D.D., Novo Mesto Sustained release pharmaceutical composition of tolterodine
ITMI20041920A1 (en) * 2004-10-11 2005-01-11 Chemi Spa PROCESS FOR THE PREPARATION OF N, N-DIISOPROPYL-3-2-HYDROXY-5-METHYLPHENYL-3-PHENYL-PROPABAMMINE
JP4513535B2 (en) * 2004-12-03 2010-07-28 住友化学株式会社 Method for producing tolterodine
US20080045602A1 (en) * 2004-12-24 2008-02-21 Casar Renata T Process for Preparation of 3-(2-Hydroxy-5Methylphenyl)-N, N-Disopropyl-3-Phenylpropylamine
US7528267B2 (en) 2005-08-01 2009-05-05 Girindus America, Inc. Method for enantioselective hydrogenation of chromenes
ES2268987B1 (en) 2005-08-05 2008-02-01 Ragactives, S.L. PROCEDURE FOR OBTAINING 3,3-DIFENYLPROPILAMINS.
KR100647068B1 (en) 2005-09-15 2006-11-23 하나제약 주식회사 Method for preparing racemic N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine
KR100686351B1 (en) * 2006-01-12 2007-02-22 주식회사 카이로제닉스 Method for preparing tolterodine racemate
DK2029567T3 (en) 2006-05-24 2010-11-29 Pfizer Ltd Process for producing benzopyran-2-ol derivatives
CA2647990C (en) 2006-06-12 2014-02-04 Claus Meese New chiral intermediate, process for producing the same and its use in the manufacture of tolterodine, fesoterodine, or the active metabolite thereof
KR100717361B1 (en) * 2006-08-07 2007-05-11 주식회사 카이로제닉스 Method for preparing tolterodine racemates and intermediates thereof
ES2477884T3 (en) 2008-08-19 2014-07-18 Xenoport, Inc. Methyl hydrogen hydrogen fumarate prodrugs, pharmaceutical compositions thereof and methods of use
MX2011006656A (en) 2008-12-24 2011-07-29 Daiichi Sankyo Co Ltd Indanyl compounds.
KR20110096547A (en) 2008-12-24 2011-08-30 다이이찌 산쿄 가부시키가이샤 Cyclic amine compounds
KR101275984B1 (en) * 2010-10-18 2013-06-18 경기대학교 산학협력단 Chroman Derivatives Having Optical Avtivity and Their Preparation Methods
CN103209949B (en) * 2010-11-09 2016-08-10 株式会社钟化 Halogenation indone class and use its optical activity indane ketone or the manufacture method of optical activity indane alcohols
EP2476665A1 (en) 2011-01-17 2012-07-18 Cambrex Profarmaco Milano S.r.l. Process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine and its salts starting from a novel intermediate
WO2012098044A1 (en) 2011-01-17 2012-07-26 Cambrex Profarmaco Milano S.R.L. Process for the preparation of n,n-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine and its salts starting from a novel intermediate
US8575174B2 (en) 2011-06-20 2013-11-05 H. Lundbeck A/S Deuterated 1-piperazino-3-phenyl-indanes for treatment of schizophrenia
CN103159657B (en) * 2011-12-08 2016-06-29 重庆华邦胜凯制药有限公司 A kind of method of oriented synthesis of unsaturated conjugated alcohol
AR094054A1 (en) * 2012-12-19 2015-07-08 H Lundbeck As 6-CHLORINE-3- (FENIL-D₅) -INDEN-1-ONA AND USE OF THE SAME
KR101380982B1 (en) 2013-04-29 2014-04-10 경기대학교 산학협력단 Chroman-2-ol Derivatives Having Optical Avtivity and Their Preparation Methods
WO2017137955A1 (en) 2016-02-14 2017-08-17 Celestis Pharmaceuticals Pvt. Ltd. Novel (r) and rac 3-(2-(allyloxy)-5-methylphenyl)-n,n-diisopropyl-3- phenylpropan-1-amine and its use for synthesis of (r) and rac-2-(3- (diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol
WO2018013739A2 (en) * 2016-07-12 2018-01-18 Chromocell Corporation Compounds, compositions, and methods for modulating sweet taste
US11535600B2 (en) 2018-12-03 2022-12-27 H. Lundbeck A/S Prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8800207D0 (en) * 1988-01-22 1988-01-22 Kabivitrum Ab NEW AMINES, THEIR USE AND MANUFACTURING
SE9203318D0 (en) * 1992-11-06 1992-11-06 Kabi Pharmacia Ab NOVEL 3,3-DIPHENYL PROPYLAMINES, THEIR USE AND PREPARATION
ZA969363B (en) * 1995-11-08 1997-11-18 Smithkline Beecham Corp An improved process for preparing aromatic ring-fused cyclopentane derivatives.
KR20000057548A (en) * 1996-12-13 2000-09-25 알프레드 엘. 미첼슨 Optically transmissive material and bond
EP0957073A1 (en) * 1998-05-12 1999-11-17 Schwarz Pharma Ag Novel derivatives of 3,3-diphenylpropylamines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871275B2 (en) 2007-08-08 2014-10-28 Inventia Healthcare Private Limited Extended release compositions comprising tolterodine

Also Published As

Publication number Publication date
BR0016785A (en) 2002-09-24
CN1414944A (en) 2003-04-30
US6310248B2 (en) 2001-10-30
NO20023189D0 (en) 2002-07-01
DE60015799D1 (en) 2004-12-16
CA2392832A1 (en) 2001-07-12
HK1052000A1 (en) 2003-08-29
SK9392002A3 (en) 2003-01-09
HUP0203816A3 (en) 2004-12-28
ZA200204066B (en) 2003-07-30
EP1496045A3 (en) 2005-03-30
DE60015799T2 (en) 2005-12-15
TWI225476B (en) 2004-12-21
CN1209342C (en) 2005-07-06
AR027138A1 (en) 2003-03-12
PT1242361E (en) 2005-01-31
NZ519079A (en) 2004-02-27
IL150275A0 (en) 2002-12-01
CZ20022255A3 (en) 2002-11-13
NO20023189L (en) 2002-07-04
KR20020062669A (en) 2002-07-26
SE9904850D0 (en) 1999-12-30
MY118906A (en) 2005-02-28
AU782796B2 (en) 2005-09-01
EP1242361A1 (en) 2002-09-25
EP1242361B1 (en) 2004-11-10
JP2003519207A (en) 2003-06-17
EP1496045A2 (en) 2005-01-12
EE200200325A (en) 2003-08-15
WO2001049649A1 (en) 2001-07-12
AU2719001A (en) 2001-07-16
ATE282019T1 (en) 2004-11-15
MXPA02006415A (en) 2002-11-29
PE20011123A1 (en) 2001-11-09
ES2228658T3 (en) 2005-04-16
PL355947A1 (en) 2004-05-31
HUP0203816A2 (en) 2003-03-28
DK1242361T3 (en) 2005-02-14

Similar Documents

Publication Publication Date Title
US6310248B2 (en) Process and intermediates
US7205425B2 (en) Optically active nitro alcohol derivatives, optically active amino alcohol derivatives, and process for producing thereof
CA2597615C (en) Process for making trans-1-((1r, 3s)-6-chloro-3-phenylindan-1-yl)-3, 3-dimethylpiperazine
JP2008531546A (en) An improved process for the synthesis of enantiomeric indanylamine derivatives
US6790998B2 (en) Phenyl inden-1-one compounds
KR101344077B1 (en) Method for Preparation of Beta-indolyl Esters Using Chiral Palladium Complexes
JP5417560B2 (en) Method for producing optically active carboxylic acid ester
KR101379383B1 (en) A process for preparing high purity of ⒮―Metoprolol
Kim et al. Stereocontrolled enantioselective addition of diethylzinc to aldehydes using new chiral aminoalcohols
JPH04308550A (en) Method of stereoselectively converting diol into alcohol
JP3134786B2 (en) 2-Azabicyclo [3.3.0] octane derivatives, their production and optical resolution of diols or amino alcohols
Ladouceur et al. 4-Phenylpyridine glucagon receptor antagonists: synthetic approaches to the sterically hindered chiral hydroxy group
JP2000178253A (en) Production of optically active pipecolic acid
Chungb Enantioselective addition of diethylzinc to aldehydes catalyzed by ethyl nipecotate-derived new chiral ligand
HK1052000B (en) Process of preparing tolterodine and analogues there of as well as intermediates prepared in the process
JP4348126B2 (en) Process for producing optically active amino alcohols
JP2005060231A (en) Process for producing novel acidic optical resolution agent and optical resolution of amines using the same
JPH04297471A (en) Production of optically active phthalide
JP2004262911A (en) Chiral alcohol derived from glucose, its production method, chiral alkoxide derived from chiral allohol, optically active alpha-aminoketone using the same and its production method

Legal Events

Date Code Title Description
AS Assignment

Owner name: PHARMACIA AB, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ANDERSSON, PHER G.;HEDBERG, CHRISTIAN;REEL/FRAME:011633/0876

Effective date: 20010313

CC Certificate of correction
CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20131030