WO2010018154A1 - Processes for the preparation of 4-oxo-octahydro-indole-1-carbocylic acid methyl ester and derivatives thereof - Google Patents

Processes for the preparation of 4-oxo-octahydro-indole-1-carbocylic acid methyl ester and derivatives thereof Download PDF

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Publication number
WO2010018154A1
WO2010018154A1 PCT/EP2009/060351 EP2009060351W WO2010018154A1 WO 2010018154 A1 WO2010018154 A1 WO 2010018154A1 EP 2009060351 W EP2009060351 W EP 2009060351W WO 2010018154 A1 WO2010018154 A1 WO 2010018154A1
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Prior art keywords
compound
formula
salt
iii
oxocyclohexyl
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PCT/EP2009/060351
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French (fr)
Inventor
Ernst Kuesters
Murat Acemoglu
Philipp Lustenberger
Gottfried Sedelmeier
Beat Schmidt
Gerhard Penn
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Novartis AG
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Novartis AG
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Priority to JP2011522496A priority Critical patent/JP5468608B2/en
Priority to MX2011001664A priority patent/MX2011001664A/en
Priority to EP09781678.9A priority patent/EP2315748B1/en
Priority to ES09781678.9T priority patent/ES2547269T3/en
Priority to CA2732095A priority patent/CA2732095C/en
Priority to HK11109931.0A priority patent/HK1155733B/en
Priority to BRPI0917492A priority patent/BRPI0917492A8/en
Priority to CN2009801306666A priority patent/CN102119151A/en
Priority to KR1020117005727A priority patent/KR101673634B1/en
Application filed by Novartis AG filed Critical Novartis AG
Priority to AU2009281218A priority patent/AU2009281218B2/en
Priority to US13/058,608 priority patent/US8084487B2/en
Priority to RU2011108663/04A priority patent/RU2513856C2/en
Priority to NZ590753A priority patent/NZ590753A/en
Publication of WO2010018154A1 publication Critical patent/WO2010018154A1/en
Priority to ZA2011/00558A priority patent/ZA201100558B/en
Priority to IL210835A priority patent/IL210835A/en
Priority to TN2011000034A priority patent/TN2011000034A1/en
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Priority to MA33679A priority patent/MA32618B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • C07D203/14—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom with carbocyclic rings directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a process for the production of carbamic acid (2- chloroethy!)(3-oxocyclohexyl)-alkyl ester enantiomers and of 1-carbalkoxy-4- ketoperhydroindole enantiomers.
  • WO 03/47581 discloses a series of acetylene derivatives having activity towards human metabotropic glutamate receptors (mGluRs).
  • mGluRs human metabotropic glutamate receptors
  • the compound (SaR ⁇ SJaRH-hydroxy ⁇ -m-toIylethynyl-octahydro-indole-i-carboxylic acid methyl ester which can be obtained in free base or acid addition salt form and has the formula (I):
  • WO 03/47581 also discloses a process for the production of the above compound which involves hydrogenation of a 1 ,5,6,7-tetrahydroindol-4-one derivative.
  • the hydrogenation step is cumbersome, low yielding and has poor selectivity for the (3aR,4S,7aR) stereoisomer. An undesirable by-product is also formed.
  • an alternative process for the production of a compound of the formula (I) or a pharmaceutically acceptable salt thereof which comprises reacting 3-ethynyltoluene with a compound of the formula (II) or a salt thereof;
  • the above reaction is preferably performed in the presence of a base which promotes deprotonation of the ethynyl group.
  • the base is an alkyllithium reagent such as n-hexyllithium.
  • the reaction may be performed in an aprotic solvent such as tetrahydrofuran.
  • a compound of formula (II) may be obtained by cyclisation of a compound of the formula or a salt thereof:
  • R 1 is a leaving group
  • Cyclisation may be performed using a base which deprotonates the 2- position of the cyclohexanone ring.
  • the base may comprise a mixture of pyrrolidine and triethylamine.
  • the reaction may be performed in an organic solvent such as toluene.
  • Suitable leaving groups represented by R 1 will be apparent to those skilled in the art and include, for example, halo, e.g. chloro, bromo or iodo, tosylates, mesylates, alkylsulphonates, e.g. methanesulfonate, and halosulphonates, e.g. fluorosulphonate.
  • the compound of formula (III) preferably comprises an excess of the (R) enantiomer as depicted in the formula above, more preferably in a substantially pure form of said enantiomer. In an embodiment, the compound of formula (III) comprises greater than 70%, more preferably greater than 90%, more preferably greater than 95% of the (R) enantiomer.
  • the desired enantiomer may be obtained by resolving an enantiomeric mixture, e.g. a racemic mixture, of a compound of formula (III).
  • resolution is performed using chiral high performance liquid chromatography (HPLC) involving the use of a chiral stationary phase.
  • a compound of formula (III) may be obtained by reacting a compound of the formula R 1 C(O)OMe with a compound of the formula (IV) or a salt thereof:
  • a compound of formula (IV) may be obtained by reacting cyclohexen-2-one with aziridine or a salt thereof.
  • the reaction may be performed in the presence of an organic solvent such as toluene. Suitable procedures are illustrated in the Examples herein.
  • the invention includes the above processes for making the compound of formula (I) as well as each step thereof and all combinations of sequential steps.
  • the compound of formula (I) may further be converted to a pharmaceutically acceptable salt form, in particular acid addition salt form.
  • Acid addition salts may be obtained in accordance with known methods, e.g. by addition of acid to the last reaction step or prior to recrystallization.
  • the invention also relates to the use of the various compounds, e.g. selected from compounds of the formulae (II) and (III), and their salts, for the production of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or the intermediate compounds may be purified and/or separated by a conventional manner such as recrystallization, column chromatography, distillation, centrifugal separation, washing or drying.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated with a pharmaceutically acceptable carrier or diluent, to form a pharmaceutical composition.
  • compositions according to the invention may be compositions for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutical acceptable carrier.
  • enteral such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutical acceptable carrier.
  • the dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • compositions may comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
  • compounds may be administered e.g. topically in the form of a cream, gel or the like, or by inhalation, e.g. in dry powder form.
  • compositions comprising an agent of the invention include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of an agent of the invention.
  • the composition may be buffered to a pH in the range of e.g. from 3.5 to 9.5, by a suitable buffer.
  • compositions of the present invention may be prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.
  • a compound of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5.
  • Activity towards mGluRs can be determined according to any of the procedures described in WO 03/047581.
  • disorders associated with irregularities of the glutamatergic signal transmission are for example epilepsy, cerebral ischemias, especially acute ischemias, ischemic diseases of the eye, muscle spasms such as local or general spasticity and, in particular, convulsions or pain.
  • Nervous system disorders mediated full or in part by mGluR5 include, for example acute, traumatic and chronic degenerative processes of the nervous system, such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse, e.g. alcohol and nicotine abuse and cocaine use disorders.
  • the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 to 1500 mg, preferably about 10 to about 1000 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
  • a compound of formula (I) can be administered either alone, or in combination with other pharmaceutical agents effective in the treatment of conditions mentioned above.
  • compounds of the invention can be used in combination with analgesic agents (opiates) or with non-steroidal anti-inflammatory drugs (NSAIDs) such as Rofecoxib (Vioxx®), Celecoxib (Celebrex®) or Lumiracoxib (Prexige®).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Rofecoxib Rofecoxib
  • Celecoxib Celecoxib
  • Lumiracoxib Prexige®
  • compounds of the invention can be used in combination with bupropione (Zyban®).
  • the invention also provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a relatively minor proportion of one or more intermediate compounds, e.g. selected from compounds of formulae (II), (III) and (IV), and salts thereof.

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  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

The present invention relates to a process for the production of (3aR, 4S, 7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (I), of carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-alkyl ester enantiomers (II), and of 1-carbalkoxy-4-ketoperhydroindole enantiomers (III).

Description

PROCESSES FOR THE PREPARATION OF "l-OXO-OCTAHYDRO-INDOLE-l-CARBOCYLIC ACID METHYL ESTER AND DERIVATIVES THEREOF.
The present invention relates to a process for the production of carbamic acid (2- chloroethy!)(3-oxocyclohexyl)-alkyl ester enantiomers and of 1-carbalkoxy-4- ketoperhydroindole enantiomers.
WO 03/47581 discloses a series of acetylene derivatives having activity towards human metabotropic glutamate receptors (mGluRs). In particular, there is disclosed the compound (SaR^SJaRH-hydroxy^-m-toIylethynyl-octahydro-indole-i-carboxylic acid methyl ester, which can be obtained in free base or acid addition salt form and has the formula (I):
Figure imgf000003_0001
(I)
WO 03/47581 also discloses a process for the production of the above compound which involves hydrogenation of a 1 ,5,6,7-tetrahydroindol-4-one derivative. The hydrogenation step is cumbersome, low yielding and has poor selectivity for the (3aR,4S,7aR) stereoisomer. An undesirable by-product is also formed.
According to the present invention, there is provided an alternative process for the production of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises reacting 3-ethynyltoluene with a compound of the formula (II) or a salt thereof;
Figure imgf000004_0001
(H)
to form the compound of formula (I) and optionally converting the compound of formula (I) to a pharmaceutically acceptable salt.
The above reaction is preferably performed in the presence of a base which promotes deprotonation of the ethynyl group. In an embodiment, the base is an alkyllithium reagent such as n-hexyllithium. The reaction may be performed in an aprotic solvent such as tetrahydrofuran.
A compound of formula (II) may be obtained by cyclisation of a compound of the formula or a salt thereof:
Figure imgf000004_0002
(III)
wherein R1 is a leaving group.
Cyclisation may be performed using a base which deprotonates the 2- position of the cyclohexanone ring. By way of example, the base may comprise a mixture of pyrrolidine and triethylamine. The reaction may be performed in an organic solvent such as toluene.
Suitable leaving groups represented by R1 will be apparent to those skilled in the art and include, for example, halo, e.g. chloro, bromo or iodo, tosylates, mesylates, alkylsulphonates, e.g. methanesulfonate, and halosulphonates, e.g. fluorosulphonate. The compound of formula (III) preferably comprises an excess of the (R) enantiomer as depicted in the formula above, more preferably in a substantially pure form of said enantiomer. In an embodiment, the compound of formula (III) comprises greater than 70%, more preferably greater than 90%, more preferably greater than 95% of the (R) enantiomer. The desired enantiomer may be obtained by resolving an enantiomeric mixture, e.g. a racemic mixture, of a compound of formula (III). In an embodiment, resolution is performed using chiral high performance liquid chromatography (HPLC) involving the use of a chiral stationary phase.
A compound of formula (III) may be obtained by reacting a compound of the formula R1C(O)OMe with a compound of the formula (IV) or a salt thereof:
Figure imgf000005_0001
(IV)
A compound of formula (IV) may be obtained by reacting cyclohexen-2-one with aziridine or a salt thereof. The reaction may be performed in the presence of an organic solvent such as toluene. Suitable procedures are illustrated in the Examples herein.
The invention includes the above processes for making the compound of formula (I) as well as each step thereof and all combinations of sequential steps. As mentioned above, the compound of formula (I) may further be converted to a pharmaceutically acceptable salt form, in particular acid addition salt form. Acid addition salts may be obtained in accordance with known methods, e.g. by addition of acid to the last reaction step or prior to recrystallization.
The invention also relates to the use of the various compounds, e.g. selected from compounds of the formulae (II) and (III), and their salts, for the production of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound of formula (I) or the intermediate compounds may be purified and/or separated by a conventional manner such as recrystallization, column chromatography, distillation, centrifugal separation, washing or drying.
The compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated with a pharmaceutically acceptable carrier or diluent, to form a pharmaceutical composition.
Pharmaceutical compositions according to the invention may be compositions for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutical acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
Pharmaceutical compositions may comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
Alternatively compounds may be administered e.g. topically in the form of a cream, gel or the like, or by inhalation, e.g. in dry powder form.
Examples for compositions comprising an agent of the invention include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of an agent of the invention. The composition may be buffered to a pH in the range of e.g. from 3.5 to 9.5, by a suitable buffer.
The pharmaceutical compositions of the present invention may be prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.
A compound of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5. Activity towards mGluRs can be determined according to any of the procedures described in WO 03/047581.
Disorders associated with irregularities of the glutamatergic signal transmission are for example epilepsy, cerebral ischemias, especially acute ischemias, ischemic diseases of the eye, muscle spasms such as local or general spasticity and, in particular, convulsions or pain.
Nervous system disorders mediated full or in part by mGluR5 include, for example acute, traumatic and chronic degenerative processes of the nervous system, such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse, e.g. alcohol and nicotine abuse and cocaine use disorders.
For all the above mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 to 1500 mg, preferably about 10 to about 1000 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
A compound of formula (I) can be administered either alone, or in combination with other pharmaceutical agents effective in the treatment of conditions mentioned above.
For the indication pain, compounds of the invention can be used in combination with analgesic agents (opiates) or with non-steroidal anti-inflammatory drugs (NSAIDs) such as Rofecoxib (Vioxx®), Celecoxib (Celebrex®) or Lumiracoxib (Prexige®).
For the indication nicotine use disorders, compounds of the invention can be used in combination with bupropione (Zyban®). The invention also provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a relatively minor proportion of one or more intermediate compounds, e.g. selected from compounds of formulae (II), (III) and (IV), and salts thereof.
The following Examples illustrate the invention.
3-(1-aziridinyl) cyclohexanone is synthesized according to literature (J. E. Dolfini et al., Tetrahedron Letters, No 25, pp. 2053-2058, 1965)
Example 1-5: Synthesis of carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-alkyl ester
21.6 mmol 3-(1-aziridinyl) cyclohexanone are dissolved in 15 ml toluene and cooled down to 00C. To the clear solution 21.6 mmol alkyl chloroformate are added within 20 minutes (exothermic reaction). The temperature is kept between 0 -100C. The yellowish to brown solution is warmed up to room temperature and stirred for further 1 hour. Solvent and excess reagents are removed under vacuum (60°C/20 mbar) and the remaining oil is treated three times with 5 ml toluene to remove not reacted alky chloroformate under vacuum yielding:
4.95 g carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-methyl ester (example 1 )
5.22 g carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-ethyl ester (example 2)
5.53 g carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-propyl ester (example 3)
5.92 g carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-butyl ester (example 4)
6.27 g carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-neopentyl ester (example 5)
Example 6-15: Synthesis of (R)- and (S)- carbamic acid (2-chloroethyl)(3-oxocyclohexyI)- alkyl ester
5 g racemic carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-alkyl ester are dissolved in 50 ml heptane/2-propanol = 1/1 (V/V) and injected onto a preparative Chiralpak-AD column (particle size: 20 μm, column dimensions: 30 cm length x 10 cm I. D.). Using heptane/2- propanol/methanol = 90/7.5/2.5 (V/V/V) as the mobile phase at room temperature and a flow rate of 400 ml/min, baseline separation is achieved within 60 min while the R-enantiomer elutes always prior to its S-enantiomer. A second chromatographic run is performed under identical conditions and the corresponding fractions are combined. The solvents are removed under vacuum yielding:
4.6 g (R)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-methyl ester (example 6) iH NMR (500 MHz, DMSO-c/e) δ ppm 1.47 (m, 1 H) 1.79 (m, 1 H) 1.92 (m, 2 H) 2.13 (d, J=1.53 Hz, 1 H) 2.25 (m, 1 H) 2.31 (dt, 1 H) 2.81 (br. m., 1 H) 3.49 (t, J=IM Hz, 2 H) 3.60 (s, 3 H) 3.61 - 3.68 (m, 2 H) 3.89 - 3.98 (m, 1 H)
4.5 g (S)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-methyl ester (example 7)
1 H NMR (500 MHz1 DMSO-Cf6) δ ppm 1.47 (m, 1 H) 1.79 (m, 1 H) 1.92 (m, 2 H) 2.13 (d, ./=1.53 Hz, 1 H) 2.25 (m, 1 H) 2.31 (dt, 1 H) 2.81 (br. m., 1 H) 3.49 (t, J=IM Hz, 2 H) 3.60 (s, 3 H) 3.61 - 3.68 (m, 2 H) 3.89 - 3.98 (m, 1 H)
4.2 g (R)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-ethyl ester (example 8)
1 H NMR (500 MHz, DMSO-Cf6) δ ppm 1.17 (t, J=7.02 Hz, 3 H) 1.47 (m, 1 H) 1.78 (m, 1 H) 1.92 (m, 2 H) 2.12 (dd, J=14.27, 1.91 Hz, 1 H) 2.25 (d, 1 H) 2.31 (dt, J=14.04, 7.02 Hz, 1 H) 2.80 (br. m., 1 H) 3.49 (t, J=7.25 Hz, 2 H) 3.63 (m, 2 H) 3.93 (m, 1 H) 4.05 (q, J=7.02 Hz, 2 H)
4.4 g (S)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-ethyl ester (example 9)
1H NMR (500 MHz, DMSO-Of6) δ ppm 1.17 (t, J=7.02 Hz, 3 H) 1.47 (m, 1 H) 1.78 (m, 1 H) 1.92 (m, 2 H) 2.12 (dd, J=14.27, 1.91 Hz, 1 H) 2.25 (d, 1 H) 2.31 (dt, J=14.04, 7.02 Hz, 1 H) 2.80 (br. m., 1 H) 3.49 (t, J=7.25 Hz, 2 H) 3.63 (m, 2 H) 3.93 (m, 1 H) 4.05 (q, J=7.02 Hz, 2 H)
3.8 g (R)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-propyl ester (example 10)
1 H NMR (500 MHz, DMSO-Cf6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.47 (qt, J=13.49, 3.87 Hz, 1 H) 1.58 (m, J=7.25, 7.00, 7.00, 7.00, 7.00 Hz, 2 H) 1.79 (br. m, 1 H) 1.92 (m, 2 H) 2.12 (m, 1 H) 2.25 (br. m, 1 H) 2.29 (dt, J=14.04, 7.02 Hz, 1 H) 2.79 (br. m., 1 H) 3.50 (m, 2 H) 3.63 (m, 2 H) 3.85 - 4.09 (m, 3 H)
3.8 g (S)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-propyl ester (example 11 )
1 H NMR (500 MHz, DMSO-Cf6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.47 (qt, J=13.49, 3.87 Hz, 1 H) 1.58 (m, J=7.25, 7.00, 7.00, 7.00, 7.00 Hz, 2 H) 1.79 (br. m, 1 H) 1.92 (m, 2 H) 2.12 (m, 1 H) 2.25 (br. m, 1 H) 2.29 (dt, J=14.04, 7.02 Hz, 1 H) 2.79 (br. m., 1 H) 3.50 (m, 2 H) 3.63 (m, 2 H) 3.85 - 4.09 (m, 3 H)
3.2 g (R)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-butyl ester (example 12) 1 H NMR (500 MHz, DMSOd6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.32 (sxt, J=7.42 Hz, 2 H) 1.47 (m, J=13.54, 3.76 Hz, 1 H) 1.55 (m, 2 H) 1.78 (br. s., 1 H) 1.92 (m, 2 H) 2.12 (del, .7=14.19, 1.68 Hz, 1 H) 2.25 (br. m, 1 H) 2.31 (dt, J=14.11 , 6.33 Hz, 1 H) 2.81 (br. m., 1 H) 3.49 (t, J=IM Hz, 2 H) 3.63 (m, 2 H) 3.93 (m, 1 H) 4.00 (t, J=6.41 Hz, 2 H)
3.4 g (S)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-butyl ester (example 13)
1 H NMR (500 MHz, DMSOd6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.32 (sxt, J=7.42 Hz, 2 H) 1.47 (m, .7=13.54, 3.76 Hz, 1 H) 1.55 (m, 2 H) 1.78 (br. s., 1 H) 1.92 (m, 2 H) 2.12 (dd, J=14.19, 1.68 Hz, 1 H) 2.25 (br. m, 1 H) 2.31 (dt, .7=14.11 , 6.33 Hz, 1 H) 2.81 (br. m., 1 H) 3.49 (t, .7=7.17 Hz, 2 H) 3.63 (m, 2 H) 3.93 (m, 1 H) 4.00 (t, .7=6.41 Hz, 2 H)
4.8 g (R)- carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-neopentyl ester (example 14)
1 H NMR (500 MHz, DMSOd6) δ ppm 0.90 (s, 9 H) 1.47 (m, 1 H) 1.79 (br. m., 1 H) 1.94 (br. m., 2 H) 2.13 (m, 1 H) 2.24 (br. m, 1 H) 2.31 (dt, .7=14.04, 6.10 Hz, 1 H) 2.82 (br. m, 1 H) 3.52 (t, J=IM Hz, 2 H) 3.64 (m, 2 H) 3.73 (br. m., 2 H) 3.94 (m, 1 H)
5.2 g (S)- carbamic acid (2-chloroethyI)(3-oxocyclohexyl)-neopentyl ester (example 15)
1 H NMR (500 MHz, DMSOd6) δ ppm 0.90 (s, 9 H) 1.47 (m, 1 H) 1.79 (br. m., 1 H) 1.94 (br. m., 2 H) 2.13 (m, 1 H) 2.24 (br. m, 1 H) 2.31 (dt, J=14.04, 6.10 Hz, 1 H) 2.82 (br. m, 1 H) 3.52 (t, .7=7.17 Hz, 2 H) 3.64 (m, 2 H) 3.73 (br. m., 2 H) 3.94 (m, 1 H)
Example 16-20: Synthesis of 1-carbalkoxy-4-ketoperhydroindole
15 mmol carbamic acid (2-chloroethyl)(3-oxocyclohexyl)-alkyl ester are dissolved in 15 ml methylene chloride. To the orange coloured solution 1.07 g pyrrolidine and 1.52 g triethylamine are added. The reaction mixture is stirred 16 h at room temperature and finally diluted with 45 ml isopropyl acetate and 30 ml of water. Under stirring the pH of the emulsion is adjusted to pH = 2 and stirring is continued for further 30 min. After phase separation the aqueous phase is extracted two times with 20 ml isopropyl acetate and the combined organic phase is washed three times with 20 ml water each. The solvent is removed under vacuum (50°C/20 mbar) yielding:
2.55 g 1-carbmethoxy-4-ketoperhydroindoie (example 16)
2.70 g 1-carbethoxy-4-ketoperhydroindole (example 17)
2.98 g 1-carbpropoxy-4-ketoperhydroindole (example 18)
3.15 g 1-carbbutoxy-4-ketoperhydroindoIe (example 19)
3.34 g 1-carbneopentoxy-4-ketoperhydroindole (example 20) Example 21-30: Synthesis of (S1S)- and (R1R)- i -carbalkoxy-4-ketoperhydroindoIe
5 g racemic i-carbaIkoxy-4-ketoperhydroindole are dissolved in 50 ml heptane/2-propanol = 1/1 (V/V) and injected onto a preparative Chiralpak-AD column (particle size: 20 1Zm, column dimensions: 30 cm length x 10 cm I. D.)- Using heptane/2-propanol/methanol = 90/7.5/2.5 (V/V/V) as the mobile phase at room temperature and a flow rate of 400 ml/min, baseline separation is achieved within 60 min while the S,S-enantiomer elutes always prior to its R1R- enantiomer. The solvents are removed under vacuum yielding:
2.5 g (S1S)- 1-carbmethoxy-4-ketoperhydroindole (example 21 )
1 H NMR (500 MHz, DMSO-O6) δ ppm 1.58 (br. m., 2 H) 1.73 (br. m., 1 H) 1.88 (m, 1 H) 2.01 (m, 1 H) 2.14 (m, 1 H) 2.19 (m, 1 H) 2.37 (td, J=10.76, 5.65 Hz, 1 H) 2.82 (m, 1 H) 3.29 (m, 2 H) 3.57 (s, 3 H) 4.04 (m, 1 H)
2.4 g (R1R)- 1-carbmethoxy-4-ketoperhydroindole (example 22)
1 H NMR (500 MHz1 DMSO-Cf6) δ ppm 1.58 (br. m., 2 H) 1.73 (br. m., 1 H) 1.88 (m, 1 H) 2.01 (m, 1 H) 2.14 (m, 1 H) 2.19 (m, 1 H) 2.37 (td, .7=10.76, 5.65 Hz1 1 H) 2.82 (m, 1 H) 3.29 (m, 2 H) 3.57 (S1 3 H) 4.04 (m, 1 H)
1.5 g (S1S)- i-carbethoxy-4-ketoperhydroindole (example 23)
1 H NMR (500 MHz, DMSO-Of6) δ ppm 1.16 (t, J=7.10 Hz1 3 H) 1.57 (m, 2 H) 1.75 (br. m., 1 H) 1.88 (m, 1 H) 2.02 (d, J=4.58 Hz1 1 H) 2.13 (m, 1 H) 2.19 (m, 1 H) 2.38 (td, J=10.64, 5.57 Hz1 1 H) 2.83 (m, 1 H) 3.28 (m, 2 H) 4.03 (m, 3 H)
2.4 g (R1R)- 1-carbethoxy-4-ketoperhydroindole (example 24)
1 H NMR (500 MHz1 DMSO-Cf6) δ ppm 1.16 (t, J=7.10 Hz, 3 H) 1.57 (m, 2 H) 1.75 (br. m., 1 H) 1.88 (m, 1 H) 2.02 (d, J=4.58 Hz, 1 H) 2.13 (m, 1 H) 2.19 (m, 1 H) 2.38 (td, J= 10.64, 5.57 Hz, 1 H) 2.83 (m, 1 H) 3.28 (m, 2 H) 4.03 (m, 3 H)
2.3 g (S1S)- i-carbpropoxy-4-ketoperhydroindole (example 25)
1 H NMR (500 MHz1 DMSO-Cf6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.56 (m, 4 H) 1.76 (br. m., 1 H) 1.88 (m, 1 H) 2.02 (m, 1 H) 2.14 (br. m, 1 H) 2.05 (m, 1 H) 2.36 (dt, J= 10.68, 5.34 Hz1 1 H) 2.83 (m, 1 H) 3.29 (m, 2 H) 3.93 (m, 2 H) 4.04 (m, 1 H)
2.1 g (R1R)- i-carbpropoxy-4-ketoperhydroindole (example 26) 1 H NMR (500 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.56 (m, 4 H) 1.76 (br. m., 1 H) 1.88 (m, 1 H) 2.02 (m, 1 H) 2.14 (br. m, 1 H) 2.05 (m, 1 H) 2.36 (dt, J=10.68, 5.34 Hz, 1 H) 2.83 (m, 1 H) 3.29 (m, 2 H) 3.93 (m, 2 H) 4.04 (m, 1 H)
2.3 g (S1S)- i-carbbutoxy-4-kβtoperhydroindole (example 27)
1 H NMR (500 MHz, DMSO-Cf6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.32 (dq, J=14.97, 7.42 Hz, 2 H) 1.54 (m, 4 H) 1.75 (br. m., 1 H) 1.88 (m, 1 H) 2.02 (m, 1 H) 2.13 (br. m, 1 H) 2.19 (m, 1 H) 2.73 (dt, J=10.83, 5.42 Hz, 1 H) 2.83 (m, 1 H) 3.29 (m, 2 H) 3.99 (m, 3 H)
2.0 g (R1R)- 1-carbbutoxy-4-ketoperhydroindole (example 28)
1 H NMR (500 MHz, DMSO-Cf6) δ ppm 0.88 (t, J=7.40 Hz, 3 H) 1.32 (dq, J=14.97, 7.42 Hz, 2 H) 1.54 (m, 4 H) 1.75 (br. m., 1 H) 1.88 (m, 1 H) 2.02 (m, 1 H) 2.13 (br. m, 1 H) 2.19 (m, 1 H) 2.73 (dt, J=10.83, 5.42 Hz, 1 H) 2.83 (m, 1 H) 3.29 (m, 2 H) 3.99 (m, 3 H)
1.7 g (S1S)- i-carbneopentoxy-4-ketoperhydroindole (example 29)
1 H NMR (500 MHz, DMSO-Cf6) δ ppm 0.90 (s, 9 H) 1.59 (m, 2 H) 1.75 (br. sm, 1 H) 1.90 (m, 1 H) 2.03 (m, 1 H) 2.14 (br. M, 1 H) 2.20 (m, 1 H) 2.36 (dt, J=10.83, 5.34 Hz, 1 H) 2.84 (m, 1 H) 3.33 (m, 2 H) 3.68 (br. m, 2 H) 4.07 (br. m., 1 H)
1.5 g (R1R)- 1-carbneopentoxy-4-ketoperhydroindole (example 30)
1 H NMR (500 MHz, DMSO-d6) δ ppm 0.90 (s, 9 H) 1.59 (m, 2 H) 1.75 (br. sm, 1 H) 1.90 (m, 1 H) 2.03 (m, 1 H) 2.14 (br. M, 1 H) 2.20 (m, 1 H) 2.36 (dt, J=10.83, 5.34 Hz1 1 H) 2.84 (m, 1 H) 3.33 (m, 2 H) 3.68 (br. m, 2 H) 4.07 (br. m., 1 H)

Claims

Claims
1. A process for the production of a compound of the formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000013_0001
(i)
which comprises reacting 3-ethynyltoluene with a compound of the formula (II) or a salt thereof:
Figure imgf000013_0002
(II)
to form the compound of formula (I) and optionally converting the compound of formula (I) to a pharmaceutically acceptable salt.
2, A process according to claim 1 , wherein the compound of formula (II) is obtained by cyclisation of a compound of the formula (III) or a salt thereof:
Figure imgf000014_0001
(ill)
wherein R is a leaving group.
3. A process according to claim 2, wherein the compound of formula (III) is obtained by reacting a compound of the formula R1C(O)OMe with a compound of the formula (IV) or a salt thereof:
Figure imgf000014_0002
(IV)
4. A process according to claim 3, wherein the compound of formula (IV) is obtained by reacting cyclohexen-2-one with aziridine or a salt thereof.
5. A process according to any preceding claim, which further comprises formulating the compound of formula (I) into a pharmaceutical composition.
6. A process for the production of a compound of the formula (II) or a salt thereof:
Figure imgf000014_0003
(H) which comprises cyclisation of a compound of the formula (III) or a salt thereof:
Figure imgf000015_0001
)OMe
(III)
wherein R1 is a leaving group.
7. A process according to claim 6, wherein the compound of formula (III) is obtained according to claim 3 or claim 4.
8. A process for the production of a compound of the formula (III) or a salt thereof:
Figure imgf000015_0002
)OMe
(III)
wherein R1 is a leaving group;
which comprises reacting a compound of the formula R1C(O)OMe with a compound of the formula (IV) or a salt thereof:
Figure imgf000015_0003
(IV)
9. A process according to claim 8, wherein the compound of formula (IV) is obtained according to claim 4.
10. A compound of the formula (II) or a salt thereof:
Figure imgf000016_0001
(H)
11. A compound of the formula (III) or a salt thereof:
Figure imgf000016_0002
(III)
wherein R1 is a leaving group, e.g. halo.
12. Use of a compound of claim 10 or claim 11 , for the manufacture of a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.
13. Use of a compound of the formula (IV) or a salt thereof:
Figure imgf000017_0001
(IV)
for the manufacture of a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.
14. Use of cyclohexen-2-one, aziridine or a salt thereof for the manufacture of a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.
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CA2732095A1 (en) 2010-02-18
KR20110042222A (en) 2011-04-25
EP2315748A1 (en) 2011-05-04
KR101673634B1 (en) 2016-11-07
JP2011530566A (en) 2011-12-22
ZA201100558B (en) 2011-10-26
CL2011000296A1 (en) 2011-11-04
CA2732095C (en) 2017-04-25
AU2009281218B2 (en) 2013-05-16
ES2547269T3 (en) 2015-10-05
CO6341608A2 (en) 2011-11-21
ECSP11010883A (en) 2011-04-29
MX2011001664A (en) 2011-03-25
RU2011108663A (en) 2012-09-20
MY151183A (en) 2014-04-30
JP5468608B2 (en) 2014-04-09

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