Classifications

• • 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
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• This invention relates to a new synthetic process to a compound having pharmacological activity.
• WO 93/18036 (SmithKline Beecham pic) describes certain indole compounds having 5-HT4 receptor antagonist activity including the compound of formula (I)
• This compound is N-[(l- n butyl-4- piperidyl)methyl]-3,4-dihydro-2H-[l,3]oxazino[3,2-a]indole-10-carboxamide, referred to herein by its code number SB-207266, (the hydrochloride salt is SB- 207266-A), which is being developed by SmithKline Beecham pic as the active ingredient in a medicament for treatment of irritable bowel syndrome.
• WO 98/07728 (SmithKline Beecham pic) describes a process for preparing
• SB-207266-A which involves the use of the N-(l- n butyl-4-piperidyl)methylamine intermediate at a later stage in the process thus resulting in an increased yield of SB- 207266-A relative to the amount of this intermediate, which is relatively expensive to produce.
• the alternative process comprises the reaction of of N-(l- n butyl-4-piperidyl)methylamine with a compound of formula (A): 00/03983
• WO98/07728 also describes the preparation of the oxazinoindole compound of the formula (A) from the corresponding indole by reaction with N-chlorosuccinimide and a 3-halo-propanol, such as 3-chloropropanol or 3-bromopropanol followed by cyclisation of the intermediate (B) by treatment with base in a suitable solvent.
• N-chlorosuccinimide in the presence of a tertiary amine which is less nucleophilic than DABCO and which has a pK j , of from 8 to 11, especially 1,4- dimethylpiperazine (DMP).
• DMP 1,4- dimethylpiperazine
• the use of the above amine in place of DABCO has been found to increase significantly the overall yield of the process.
• the former amine also has the following advantages over DABCO:- a) it is non-hygroscopic; b) it does not react with dichloromethane, a preferred solvent for the reaction; c) the product (C) is more stable allowing extended addition times and better temperature control; d) quicker wash separations are possible during commercial manufacture; and e) levels of the corresponding 2-methoxy compound, as an impurity, do not increase with extended process times.
• reaction is conveniently effected in an organic solvent such as dichloromethane or chloroform at a temperature in the range -20° C to +20° C.
• me tcbuning pro ⁇ uct of formula (C) can be used for the next step in the synthesis of SB-207266 e.g as described in WO 98/07728 without any need for isolation or purification.
• Methyl 2-(3-chloropropoxy)-indole-3-carboxyIate ( formula (B) ) A mixture of methyl indole-3-carboxylate and dichloromethane is cooled to 0° C. 1,4- dimethylpiperazine (0.55eq.) and N-chlorosuccinimide (1.1 eq) are added and the mixture left to stir for two hours to give slurry containing the compound of formula (C) above. The resulting slurry is added to a solution of 3-chloropropanol (1.1 eq) and trichloroacetic acid (0.12 eq) in dichloromethane, maintaining the temperature below 0° C.
• reaction mixture is left to stir for half an hour, then washed with 10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water.
• the organic solution is dried over sodium sulphate, filtered and the solvent evaporated.
• Toluene is added and the mixture stirred at 0-5° C for one hour.
• the product is then filtered, washed with toluene and dried to give the title product in 83 % yield.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Indole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

Family

ID=10835641

Family Applications (1)

Country Status (8)

Cited By (3)

Citations (1)

• 1998
  • 1998-07-16 GB GBGB9815483.4A patent/GB9815483D0/en not_active Ceased
• 1999
  • 1999-07-13 JP JP2000560092A patent/JP3842555B2/ja not_active Expired - Fee Related
  • 1999-07-13 DE DE69938661T patent/DE69938661D1/de not_active Expired - Lifetime
  • 1999-07-13 EP EP99938233A patent/EP1097135B1/en not_active Expired - Lifetime
  • 1999-07-13 AT AT99938233T patent/ATE394374T1/de not_active IP Right Cessation
  • 1999-07-13 ES ES99938233T patent/ES2307339T3/es not_active Expired - Lifetime
  • 1999-07-13 WO PCT/EP1999/004943 patent/WO2000003983A1/en not_active Ceased
  • 1999-07-13 CA CA2337248A patent/CA2337248C/en not_active Expired - Fee Related
• 2006
  • 2006-03-20 JP JP2006076859A patent/JP4511484B2/ja not_active Expired - Fee Related

Patent Citations (1)

Also Published As

Similar Documents

Legal Events