Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
  • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
  • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
  • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
  • B01J23/44—Palladium
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
  • B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
  • B01J23/74—Iron group metals
  • B01J23/755—Nickel

Definitions

• the present invention relates to a method for the preparation of key intermediates in the process for the preparation of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
• Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure:
• Citalopram can be prepared by several disclosed methods. A method and an intermediate for the preparation of citalopram were described in U.S. Pat. No 4,650,884. Commercially useful processes are disclosed in International patent application Nos. WO 98019511, WO 98019512 and WO 98019513.
• this key intermediate may be obtained in a high yield as a very pure product by a new catalytic process in which a halogen or a group of the general formula CF 3 —(CF 2 ) n —SO 2 — wherein n is any suitable whole number between 0 and 4, situated in the 5-position of a 3-H-isobenzofuran-1-one, is exchanged with a cyanide group.
• the key intermediate is then subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N.N-dimethylaminopropyl magnesium halogenide, respectively, whereby citalopram is obtained.
• the present invention relates to a novel method for the preparation of an intermediate in the preparation of citalopram comprising reacting a compound of Formula IV
• R′ is Cl, Br, I or a group of the formula CF 3 —(CF 2 ) n —SO 2 —, wherein n is 0-4, with a cyanide source in the presence or absence of a catalyst, whereby 5-cyano-isobenzofuran-1-one is obtained.
• This intermediate product can be further reacted to citalopram as described above.
• reaction of IV to 5-cyanophtalide may be carried out in more convenient solvents, at a low temperature and at a minimal excess of CN ⁇ .
• the process has environmental advantages in that it only uses small amounts of heavy metals.
• the cyano sources may conveniently be selected from a group consisting of cyanide sources such as (R′′ 4 N)CN wherein each R′′ represents C 1-8 -alkyl optionally two R′′ together with the nitrogen form a ring structure; NaCN, KCN, Zn(CN) 2 or Cu(CN).
• the reaction of the present invention is performed in the presence or absence of a catalyst.
• the catalysts are i.e. Ni (0), Pd(0) or Pd(II) catalysts as described by Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990, (1988).
• Preferred catalysts are Ni(PPh 3 ) 3 or Pd(PPh 3 ) 4 , or Pd(PPh) 2 Cl 2 .
• a Nickel(0) complex is prepared in situ before the cyanide exchange reaction by reduction of a Nickel(II) precursor such as NiCl 2 or NiBr 2 by a metal, such as zinc, magnesium or mangan in the presence of excess of complex ligands, preferably triphenylphosphin.
• a Nickel(II) precursor such as NiCl 2 or NiBr 2
• a metal such as zinc, magnesium or mangan in the presence of excess of complex ligands, preferably triphenylphosphin.
• the Pd or Ni-catalyst is conveniently used in an amount of 0.5-10, preferably 2-6, most preferably about 4-5 mol %.
• Cu + and Zn 2+ may be added to the reaction mixture in substoichiometric amounts and may function as recycleable cyanide sources, which receives the cyanide from other cyanide sources such as NaCN or KCN.
• Substoichiometric amounts of Cu + and Zn 2+ respectively, means 1-20%, preferably 5-10%.
• the reactions may be performed in any convenient solvent as described in Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990, (1988).
• Preferred solvents are acetonitrile, ethylacetate, THF, DMF or NMP;
• a compound of Formula IV wherein R is Cl is reacted with NaCN in the presence of a Ni(PPh 3 ) 3 which is preferably prepared in situ as described above.
• a compound of formula IV, wherein R is Br or I is reacted with KCN, NaCN, CuCN or Zn(CN) 2 in the presence of Pd(PPh 3 ) 4 .
• substoichiometric amounts of Cu(CN) and Zn(CN) 2 are added as recycleable cyanide sources.
• the Cu(CN) is the cyanide source and without catalyst.
• the reaction is performed at elevated temperature.
• the reaction is performed as a neat reaction i.e. without added solvent.
• the reaction is performed in an ionic liquid of the general formula R 4 N + , X ⁇ , wherein R are alkyl-groups or two of the R groups together form an ring and X ⁇ is the counterion.
• R 4 N + X ⁇ represents
• the reaction is conducted with apolar solvents such as benzene, xylene or mesitylene and under the influence of microwaves by using i.e. Synthewave 1000TM by Prolabo.
• the reaction is performed without added solvent.
• the temperature ranges are dependent upon the reaction type. If no catalyst is present preferred temperatures are in the range of 100-200° C. However, when the reaction is conducted under the influence of microwaves the temperature in the reaction mixture may raise to above 300° C. More preferred temperature ranges are between 120-170° C. The most preferred range is 130-150° C.
• the preferred temperature range is between 0 and 100° C. More preferred are temperature ranges of 40-90° C. Most preferred temperature ranges are between 60-90° C.
• reaction conditions are conventional conditions for such reactions and may easily be determined by a person skilled in the art.

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• 1999
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