Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/50—Organo-phosphines
  • C07F9/505—Preparation; Separation; Purification; Stabilisation
  • C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
  • C07F9/5072—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure P-H
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F17/00—Metallocenes
  • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
  • C07F9/65683—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine

Definitions

• This invention relates to processes suitable for the large-scale preparation of enantiomerically-enriched cyclic phosphines, especially those useful as ligands in asymmetric hydrogenation catalysts.
• Chiral cyclic phosphines are useful ligands for asymmetric catalysis.
• chiral ligands of the DuPHOS and BPE series respectively represented by formulae (1) and (2)
• R 1 and R 2 are typically C M linear or branched alkyl, and enantiomeric forms thereof, can be used to prepare rhodium and ruthenium complexes, which are effective and versatile catalysts for asymmetric hydrogenation of a diverse range of substrate types.
• R 1 and R 2 are typically C M linear or branched alkyl, and enantiomeric forms thereof, can be used to prepare rhodium and ruthenium complexes, which are effective and versatile catalysts for asymmetric hydrogenation of a diverse range of substrate types.
• Such catalysts are eminently suitable for industrial applications, especially for the provision of chiral pharmaceutical intermediates in high enantiomeric purity.
• the development of manufacturing processes requires in turn large amounts of a ligand (1) or (2), e.g. in kilogramme quantity or greater.
• a ligand (1) or (2) e.g. in kilogramme quantity or greater.
• US-A-5532395 describes the preparation of (S,S)-methyl DuPHOS from 0.8 g of l,2-bis(phosphino)benzene, in which a yield of 78% is achieved.
• the yield of methyl DuPHOS can fall to below 30%. Overall, such lowering of yield has an adverse effect on the economics of the process.
• Wilson and Pasternak, Synlett 4:199-200 discloses the preparation of chiral phosphines for use in an asymmetric Staudinger reaction.
• US-A-5399771 discloses the preparation of BINAP using diphenylphosphine, an amine base and a nickel catalyst.
• GB-A-2262284 discloses the preparation of tertiary phosphines. Summary of the Invention
• This invention is based on the discovery that an efficient, high-yielding preparation of a cyclic phosphine is facilitated by a new mode of reagent addition. More specifically, a process for the preparation of a cyclic phosphine from the corresponding primary phosphine and a bifunctional alkylating agent, wherein alkylation, and displacement of each functional group, occurs in the presence of a strong base, comprises adding the strong base, in an amount sufficient for cyclisation, to a preformed mixture or reaction product of the primary phosphine and alkylating agent. It is surprising that high yields are achieved in this process, given the potential for side-reactions, which an individual of ordinary skill in the art might predict.
• the bifunctional alkylating agent is susceptible to ⁇ -elimination by reaction with a strong base.
• ⁇ -elimination is not observed as a major reaction pathway.
• this process allows the preparation of phosphines bearing very hindered functional groups such as tert-b ty ⁇ through substitution at neopentyl-like centres of the alkylating agent.
• simplicity of process operation is another benefit when compared to the original protocol, since all of the base required to mediate the reaction is added in a single operation, after the reaction vessel has been charged with all other reactants.
• the process of this invention preferably comprises the addition of at least 2m equivalents of a strong base to a mixture or reaction product of the primary phosphine and at least m equivalents of the bifunctional alkylating agent.
• the cyclic phosphine, the primary phosphine and the bifunctional alkylating agent that are used in this invention are preferably respectively of formula (3), (4) and (5)
• R 1 and R 2 are independently H, alkyl, cycloalkyl, aryl, aralkyl or alkaryl, provided that both are not H, R 3 is aryl, alkyl, cycloalkyl, aralkyl, alkaryl, or an organometallic residue such as ferrocenyl; m is 1 or 2; n is in the range 1-4; and X and X 1 are the same or different nucleofugal leaving groups, optionally linked to form a ring.
• the cyclic phosphine ring in (3) may optionally form part of a fused polycyclic ring system.
• any base capable of effecting complete deprotonation of a P-H bond is suitable for use in the novel process.
• Commercially available organolithium bases are ideal for this purpose and alkyllithiums are preferred, especially n-butyllithium and sec-butyllithium.
• a variety of solvents may be used, particularly ethereal solvents such as tetrahydrofuran (THF). diglyme, diethyl ether or t-butyl methyl ether.
• THF tetrahydrofuran
• hydrocarbon solvents e.g. hexanes, such as might be used for dissolution of an organolithium base, are compatible as cosolvents.
• a preferred embodiment of the present invention is a process for preparation of enantiomerically-enriched ligands of formula (3) , from enantimerically-enriched alkylating agents of formula (5).
• the degree of enrichment is typically at least 70% ee, preferably at least 80% ee, more preferably at least 90% ee, and most preferably at least 95% ee.
• R 1 and R 2 are orientated trans to one another. Usually, although not necessarily, R 1 and R 2 are the same. This encompasses ligands of the
• the process of the present invention is especially advantageous, since transfer of a solution of lithiated phenylphosphine between reaction vessels is avoided, thereby reducing the exposure risk to this noxious and foul-smelling substance.
• preferred bifunctional alkylating agents are those prepared from the corresponding single enantiomer 1,3- and 1,4-diols.
• Cyclic sulphate derivatives are preferred, although bis(aryl)sulphonates or bis(alkyl)sulphonates, such as ditosylates, can be used with equal facility.
• 1,4-Diol precursors of phospholane ligands (1) and (2) can be prepared either by electrochemical Kolbe coupling [see Burk et al, Organometallics (1990) 9:2653] or more conveniently via biocatalytic resolution of racemic diols [Berens, Proceedings ofChiral Europe 1996 (Spring Innovations Ltd.), p. 13].
• 1,3-Diol precursors of phosphetanes (6) are easily accessible by asymmetric hydrogenation of the corresponding 1,3-diketones (for lead references, see WO 98/02445).
• Example 1 l,2-bis((2R,5R)-2,5-Dimethylphosphol no) benzene ( ⁇ )-MeDuPHOS A solution of n-BuLi in hexanes (2.958 mol; 1.183 L of 2.5 N solution), diluted with diethyl ether (2.5 L), was added over 4 hours to a stirred mixture of 1,2- bis(phosphino)benzene (100 g, 0.7042 mol) and the cyclic sulfate (4R,7R)-4,7-dimethyl- 2,2-dioxo-l,3,2-dioxathiepane (266.5 g, 1.479 mol, 5% excess) in THF (8 L), under a nitrogen atmosphere, whilst maintaining an internal temperature of 10-15 °C.
• Example 5 l,2-Bis((2-S,5 ⁇ 2,5-d.ethylphospholano)ethane (tS,5)-Et-BPE l,2-Bis(phosphino)ethane (12.0 g, 0.1276 mol) was added to a solution of the cyclic sulfate (4R,7R)-4,7-diethyl-2,2-dioxo-l,3,2-dioaxathiepane (55.9g, 0.2683 mol, 5% excess) in 1 L of THF, under nitrogen.
• Example 6 l,l'-bis((2S,4S)-2,4-diisopropylphosphetan-l-yI)ferrocene
• a dropping funnel which was attached to the middle neck of the flask was charged with a solution of 1.3 N sec-BuLi (31.0 ml, 40.3 mmol) in pentanes (100 mL).
• Example 7 l, -bis((2-y,45)-2,4-di- ⁇ eri'-butylphosphetan-l-yl)ferrocene
• a dropping funnel which was attached to the middle neck of the flask was charged with a solution of 1.3 N sec-BuLi (27.1 ml, 35.2 mmol) in pentanes (50 mL).

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• 1998
  • 1998-05-11 US US09/530,845 patent/US6545183B1/en not_active Expired - Lifetime
  • 1998-11-05 EP EP98952862A patent/EP1028967B1/en not_active Expired - Lifetime
  • 1998-11-05 CA CA002307192A patent/CA2307192A1/en not_active Abandoned
  • 1998-11-05 JP JP2000520453A patent/JP4397524B2/ja not_active Expired - Fee Related
  • 1998-11-05 WO PCT/GB1998/003321 patent/WO1999024444A1/en not_active Ceased
  • 1998-11-05 AU AU10410/99A patent/AU1041099A/en not_active Abandoned
  • 1998-11-05 AT AT98952862T patent/ATE206128T1/de not_active IP Right Cessation
  • 1998-11-05 ES ES98952862T patent/ES2162473T3/es not_active Expired - Lifetime
  • 1998-11-05 DE DE69801841T patent/DE69801841T2/de not_active Expired - Lifetime

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