Title of Invention

PROCESS FOR PRODUCING RACEMIZED ATROPISOMERIC BIS (PHOSPHINE OXIDE) COMPOUNDS

Abstract

The present invention is concerned with a novel process for the racemization of atropisomeric bis(phosphine oxide) compounds of formula I in their (5) or (R) or non-racemic form) for the preparation of optical active bisphosphine ligands) which form optical active complexes with transition metals. These complexes are used as catalysts in a number of asymmetric reactions. The racemization is thermal and carried out in high or low boiling solvent) under normal or elevated pressure at 10<sup>5</sup> to 3.5xl0<sup>7</sup> Fa. The heating is performed in a system which allows heating up to 400°C (reactor) autoclave) aluminum block) round-bottom flask with heating/stirring mantle and the like) or by microwave irradiation or in the melt at a temperature from 260 to 400°C, preferably from 280 to 380°C, batchwise or in a continuous manner.

Full Text

The present invention is concerned with a novel process for the racemization of atropisomeric compounds of formula I, The optical active compounds of formula 1 above are known and are intermediates for the preparation of optically active bisphosphine ligands of formula II, which form optically active complexes with transition metals. These complexes are used as catalysts in a number of asymmetric reactions. In the synthesis of optically active intermediates of formula 1 and ligands of formula 11 performed by known processes usually a racemic mixture (mixture of equal amounts of both enantiomers) of the product, is obtained which has to be resolved for the preparation of the optical active ligands of formula II, which are used for the preparation of catalysts. The synthesis of optically active bisphosphine ligands of formula II thus involves the formation of a racemic mixture of the bis(phosphine oxide) of formula I, subsequent racemic resolution and reduction to obtain the desired enantiomer or reduction to the racemic bisphosphine of formula II followed by racemic resolution, The object of the invention is to provide a method to make use of the undesired enantiomer of the intermediate of formula I in order to improve the effiC1ency of the synthesis of optical active ligands of formula 11, The present invention is thus concerned with a novel process for the racemization of atropisomeric compounds of formula I, which are present in the (R) or (S) form or a non-racemic mixture of the (R) and (S) form and wherein characterized in that the racemization is thermal and carried out at a temperature from 260 to 400°C, preferably from 280 to 380°C. The term "racemization" signifies the transition of an optical active compound to the corresponding racemate, which signifies a mixture of equal amounts of both enantiomers. The term "atropisomeric" indicates the stereochemistry of compounds in which the free rotation along a bond is hindered and optical activity results. Atropisomerism is a speC1al case of axial chirality’s. The term "C1-8-alkyl" signifies in the scope of the present invention hydrocarbons with 1 to 8 carbon atoms, i.e. straight-chain or branched alkyl groups such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isomerl, tert.-hexyl, heftily and octyl. The term "C1_s-alkoxy" signifies a C1-8-alkyl group as defined above which is bonded via an oxygen atom. Methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like can be mentioned as example. The term "substituted phenyl" signifies in the scope of the present invention phenyl groups which are monosubstituted in the meta- or para-position, preferably in the para-position. Suitable substituents for the phenyl group are C1.g-alkyl, preferably methyl; or C1-8-alkoxy, preferably methoxy; or di-C1.s-alkylamino, preferably dimetylamino; or trialkylsilyl, preferably trimethylsilyl; or substituted by a phenyl group. According to the invention, the racemization of the compounds of the formula I is carried out by heating the compound in a solvent or in the melt at a temperature from 260 to 400°C. The heating is carried out in a device which allows for heating up to 400°C. For small scale the heating can be carried out e.g. with a heating / stirring mantel, an aluminum heating block, an electrically heated reactor or autoclave and the like or by microwave irradiation. For larger scale the heating can be carried out e.g. in reactors or autoclaves. The reaction is carried out batchwise or in a continuous manner. In a preferred way, the racemization of the compounds of the formula I is carried out in a high boiling solvent at a temperature from 260 to 400°C batchwise or in a continuous manner and optionally under pressure at 10" to 3.5x107 Pa or preferably at 108 to 107 Pa. Suitable high boiling solvents are compounds of formula wherein R5 and R6 each independently signify hydrogen or lower alkyl (C2Q) and n is 2,3,4,5,6,7 or higher to signify a polyethylene chain. Examples of solvents of formula III are tetraethylene glycol, tetraethylene glycol dimethyl ether, polyethylene glycol monomethyl ether 350, polyethylene glycol dimethyl ether 400 or polyethylene glycol 350, polyethylene glycol 400, polyethylene glycol 550 and polyethylene glycol 725. Further suitable high boning solvents are solvents of formula wherein R and R is as mentioned above and wherein n is as mentioned above to signify)" a polypropylene)" chain. A preferred solvent of formula IV is polypropylene glycol 725. A further preferred solvent is polyoxyethylen-sorbitan-monooleal. The reaction can also be carried out in inorganic salt melts. In another preferred aspect of the invention the racemization of the compounds of the formula I is carried out in a low boiling organic solvent under pressure at 10 to 3.5x107 Pa, preferably at 105 to 10"" Pa. Suitable solvents are aromatic solvents like benzene, toluene, xylene, or alcohols like methanol, ethanol, propanol, butanol, or a mixture of the mentioned solvents. Preferred solvents are toluene, ethanol or a mixture of both solvents. According to the invention the racemization is carried out batchwise i.e. by a reaction in which the reactant is added to a reaction system {e.g. round flask) once and after the reaction the product is separated. In the alternative, according to the invention, the racemization is carried out in a continuous manner i.e. by a continuous running reaction in which the reactant is continuously added to a reaction system (e.g. reactor) and the product is continuously separated. In a further preferred embodiment, the racemization is carried out in the melt at a temperature from 260 to 400°"C under normal or elevated pressure at 103 to 3x105 Pa or in a preferred way at a temperature from 280 to 380°C and the same pressure. In a preferred embodiment a specific amount of the optical active or non-racemic mixture of the intermediate of formula ! is heated in a high or low boiling solvent or in the melt form under argon or under nitrogen. The heating is carried out in a device which allows for heating up to 40Q°C. For small scale the heating can be carried out e.g. with a heating / stirring mantel, an aluminum heating block, an electrically heated reactor or autoclave and the like or by microwave irradiation. For larger scale the heating can be carried out e.g. in reactors or autoclaves. When a low boiling solvent is used the compound of formula I is heated in an autoclave under elevated pressure at 10" to 3.5x10" Pa. The reaction is carried out batchwise or in a continuous manner. After the reaction, a racemic resolution is carried out and then the (R) or (S) form of the bis(phosphine oxide) of formula I is reduced to the (R) or (S) form of bisphosphine hgands of formula II. Or in an alternative, after the racemization, a reduction of the racemic mixture of compound of formula I to ligands of formula II is carried out and then a racemic resolution is carried out to the (R) or (S) form of the bisphosphine ligands of formula II. The invention is further concerned with the use of the inventive process for the preparation of atropisomeric ligands of the formula II in the pure (R) or (S) form wherein the symbols are defined as above, characterized in that a) the racemic mixture of bis{phosphine oxides) of formula ! is resolved and b) the (R) or (S) form of the bis(phosphine oxide) of formula I is reduced to the (R) or (S) form of the bisphosphine ligand of formula II or a) the racemic mixture of bis{phosphine oxides) of formula I is reduced to form a racemic mixture of bisphosphine ligands of formula II and b) a racemic resolution of the racemic mixture of ligands of formula II is carried out to obtain the (R) or (S) form of the bisphosphine ligand of formula II. The preparation of compounds of formula I is known and described for example in US 5,274,125. Both, the racemic resolution and the reduction of compounds of formula I to compounds of formula II are known and described for example in Helvetica Chimica Acta Vol.74(1991)p370etseq. In a typical reaction, the thermal racemization is carried out with a compound of formula 1 in which R1 signifies methoxy, R2 and R" signify hydrogen, and R4 signifies phenyl ({R) or (S)-MeOBIPHEPO) in a high boiling solvent or in the melt at a temperature from 260 to 400""C under normal or elevated pressure at 105 to 3.5x10" Pa or in a low boiling organic solvent at the same temperature under elevated pressure at 104 to 3.5xl0" Pa. Compounds of formula I are valuable intermediates in the production of biphosphine ligands of formula II, which are used for the formation of complexes with transition metals, especially with transition metals of Group VHl, such as, for example, ruthenium, rhodium or iridium. These complexes are useful as catalysts in asymmetric reactions such as asymmetric hydrogenations. Complexes of diphosphine ligands with transition metals as well as their use for asymmetric reactions such as asymmetric hydrogenations are known and are described, for example, in US Patent 5,430,191. The following examples illustrate the invention and in no manner represent a limitation thereof In these examples the abbreviations used have the following significances: HPLC high performance liquid chromatography NMR nuclear magnetic resonance spectroscopy rt room temperature HV high vacuum e.e. enantiomeric excess TLC thin layer chromatography min minute(s} hr hour(s) MeOBIPHEPO (6,6"-dimethoxybiphenyl-2,2"-diyljbis(diphenylphosphine oxide) DiMeOBIFHEPO (5,5",6,6"-tetramethoxybiphenyl-2,2"-diyl)bis(diphenyl- phosphine oxide) pTol-MeOBlPHEPO (6,6"-dimethoxybiphenyI-2,2"-diyl}bis(di-p-toI)"lphosphine oxide) PEG 400 polyethylene glycol 400 Tween 80 polyoxyethylen-sorbitan-monooleat Ail temperatures are given in degrees Celsius. Example 1 Racemization of (S)-MeOBIPHEPO in polyethylene glycol. 1.1) A 100 ml 2-neck round bottom flask equipped with stirring bar and distillation bridge was charged under argon with 10.0 g (16.28 mmol) of (S)-MeOBlPHEPO 199.2 % ee; HPLC-purity: 99.6 %] and 50 ml of polyethylene glycol. The mixture was heated for 2 hr. The internal reaction temperature rose from it to 317°C within 1 hr. The resulting solution was further stirred for 1 hr whereby the temperature rose to 344°C and ca. 5 ml of a yellow liquid was collected by distillation. The reaction mixture was cooled to it, 100 m! of dichloromethane were added and the solution was washed with water (3 x 40 ml). The organic phase was dried over MgSO2, filtered and the filtrate concentrated to ca. 50 ml. Then, 50 ml of methanol was added and the mixture was concentrated to a volume of ca, 30 ml. This procedure was repeated two more times. The resulting suspension was kept overnight in the refrigerator, the crystals were filtered, washed with cold methanol (2x10 ml) and dried to afford 9.64 g of (RS}-(MeOBiPHEPO) as an off-white solid, HPLC-purity: 96.4 %; m.p. 310-31 l^C. According to an HPLC-analyses on a chiral column (china! HPLC) this material consisted of a mixture of 50.4 % (S)-(MeOBIPHEPO) and 49.6 % (R)-(MeOBlPHEPO). [af\) = -0.09 (c =1.12, CHCl,,). In an analogous experiment, 10 g of (S}-(MeOBIPHEPO) was treated at a maximum temperature of 337°C for 2.5 hr to afford 9.56 g of (RS)-(MeOBIPHEPO); HPLC-purity: 95.6 %; chiral HPLC: 50.5 % (S)-(MeOBIPHEPO) and 49.5 % (R)-(MeOBIPHEPO). Example 1-2-1.8 In the following examples (S}-MeOBIPHEPO was racemized in the following high boiling solvents: tetraethylene glycol, tetraethylene glycol dimethyl ether, polyethylene glycols 350, 400 and 550, respectively, polypropylene glycol 725 and Tween 80. The results are compiled in Table 1. In all examples a suspension of 150 mg (0.24 mmol) of (S)-MeOBIPHEPO in 2.0 ml of the solvent was heated in a glass tube in an aluminum heating block at 330°C for 70 min or 350°C for 40 min. After cooling to rt, the reaction mixture was worked-up and analyzed by HPLC. a) Procedure 1: Dissolved in CH3Cl2:, washed with H2O, dried over Na2S04, filtered and evaporated. Procedure 2: Precipitated by addition of hexane and then collected by filtration. Procedure 3: Precipitated by addition of hexane / toluene. The precipitate was collected by filtration, washed with 3 portions of hexane and dried. b) HPLC-analysis on a chira! column. Example 2 Continuous racemization of (R)-MeOBIPHEPO in ethanol. 100 g of (R)-MeOBIPHEPO was dissolved under argon in 1500 ml of ethanol and pumped through a preheated at 200°C and then through a heated pipe reactor at 350°C. The residence time in the pipe reactor was 15.6 min at a flow rate of 8 ml/min, the pressure increased to 3x10^ Pa. The reaction solution was cooled to rt. Filtration of the crystalline precipitate afforded 63.21 g of a white powder; HPLC-purity 94.7 % {RS)-MeOBIPHEPO; chiral HPLC 50:50 mixture of (R)-MeOBlPHEPO and (S)-MeOBIPHEPO; calculated yield 60 %. From the mother liquor an additional of 29.75 g of solid material was isolated; HPLC-purit}" 60.4 % (RS)-MeOBlPHEPO; chiral HPLC 50:50 mixture of (R)-MeOBIPHEPO and [S)-i\leOBIPHEPO; calculated yield 18 %; total yield 78 %. In an analogous experiment the reaction was accomplished with a residence time in the pipe reactor of 10.2 min at a flow rate of 12.2 ml/min. The result was the same as described above. Example 3 Batch racemization of (R)-MeOBlPHEPO in ethanol. 3.1) An autoclave was charged with 1.0 g of (R)-MeOBIPHEPO and 12.5 ml of ethanol, closed and flushed with argon. After heating up to 350°C in a meta! bath, the pressure increased to 1.37x10^ Pa. After 30 min the reaction was stopped. The brown solution was evaporated under reduced pressure {52°C/5.1xlO^ Pa) to afford 1.0 g of a brown residue of {RS)-MeOBIPHEPO; HPLC purity 84 %; chiral HPLC 53.5 % (R)-MeOBlPHEPO and 46.5 % (S)^MeOBlPHEPO. Further recompilations of (R)-MeOBIPHEPO under pressure were carried out in various solvents as described in example 3.2 - 3.8. The results are compiled in Table 2. Example 4 Racemization of (S)-MeOBIPHEPO in the melt. 4.1) Ten test tubes were charged with 1.0 g each of (S)-MeOBlPHEPO, for a total of 10.0 g (16.3 mmol). The test tubes were heated in the aluminum block at 350°C for 20 min. After cooling, the oily, brown content of the test tubes was transferred into a round bottom flask using ca. 200 ml of methylene chloride and 200 ml of methanol. The solution was concentrated to a volume of ca. 50 ml and 200 ml of methanol was added. After concentration to ca. 50 ml, the resulting suspension was kept overnight in the refrigerator. The crystals were collected by filtration, washed with cold methanol and dried to afford 8.9 g of (RS)-MeOBIPHEPO as off-white powder; HPLC purity 97 %; chiral HPLC 51 % {S)-MeOBIPHEPO and 49 % (R)-MeOBiPHEPO; calculated yield: 86 %. 4.2) An autoclave with stirring bar was charged with 50.0 g of (R)-MeOBIPHEPO, closed and flushed with argon. The reaction was heated to 350°C. The heating was stopped after 45 min. After cooling to rt, the light yellow solid compound obtained was dissolved in 150 ml of CH2CI., the solution transferred into a round bottom flask and evaporated under reduced pressure {50°C/4xlO^ Paj. The solid residue was dissolved in 150 ml of MeOH (70 °C, reflux) and crystallized in the refrigerator at 4°C overnight. The crystals were collected by filtration, washed with cold methanol (50 ml) and dried (70°O6.5xl0^ Pa) to afford 42.56 g (yield: 85.1 %) of (RS)-MeOBIPHEPO as off-white powder; chiral HPLC 49.9 % (S)-MeOBIPHEFO and 50.1 % (R)-MeOBIPHHPO. Example 9 Racemization of (S)-MeOBlPHEPO in an organic solvent under microwave irradiation A reactor tube of 40 x 260 mm fitted with a mechanical stirrer, a reflux condenser and an argon inlet tube was charged with 10.0 g (16.3 mmol) of (S)-MeOBIPHEPO and 50 ml of polyethylene glycol 400. The reactor tube was placed in a microwave reactor. The suspension was stirred under microwave irradiation. The internal reaction temperature rose from rt to 280°C within 6 min. This temperature was maintained for an additional 64 min. The reactor tube was then removed and allowed to cool. The resulting brown-black solution was analyzed by HPLC on a chiral column and found to contain 52.4 % of (S)-MeOBIPHF.PO and 46.6 % of (R)-MeOBIPHEPO. Work-up and crystallization from methanol afforded 8.9 g (89 %) of (RS>-MeOBIPHEPO as an off-white solid; chiral HPLC 50.4 % (S)-MeOBIPHEPO and 49.6 % (R)-MeOBIPHEPO. WE CLAIM: 1, A process for producing raccmized atropisomcric compounds of formula ! which arc present in the (R) or (S) fonn or a non-raccniic mixture of the (R) and (S) form and wherein R signifies C1-s-alkoxy and R2 signilies li\drogen. C1-8-alkoxy or R1and R2 together signify methylenedioxy or ethylenedioxy" R" signifies hydrogen. C1-8-alkyl or C1-8 and R signifies phenyl or substituted phen>l. characterized in that the racemization is thermal and carried out at a temperature from 260 to 400° C preferable from 280 to 380° C. 2.The proeess as claimed in claim I. wherein the racemization is carried out in a solvent or in the melt. 3. Ihe process as claimed in claim 2. wherein the racemization is carried out thermally by heating or by microwave irradiation and the reaction is carried out balchwisc or in a continuous manner. 4. The process us claimed in claim 3. wherein the racemization is carried out in a high boiling solvent at a temperature from 260 to 400° C. and optionally- under pressure at 104 to3.5*107Pa 5. The process as claimed in claim 4. wherein the racemization is carried out in a high boiling solvent of formula n is 2.3,4.5,6.7 or higher to signify a polyelhylenoxy chain or a high boiling 6. The process as claimed in claim 5, wherein the high boiling solvcnt is lelraeth\ lenc glycol, tetraethylene glycol dimethyl ether, polyethylene glycol monomcih\l elher 350. polyethylcnc glycol dimethyl ether 400, pol\elhylene glycol 350. polycth\"lene glycol 400. polyethylene glycol 550. polyethylene glycol 725, polypropylene glycol 725 or polyoxyethjien-sorbitan-monooleat, 7. The process as claimed in claim 3. wherein the racemization is carried out in a low boiling sohenl under pressure at lO5 to 3.5x107 Pa. preferably at 105 to 10 Pa. 8. The process as claimed in claim 7. wherein the low boiling solients are aromatic solvents or alcohols or a mixture of" the mentioned solvents such as herein described.

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