AU712507B2 - Chiral ruthenium (II) BINAP and t-BINAP compounds - Google Patents

Description

S F Ref: 341281D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

*c U U

U.

Name and Address of Applicant: Actual Inventor(s): Merck Co., Inc.

126 East Lincoln Avenue Rahway New Jersey 07065 UNITED STATES OF AMERICA Joseph D. Armstrong III, Lisa DiMichele, Alan W.

Douglas, Jennifer L. Keller, Steven A. King, Andrew S.

Thompson and Thomas R. Verhoeven Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia fnQ P r r 0 I^ nr( Address for Service: Invention Title: j J L'JI 'I jJ 'I j 'd JW 3W V c II er y- Kcteamides- Ckr~ ~t Aeni0em' k.AP C l) B CrNR* The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845 Chiral Ruthenium (II) BINAP and t-BINAP Compo-inds Summary of the Invention The present invention relates to chiral ruthenium (II) BINAP and t-BINAP compounds.

Brief Description of the Figures Figure 1: 250 MHz 1 H NMR of [(C2H)2NH 2

]+[RU

2 CI5((R)-BINAP) 2 -*oCH 3 Ph in CD 2 2 at room temperature.

Figure 2: Expansion of the 3.0 ppm to 3.5 ppm region of 400.13 MHz 1 H NMR of [(C2HS) 2

NH

2 +[RU2CI5((R)-BINAP)2-0CH 3 Ph in CD 2

CI

2 at -40 0 C. is the fully coupled spectrum of this region; (b) is the decoupled spectrum of this region resulting from the irradiation of the peak at 8.53 ppm; and (c) is the decoupled spectrum of this region resulting from the irradiation of the peak at 1.41 ppm.

Detailed Description of the Invention The compounds of the present invention are as follows: A compound of structural formula: Cl np/I ~C I l Cl .pp, 15is or solvates thereof wherein P Prepresents BINAP or t-BINAP.

A compound of structural formula: r H 2 Cl Cl Ru-s >Ru CI H 2 or solvates thereof wherein P P represents BINAP or t-BINAP.

A compound of structural formula: 0

U

U.

OU

U

U U U U U 0

U

e [Et 2

NH

2 or solvates thereof wherein P P represents BINAP or t-BINAP.

Abbreviations BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl t-BINAP 2,2'-bis(di-p-tolylphosphino)-1,1 '-binaphthyl BINAP in the present application represents all chiral ligands of 2,2'-bis (diarylphosphino)-1,1'binaphthyl and it is understood that although the specific stereochemistry is not recited that the ligand utilised is either the R- or the S-antipode. The selection of the R- or the S- [R:\LIBAAj07612.doc:TAB 2 BINAP ligand will determine the stereochemistry of the P- or y-hydroxyesters and p- or yhydroxyamides produced.

*The asterisk is being used to represent a specific enantiomer which is dependent on the stereochemistry of the BINAP employed.

1 N/mm 2 is equivalent to approximately 0.145 psi Boc t-butyloxycarbonyloxy Ms methanesulfonyl COD Cyclooctadienyl om overlapping multiplet The following examples further illustrate the use of the process for the preparation of the compounds of Formula I and the use of this catalyst in this process and, as such, are not to be considered or construed as limiting the invention recited in the appended claims.

Example 1 Catalyst Preparation e Ph2P (PhCH3)2P Ph 2 P (PhCH 3 2

P

P P represents (BINAP) or (t-

BINAP)

Step A: Preparation of [(C2H5)2NH2]+[Ru 2 CI5((R)-BINAP) 2

]-.CH

3 Ph Structure 12 (Cyclooctadienyl)ruthenium dichloride (214 mg, 0.76 mmol) and (R)-BINAP (500mg, 0.80mmol) were placed in a 50ml round bottom flask and connected to a double ended filter (Kontes #215500-6044) with a 100ml round bottom flask at the opposite end.

Aa07612 EDITORIAL NOTE NUMBER 89399/98 THIS SPECIFICATION DOES NOT CONTAIN PAGES 3 TO 11 Vacuum grease was used to ensure an air-tight seal. Rubber bands were a simple and effective way of holding the apparatus together. The entire apparatus was evacuated and filled with nitrogen. Dry toluene (17 mL) and dry triethylamine (1.7 mL), which had been deoxygenated with flowing nitrogen for several minutes, were added via the lower side arm. The vessel was sealed and the mixture heated to 140°C producing a deep brick red colored solution. After 4 hours the apparatus was allowed to cool to room temperature with vigorous stirring while the catalyst precipitated. The apparatus was vented to nitrogen and inverted to filter the product using vacuum on the lower side arm and nitrogen on the upper. The precipitate was washed with deoxygenated toluene (17 mL), and the flask containing the filtrate was exchanged for an empty one. (31P NMR showed that the filtrate contained none of the desired product.) The entire apparatus was put 15 under vacuum and the product was dried overnight to give 470 mg of a dark red solid: 1 H NMR (CD2Cl2, 400.13 MHz) D 8.53(br s, 2H), 8.07 J=8.8 Hz, 4H), 7.82 J=8.3 Hz, 2H), 7.65 6H), 7.55 4H), 7.47 4H), 7.4-7.1 18H), 6.95 2H), 6.84 J=7.4 Hz, 2H), 6.8-6.7 (om, 20 4H), 6.7-6.6 (om, 4H), 6.6-6.5 (om, 12H), 3.24 (br m, 6H), 2.3 (s,3H), 1.45 J=7.3 Hz, 9H) [See figure 1 for 1 H NMR spectrum]; 3 1 p NMR (CD2C12, 161.98 MHz) a 56.5 J=38.0 Hz), 52.3 J=38.0 Hz); Analysis Calc'd for C99H84Cl5NP4Ru2: C 66.39, H 4.73, N 0.78, Cl 9.90, P 6.92; Found C 66.06, H 4.74, N 0.74, Cl 9.79, P 6.91.

Decoupling and spiking experiments unequivocally established the presence of diethylammonium ion. At -40°C the methylene protons of the diethylammonium appear as two multiplets at 3.2 ppm. [See figure 2 for 1H NMR spectrum] When the triplet at 1.4 ppm was irradiated the signal at 3.2 ppm appears as two doublets of triplets. [See figure 2 for 1 H NMR spectrum] When the broad singlet at 8.53 ppm is irradiated the signal at 3.2 ppm appears as two doublets of quartets. [See figure 2 for 1H NMR spectrum]. When 12diethylamine was added to the solution the signal at 3.2 ppm was seen to coalesce with the diethylamine signal. Triethylamine did not produce this behavior.

CIl C /q 'Ci-HUp

CI

13 Ph 2 P or(PhCH) 2

P

*P P represents P or PhCH Ph 2 P (PhCH3)2 Step B: Preparation of RuC14((R)-BINAP)2 Structure 13 20 The catalyst 12 (12 mg, 6.7 gmol) was loaded into a gas tight NMR tube (available from Wilmad) which was evacuated and refilled with nitrogen. Dry methylene chloride-d2 (0.8 mL) was deoxygenated by bubbling with nitrogen for 2 minutes. It was added with a thin needle by partially unstoppering the tube while nitrogen was flowing through the plug, flushing air away from its mouth. The atmosphere over the solvent was immediately purged by carefully evacuating and refilling with nitrogen. Catalyst dissolution was aided by the use of sonication or a vortex mixer. Methanesulfonic acid (4 gL, 62 gmol) was added to give the desired product: 1 H NMR (CD2Cl2, 400.13 MHz) a 8.14 J=7.9 Hz, 2H), 8.10 (d,d, J=9.1,1.6 Hz, 2H), 7.73 J=7.9 Hz, 2H), 7.65 J=7.5 Hz, 2H), 7.59 2H), 7.55-7.35 (om, 22H), 7.26-7.09 (om, 18H), 6.82-6.77 (om, 4H), 6.15 4H), 6.05 J=8.7 Hz, 2H), 5.83 (dd, J=12.3, 7.9 Hz, 13 4H); 3 1P NMR (CD2CI2, 161.98 MHz) D 62.6 J=40.3 Hz), 13.7 (d, J=40.3 Hz).

S

H

2 C 1

P

RU

H

2 14 PhP(PhCH)P P P represents Ph2' or P C 32 so. Step C: Preparation of rRuC14R BNAP)( H94-rel so. 0 A gas tight NMR tube containing 13 was put under a hydrogen atmosphere by evacuating and filling with hydrogen at a positive pressure of 8 psi. To ensure saturation of the solution, the tube a was put on a vortex mixer while attached to the manifold and stirred for 10 minutes.

so The I 1 H and 3 1 p spectra indicate that the hydrogen adduct is a mixture of conformational or configurational forms.

I H NMR (CD2Cl2, 400.13 MHz) D 8.2-5.8 -9.85, -10.08, -10.2, -10.88, -11.12, -11.52; 3 1 p NMR (CD2CI2, 161.98 MHz) D 58.8 (d, J=29.7 Hz), 56.2 J=30.4 Hz), 55.1 J=32.4 Hz), 54.9 J=31.7 Hz), 51.7 J=29.7 Hz), 50.9 J=31.0 Hz), 50.5 J=33.1 Hz), 48.5 J=31.7 Hz), 47.2 J=30.4 Hz), 46.7 J=33.1 Hz), 46.4 (d, J=32.4 Hz), 44.9 J=3 1.0 Hz).

The species 13 and 14 have been shown to be active catalysts as demonstrated in the following experiment: 14- To the above mixture methyl acetoacetate (20 pL) and methanol (100 gL) were added, and the NMR signals for species 14 immediately disappeared and methyl 4 -hydroxybutyrate and 13 appeared. After standing over night, the hdroxy product was isolated.

Examination of the (S)-Mosher ester of methyl 4 -hydroxybutyrate showed the product to be >90 enantiomeric excess.

EXAMPLE 2 10 _25_2_2NlRuC15 ((R)-t-BINAP ]toluene *0 I ^P(PhCH)2

H

3 2 1.4 hr, 1400C, Ph u C RuCl 2 (COD)n- -P(PhCH3)2 2. filter S2P(PhCH 3 3. Crystallize from heptanes *i PhCH PhCH [Et 2

NH

2 PhCH3 P, Cl P CI-Ru-CI-Ru-CI p Cl p

N:_

I PhCH 3

/I

PhCH CH3Ph fi CPhCH 3 To a 50 mL round bottom flask was charged 500 mg of (S)-t-BINAP 1, 197 mg of RuCl2[COD]n polymer 2, 1.4 mL of Et3N and 17 mL of degassed toluene. The flask was sealed and heated to 140 0 C for 6 hours. The dark red homogeneous solution was cooled to ambient temperature and the solution was concentrated under reduced pressure to 8 mL. Then 12 mL of heptanes was added and the solution was stirred for one hour. The Ruthenium polymer precipitated and was filtered off via double ended filter. The homogeneous solution was concentrated under reduced pressure to 8 mL. Then 12 mL of heptanes was added and the solution was stirred for one hour. The catalyst precipated and was filtered off via doubled ended funnel (schlenk ware).

The precitate was dried under vacuum, giving 300 mg of light yellow solid for 55% yield.

EXAMPLE 3 (C2H5 2jNH21+RuC 1 5((R)-BINAP)21:xyvlene (Cyclooctadienyl)ruthenium dichloride (2.14 g, 7.6 mmol) and (R)-BINAP (5.00 g, 8.0 mmol) were placed in a 50 mL round bottom flask and connected to a double ended filter (Kontes #215500- 15 6044) with a 1000 mL round bottom flask at the opposite end. Vacuum grease was used to ensure an air-tight seal. The entire apparatus was evacuated and filled with nitrogen. Dry xylenes (170 mL) and dry triethylamine (17 mL), which had been deoxygenated with flowing nitrogen for several minutes, were added via the lower side arm. The mixture was heated to 140 0 C producing a deep brick red colored solution. After 4 hours the apparatus was allowed to cool to room temperature with vigorous stirring while the catalyst precipitated. The apparatus inverted to filter the product using vacuum on the lower side arm and nitrogen on the upper. The precipitate was washed with deoxygenated xylene (17 mL), and the flask containing the filtrate was exchanged for an empty one. The entire apparatus was put under vacuum and the product was dried overnight to give 440 mg of a dark red solid: 1H NMR (CD2C12, 400.13 MHz) a 8.07 J=8.8 Hz, 4H), 7.82 J=8.3 Hz, 2H), 7.65 J=8.3 Hz, 6H), 7.55 4H), 7.47 4H), 7.4-7.1 (om, 20H), 6.95 2H), 6.84 J=7.4 Hz, 2H), 6.8- 6.7 (om, 4H), 6.7-6.6 (om, 4H), 6.6-6.5 (om, 12H), 3.24 6H), 2.3 (3 singlets, 6H), 1.45 J=7.3 Hz, 9H); 3 1 p NMR (CD2C12, 161.98 MHz) D 56.5 J=38.0 Hz), 52.3 J=38.0 Hz).

-16- EXAMPLE 4 t-Butvl 3 -hvdroxv-6-methoxv hexanoate O 0 0 0O 0 OH 10x^ 00 o 2 3 Step A: Preparation of t-butyl 3-keto-6-methoxy hexanoate 10 (Ketoester 2) The dianion of methyl acetoacetate, generated with sodium hydride and n-butyl lithium in THF at -15 0 C, is alkylated with 1.2 equivalents of bromoethyl methyl ether. The reaction proceeds in 6-8 hours to a level of 3 wt% residual starting material and is worked up with methyl t-butyl ether (MTBE) and saturated ammonium chloride solution. Residual methyl acetoacetate 159 0 C) is removed by flushing crude product with four to seven volumes of xylene to provide the alkylated ketoester containing <0.25 wt% methyl acetoacetate in 73- 77% yield.

20 The methyl ester is transesterified to the t-butyl ester in 95 :5-toluene:t-butanol by refluxing the solvent through 5A molecular sieves. The boiling point of the solvent mixture is 107-111 C, well above the boiling point of t-butanol, which can be slowly lost from the vessel and must be replaced as needed. After concentration, the t-butyl ester is produced in 95% yield with remaining methyl ester.

Step B: Preparation of t-butyl 3 -hydroxy-6-methoxy hexanoate (3hydroxvester 3) The hydrogenation catalyst [(C2H5)2NH2]+[Ru2Cl5((R)-

BINAP)

2 is not commercially available and must be prepared from [RuCl2(COD)]n and (R)-BINAP (see Example Twenty gram batches are conveniently prepared in a 1L flask. Use of a double ended filter allows convenient isolation of the product on this scale. The catalyst, which can be handled and weighed in air, should be stored under nitrogen.

i ri_ i~ __C -17- Asymmetric reduction of ketoester 2 is conducted in methanol at 45C under 1034 N/mm 2 (150 psi) hydrogen with 0.09 mol% (0.4 wt%) [(C2H5)2NH2]+[Ru2Cl5((R)-BINAP) 2 The reaction mixture should be deoxygenated with nitrogen and the vessel thoroughly evacuated and flushed with nitrogen prior to pressurization with hydrogen. The reaction is exothermic and requires periodic cooling to maintain the temperature at 450. After 4 hours hydrogen uptake is complete and the catalyst is precipitated with hexane and filtered away.

Concentration provides a >97% yield of the alcohol whose enantiomeric excess is determined to be 97% by proton NMR analysis of the derived Mosher ester.

The hydrogenation reaction is very susceptible to the presence of basic impurities and acidification of these with small amounts of strong acid is required.

Transesterification during the reaction can result from either high temperatures or the presence of excess amounts of acid.

Thus, the reaction temperature should be kept at 450 and the minimum S* possible amount of HCI should be used.

20 EXAMPLE tert-Butvl 3(R)-hvdroxvbutvrate 0 OH O CH3 OO- 0CH 3 16 tert-Butyl acetoacetate [15] (14.5 g, 90 mmol) and methanol mL) were mixed and deoxygenated with flowing nitrogen for minutes in a septum covered Parr shaker bottle. The catalyst prepared as described above (36 mg, 0.02 mmol) was added along with 2N HCI (0.041 mL, 0.082 mmol). The mixture was transferred to a standard Parr shaker apparatus and flushed by evacuating and refilling with nitrogen and then hydrogen several times. The apparatus was heated at with shaking under 50 psi of hydrogen. After 20 min the reaction -18became a homogeneous clear yellow solution which took up hydrogen for approximately eight hours. At this time the reaction was complete and the mixture was cooled and diluted with hexane (30 mL) to precipitate the catalyst, which was filtered away. The filtrate was concentrated to give tert-butyl 3 (R)-hydroxybutyrate [16] (14.5 g, 97%).

EXAMPLE 6 10 tert-Butyl 3 (R)-hvdroxvbutvrate Following the procedure described in Example 3 with the exception that 2N H2S04 was substituted for the 2N HCI tert-butyl acetoacetate was reduced to the titled product.

EXAMPLE 7 r

OH

H

H

NHCH

3 Boc O

O

17 MW 272.31 0.75% HCI, MeOH 0.25% [Et 2

NH

2 ]+[Ru 2 C 5

((S)-BINAP)

2 40 psi H 2 22h, 60 0

C

OH

NHCH 3 Boc OH 0 18 MW 274.31 In a 25 mL round bottom flask with a septum the P-keto amide 1 (1 g) was dissolved in methanol (4 mL). The solution was deoxygenated with nitrogen for 20 minutes and then the finely ground [(C2H5)2NH2]+[Ru2Cl5((S)-BINAP)2]- catalyst (15.5 mg) (prepared as described in Example 1) was added. The solution was degassed with nitrogen for 5 minutes and 2N hydrochloric acid (0.092 mL) was -19added. The mixture was cannulated into the reaction pressure vessel.

The apparatus was heated at 60 0 C with shaking under 40 psi of hydrogen for 20 hours.

After 20 h the reaction mixture was removed from the reaction pressure vessel. The vessel was rinsed with methanol (3 mL) which was combined with the reaction mixture. The solution was concentrated under reduced pressure to an off-white solid.

The crude reaction mixture gave a 87:13 ratio of the R:S hydroxy esters.

The yield was 100%.

EXAMPLE 8

HO

H 0.75% HCI, MeOH H NHCH3 N

NHC

3 0.25% [Et 2

NH

2 ]+[Ru 2

CI

5

((S)-BINAP)

2 HCI O O 40 psi H 2 22h, 600C

HHCI

MW 208.65

H

20 1 N HC H3

N

H OH 0

*HCI

MW 210.65 In a 25 mL round bottom flask with a septum the P-keto amide HCL salt 19 (1 g) was dissolved in methanol (16 mL). The solution was deoxygenated with nitrogen for 20 minutes and then the finely ground [(C2H5)2NH2]+[Ru2C15((S)-BINAP) 2 catalyst (20.2 mg) (prepared as described in Example 1) was added. The solution was degassed with nitrogen for 5 minutes and 2N hydrochloric acid (0.120 mL) was added. The mixture was cannulated into the reaction pressure vessel. The apparatus was heated at 60 0 C with shaking under psi of hydrogen for 20 hours.

i-CILII-IIX After 20 h the reaction mixture was removed from the reaction pressure vessel. The vessel was rinsed with methanol (3 mL) which was combined with the reaction mixture. The solution was concentrated under reduced pressure to an off-white solid. The crude reaction mixture gave a 97:3 ratio of the R:S hydroxy amides.

The yield was EXAMPLE 9 S1 OMs 'H 0.75% HCI, MeOH

NNHCH

3

N

Boc O O 0.25% [Et 2

NH

2 ]+[Ru 2 CIs((S)-BINAP) 2 S. 150 psi H 2 20h, 40 0

C

21 OMs MW363.40

NHCH

3

N

Boc OH

O

22 20 22 MW 265.40 o* In a 25 mL round bottom flask with a septum the 3-keto amide mesylate 21 (0.957 g) was dissolved in methanol (2.5 mL). The solution was deoxygenated with nitrogen for 20 minutes and then the finely ground [(C2H5)2NH2]+[Ru2Cl5((S)-BINAP) 2 catalyst (11 mg) (prepared as described in Example 1) was added. The solution was degassed with nitrogen for 5 minutes and 2N hydrochloric acid (0.020 mL) was added. The mixture was cannulated into the reaction pressure vessel. The apparatus was heated at 40 0 C with stirring under 150 psi of hydrogen for 20 hours.

After 20 h the reaction mixture was removed from the reaction pressure vessel. The vessel was rinsed with methanol (3 mL) which was combined with the reaction mixture. The solution was -21 concentrated under reduced pressure to an off-white solid. The crude reaction mixture gave a 91:9 ratio of the R:S hydroxy amide mesylates.

The yield was EXAMPLE (R)-Trans-2-Methoxvcarbonvlcvclopentanol 2 -Methoxycarbonyl-cyclopentanone (4.26 g) was dissolved in methanol (5 mL) and 0.1 mL IN HCI was added. The mixture was deoxygenated, 1 (36 mg) was added and the mixture was exposed to hydrogen at 40 psi and 400 in a Parr shaker apparatus. After 6 h the reaction was complete, providing a single product (4.10 g) in >95% ee: 1 H NMR (CDC13, 250 MHz) 4.40 J=7.5 Hz, 1H), 3.71 3H), 2.65 J=7.2 Hz, 1H), 2.1-1.5 6H).

EXAMPLE 11 Methyl 3 -Hvdroxv-2-methvlbutvrate Methyl 2 -methylacetoacetate was hydrogenated under the 20 conditions set forth in Example 2 or 3, to give a 6:4 mixture of trans:cis product. Enantiomeric excess of the major isomer was >97%.

EXAMPLE 12 Methyl A mixture of methyl levulinate (10.0 g, 77 mmol), methanol (10 mL) and concentrated HC1 (0.4 mL) was deoxygenated with bubbling nitrogen for 2 minutes. [(C2H5)2NH2]+[Ru2C15((R)- BINAP)2]- (50 mg) was added and the mixture placed in a standard Parr shaker apparatus. After evacuating and flushing with nitrogen three times, the mixture was evacuated and exposed to 40 psi hydrogen pressure at 40 0 C for 48 h. The solvent was removed in vacuo to give the product (9.90g, 99% yield) which was identical to a commercially available (Aldrich) racemic sample by 1H NMR. The optical purity was shown to be 99:1 by obtaining proton NMR spectrum of the product (1 -22mL) and (S)-(+)-2,2,2-trifluro-l-(9-anthryl)ethanol (27 mg) in CDC13.

Peak assignments were made by spiking with a sample of the racemate.

Methyl 5-(R)-hydroxyvalerate spontaneously lactonizes to give y-valerolactone.

EXAMPLE 13 Ethyl 3-hydroxybutvrate This was prepared from ethyl acetoacetate in ethanol 10 according to the procedure of Example 4 or 5. Enantiomeric excess was measured to be 97%. 1H NMR (CDC13, 250 MHz) 4.20 1H), 4.10 J=7.5 Hz, 1H), 2.51 2H), 1.2

Claims (3)

1. A compound of structural formula: Cl Cl or solvates thereof wherein 'P P represents BINAP or I-B INAP.

2 Acopund of structural formula: CI U Cl H 2 or solvates thereof wherein P represents BINAP or t-BINAP.

3. A compound of structural formula: E) [E2H] R C* P\ .I a.l P io or sovtsteefweenrpeet IA rtBN Dae 5 etmbr19 MECK CO,.NC MERCKSO CoERUSOC Aa07612