GB2351735A - Synthesis of (r)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol by asymmetric hydrogenation - Google Patents
Synthesis of (r)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol by asymmetric hydrogenation Download PDFInfo
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- GB2351735A GB2351735A GB0016255A GB0016255A GB2351735A GB 2351735 A GB2351735 A GB 2351735A GB 0016255 A GB0016255 A GB 0016255A GB 0016255 A GB0016255 A GB 0016255A GB 2351735 A GB2351735 A GB 2351735A
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- bis
- trifluoromethyl
- ethan
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
- C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12C—BEER; PREPARATION OF BEER BY FERMENTATION; PREPARATION OF MALT FOR MAKING BEER; PREPARATION OF HOPS FOR MAKING BEER
- C12C11/00—Fermentation processes for beer
- C12C11/02—Pitching yeast
Abstract
A process for the preparation of a compound of the formula: <EMI ID=1.1 HE=24 WI=30 LX=687 LY=748 TI=CF> <PC>comprises:<BR> ```treating a compound of the formula: <EMI ID=1.2 HE=25 WI=31 LX=691 LY=1118 TI=CF> <PC>with hydrogen gas in the presence of a phosphine-ruthenium catalyst, a chiral diamine co-catalyst and a base in a solvent;<BR> ```to give the compound of the formula: <EMI ID=1.3 HE=24 WI=30 LX=698 LY=1541 TI=CF> This compound is used as intermediate with synthesis of compounds having pharmacological activity e.g. substance P (neurokinin) receptor antagonists.
Description
20489 2351735
TITLE OF THE INVENTION PROCESS FOR THE SYNTHESIS OF (R)-1-(3,5BIS(TRIFLUOROMETHYL)PHEWL)ETHAN- 1 -OL BY ASYMMETRIC HYDROGENATION
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of (R)- 1 (3,5-bis(trifluoromethyl)phenyl)ethan-l-ol which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of (R)- 1 -(3,5-bis(trifluoromethyl)phenyl)ethan- 1 -ol which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of (R)-1(3, 5-bis(trifluoromethyl)phenyl)ethan-l-ol result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of (R)-1-(3,5bis(trifluoromethyl)phenyi)ethan-l-ol in relatively high yield and enantiomeric purity.
It will be appreciated that (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan1-ol is an important intermediate for a particularly usef ' ul class of therapeutic agents. As such, there is a need for the development of a process for the preparation of (R)- 1 (3,5-bis(trifluoromethyl)phenyl)ethan-l-ol which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol via a very simple, short and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of (R)-1(3,5bis(trifluoromethyl)phenyl)ethan-l-ol. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula:
20489 9H CF3 Me CF3 This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of 5 inflammatory diseases, psychiatric disorders, and emesis.
DETAILED DESCRII11FION OF THE INVENTION The present invention is directed to processes for the preparation of (R)I-(3,5-bis(trifluoromethyl)phenyl)ethan-l-oI of the formula:
9H CF3 Me CF3 A preferred embodiment of the general process for the preparation of (R)-I-(3,5-bis(trifluoromethyl)phenyl)ethan-l-oI is as follows:
0 011 CF3 Phosphine-Ru catalyst CF3 Me Diamine co-catalyst Me BH ase CF3 2, Alcohol CF3 In accordance with the present invention, the treament of 1-(3,5 bi s(tri fluoromethyl)-phenyl)ethan- I -one with hydrogen in the presence of a phosphine-ruthenium catalyst, a chiral diamine co-catalyst and optionally in the presence of a base provides (R)-I-(3,5-bis(trifluoromethyl)-phenyl)ethan- l-oI in higher yields, in greater entantiomeric purity and in a more efficient route than the processes disclosed in the art.
20489 In a preferred embodiment, the present invention is directed to a process for the preparation of (R)-I-(3,5-bis(trifluoromethyl)phenyl)ethan-l-oI which comprises the asymmetric hydrogenation of 1-(3,5- bis(trifluoromethyl)-phenyl)ethanI-one in the presence of a phosphine- ruthenium catalyst, a chiral diamine co-catalyst and a base in a solvent to give (R)-I-(3,5bis(trifluoromethyl)phenyl)ethan-l-ol.
A specific embodiment of the present invention concerns a process for the preparation of (R)-I-(3,5-bis(trifluoromethyl)phenyl)ethan-l-oI of the formula:
OH CF3 Me CF3 which comprises:
treating 1-(3,5-bis(trifluoromethyl)phenyl)ethan- I -one of the formula:
0 CF3 CH3 CF3 with hydrogen in the presence of a phosphine-ruthenium catalyst, a chiral diamine co-catalyst and optionally in the presence of a base in a solvent; to give (R)-I-(3,5-bis(trifluoromethyl)phenyl)ethan-l-oI of the formula:
OH CF3 Me CF3 In the present invention, it is preferred that the phosphine-ruthenium catalyst is selected from (S,S)-2,3-0-isopropylidene-2,3-dihydroxy-1, 4bis(diphenylphosphino)butane ruthenium chloride (i.e. (S,S)-DIOPRuCl2), (S)-2,2- 20489 bis(diphenylphosphino)- 1, P-binaphthyl ruthenium chloride (i.e. (S)BinapRUC12).
(S)-TolBinapRuC12, and (S)-Phanephos-RuC12- In the present invention, it is more preferred that the phosphine-ruthenium catalyst is (S)-2,2'bis(diphenylphosphino)- 1,1'-binaphthyl ruthenium chloride ((S)-BinapRUC]2), (S)-Phanephos-RuC12. or (S,S) 2,3-0-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane ruthenium chloride (i.e. (S,S)-DIOPRuCI2). The phosphine-ruthenium catalyst is preferably present at a concentration of about 0.1-1 mol% and more preferably about 0.5 mol%.
0.,,%%-PPh2 = DIOP PPh2 PPh2 PPh2 = Binap PPh2 Phanephos PPh2 In the present invention, it is preferred that the chiral diamine co- catalyst is selected from (R,R)-cyclohexane diamine (R,R)CHXD, (R,R)DPEN, or (R)-DAEPEN. In the present invention, it is more preferred that the chiral diarnine co-catalyst is (R,R)-cyclohexane diamine. The chiral diamine co-catalyst is preferably present at a concentration of about 0. 1 -1 mol% and more preferably about 0.6 mol%.
In the present invention, it is preferred that the base is selected from potassium tert-butoxide, potassium hydroxide and sodium hydroxide. In the present invention, it is also preferred that the base is selected from potassium tert-butoxide and potassium hydroxide. In the present invention, it is more preferred that the base is potassium tert-butoxide.
20489.
In the present invention, it is preferred that the hydrogen is present as hydrogen gas, preferably at a pressure of 20-100 psi, and more preferably at a pressure of about 60 psi.
Preferred solvents for conducting the instant process include alcoholic solvents. More preferred solvents include isopropanol, ethanol, methanol, isobutanol or n-butanol. The most preferred solvent is isopropanol.
The (R)-I-(3,5-bis(tfifluoromethyl)phenyl)ethan-l-oI obtained in accordance with the present invention may be used as starting material in further reactions directly or following purification.
The starting materials and reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
2M9 EXAMPLE I
3.5-Bis(trifluoromethyl)bromobenzene CF3 Sulfuric Acid CF3 Acetic Acid -Br DBH CF3 C. F3 Materials MW Density Amount Mmol Equiv.
1,3-Bis(trifluOro- 214.1 1.38 107 g 500 1.0 methyl)benzene 96%1-1,SO, 142 mL Glacial HOAc 22 mL 1,3-Dibrorno-5,5- 285.93 77.25 g 270 1.08 (Br) dimethylhydantoin 5N Aq NaOH 75 mL To glacial acetic acid (22.0 mL), cooled to 15 T in a I L 3-neck round bottom flask (equipped with mechanical stirrer, thermocouple, and addition funnel), was added concentrated (96%) sulfuric acid (142 mL) in one portion. An exothermic heat of solution raised the temperature to 35 'C. After cooling to 25 'C, 1,3- bis(trifluoro-methyl)benzene (107 g, 500 mmol) was added. With the acid mixture rapidly stirring, 1,3-dibromo-5,5-dimethylhydantoin (77.25 g; 270 mmol) was added over 2 min to give a multiple phase mixture (solid and two liquid). An exothermic reaction occured that raised the internal temperature to -40 'C Oacket cooling at 15 Q. After the reaction temperature began to drop (after 5 min) the reaction mixture was maintained at 45 'C for 4.5 hr.
The rate and selectivity of the bromination is highly dependent on the agitation of the two phase reaction. Slower stirring increases the amount of bisbromination and slows the overall rate of reaction. The reaction mixture remains heterogeneous throughout the reaction and the organic phase separates when agitation is interrupted. At the end of the reaction, the phases separate slowly (bromide density = 1.699). The rate of bromination is also dependent on the ratio of acetic to sulfuric acid.
20489 Progress of the reaction is monitored by GC analysis, as follows.
Sample: -50 gl of mixed phase, dilute with cyclohexane (1.5 mL), wash with water (I mL), then 2N NaOH (I mL), separate and inject.
Resteck RTX-1701 [60 meter x 0.320 mm]: 100 'C; ramp: 5 'C/min to 200 'C; 200 T for 10 min; Flow 1. 15 mUmin R,:1,3-bis(tfifluoromethyl)benzene: 7.0 min 3,5-bis(tfifluoromethyl)bromobenzene: 9.4 min Biaryl: 19.2 min The mixture was cooled to 2 'C and poured slowly into cold water (250 mL). The mixture was stirred vigorously for 10 min, allowed to settle, and the lower organic layer was separated and washed with 5N NaOH (75 m.L) to give 145.1 g of a clear, colorless organic layer.
The assay yield of 1,3-bis(trifluorornethyl)bromobenzene was 93.7% (137.3 g, 469 mmol), which contained 0.6% 1,3-bis(trifluoromethyl)benzene, 1.0% 1,2-dibromo-3,5-bis(trifluoromethyl)benzene, and 0.3% 1,4-dibromo-3,5-bis (trifluoromethyl)benzene. Total isomer byproducts measured by GC were 2.0 mol %.
EXAMPLE2
1-(3.5-Bis(trifluoromethyl)phenyl)ethan- I -one 0 CF3 Br 1) Mg CF3 THF ACH3 2) AC20 F3 CF3 20489 Materials MW Density Amount Mmol Equiv 3,5-Bis(trifluoromethyl)- 293.03 1.699 g/L 29.3 g 98.0 1.0 bromobenzene Magnesium granules, 20 24.3 5.10 g 2. 1 mesh Acetic Anhydride 102.1 1 40 mL 423 4.5 ___A.08__g1L THF (KF=60 gg/mL) 260 mL NME 650 mI, Water 300 mI, 50% NaOH 40 mI, Product 3',5'-Bis(trifluoro- 256.14 20.3 g 79.0 82% methyl)acetophenone__ Yield To a 500 mL 3-neck round bottom flask equipped with an addition funnel, N2 inlet, and a Teflon coated thermocouple was added magnesium granules 5. 10g,21Ommol)andTHF(20OmL). The mixture was heated to reflux. 3, 5Bis(trifluoromethyl)bromobenzene (29.3 g, 98 mmol) was dissolved in 30 mI, of TflE Some bromide solution (5 mL) was added to the gently refluxing magnesium slurry over 2 minutes to initiate the Grignard reaction. After Grignard initiation, the remaining bromide was added over 1 hour.
An initial induction period of 5 minutes is generally allowed for. If the reaction does not initiate, another 5% charge of bromide solution is added. If the reaction still does not initiate after a bromide charge of 10%, 100 mg of iodine is added. The reaction exotherm was controlled by slowing or stopping the bromide addition if the reaction appeared too violent.
After complete bromide addition (- 60 minutes), the dark brown solution was heated at gentle reflux for an additional 30 minutes.
The reaction was monitored by HPLC (sample preparation: 100 gL sample quenched into 3.5 mL of 1: 1 THR2N FICI, then diluted to 100 mL in 65:35 acetonitrile:p11 6 buffer). Grignard formation was considered complete when the bromide level is less that 1 mol%.
After cooling to ambient temperature in a water bath, the mixture was transferred via cannula to a IL addition funnel. THF (10 mL) was used as rinse. This solution was then added to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at - 15 'C over 1 hr. The dark brown mi xture was warmed to 10 T in a 20489 water bath, and water (300 mL) was added over 3 minutes. The biphasic mixture was vigorously stiffed while 50% NaOH was added dropwise over I hr, until a pH of 8.0 was maintained for 5 minutes. MTBE (300 mQ was added, the layers were separated and the aqueous layer was further extraced with MTBE Q x 150 mL). The organic layers were combined and assayed (22.4 g ketone), then concentrated in vacuo at bath temperature of 32 'C (50-80 torr). The concentrate was then distilled at atmospheric pressure and 20.7 g (82% yield based on LC purity) of colorless oil was collected at 150-189 OC, with the bulk collected at 187-189 "C.
BPLC Assay: 97.7 LCAP Method: Luna C 18 Acetonitri le:O. I% aq H3PO4 75:25 to 95:5 over 20 min; maintain 5 min.
R, (min):
Phenol 5.2 Ketone 6.3 Aromatic 7.3 Bromide 9.7 Dimer 13.3 GC Assay: 95.5 GCAP Method: Resteck RTX-1701 (60 meter x 0.320 mm] OC to 200 OC @ 5 "CImin; 200 "C for 10 min; Flow 35 cm/sec constant flow.
Rt (min):
1,3-bis(trifluoromethyl)benzene 4.4 Acetic anhydride 5.6 Methyl Ketone 10.6 A 3,5-bis(trifluoromethyl)bromobenzene 6.2 Bis adduct 19.6 20489 EXAMPLE 3 (R)-1-(3,5-Bis(trifluoromethVI)Dhenyl)ethan- 1 -ol CF3 0 (S,S)-DIOPRUC12-DIVIF OH Me (R,R)-Cyclohexane CF3 Me diarnine K0t-BulIPA CF3 60 PSI H2 CF3 PPh2 P1Ph2 DIOP To a pressure tube under an inert atmosphere was added 36.6 mg (S,S)- DIOP-rutheniurndichloride. The tube was charged with 8 ml of a 0. 1 M solution of KOtBu in degassed IPA and 7 m] of degassed IPA. 0.6 mI of a 12.4 mglml solution of (R,R)-cyclohexanediamine was added. The reaction solution which was yellow in color was aged for 0.5 h. 3.5 m] of degassed 1-(3,5bis(trifluoromethyl)phenyl)ethan- 1 -one was then added. The apparatus was then put under 60 PSI of H2 for 15hrs.
Assay of the reaction by chiral GC (B-DEX, 60m x 0.25 gm, 150 C isothermal) showed 96% conversion of the ketone to the alcohol with ee = 77%.
The ruthenium-phosphine complex was synthesized by mixing the phosphine ligand and Ru(C12)-Benzene complex in degassed DMIF (lg ruthenium/ 10 mI DlYM. The red solution is heated to 90 C for 20 minutes. The solution was then concentrated at 55 'C in vacuo to give a red solid.
20489 While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above. Likewise, the specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
1 20489 WHAT IS CLAUVIIED IS:
I A process for the preparation of a compound of the formula:
OH CF3 Me CF3 which comprises: treating a compound of the formula:
0 CF3 CH3 Z CF3 with hydrogen gas in the presence of a phosphine-ruthenium catalyst, a chiral diamine co-catalyst and a base in a solvent; to give the compound of the formula:
OH CF3 Me CF3 20489
Claims (1)
- 2. The process of Claim 1 wherein the phosphine-ruthenium catalyst isselected from: (S)-2,2-bis(diphenylphosphino)-1,1-binaphthyl ruthenium chloride, (S)-Phanephos-RuC12, and (S,S)-2,3-0-isopropylidene-2,3dihydroxy-1,4bis(diphenylphosphino)butane ruthenium chloride.3. The process of Claim 1 wherein the chiral diamine co-catalyst is (R,R)cyclohexane diamine.4. The process of Claim 1 wherein the base is potassium tert10 butoxide.5. The process of Claim 1 wherein the hydrogen gas is present at a pressure of about 60 psi.6. The process of Claim 1 wherein the solvent is isopropanol.7. A process for the preparation of (R)- 1 -(3,5 bis(trifluoromethyl)phenyi)eth.in-1-ol which comprises:the reaction of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan- 1 -one with hydrogen gas in the presence of a phosphine-ruthenium catalyst which is selected from: (S)-2,2-bis(diphenyl-phosphino)-1,1'-binaphthyl ruthenium chloride, (S) Phanephos-RuC12, and (S,S)-2,3-0-isopropylidene-2,3-dihydroxy-1,4- bis(diphenylphosphino)butane ruthenium chloride; (R,R)-eyclohexane diarnine and potassium tert-butoxide in isopropanol to give (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14199699P | 1999-07-01 | 1999-07-01 |
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| Publication Number | Publication Date |
|---|---|
| GB0016255D0 GB0016255D0 (en) | 2000-08-23 |
| GB2351735A true GB2351735A (en) | 2001-01-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0016255A Withdrawn GB2351735A (en) | 1999-07-01 | 2000-06-30 | Synthesis of (r)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol by asymmetric hydrogenation |
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| GB (1) | GB2351735A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1276745B1 (en) * | 2000-03-30 | 2011-01-12 | Chirotech Technology Limited | Ruthenium-diphosphine complexes and their use as catalysts |
| US8691718B2 (en) | 2005-09-20 | 2014-04-08 | Takeda Pharmaceutical Company Limited | Diphosphine ligand and transition metal complex using the same |
-
2000
- 2000-06-30 GB GB0016255A patent/GB2351735A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1276745B1 (en) * | 2000-03-30 | 2011-01-12 | Chirotech Technology Limited | Ruthenium-diphosphine complexes and their use as catalysts |
| US8691718B2 (en) | 2005-09-20 | 2014-04-08 | Takeda Pharmaceutical Company Limited | Diphosphine ligand and transition metal complex using the same |
| US8981147B2 (en) | 2005-09-20 | 2015-03-17 | Takeda Pharmaceutical Company Limited | Diphosphine ligand and transition metal complex using the same |
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| Publication number | Publication date |
|---|---|
| GB0016255D0 (en) | 2000-08-23 |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |