WO2009004350A1

WO2009004350A1 - Methods for preparing bortezomib and intermediates used in its manufacture

Info

Publication number: WO2009004350A1
Application number: PCT/GB2008/002302
Authority: WO
Inventors: Michal Janca; Petr Dobrovolny
Original assignee: Pliva Hrvatska D.O.O.; Bucks, Teresa Anne
Priority date: 2007-07-03
Filing date: 2008-07-02
Publication date: 2009-01-08

Abstract

Provided herein are methods for preparing bortezomib and intermediates useful in the preparation of bortezomib. The present methods unexpectedly provide superior yields and purities, including optical purities, of bortezomib and the intermediates for the preparation of bortezomib.

Description

METHODS FOR PREPARING BORTEZOMIB AND INTERMEDIATES USED IN ITS

MANUFACTURE

FIELD OF THE INVENTION

[0001] The present invention relates generally to the synthesis of boronic acid and ester compounds. In particular it relates to the preparation of bortezomib and intermediates for the preparation of bortezomib.

BACKGROUND

[0002] Bortezomib, also known as N-(pyrazin-2-yl)carbonyl-L-phenylalanine-L-leucine boronic acid, is a biologically active compound having the following structure.

[0003] Bortezomib is an N-acylated dipeptide analog of phenylalanyl-leucine in which

B(OH)₂ replaces the C-terminal carboxylic acid. Physiologically, bortezomib acts to inhibit proteasome and has been clinically approved for use in treating mantle cell lymphoma and multiple myeloma. Bortezomib has been previously prepared as disclosed in U.S. Patent Publication 2005/020047 ('047 application).

BRIEF DESCRIPTION OF THE FIGURES

[0004] FIGURE 1 shows a process for preparation of bortezomib as described herein.

DETAILED DESCRIPTION

[0005] It has been found that the methods of producing bortezomib described herein provide surprising and unexpectedly improved yields and purities of bortezomib and intermediates for the synthesis of bortezomib. Figure I shows a synthetic route to bortezomib from a compound of formula I using methods of the invention. Briefly, the known boronic acid ester having formula I is halogenated by exposure to a lithium amide base, dichloromethane, and a Lewis acid in THF to give a compound of formula II. The latter compound is converted to the silyl amine (formula III) using a salt of hexamethyldisilazane and then to the ammonium salt (formula IV) upon exposure to a suitable acid. A salt of the N-pyrazinyl-phenylalanine (formula V) is then coupled to the compound of formula IV without the use of any additional base to give the boronate ester of formula VI. The pinanediol ester group is removed under acidic conditions to give the boronic acid, bortezomib (formula VII). This synthetic route takes advantage of several unexpected discoveries.

[0006] First, a key improvement to previous methods of bortezomib synthesis includes the use of a very high percentage of tetrahydrofuran in the halogenation of the compound of formula I to provide the compound of formula II. The use of tetrahydrofuran has previously been criticized as resulting in dramatic reductions in diastereomeric ratios (see e.g. U.S. Patent Publication 2005/020047, paragraph 44) unless rigorously dried equipment, solvents and reagents are used. Yet, using only routine procedures to exclude moisture, it has been found that the product obtained from the present method improves not only the yield and purity of the compound of formula II, but also the yield and purities of the final product, bortezomib, compared to the use of other solvents (such as tert-butyldimethylether) or lower percentages of THF.

[0007] Thus, in one embodiment, the invention provides methods for preparing a compound of formula II comprising exposing a compound of formula I

to a lithium amide base and a transition metal halide in a solvent comprising dichloromethane (e.g., 2-5%) and at least 95 % tetrahydrofuran by volume, under conditions suitable to provide the compound of formula II

II

[0008] Preferably, the solvent comprises about 95.5 % tetrahydrofuran and about 4.5% dichloromethane by volume. By use of the present methods, the compound of formula II was prepared in 91-95% yield and contained only 3-5% starting material. By contrast, the method used in the '047 application provided the compound of formula II in only 77-85% yield and contained 10-15% starting material.

[0009] Without wishing to be bound by theory, it is believed that formation of the compound of formula II proceeds via a Lewis acid promoted rearrangement of a boron "ate" complex. Suitable lithium amide bases for such reactions are known in the art and include, but are not limited to, lithium diisopropyl amide, lithium diethylamide, and lithium dimethylamide. Typical concentrations of the lithium amide base used in the present reaction may range from about 0.5 M to about 2 M. Likewise, suitable Lewis acids for use in the present reaction include transition metal halide such as, but not limited to, ZnCl₂, ZnBr₂, FeBr₃, FeCl₃, or a mixture of any two or more thereof. The present transformation may be carried out a temperature ranging from about -70 °C to about 10 ⁰C. Preferably, the present halogenation is carried out, at least initially, at a temperature ranging from about -70 ⁰C to about -60 ⁰C.

[0010] The present methods of synthesizing bortezomib may further include exposing the compound of formula II to the salt of a silylamine such as, e.g., lithium hexamethyldisilazane, sodium hexamethyldisilazane, or potassium hexamethyldisilazane, under conditions suitable to provide a compound of formula III

III

[0011] Suitable conditions for the formation of the compound of formula III include carrying out the reaction in a solvent comprising tetrahydrofuran or a mixture of tetrahydrofuran and methylcyclohexane. Formation of the silylamine may be carried out at temperatures ranging from -60°C to 30°C or from -30°C to 30°C. In some embodiments, the temperature ranges from -20⁰C to about 25⁰C. Prepared in accordance with the present methods, the compound of formula III was obtained in 89-93% yield and containing 0.6-0.8% of an isomer of the compound of formula III. In contrast, preparation of the compound of formula III according to the method disclosed in the '047 patent resulted in only 75-80% yield and contained 8-10% of the second isomer.

[0012] Methods of preparing bortezomib may further include contacting the compound of formula III with a suitable acid to provide a compound of formula IV

Suitable acids for desilylation of silylamines are known in the art and include those strong enough to remove the silyl groups without substantially degrading the reactant (formula III) or product (formula IV). For example, suitable acids include but are not limited to C_1-10 alkanoic acids such as formic and acetic acids, C_2-10 perhaloalkanoic acids such as trifluoroacetic acid and trichloroacetic acid, HCl, HBr, or C_1-6 sulfonic acids such as methanesulfonic acid and triflic acid. In some embodiments, trifluoroacetic acid is used. Formation of the compound of formula IV may be carried out at temperatures ranging from about -30°C to about 25°C over the course of 0.5 to 2.5 hours. The purity of the compound of formula IV produced by present methods was 99.8% or greater with only 0.04-0.1% of a second isomer of the compound produced. In contrast, the process disclosed in the '047 application yielded a purity of only 87-94% and a content of 5-6% of a second isomer of the compound of formula IV.

[0013] The present synthesis of bortezomib is a convergent synthesis in which the ammonium compound of formula IV is coupled to a phenylalanine derivative of formula V. The latter compound may be readily made using standard techniques. For example, a suitably C- protected derivative of phenylalanine, e.g. the phenylalanine methyl ester may be coupled to pyrazine carboxylic acid using any standard technique for the formation of amide bonds, particularly those used in peptide synthesis. The resulting ester of N-(pyrazine-2-ylcarbonyl)-L- phenylalanine may be hydrolyzed to give the corresponding salt (formula V), which may be used for coupling with the compound of formula IV. Methods of hydrolysis are well known in the art and typically include exposing an ester to a solution of metal hydroxide in water, alcohol, or mixtures of water and various alcohols or other organic solvents.

[0014] The present methods may further include contacting a compound of formula V

V

wherein Z is a lithium, sodium, potassium, rubidium, calcium, or magnesium cation,

with a coupling agent and the compound of formula IV

under conditions suitable to provide a compound of formula VI

VI

[0015] The coupling may be effected with any suitable agent for amide bond formation such as coupling agents used for peptide synthesis. Such coupling agents include but are not limited to TBTU, DIP, DCC, EDC, HBTU, HCTU, TCTU₅ HATU, PyBOP, and PyABOP. Use of the compound of formula V, i.e., a salt of the carboxylic acid, advantageously avoids the use of an organic amine as a base and provides superior yields to known methods of forming the compound of formula VI. While not wishing to be bound by theory, it is believed that the use of a salt of the N-(pyrazine-2-ylcarbonyl)-L-phenylalanine significantly reduces cleavage of the boronic acid group that results in formation of the byproduct, N-(pyrazine-2-ylcarbonyl)-L- phenylalanine-L-leucine. Thus, the present methods produced only about 1.5% of the byproduct compared to 10% using the method of the '047 application.

[0016] The present methods of synthesis of bortezomib may include exposing a compound of formula VI to a sufficient amount of acid to produce a compound of formula VII or its cyclic anhydride

VII

For example, HCl, HBr, or combinations of HCl and/or HBr with a boronic acid such as 2- methylpropylboronic acid may be used. In some embodiments, the reaction is conducted in the presence of a non-polar solvent in which pinanediol is soluble but the product boronic acid is not.

[0017] Improved methods of isolating bortezomib after deprotection are also provided.

The procedure disclosed in the '047 application requires the use of sodium hydroxide, which can cause decomposition of the bortezomib. In the present methods, the non-polar solvent is removed and the remaining residue is taken up in another solvent (e.g., dichloromethane) and precipitated with, e.g., diisopropylether to give bortezomib with enhanced final purity.

[0018] All publications, patent applications, issued patents, and other documents referred to in this disclosure are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0019] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

[0020] The following abbreviations are used in the Examples and throughout this disclosure. DCC Dicyclohexylcarbodiimide

DIP Diisopropylcarbodiimide

EDC 1 -(3-Dimethylaminopropyl)-3 -ethyl-carbodiimide hydrochloride g Gram(s) GC Gas Chromatography

HATU 2-(7-Aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate HBTU O-(Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate HCTU 1H-Benzotriazolium 1-

[δz5'(dimethylamino)methylene]

-5chloro-,hexafluorophosphate (l-),3-oxide

LDA Lithium diisopropylamide ml Milliliter(s)

PyABOP 7-Aza-benzotriazole- 1 -yl-oxy-tris- pyrrolidinophosphonium hexafluorphosphate

PyBOP Benzotriazole- 1 -ly-oxy-tris- pyrrolidinophosphonium hexafluorphosphate

THF Tetrahydrofuran TBTU 2-(lH-Benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate

TCTU 2-(lH-6-Chloro-benzotriazole-l-yl)-l,l,3,3- tetramethyluronium tetrafluoroborate

Example 1: Preparation of (lR)-(S)-Pinanediol-l-ammonium trifluoroacetate-3-methyIbutane-l-boronate

Step 1: (S)-Pinanediol 2-methylpropane-l-boronate

[0021] A reaction mixture containing (+)-pinanediol (6.9 g) and 2-methylpropylboronic acid (4.4 g) and diethylether (49.3 ml) was stirred for 23 hours at laboratory temperature, than dried over Na₂SO₄ (16.5 g). The sulfate was filtered off and washed with diethylether (69.4 ml), and the resulting solution was concentrated. The product was obtained as colorless oil (9.9 g, purity 100 % (GC), yield 97.2 %). MS (m/z): 236, 221, 195, 167, 140, 134, 83, 67, 55, 43; ¹H- NMR (DMSO-d₆): δ= 4.27 (IH, dd, J=2.1 Hz, 8.7 Hz); 2.30 (IH, m); 2.18 (IH, m); 1.96 (IH, t, J=5.4 Hz); 1.86 (IH, m); 1.79 (IH, sx, J-6.8 Hz); 1.69 (IH, m); 1.30 (3H, s); 1.25 (3H, s); 1.02 (IH, d, J=I 0.6 Hz); 0.9 (3H, d, J-6.6 Hz); 0.81 (3H, s); 0.69 (2H, m)).

Step 2: (IS)-(S) -Pinanediol l-chloro-3-methylbutane-l-boronate

[0022] Under an inert atmosphere of argon, 6.0 g (S)-pinanediol-2-methylpropane-l- boronate was charged to jacketed flask (250 ml) together with 36.0 ml THF and 9 ml dichloromethane. The mixture was cooled to -65°C. A 1.5 M LDA solution in THF (22.08 ml) was added to the mixture over a period of 5 minutes and the mixture stirred for additional 20 minutes at -65⁰C. A 0.5M ZnCl₂ solution in THF (135.0 ml ) was added drop wise to the reaction over a period of 18 minutes. The reaction mixture was warmed up to -45 °C and stirred at this temperature for 30 minutes. The mixture was further warmed to 10°C over a period of 90 minutes. 10% H₂SO4 (33.0 ml) was added and mixture warmed up to 25⁰C. tert-Buthylmethyl ether (36.0 ml) was added and mixture was transferred to separatory funnel. The jacketed (250 ml) flask was washed with 20.0 ml of water and layers were separated. The organic layer was extracted with 90.0 ml H₂O; 90.0 ml H₂O + 0.5ml 10% H₂SO_{4 ,} 90.0 ml H₂O + 1.5ml 10% H₂SO₄; 90.0 ml +1.5ml 10% H₂SO₄; 90.0 ml 10% NaCl. The organic layer was poured to 250 ml flask and dried over Na₂SO₄ (57.56 g) and stored in fridge over night. The next day the Na₂SO₄ was filtered off and washed with 2 x 50.0 ml tetrahydrofuran and residue evaporated to dryness (50°C, p_mm= 6 mbar ). The product was isolated as oil (7.7 g, 97.0 % yield) with purity 91.7 % (GC) and content of starting material 4.9 %. MS (m/z): 284, 283, 269, 248, 214, 199, 173, 158, 145, 134, 118, 117, 83, 67, 55, 43)

Step 3 : (1R~)-(S^*)-Pinanediol 1 bis(trimethylsilyl^')amino-3-butane-l-boronate

[0023] Under an inert atmosphere of argon, 25.61 ml of a 1.0 M LiHMDS solution in tetrahydrofuran was charged to a jacketed flask (250 ml) and cooled down to -20°C. (IS)-(S) - Pinanediol 1-chloro —3- methylbutane — 1- boronate from the previous step (7.7 g) was dissolved in methylcyclohexane (20.97 ml) in another flask and added to the LiHMDS solution at -20⁰C. The flask was washed 2 x 4.62 ml methylcyclohexane and the washings added to the LiHMDS solution. The mixture was warmed up to -15°C and stirred for 65 minutes. The mixture was further warmed up to 25°C over a period of 25 minutes. The resulting mixture was transferred to a 250 ml flask and the jacketed (250 ml) flask was washed 2 x 5 ml hexane + 30 ml hexane and the resultant solution was concentrated to dryness under vacuum at 50⁰C. 10 ml of hexane was used for the preparation of a suspension of 0.78 g CELITE which was transferred to a filtration apparatus with a PTFE filter (45 μm). The product was dissolved in 30 ml of hexane and filtered through CELITE. The CELITE was washed with hexane (50 ml). The filtrate was transferred to 100 ml flask and concentrated in vacuum to dryness (50⁰C, p_mm=5 mbar). The product was isolated as oil (10.1 g, 91.62 % yield, purity 92.5 %), content of second isomer was 0.65 % (GC) and content of starting material 3.3 %; MS (m/z): 409, 394, 352, 336, 242, 202, 147, 135, 100, 93, 73, 43). Step 4 : (1 R^")-(S)-Pinanediol-1 -ammonium trifluoroacetate-3-methylbutane-l-boronate

[0024] Under inert atmosphere of argon, trifluoroacetic acid (4.17 ml) was added to a jacketed flask and addition was completed by isopropylether (54.83 ml). The resulting solution was cooled to -10°C and a solution of (lR)-(S)-pinanediol-l-bis(trimethylsilyl)arnino-3-butane- 1-boronate from previous step (10.1 g) in methylcyclohexane (23.17 ml ) and isopropylether (in total 22.8 ml, 4.26 ml for washing) was added over a period of 10 minutes. The resulting mixture was stirred for 150 minutes at - 10 ⁰C then warmed up to 20°C. The suspension was filtered, the jacketed flask was washed with 2 x 71.36 ml of isopropylether, and the isolated product was washed with 3 x 17.41 ml of isopropylether and dried in vaccuo at 45°C. The title product was obtained as white crystals (5.9 g , purity 99.8 % (GC), [α]_D ²⁵: +13.0°, impurity: 0.04 % of second isomer, yield 68.3 %)

Step 5: Recrystallization of (lR^")-(SVPinanediol-l-ammoniumtrifluoroacetate-3-methylbutane- 1-boronate

[0025] ( 1R)-(S)-Pinanediol- 1 -ammonium trifluoroacetate-3 -methylbutane-1 -boronate from the previous step was dissolved in a beaker using trifluoroacetic acid (8.75 ml), and the resulting solution was transferred to a jacketed flask; the beaker was rinsed with isopropylether (16.8 ml) and the rinsing added to the jacketed flask. The resulting mixture was cooled down to 4°C and stirred for 10 minutes. The mixture was warmed up to 16⁰C, and isopropylether (72.7 ml) was added over a period 6 minutes and the mixture stirred an additional 10 minutes. The mixture was then cooled down to -5°C and stirred for 150 minutes. From - 5 ⁰C the mixture was warmed to 20°C and filtered. The jacketed flask was washed with 2 x 27.8 ml of isopropylether, filtered, and the filter cake was washed with 27.8 ml of isopropylether. The title product was dried in vacuo at 45 ⁰C to provide white woolly crystals (4.0 g, yield 74.4 %, under analytical evaluation). MS (m/z): 265, 222, 208, 135, 93, 74, 55, 43; IR (cm^"1): 3049, 2987, 2961, 2872, 1678, 1420, 1392, 1203, 1178, 1141, 721; ¹H-NMR (DMSOd₆): δ= 7.78 (3H, b); 4.44 (IH, dd, J=2 Hz, 8.9 Hz); 2.80 (IH, m); 2.34 (IH, m); 2.20 (IH, m); 2.01 (IH, t, J=5.4 Hz); 1.89 (IH, m); 1.75 (IH, m); 1.72 (IH₅ sx, J=6.6 Hz); 1.48 (2H, m); 1.37 (3H, s); 1.26 (3H, s); 1.10 (IH, d, J=10.8 Hz); 0.87 (6H, d, J=6.6 Hz) 0.83 (3H,s); DSC (⁰C): 175.2, 177.2, 182.4, 187.8, 196.3; TGA: -0.05% (28-110°C), -2.81% (110-168⁰C); XRPD (° 2Θ): 8.08, 8.87, 11.72, 16.10, 17.69, 19.47, 20.15, 23.49.

Example 2: Preparation of N-(Pyrazine-2-ylcarbonyI)-L-phenylalanine sodium salt

Step 1: Methylester ofN-(pyrazin-2-yl-carbonyl)-L-phenylalanine

[0026] The methyl ester of phenylalanine (7.5 g), pyrazinecarboxylic acid (4.4 g), TBTU

(12.8 g) and dichloromethane (200 ml) were charged to a 250 ml jacketed flask. The mixture was cooled down to 0⁰C and 18.2 ml of diisopropylethylamine were added drop wise. After 30 minutes of stirring at 0 °C, the mixture was warmed to 25 ⁰C over a period of 90 minutes and then transferred to a separatory funnel. The jacketed flask was rinsed with dichloromethane (10 ml) and liquid transfered to the separatory funnel. The reaction mixture was extracted with 3* 225 ml of water and dried over Na₂SO₄ (14.5 g). The sulfate was filtered off and washed with 3^χ 10 ml of dichloromethane. The filtrate was concentrated (40 °C, p_mm ⁼ 30 mbar) to an oily residue (13.3 g, purity 90.0 %, yield 76.0 %). IR (cm⁴): 3443, 3308, 1753, 1705, 1605, 1497, 1454, 1440, 1405, 1368, 765, 749, 736, 697, 627).

Step 2 : N-(Pyrazine-2-ylcarbonyl)-L-phenylalanine sodium salt

[0027] The methyl ester of N-(pyrazin-2-yl-carbonyl)-L-phenylalanine (13.3 g) from the previous step was dissolved in methyl alcohol (23.3 ml) and added to a 100 ml flask. 2M solution of NaOH in water was added (23.3 ml). The resulting solution was stirred for 150 minutes, than 200 ml of methanol was added followed by addition of 1064 ml of diisopropylether. The resulting suspension was filtered, and the product was washed with 2^χ 100.0 ml of diisopropylether. The title product was isolated as a white wool and dried in vacuo at 45⁰C (8.6 g, purity 95.7 %, yield 63,2 %; MS (m/z): 565 [2M+Na]⁺; IR (cnf¹): 3367, 1655, 1616, 1522, 1454, 1402, 1022, 699; 294 [M+Na]⁺; ¹H-NMR (DMSO-d₆): δ= 9.18 (IH, d, J=1.5 Hz); 8.83 (IH, d, J=2.5 Hz); 8.65 (IH, dd, J=1.5 Hz, 2.5 Hz); 8.63 (IH, ABMX, J=6.4 Hz); 7.14- 7.06 (5H, m); 4.24-4.20 (IH, ABMX); 3.25-3.13 (2H, ABMX)).

Example 3: Preparation of Bortezomib anhydride

Step 1: (IR)-(S)- Pinanediol N-(pyrazine-2-ylcarbonyl)-L-phenylalanine-L-leucine boronate

[0028] N-(Pyrazine-2-ylcarbonyl)-L-phenylalanine sodium salt (1.8 g) and TBTU (2.2 g) were suspended in dichloromethane (115 ml ) in a beaker. The suspension was charged to a jacketed flask and the beaker was washed with dichloromethane (115 ml). The suspension was cooled to 0°C and stirred for 30 minutes. (1R)-(S)-Pinanediol 1-ammonium trifluoroacetate-3- methylbutane-1 -boronate (2.3 g) in dichloromethane (115 ml) was charged to the jacketed flask, the beaker was washed with dichloromethane (115 ml), and the washing added to the jacketed flask. The resulting mixture was stirred for 30 minutes at 0⁰C. The mixture was then warmed from O⁰C to 25°C over a period of 150 minutes and stirred over night (21 hours). The mixture was extracted with 2 x 230 ml H₂O, 2 x 230 ml 1% H₃PO_4, 1 x 230 ml and 1 x 195 ml 2% K₂CO_3, 2 x 230 ml 10% NaCl , 2 x 230 ml H₂O. The organic layer was transferred to a 500 ml flask and dried over Na₂SO₄ (26.5 g) which was subsequently filtered off and washed with 100 ml dichloromethane. The title product was isolated by evaporation to provide an oil (2.77 g, purity 84.0 %, yield 87.1 %); MS (m/z): 1053 βM+NEUf, ¹⁰³⁶ [2M+H]⁺, 519 [M+H]⁺.

Step 2: Bortezomib anhydride

[0029] (IR)-(S)- Pinanediol N-(pyrazine-2-ylcarbonyl)-L-phenylalanine-L-leucine boronate (2.8 g) prepared in previous step was charged to a 250 ml flask along with methanol (23.0 ml), hexane (21.0 ml), IN HCl (11.6 ml) and 2-methylρroρylboronic acid (0.92 g). The reaction mixture was stirred over night, separated and extracted with 2 x 21.0 ml hexane. The hexane layers were discarded and the residue extracted with 2 x 25 ml of dichloromethane. The combined dichloromethane fractions were evaporated to dryness. The resulting residue was subsequently dissolved in ethyl acetate and precipitated with diisopropyl ether to yield the product, bortezomib. (1.58 g, purity 98.5-101 %; yield 80 %; MS (m/z): 1099 [MfH]⁺, 733 [2/3M+H]⁺, 367 [1/3M+H-H₂O]⁺; IR (cm^{^1}): 3389, 2954, 2929, 1674, 1521, 1466, 1398, 1386, 1366, 1331, 1280, 1201, 1020, 700; ¹H-NMR (DMSO-d₆): δ= 9.28-8.41 (2H, m); 9.11-8.60 (IH₅ m); 8.67 (IH, ABMX, J=10.1 Hz); 7.75 (IH, ABMX, J=6.5 Hz, 6.7 Hz, 17.6 Hz); 7.35-6.96 (IH, m); 7.29-7.04 (2H, m); 7.23-7.10 (2H, m); 4.80 (IH, ABMX, J-16 Hz); 3.17 (IH, ABMX, J=14.3 Hz, 14.4 Hz, 16 Hz); 3.10 (IH, ABMX, J=13.8 Hz, 17.6 Hz, 18.5 Hz, 19.5 Hz); 3.07 (IH, ABMX₅ J=14.3 Hz, 14.4 Hz, 16 Hz); 1.56 (IH, ABMX, J=13.05 Hz); 1.39 (IH, ABMX, J=13.1 Hz, 13.8 Hz); 1.32 (IH, ABMX, J=13.1 Hz, 13.8 Hz); 0.84 (6H, AX3, J=12.7 Hz).

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method comprising exposing a compound of formula I

I

to a lithium amide base and a transition metal halide in a solvent comprising dichloromethane and at least 95 % tetrahydrofuran by volume, under conditions suitable to provide a compound of formula II

II

2. The method of claim 3, wherein the solvent comprises about 95.5 % tetrahydrofuran and about 4.5% dichloromethane by volume.

3. The method of claim 1 wherein the lithium amide base is lithium diisopropyl amide, lithium diethylamide, or lithium dimethylamide.

4. The method of claim 4 wherein the concentration of the lithium amide base ranges from about 0.5 M to about 2 M.

5. The method of claim 1 wherein the transition metal halide is ZnCl₂, ZnBr₂, FeBr₃, FeCl₃, or a mixture of any two or more thereof.

6. The method of claim 1 wherein the method is carried out a temperature ranging from about -70 ⁰C to about 10 °C.

7. The method of claim 1 wherein the method is carried out a temperature ranging from about -70 ⁰C to about -60 °C.

8. The method of claim 1 further comprising exposing the compound of formula II to lithium hexamethyldisilazane, sodium hexamethyldisilazane, or potassium hexamethyldisilazane under conditions suitable to provide a compound of formula III

III

9. The method of claim 8 wherein the formation of the compound of formula III is carried out in a solvent comprising tetrahydrofuran.

10. The method of claim 8 wherein the formation of the compound of formula III is carried out in a solvent comprising methylcyclohexane and tetrahydrofuran.

11. The method of claim 8 further comprising contacting the compound of formula III with a suitable acid to provide a compound of formula IV

IV

12. The method of claim 11 wherein the acid is a Ci_-10 alkanoic acid, C_2-10 perhaloalkanoic acid, HCl, HBr, or C_1-6 sulfonic acid.

13. The method of claim 11 wherein the acid is trifluoroacetic acid.

14. A method comprising contacting a compound of formula V

V wherein Z is a lithium, sodium, potassium, rubidium, calcium, or magnesium cation, with a coupling agent and the compound of formula IV

IV under conditions suitable to provide a compound of formula VI

VI

15. The method of claim 12 wherein the coupling agent is TBTU, DIP, DCC, EDC, HBTU, HCTU, TCTU, HATU, PyBOP, or PyABOP.

16. The method of claim 12 further comprising exposing a compound of formula VI to a sufficient amount of acid to produce a compound of formula VII

VII

17. The method of claim 16 wherein the acid is HCl or HBr.

18. The method of claim 16 wherein the exposure of the compound of formula VI to acid is carried out in the presence of a non-polar solvent in which pinanediol is soluble but the compound of formula VII is not.