Intermediates useful in the preparation of halichondrin compounds and methods for preparing the same

Abstract

The invention relates to intermediates useful in the preparation of halichondrin compounds, methods for preparing the same and use thereof, such as halichondrins, eribulin, or their analogs. The intermediates, the methods and use thereof are used for the synthesis of the C20-C26 fragment of halichondrin compounds. The raw materials in the synthetic route of the invention are cheap and easily obtained, the sources and the qualities of the raw materials are reliable. The choice of the methods useful in the synthesis of chiral central structures are based on the structural characteristics of the reactants, thus effectively improving the synthesis efficiency, reducing the difficulties and risks of product quality control, and avoiding the use of highly toxic and expensive organotin catalysts to significantly decrease costs and improve environmental friendliness.

Claims

1. A method for preparing a compound of Formula (8), comprising: hydrolyzing a compound of Formula (7) in a solvent to obtain the compound of Formula (8): ##STR00022## wherein, R.sub.1 is a hydroxyl protecting group; R.sub.2 and R.sub.3 are the same or different, and independently selected from H and OR.sub.a, and R.sub.a is independently selected from the group consisting of H, C.sub.1-10 alkyl, R.sub.bSO.sub.2, wherein R.sub.b is C.sub.1-10 alkyl; or R.sub.2 and R.sub.3 together with a carbon atom to which they are bonded to represent a carbonyl group; and X is halogen or sulfonyloxy.

2. A compound chosen from ##STR00023## wherein, R.sub.1 is a hydroxyl protecting group; R.sub.2 and R.sub.3 are the same or different, and independently selected from H and OR.sub.a, and R.sub.a is independently selected from the group consisting of H, C.sub.1-10 alkyl, and R.sub.bSO.sub.2, wherein R.sub.b is C.sub.1-10 alkyl; or R.sub.2 and R.sub.3 together with a carbon atom to which they are bonded represents a carbonyl group; X is halogen or sulfonyloxy; and R.sub.4 is C.sub.1-10 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl, and R.sub.5 is a silyl group.

3. A method for preparing halichondrins, eribulin, pharmaceutically acceptable salts thereof or C20-C26 fragment thereof, comprising hydrolyzing the compound of Formula (7) in the solvent to obtain the compound of Formula (8) according to claim 1.

4. The method for preparing the compound of Formula (8) of claim 1, further comprising oxidizing a compound of Formula (6) to form the compound of Formula (7) in which R.sub.2 and R.sub.3 together with the carbon atom to which they are bonded represent a carbonyl group: ##STR00024##

5. The method for preparing the compound of Formula (8) of claim 1, further comprising preparing the compound of Formula (7), wherein R.sub.2 is H and R.sub.3 is OH, from a compound of Formula (5) and O═CH—(CH.sub.2).sub.3—O—R.sub.1: ##STR00025##

6. The method for preparing the compound of Formula (8) of claim 5, further comprising the step of preparing the compound of Formula (5) by coupling a compound of Formula (4) and thiazoline-2-thione: ##STR00026##

7. The method for preparing the compound of Formula (8) of claim 6, further comprising the step of preparing the compound of Formula (4) by hydrolyzing a compound of Formula (3): ##STR00027## wherein, R.sub.4 is C.sub.1-10 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.

8. The method for preparing the compound of Formula (8) of claim 7, further comprising the step of preparing the compound of Formula (3) from a compound of Formula (2) in presence of a halogenation reagent containing X, wherein X is halogen: ##STR00028## wherein, R.sub.5 is a silyl group.

9. The method for preparing the compound of Formula (8) of claim 8, further comprising the step of reacting a compound of Formula (1) with a Grignard reagent R.sub.6MgX or R.sub.6Li, wherein R.sub.6 is ##STR00029## and X is halogen, to obtain the compound of Formula (2): ##STR00030##

10. The method for preparing the compound of Formula (8) of claim 9, further comprising the step of recrystallizing the compound of Formula (2) once, twice, or more times.

11. The method for preparing the compound of Formula (8) of claim 10, further comprising the step of preparing the compound of Formula (1) from an oxazolidinone chiral auxiliary (S)-(−)-4-R.sub.4-2-oxazolidinone and an acyl compound, the acyl compound being an ester, a carboxylic acid, an acyl halide, or an acid anhydride: ##STR00031##

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1: Schematic illustration of synthetic routes in Example 1 of the invention.

EXAMPLES

(2) The above and other features and advantages of the invention are explained and illustrated in more detail in the following by describing the examples of the invention. It should be understood that the following examples are intended to give an exemplary description of the technical solutions of the invention, rather than any limitation on the scope of protection of the invention as defined by the claims and their equivalents.

(3) Unless otherwise specified, the materials and reagents herein are commercially available products or can be prepared by those skilled in the art according to the prior art.

(4) It should be understood by those skilled in the art that the raw materials, reagents, intermediates, target compounds or reactions in the following examples are all exemplary technical solutions of the above-mentioned compounds of general formula or their reactions, one or more of the specific compounds or reactions can be combined with the above general technical solutions of the invention, and the combined technical solutions should be understood as the technical solutions described in the specification.

(5) Unless otherwise specified, the yields in the following examples are acceptable as the purities of products are more than 99.5%.

Example 1: Method 1 for Preparing Compound 8 (See FIG. 1)

(6) 1.1 Preparation of Compound 1

(7) Method 1

(8) (S)-4-phenyl-2-oxazolidinone (15.6 g) was added into a 500 mL three-necked flask, and dissolved by adding dry THF (200 mL). The solution was purged with argon for protection, then cooled to −78° C., and added with a solution of n-BuLi in THF (2.5 M, 38 mL) dropwise (The internal temperature was maintained not more than −60° C.). The reaction was kept at −78° C. for 15 mins after the dropwise addition. The mixture was added with crotonoyl chloride (10 g), and the reaction was kept at −78° C. for 30 mins after the dropwise addition. Then the temperature was increased to 0° C. and the reaction was kept for 1.5 hours. After completion of the reaction detected by TLC, the solution was quenched by slowly adding a saturated solution of ammonium chloride. The mixture was stirred well until the solid was completely dissolved and clearly layered. The layers were separated. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined. The combined organic phase was washed once with a saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained concentrate was added with ethyl acetate (100 mL), and dissolved by heating under reflux. Crystals were precipated when the solution was added with n-hexane (500 mL), cooled down, and stirred. After filtration, 17.7 g of a white solid product with a yield of 80% was obtained.

(9) Method 2:

(10) (S)-4-phenyl-2-oxazolidinone (60 g) was added into a 2000 mL three-necked flask, and dissolved by adding with non-anhydrous THF (1200 mL). LiCl (26.4 g) and TEA (91.2 mL) was added into the solution at room temperature, and then crotonic anhydride (82.2 mL) was added dropwise. The internal temperature was maintained not more than 25° C. After the dropwise addition, the reaction was kept at room temperature for 3 hours. Until the spots of the starting material of (S)-4-phenyl-2-oxazolidinone disappeared that was monitored by TLC, water (800 mL) was added to dissolve the solid in the reaction solution. The solution was layered, and separated. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined. The combined organic phase was washed once with a saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained concentrate was added with ethyl acetate (400 mL), and dissolved by heating under reflux. Crystals were precipated when the solution was added with n-hexane (2000 mL), cooled down, and stirred. After filtration, 72 g of a white solid product with a yield of 85% was obtained.

(11) .sup.1H NMR (400 MHz,) δ 7.44-7.23 (m, 6H), 7.21-6.96 (m, 1H), 5.47 (dd, J=8.7, 3.9 Hz, 1H), 4.68 (t, J=8.8 Hz, 1H), 4.26 (dd, J=8.9, 3.9 Hz, 1H), 1.92 (dd, J=6.9, 1.6 Hz, 3H).

(12) 1.2 Preparation of Compound 2

(13) 1) Preparation of (1-Bromovinyl)Trimethylsilane

(14) Vinyltrimethylsilane (100 g) was added into a 2000 mL three-necked flask, and then cooled between −35° C. and −30° C. Bromine water was slowly added dropwise, while heat was violently released. The internal temperature was maintained between −30° C. and −10° C. during the dropwise addition (when the internal temperature was lower than −30° C., the reaction system became solid). After the dropwise addition, the temperature rose naturally to room temperature. Diethylamine (676 mL) was slowly added. At the beginning of the addition, heat was released. After the dropwise addition, the reaction solution was heated under reflux for 1.2 hours. After the completion of reaction, the reaction solution was cooled to room temperature, and diluted by adding with diethyl ether (1000 mL), washed 2-3 times with water and then with 2N hydrochloric acid until the pH value of the aqueous layer to 1. The organic phase was successively washed once with saturated sodium bicarbonate and once with saturated sodium chloride, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The concentrate was distilled under reduced pressure. 80 g of the fraction (between 38° C. to 42° C.) was collected. The yield was 45%.

(15) .sup.1H NMR (400 MHz, Chloroform-d) δ 6.27 (s, 1H), 6.19 (s, 3H), 0.20 (s, 9H).

(16) 2) Preparation of Compound 2

(17) Mg particles (8.4 g) and iodine particles (1-2 particles) were added into a three-necked flask, and the flask was purged with argon for protection. (1-bromovinyl)trimethylsilane

(18) (62.7 g) was dissolved in dry THF (159 mL), and part of the solution (20 mL) was added into the above three-necked flask at room temperature. The three-necked flask was heated. When the reaction was initiated in the flask, and the reaction mixture was refluxed, the THF solution was continuously added dropwise. The reaction solution was kept under refluxing. After the dropwise addition, the reaction flask was placed in an oil bath and the reaction solution was heated under refluxing for 1 h. A Grignard reagent was prepared.

(19) CuI (6.69 g) was added into a 1000 mL three-necked flask, and THF was added. The flask was purged with argon for protection. The solution was cooled to −40° C., and the above Grignard reagent was added dropwise. The internal temperature was maintained not more than −30° C. After the dropwise addition, the reaction was kept at −40° C. for 0.5 h. A solution of compound 1 in THF (40.45 g/40 mL THF) was then added dropwise. After the addition, the temperature was increased to 0° C. and the reaction mixture was reacted for 2 hours. Until the spots of compound 1 disappeared that was monitored by TLC, the reaction solution was quenched by slowly adding a saturated solution of ammonium chloride, stirred vigorously for 4-6 hours to give two clear phases. The layers were separated. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined. The combined organic phase was washed twice with a saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 57 g of a crude product. The crude product was dissolved in 570 mL n-hexane at room temperature. The solution was placed in a refrigerator at −20° C., and let stand while crystals were precipated. The next day, the solution was filtered when cold. The filtrate was washed with cold n-hexane to give 42 g of a white solid. After secondary recrystallization, a product with a purity of 99.94% was obtained.

(20) .sup.1H NMR (500 MHz, Chloroform-d) δ 7.63-7.26 (m, 5H), 5.74 (d, J=1.9 Hz, 1H), 5.51 (dd, J=8.7, 3.8 Hz, 1H), 5.42 (d, J=2.2 Hz, 1H), 4.76 (t, J=8.8 Hz, 1H), 4.35 (dd, J=9.0, 3.8 Hz, 1H), 3.30 (q, J=9.4 Hz, 1H), 3.08-2.84 (m, 2H), 1.09 (d, J=6.2 Hz, 3H), 0.12 (s, 9H).

(21) 1.3 Preparation of Compound 3

(22) Iodine (43.2 g) was dissolve in DCM (752 mL), and the raw material 2 (18.8 g) was added in batches at 0° C. After the addition, the temperature was increased to room temperature and the mixture was reacted for about 12-20 hours. When the spots of the raw material disappeared that was monitored by TLC, the reaction mixture was quenched by adding a saturated sodium sulfite solution, stirred vigorously until the purple color of the solution faded and became colorless. The solution layers were separated. The aqueous layer was extracted once with DCM. The organic phases were combined and dried by adding anhydrous sodium sulfate. The combined organic phase was filtered. The filtrate was concentrated to give 20 g of a crude product. The crude product was purified by column chromatography to obtain 15 g of a product. The product was heated and dissolved in a mixed solvent of n-hexane and ethyl acetate (70 mL). Crystals were precipitated when the solution was cooled down and stirred. 9.4 g of a white solid with a yield of 43% was obtained.

(23) .sup.1H NMR (500 MHz, Chloroform-d) δ 7.41-7.27 (m, 5H), 6.09 (d, J=1.6 Hz, 1H), 5.62 (d, J=1.6 Hz, 1H), 5.43 (dd, J=8.8, 4.0 Hz, 1H), 4.70 (t, J=8.8 Hz, 1H), 4.27 (dd, J=9.0, 4.0 Hz, 1H), 3.23 (dd, J=16.9, 6.6 Hz, 1H), 2.85 (dd, J=16.9, 7.0 Hz, 1H), 2.56 (q, J=6.8 Hz, 1H), 1.04 (d, J=6.7 Hz, 3H).

(24) 1.4 Preparation of Compound 4

(25) The raw material 3 (14.27 g) was dissolved in a mixed solution of THF-H.sub.2O (148 mL-37 mL). The mixture was then cooled to about −5° C., successively added with hydrogen peroxide (35%, 15.8 mL) and an aqueous solution of lithium hydroxide monohydrate (3.1 g/30 mL H.sub.2O) dropwise. After the dropwise addition, the reaction was kept at 0° C. for 2 hours. When the spots of the raw material disappeared that was monitored by TLC, the temperature of the reaction solution was increased to room temperature. A saturated solution of sodium sulfite was slowly added, until the potassium iodide starch test papers did not change color. THF was removed by distillation under reduced pressure. The aqueous phase was washed 2-3 times with DCM, until no more (S)-4-phenyl-2-oxazolidinone. The aqueous phase was added into a round-bottom flask, cooled to 0° C., and the pH of the aqueous phase was adjusted to 1 with a 10% diluted solution of hydrochloric acid. Then the solution was extracted 2-3 times with DCM, dried, and filtered. The filtrate was concentrated to obtain compound 4.

(26) .sup.1H NMR (400 MHz, Chloroform-d) δ 6.21 (s, 1H), 5.90-5.59 (m, 1H), 2.62-2.54 (m, 1H), 2.54-2.46 (m, 1H), 2.31 (dd, J=15.0, 6.4 Hz, 1H), 1.11 (d, J=6.5 Hz, 3H).

(27) 1.5 Preparation of Compound 5

(28) The above obtained compound 4 was dissolved in DCM (185 mL), to which thiazoline-2-thione (4.84 g), EDCI (8.86 g) and DMAP (0.7 g) were added at room temperature. The reaction was kept at room temperature for 4-6 hours. When the spots of the raw material disappeared that was monitored by TLC, the reaction mixture was quenched by adding a saturated sodium bisulfate solution, and stirred. The solution layers were separated. The aqueous phase was extracted twice with DCM, and the organic phases were combined. The combined organic phase was successively washed with a saturated sodium bicarbonate solution and with a saturated sodium chloride solution, then dried by adding anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The concentrate was purified by column chromatography to obtain 10.06 g of a yellow syrup-like product (solidified during standing or freezing) with a yield of 80%.

(29) .sup.1H NMR (400 MHz, Chloroform-d) δ 6.22 (dd, J=1.6, 0.9 Hz, 1H), 5.76 (d, J=1.7 Hz, 1H), 4.65-4.45 (m, 2H), 3.47 (dd, J=17.1, 7.3 Hz, 1H), 3.35-3.22 (m, 2H), 1.10 (d, J=6.7 Hz, 3H).

(30) 1.6 Preparation of Compound 6

(31) 1) Preparation of 4-((t-butyldiphenylsilyl)oxy)butanal

(32) Step 1: 1,4-butanediol (100 mL) was added into a 2000 mL three-necked flask at room temperature, to which DCM (1300 mL), triethylamine (59 mL) and DMAP (4.7 g) were added, and then TBSCl was slowly added dropwise. After the dropwise addition, the reaction was kept at room temperature overnight (about 17 hours). When the spots of the raw material TBSCI disappeared that was monitored by TLC, the reaction mixture was quenched by adding a saturated solution of ammonium chloride. The solution layers were separated. The aqueous layer was extracted twice with DCM, and the organic phases were combined. The combined organic phase was washed once with a saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The concentrate was purified by column chromatography to obtain 108 g of a syrup-like product with a yield of 80%.

(33) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.89-7.56 (m, 4H), 7.53-7.35 (m, 6H), 3.68 (dt, J=15.2, 5.9 Hz, 4H), 1.74-1.59 (m, 4H), 1.05 (s, 9H).

(34) Step 2: 4-((tert-butyldiphenylsilyl)oxy)butanol (11.6 g) was dissolved in dry DCM (71 mL), and then cooled to 0° C. The solution was successively added with dry DMSO (12.6 mL) and DIPEA (15.4 mL), and added with sulfur trioxide-pyridine (11.3 g) in batches. The internal temperature was maintained not more than 10° C. After the addition, the temperature was increased to room temperature and the mixture was reacted for 0.5-1 h. When the spots of the raw material disappeared that was monitored by TLC, the reaction mixture was quenched by adding water, washed once with 1N diluted hydrochloric acid. The aqueous layer was extracted once with DCM, and the organic phases were combined. The combined organic phase was successively washed once with a saturated sodium bicarbonate solution and with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a syrup-like product, which was directly used in the next reaction, so it was freshly prepared just before use.

(35) .sup.1H NMR (400 MHz, Chloroform-d) δ 9.79 (s, 1H), 7.65 (t, J=7.6 Hz, 4H), 7.52-7.30 (m, 6H), 3.79-3.49 (m, 2H), 2.55 (d, J=6.7 Hz, 2H), 1.88 (t, J=8.3 Hz, 2H), 1.04 (s, 9H).

(36) 2) The raw material 5 (10.1 g) was added into a 1000 mL three-necked flask, dissolved by adding dry DCM. The flask was purged with argon for protection. The reaction solution was then cooled to 0° C., to which titanium tetrachloride (3.4 mL) was added dropwise, and triethylamine (3.58 mL) was rapidly added. The reaction was kept at 0° C. for 1 h. A DCM solution of 4-((t-butyldiphenylsilyl)oxy)butanal (11 g/20 mL) was added dropwise. After the dropwise addition, the reaction was kept at 0° C. for 4-6 hours. The reaction mixture was quenched by adding a saturated sodium chloride solution. The solution layers were separated. The aqueous layer was extracted twice with DCM, and the organic phases were combined. The combined organic phase was successively washed twice with a saturated sodium bicarbonate solution and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The concentrate was purified by column chromatography to obtain 13.1 g of a yellow syrup-like product with a yield of 84%.

(37) Compound 6 Containing Four Diastereomers

(38) Isomer A: .sup.1H NMR (400 MHz, Chloroform-d) δ 7.65 (ddd, J=7.9, 4.3, 1.8 Hz, 4H), 7.44-7.35 (m, 6H), 6.37 (dd, J=1.3, 0.6 Hz, 1H), 5.84 (d, J=1.4 Hz, 1H), 5.26 (dd, J=10.0, 3.8 Hz, 1H), 4.56 (td, J=7.4, 5.8 Hz, 2H), 3.69 (t, J=6.1 Hz, 3H), 3.23-3.07 (m, 2H), 2.85 (d, J=10.1 Hz, 1H), 2.67 (dd, J=9.9, 6.6 Hz, 1H), 1.88-1.56 (m, 3H), 1.07 (d, J=6.7 Hz, 3H), 1.04 (s, 9H).

(39) Isomer B: .sup.1H NMR (400 MHz, Chloroform-d) δ 7.72-7.63 (m, 4H), 7.45-7.34 (m, 6H), 6.17 (s, 1H), 5.76-5.73 (m, 1H), 4.74 (dd, J=10.3, 3.4 Hz, 1H), 4.56 (ddd, J=11.9, 7.5, 2.1 Hz, 1H), 4.38-4.26 (m, 1H), 3.72-3.62 (m, 3H), 3.41 (ddd, J=12.3, 11.0, 7.5 Hz, 1H), 3.13 (ddd, J=10.9, 7.3, 2.1 Hz, 1H), 2.87 (d, J=10.9 Hz, 1H), 2.67 (dd, J=10.3, 6.4 Hz, 1H), 2.21-2.06 (m, 1H), 1.97-1.72 (m, 2H), 1.15 (d, J=5.7 Hz, 3H), 1.04 (s, 9H).

(40) Characteristic peak of isomer C: .sup.1H NMR (400 MHz, Chloroform-d) δ 6.22 (dt, J=1.8, 0.9 Hz, 1H), 5.72 (d, J=1.5 Hz, 1H), 5.38 (dd, J=9.7, 5.3 Hz, 1H).

(41) Characteristic peak of isomer D: .sup.1H NMR (400 MHz, Chloroform-d) δ 6.19-6.18 (m, 1H), 5.76-5.75 (m, 1H), 4.96 (dd, J=10.6, 5.2 Hz, 1H).

(42) 1.7 Preparation of Compound 7

(43) The raw material 6 (13.07 g) was dissolved in dry DCM (40 mL), and then cooled to 0° C. The solution was successively added with dry DMSO (6.95 mL) and DIPEA (8.54 mL), and added with sulfur trioxide-pyridine (6.23 g) in batches. The internal temperature was maintained not more than 10° C. After the addition, the temperature was increased to room temperature and the mixture was reacted for 0.5-1 h. When the spots of the raw material disappeared that was monitored by TLC, the reaction mixture was quenched by adding water, and washed once with 1N diluted hydrochloric acid. The aqueous layer was extracted once with DCM, and the organic phases were combined. The combined organic phase was successively washed once with a saturated sodium bicarbonate solution and with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a syrup-like product, which was purified by column chromatography to obtain 10.4 g of a product with a yield of 80%.

(44) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.92-7.54 (m, 10H)(A/B), 7.39 (q, J=7.8, 7.1 Hz, 10H) (A/B), 6.25 (d, J=8.5 Hz, 1H) (A), 6.21 (s, 2H) (A/B), 5.77 (d, J=1.7 Hz, 1H) (A), 5.75 (d, J=1.7 Hz, 1H) (B), 5.07 (d, J=9.4 Hz, 1H)(A), 4.61-4.08 (m, 2H) (A/B), 4.26-4.05 (m, 2H) (A/B), 3.69-3.61 (m, 4H) (A/B), 3.33-3.13 (m, 4H) (A/B), 3.00-2.86 (m, 1H)(A), 2.79 (dt, J=15.2, 7.8 Hz, 5H) (A/B), 1.81 (q, J=6.9 Hz, 3H) (A), 1.12 (d, J=6.7 Hz, 3H) (A), 1.09 (d, J=6.5 Hz, 2H) (B), 1.05 (s, 18H) (A/B).

(45) 1.8 Preparation of Compound 8

(46) The raw material 7 (10.4 g) was dissolved in a mixed solvent of THF and H.sub.2O (120 mL/30 mL). The solution was added with lithium hydroxide monohydrate (6.54 g) at room temperature. The reaction mixture was kept at room temperature and stirred for 6-8 hours. After the completion of reaction, the reaction mixture was added with water. The solution layers were separated. The aqueous layer was extracted with n-hexane, and the THF layer was concentrated under reduced pressure. The concentrate was then dissolved by adding n-hexane. The organic phases were combined. The combined organic phase was washed with a saturated sodium dihydrogen phosphate, and with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The concentrate was purified by column chromatography to obtain 7.08 g of a product with a yield of 87%.

(47) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.65 (dd, J=7.8, 1.5 Hz, 5H), 7.54-7.27 (m, 5H), 6.16 (dd, J=1.5, 0.8 Hz, 1H), 5.70 (d, J=1.7 Hz, 1H), 3.78-3.55 (m, 2H), 2.63 (dd, J=16.4, 6.5 Hz, 1H), 2.52 (td, J=7.1, 1.5 Hz, 3H), 2.29 (dd, J=16.3, 6.6 Hz, 1H), 1.88-1.75 (m, 2H), 1.05 (s, 9H), 1.02 (d, J=6.5 Hz, 3H).